ADVERSE REACTIONS SECTION.

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)]. Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1)]. Most common adverse reactions (incidence >=10% with 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 to <12 years are pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Global Blood Therapeutics, Inc. at 1-833-GBT-4YOU (1-833-428-4968) 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 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 OlderThe 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 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 an adverse reaction occurred in 48% (42/88) of patients who received OXBRYTA. Most frequent adverse reactions requiring dosage modifications occurring in more than two patients who received OXBRYTA 1,500 mg included diarrhea and rash.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 difference of >3% compared to placebo are summarized in Table 4.Table 4: Adverse Reactions (>=10%) in Patients Receiving OXBRYTA with Difference Between Arms of >3% Compared to Placebo in HOPEAdverse ReactionAdverse reactions were Grades or except for Grade headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3) OXBRYTA1,500 mg(N=88)Placebo(N=91)Headache32%25%Diarrhea23%11%Abdominal PainAbdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain 23%16%Nausea19%10%RashRash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash 15%11%Pyrexia15%8%Clinically relevant adverse reactions occurring in <10% of patients included:Drug hypersensitivity. Drug hypersensitivity. Pediatric Patients to <12 YearsThe safety of OXBRYTA in pediatric patients to <12 years with SCD was evaluated in an open-label, Phase study [see Clinical Studies (14.2)]. In this study, 45 patients 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 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 to <12 years was similar to that seen in adults and pediatric patients 12 years and older.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Voxelotor is hemoglobin (HbS) polymerization inhibitor that binds to HbS with 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.. 12.2 Pharmacodynamics. The pharmacodynamic effect of voxelotor treatment demonstrated dose-dependent increase in Hb oxygen affinity as determined by the change in p50 (partial pressure of oxygen at which Hb oxygen saturation of 50% is achieved) that was linearly correlated with voxelotor exposure.The pharmacodynamic effect of voxelotor treatment also demonstrated dose-dependent reduction in clinical measures of hemolysis (indirect bilirubin and reticulocytes).. Cardiac ElectrophysiologyAt plasma concentrations approximately 2-fold above therapeutic concentrations, voxelotor does not prolong QT interval to any clinically relevant extent.. 12.3 Pharmacokinetics. Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs. Steady-state after repeated administration is reached within days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD.Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole BloodBased on the 72-week population pharmacokinetic analysis. PK ParameterVoxelotor 1,500 mgGeometric Mean (%CV)Plasma PKAUC0-24h (ughr/mL)278 (28.4)Cmax (ug/mL)14 (24.5)Half-life (hours)38.7 (30.2)Whole Blood PKAUC0-24h (ughr/mL)3,830 (33.5)Cmax (ug/mL)180 (31)In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole.. AbsorptionThe median plasma and whole blood Tmax of voxelotor after oral administration is hours. The mean peak concentrations in whole blood and RBCs are observed between and 18 hours after oral administration.. Effect of FoodA high-fat, high-calorie meal increased voxelotor AUC by 42% and Cmax by 45% in whole blood relative to AUC and Cmax in the fasted state. Similarly, AUC increased by 42% and Cmax increased by 95% in plasma.. DistributionVoxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 and 72.3 in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD.. EliminationThe geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.1 L/h in plasma in patients with SCD.. MetabolismIn vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9.. ExcretionFollowing the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min).. Pediatric PatientsThe pharmacokinetic exposures of voxelotor in whole blood and plasma were similar between pediatric patients to <17 years and adults following the recommended dosage [see Dosage and Administration (2)].. Patients with Renal ImpairmentThere was no clinically significant effect of renal function on the excretion of voxelotor. Following single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m2) were 25% lower compared to healthy controls.The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis.. Patients with Hepatic ImpairmentThe voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function.. Patients with HbSC GenotypeVoxelotor steady state whole blood AUC and Cmax were 50% and 45% higher in HbSC genotype patients (n=11) compared to HbSS genotype (n=220) patients and voxelotor steady state plasma AUC and Cmax were 23% and 15% higher in HbSC genotype patients compared to HbSS genotype patients.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Strong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with itraconazole increased voxelotor AUC in healthy subjects by 11%.. Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor: concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 40%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 24%.. Effect of Acid Reducing Agents on Voxelotor: coadministration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure.. Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2.5-fold.. Effect of Voxelotor on P-gp: concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to clinically relevant extent.. In Vitro Studies. CYP Enzymes: voxelotor is reversible and time-dependent inhibitor as well as an inducer of CYP2B6.. Transporter Systems: voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adults and Pediatric Patients 12 Years and Older. The efficacy and safety of OXBRYTA in SCD was evaluated in HOPE, Phase randomized, double-blind, placebo-controlled, multicenter trial [NCT 03036813]. In this study, 274 patients were randomized to daily oral administration of OXBRYTA 1,500 mg (N=90), OXBRYTA 900 mg (N=92), or placebo (N=92). Patients were included if they had from to 10 vasoocclusive crisis (VOC) events within 12 months prior to enrollment and baseline hemoglobin (Hb) >=5.5 to <=10.5 g/dL. Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. Randomization was stratified by patients already receiving hydroxyurea (yes, no), geographic region (North America, Europe, Other), and age (12 to <17 years, 18 to 65 years). The trial excluded patients who received red blood cell (RBC) transfusions within 60 days and erythropoietin within 28 days of enrollment, had renal insufficiency, uncontrolled liver disease, were pregnant, or lactating.The majority of patients had HbSS or HbS/beta0-thalassemia genotype (90%) and were receiving background hydroxyurea therapy (65%). The median age was 24 years (range: 12 to 64 years); 46 (17%) patients were 12 to <17 years. Median baseline Hb was 8.5 g/dL (5.9 to 10.8 g/dL). One hundred and fifteen (42%) had VOC event and 159 (58%) had to 10 events within 12 months prior to enrollment. In the OXBRYTA 1,500 mg group, 63 (70%) patients completed the study through Week 72.Efficacy was based on Hb response rate defined as Hb increase of >1 g/dL from baseline to Week 24 in patients treated with OXBRYTA 1,500 mg versus placebo. The response rate for OXBRYTA 1,500 mg was 51.1% (46/90) compared to 6.5% (6/92) in the placebo group (p 0.001). No outlier subgroups were observed. The distribution of Hb change from baseline for individual patients completing 24 weeks of treatment with OXBRYTA 1,500 mg or placebo is depicted in Figure 1.Figure 1:Subject-level Change from Baseline in Hemoglobin at Week 24 in Patients Who Completed 24 Weeks of TreatmentApproximately 83% of all randomized patients completed 24 weeks of treatment. Additional efficacy evaluation included change in Hb and percent change in indirect bilirubin and percent reticulocyte count from baseline to Week 24 (Table 6).Table 6: Adjusted Mean (SE) Change from Baseline to Week 24 in Hemoglobin and Clinical Measures of HemolysisOXBRYTA 1,500 mg QD(N=90)Placebo(N=92)P ValueQD once daily; SE standard errorHemoglobin1.1 g/dL(0.1)-0.1 g/dL(0.1)< 0.001Indirect Bilirubin-29.1%(3.5)-2.8%(3.5)< 0.001Percent Reticulocyte Count-18.0%(4.7)6.8%(4.7)< 0.001. Figure 1. 14.2Pediatric Patients to <12 Years. The efficacy and safety of OXBRYTA in patients to <12 years with SCD was evaluated in an open-label, multi-center, Phase trial [NCT 02850406]. In this study, 45 patients to <12 years and 11 patients 12 to <17 years received OXBRYTA. Patients to <12 years received tablets for oral suspension based on body weight at baseline. 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. Patients 12 to <17 years received OXBRYTA 1,500 mg once daily.Patients were included if their baseline hemoglobin (Hb) was <=10.5 g/dL. Eligible patients on stable doses of hydroxyurea for at least 90 days were allowed to continue hydroxyurea therapy throughout the study. The trial excluded patients who had VOC event within 14 days prior to enrollment, received red blood cell (RBC) transfusions within 30 days of enrollment, and had renal insufficiency or uncontrolled liver disease.All patients had HbSS or HbS/beta0-thalassemia genotype (100%) and most were receiving background hydroxyurea therapy (80%). The median age was years (range: to 15 years); 45 (80%) patients were to <12 years. In this age group, mean baseline Hb was 8.6 g/dL (range: 6.1 to 10.5 g/dL).Efficacy was based on Hb response rate, which is defined as Hb increase of >1 g/dL from baseline to Week 24. Hb response rate for OXBRYTA in patients aged to <12 years who took at least one dose of OXBRYTA was 36% (16/45) (95% CI: 21.6%, 49.5%).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 OlderThe 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 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 an adverse reaction occurred in 48% (42/88) of patients who received OXBRYTA. Most frequent adverse reactions requiring dosage modifications occurring in more than two patients who received OXBRYTA 1,500 mg included diarrhea and rash.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 difference of >3% compared to placebo are summarized in Table 4.Table 4: Adverse Reactions (>=10%) in Patients Receiving OXBRYTA with Difference Between Arms of >3% Compared to Placebo in HOPEAdverse ReactionAdverse reactions were Grades or except for Grade headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3) OXBRYTA1,500 mg(N=88)Placebo(N=91)Headache32%25%Diarrhea23%11%Abdominal PainAbdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain 23%16%Nausea19%10%RashRash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash 15%11%Pyrexia15%8%Clinically relevant adverse reactions occurring in <10% of patients included:Drug hypersensitivity. Drug hypersensitivity. Pediatric Patients to <12 YearsThe safety of OXBRYTA in pediatric patients to <12 years with SCD was evaluated in an open-label, Phase study [see Clinical Studies (14.2)]. In this study, 45 patients 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 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 to <12 years was similar to that seen in adults and pediatric patients 12 years and older.

DOSAGE & ADMINISTRATION SECTION.

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 to less than 12 years: Dosing with OXBRYTA is based on body weight. See Table 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 to less than 12 years: Reduce the dose of OXBRYTA based on body weight. See Table for complete dosing recommendations. (2.4). Adults and pediatric patients 12 years and older: 1,500 mg orally once daily. (2.1). Pediatric patients to less than 12 years: Dosing with OXBRYTA is based on body weight. See Table for complete dosing recommendations. (2.2). Adults and pediatric patients 12 years and older: 1,000 mg orally once daily. (2.3). Pediatric patients to less than 12 years: Reduce the dose of OXBRYTA based on body weight. See Table for complete dosing recommendations. (2.4). 2.1Recommended Dosage for Adults and Pediatric Patients 12 Years and Older. The recommended dosage of OXBRYTA is 1,500 mg orally once daily.. 2.2Recommended Dosage for Pediatric Patients Years to Less Than 12 Years. For pediatric patients years and older, select the appropriate product (OXBRYTA tablets or OXBRYTA tablets for oral suspension) based on patients ability to swallow tablets and patient weight.The recommended dosage of OXBRYTA for pediatric patients years to less than 12 years is shown in Table 1.Table 1: Recommended OXBRYTA Dosage in Pediatric Patients Years to Less Than 12 YearsBody WeightRecommended Dose (once daily)40 kg or greater1,500 mg20 kg to less than 40 kg900 mg10 kg to less than 20 kg600 mg. 2.3Recommended 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)]. 2.4Recommended Dosage for Pediatric Patients Years to Less Than 12 Years with Hepatic Impairment. The recommended dosage of OXBRYTA in pediatric patients 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 Years to Less Than 12 Years with Severe Hepatic Impairment (Child Pugh C)Body WeightRecommended Dose (once daily)40 kg or greater1,000 mg (two 500 mg tablets)or900 mg (three 300 mg tablets for oral suspension)20 kg to less than 40 kg600 mg10 kg to less than 20 kg300 mg. 2.5Recommended Dosage of OXBRYTA for Adults and Pediatric Patients 12 Years and Older When Used with Concomitant Strong or Moderate CYP3A4 Inducers. CYP3A4 InducersAvoid 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.. 2.6Recommended Dosage of OXBRYTA for Pediatric Patients Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers. CYP3A4 InducersAvoid 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 for dosage.Table 3: OXBRYTA Recommended Dosage for Pediatric Patients Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 InducersBody WeightRecommended Dose (once daily)Concomitant Use of Strong CYP3A4 InducersConcomitant Use of Moderate CYP3A4 Inducers40 kg or greater2,500 mg (five 500 mg tablets) or2,400 mg (eight 300 mg tablets for oral suspension)2,000 mg (four 500 mg tablets) or2,100 mg (seven 300 mg tablets for oral suspension)20 kg to less than 40 kg1,500 mg1,200 mg10 kg to less than 20 kg900 mg900 mg. 2.7Important Administration Instructions. Administer OXBRYTA orally, once daily with or without food. If dose is missed, or not administered entirely, resume dosing the following day.OXBRYTA may be given with or without hydroxyurea.. OXBRYTA 500 mg TabletsPatients should swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets.. OXBRYTA 300 mg Tablets for Oral SuspensionPatients should disperse tablets for oral suspension immediately before administration in cup and in room temperature clear liquid (such as drinking water or clear soda) before swallowing.Do not swallow whole, cut, crush, or chew the tablets for oral suspension.Recommended Daily DoseNumber of Tablets for Oral SuspensionMinimum Recommended Volume of Clear Drink300 mg15 mL (1 teaspoon)600 mg210 mL (2 teaspoons)900 mg315 mL (3 teaspoons)1,200 mg420 mL (4 teaspoons)1,500 mg525 mL (5 teaspoons)2,100 mg735 mL (7 teaspoons)2,400 mg840 mL (8 teaspoons)After the tablets start to disintegrate, swirl the contents of the cup until the tablets are dispersed, wait to minutes, swirl the contents of the cup again, and then orally administer the contents of the cup. The tablet(s) will not completely dissolve; there will still be small tablet clumps in the mixture.Resuspend any residue left in the cup in more clear drink and administer. Repeat until no tablet residue is left in the cup.Tablets for oral suspension may be substituted for tablets in adults and pediatric patients 12 years and older with difficulty swallowing the tablets. Use the number of tablets for oral suspension needed to achieve the recommended dose.. After the tablets start to disintegrate, swirl the contents of the cup until the tablets are dispersed, wait to minutes, swirl the contents of the cup again, and then orally administer the contents of the cup. The tablet(s) will not completely dissolve; there will still be small tablet clumps in the mixture.. Resuspend any residue left in the cup in more clear drink and administer. Repeat until no tablet residue is left in the cup.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with 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). Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with 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). 7.1Effect of Other Drugs on Voxelotor. Strong or Moderate CYP3A4 InducersCoadministration 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 strong or moderate CYP3A4 inducer is unavoidable [see Dosage and Administration (2.5, 2.6) and Clinical Pharmacology (12.3)]. 7.2Effect 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 narrow therapeutic index. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s).. 7.3Laboratory 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Hypersensitivity ReactionsAdvise patients that serious hypersensitivity reactions may occur, and to notify their healthcare providers if they develop generalized rash, urticaria, shortness of breath, facial swelling and eosinophilia [see Warnings and Precautions (5.1)].. BreastfeedingAdvise women not to breastfeed while they are on OXBRYTA therapy [see Use in Specific Populations (8.2)].. Dosage and AdministrationTo avoid dosing error from using the wrong formulation of OXBRYTA, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see Dosage and Administration (2) and How Supplied/Storage and Handling (16)].Advise patients to:Store OXBRYTA at 20C to 30C (68F to 86F).Continue taking OXBRYTA every day for as long as their physician tells them.Do not take St Johns wort while taking OXBRYTA.Swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets.Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension. Disperse OXBRYTA tablets for oral suspension in room temperature clear drink (such as drinking water, or clear soda) before administration. The amount of liquid needed to disperse the tablets for oral suspension will depend on the dose (number of tablets prescribed) [see Dosage and Administration (2.7)].Take OXBRYTA with or without food.If dose is missed or not consumed entirely, resume dosing the following day [see Dosage and Administration (2.7)].. Store OXBRYTA at 20C to 30C (68F to 86F).. Continue taking OXBRYTA every day for as long as their physician tells them.. Do not take St Johns wort while taking OXBRYTA.. Swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets.. Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension. Disperse OXBRYTA tablets for oral suspension in room temperature clear drink (such as drinking water, or clear soda) before administration. The amount of liquid needed to disperse the tablets for oral suspension will depend on the dose (number of tablets prescribed) [see Dosage and Administration (2.7)].. Take OXBRYTA with or without food.. If dose is missed or not consumed entirely, resume dosing the following day [see Dosage and Administration (2.7)].

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USEOXBRYTA(R) [ox brye ta](voxelotor)tablets for oral suspension 300 mgThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 12/2021 This Instructions for Use contains information on how to take OXBRYTA tablets for oral suspension. Read this Instructions for Use before you or your child start taking OXBRYTA tablets for oral suspension for the first time and each time you or your child get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your childs medical condition or treatment. Talk to your healthcare provider or pharmacist if you have questions about how to take or give the prescribed dose of OXBRYTA tablets for oral suspension.Important Information You Need to Know Before Taking OXBRYTA Tablets for Oral Suspension:Take OXBRYTA tablets for oral suspension exactly as your healthcare provider tells you.Your healthcare provider will tell you how many OXBRYTA tablets for oral suspension you will need for your or your childs dose.OXBRYTA comes in two different dosage forms. Each time you receive your or your childs prescription, check the bottle to make sure that you received the prescribed dosage form of OXBRYTA tablets for oral suspension. OXBRYTA tablets for oral suspension are light yellow to yellow, round shaped, and marked with 300 D on one side. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension.You must first mix OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water or clear soda, before swallowing.If you or your child miss dose of OXBRYTA tablets for oral suspension or if the entire dose is not taken, skip that dose and return to the normal dosing schedule the next day.For more information about OXBRYTA tablets for oral suspension, see the Patient Information leaflet.Gather suppliesYou will need the following texts to prepare the dose of OXBRYTA tablets for oral suspension (not included with OXBRYTA tablets for oral suspension):a teaspoona small cuproom temperature clear drink, such as drinking water or clear soda.You will also need:the prescribed number of OXBRYTA tablets for oral suspension needed for your dose.Preparing dose of OXBRYTA tablets for oral suspensionStep 1.Wash and dry your hands well before preparing the dose. Step 2.Pour room temperature clear drink into the cup. The table below shows the amount of clear drink needed for your prescribed dose. You may add more clear drink if needed to mix the tablets.Number of OXBRYTA Tablets for Oral SuspensionAmount of Clear Drink11 teaspoon (5 mL)22 teaspoons (10 mL)33 teaspoons (15 mL)44 teaspoons (20 mL)55 teaspoons (25 mL)77 teaspoons (35 mL)88 teaspoons (40 mL) Step 3.Add the prescribed number of OXBRYTA tablets for oral suspension into the cup.Step 4.Swirl the cup until the tablet(s) break apart (disperse) in the drink. Be careful not to spill the mixture.The tablet(s) will not completely dissolve. You will still see small tablet clumps in the mixture.If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make new dose. Step 5.Wait for to minutes. Giving the doseStep 6.Swirl the cup again. Take or give all of the prepared medicine right away.If giving to child, make sure that your child is upright when drinking the medicine mixture. Step 7.Add or teaspoons of room temperature clear drink to the cup to make sure the full dose is taken. Swirl the cup until the remaining medicine is mixed and take or give it right away.Repeat this step until no more medicine is left in the cup.After all the medicine is taken, you or your child may drink more water or any type of drink. Step 8.Wash the teaspoon and cup with warm soap and water.Storing OXBRYTAStore OXBRYTA between 68F to 86F (20C to 30C).The OXBRYTA bottle comes with child-resistant closure.The OXBRYTA tablets for oral suspension bottle contains polyester coil. Do not eat the polyester coil.Keep OXBRYTA and all medicines out of the reach of children.Disposing of OXBRYTAWhen all the tablets in the bottle have been taken, throw away the bottle. Safely dispose of (throw away) OXBRYTA that is out of date or no longer needed using your local household waste guidelines.Manufactured for: Global Blood Therapeutics, Inc. South San Francisco, CA 94080, USA.OXBRYTA(R)(C) 2021 Global Blood Therapeutics, Inc. All rights reserved.For more information, call 1-833-428-4968 (1-833-GBT-4YOU) or go to www.OXBRYTA.com.. Take OXBRYTA tablets for oral suspension exactly as your healthcare provider tells you.. Your healthcare provider will tell you how many OXBRYTA tablets for oral suspension you will need for your or your childs dose.. OXBRYTA comes in two different dosage forms. Each time you receive your or your childs prescription, check the bottle to make sure that you received the prescribed dosage form of OXBRYTA tablets for oral suspension. OXBRYTA tablets for oral suspension are light yellow to yellow, round shaped, and marked with 300 D on one side. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.. Do not swallow whole, cut, crush, or chew OXBRYTA tablets for oral suspension.. You must first mix OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water or clear soda, before swallowing.. If you or your child miss dose of OXBRYTA tablets for oral suspension or if the entire dose is not taken, skip that dose and return to the normal dosing schedule the next day.. For more information about OXBRYTA tablets for oral suspension, see the Patient Information leaflet.. teaspoon. small cup. room temperature clear drink, such as drinking water or clear soda.. the prescribed number of OXBRYTA tablets for oral suspension needed for your dose.. The tablet(s) will not completely dissolve. You will still see small tablet clumps in the mixture.. If you spill any medicine, clean up the spill. Throw away the rest of the prepared medicine and make new dose.. If giving to child, make sure that your child is upright when drinking the medicine mixture.. Repeat this step until no more medicine is left in the cup.. After all the medicine is taken, you or your child may drink more water or any type of drink.. Store OXBRYTA between 68F to 86F (20C to 30C).. The OXBRYTA bottle comes with child-resistant closure.. The OXBRYTA tablets for oral suspension bottle contains polyester coil. Do not eat the polyester coil.. Figure. Step 2. Step 3. Step 4. Step 5. Step 6. Step 7.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 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 to <12 years for SCD is supported by evidence from an open-label, Phase study. The study enrolled 45 pediatric patients aged 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 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)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Voxelotor is absorbed into plasma and is then distributed predominantly into RBCs due to its preferential binding to Hb. The major route of elimination of voxelotor is by metabolism with subsequent excretion of metabolites into urine and feces. The PK are linear and voxelotor exposures increased proportionally with either single or multiple doses (Table 5) in whole blood, plasma, and RBCs. Steady-state after repeated administration is reached within days and exposures of voxelotor are consistent with accumulation predicted based on single dose data in patients with SCD.Table 5: Pharmacokinetics Parameters of Voxelotor in Plasma and Whole BloodBased on the 72-week population pharmacokinetic analysis. PK ParameterVoxelotor 1,500 mgGeometric Mean (%CV)Plasma PKAUC0-24h (ughr/mL)278 (28.4)Cmax (ug/mL)14 (24.5)Half-life (hours)38.7 (30.2)Whole Blood PKAUC0-24h (ughr/mL)3,830 (33.5)Cmax (ug/mL)180 (31)In healthy subjects, voxelotor exposures were comparable when administered as tablet for oral suspension dispersed in water or as oral tablet swallowed whole.. AbsorptionThe median plasma and whole blood Tmax of voxelotor after oral administration is hours. The mean peak concentrations in whole blood and RBCs are observed between and 18 hours after oral administration.. Effect of FoodA high-fat, high-calorie meal increased voxelotor AUC by 42% and Cmax by 45% in whole blood relative to AUC and Cmax in the fasted state. Similarly, AUC increased by 42% and Cmax increased by 95% in plasma.. DistributionVoxelotor apparent volume of distribution of the central compartment and peripheral compartment are 333 and 72.3 in plasma, respectively. Protein binding is 99.8% in vitro. The blood-to-plasma ratio is approximately 17:1 in patients with SCD.. EliminationThe geometric mean (%CV) terminal elimination half-life of voxelotor in patients with SCD is 38.7 hours (30.2%) with concentrations in plasma, whole blood, and RBCs declining in parallel. The apparent oral clearance of voxelotor was estimated as 6.1 L/h in plasma in patients with SCD.. MetabolismIn vitro and in vivo studies indicate that voxelotor is extensively metabolized through Phase (oxidation and reduction), Phase II (glucuronidation) and combinations of Phase and II metabolism. Metabolism of voxelotor is mediated by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9.. ExcretionFollowing the administration of radiolabeled voxelotor, approximately 62.6% of the dose and its metabolites are excreted into feces (33.3% unchanged) and 35.5% in urine (0.08% unchanged).. Specific PopulationsNo clinically significant differences in the pharmacokinetics of voxelotor were observed based on age (12 to 59 years), sex, body weight (28 to 135 kg), or mild to severe renal impairment (creatinine clearance [CLcr] 15-89 mL/min).. Pediatric PatientsThe pharmacokinetic exposures of voxelotor in whole blood and plasma were similar between pediatric patients to <17 years and adults following the recommended dosage [see Dosage and Administration (2)].. Patients with Renal ImpairmentThere was no clinically significant effect of renal function on the excretion of voxelotor. Following single 900 mg dose of voxelotor, whole blood exposures in subjects with severe renal impairment (eGFR <30 mL/min/1.73 m2) were 25% lower compared to healthy controls.The unbound plasma concentrations were comparable. OXBRYTA has not been evaluated in patients with end stage renal disease requiring dialysis.. Patients with Hepatic ImpairmentThe voxelotor AUC in whole blood were 14% and 15% higher in subjects with mild and moderate hepatic impairment (Child Pugh and B) and 90% higher in subjects with severe hepatic impairment (Child Pugh C) compared to subjects with normal hepatic function.. Patients with HbSC GenotypeVoxelotor steady state whole blood AUC and Cmax were 50% and 45% higher in HbSC genotype patients (n=11) compared to HbSS genotype (n=220) patients and voxelotor steady state plasma AUC and Cmax were 23% and 15% higher in HbSC genotype patients compared to HbSS genotype patients.. Drug Interaction Studies. Clinical Studies and Model-Informed Approaches. Effect of Strong CYP3A4 Inhibitors on Voxelotor: concomitant use of OXBRYTA with itraconazole increased voxelotor AUC in healthy subjects by 11%.. Effect of Strong or Moderate CYP3A4 Inducers on Voxelotor: concomitant use of OXBRYTA with rifampin (a strong CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 40%, and efavirenz (a moderate CYP3A4 inducer) is predicted to decrease voxelotor AUC in patients by up to 24%.. Effect of Acid Reducing Agents on Voxelotor: coadministration of omeprazole (proton pump inhibitor) with OXBRYTA did not alter voxelotor exposure.. Effect of Voxelotor on CYP450 Enzymes: in vivo voxelotor inhibits CYP3A4, but not CYP1A2, CYP2C9, CYP2C19, CYP2C8, or CYP2D6. The observed exposure increase of the CYP3A4 substrate midazolam in healthy subjects was 1.6-fold and the predicted increase in patients after multiple dosing is 2.5-fold.. Effect of Voxelotor on P-gp: concomitant use of OXBRYTA with digoxin (a P-gp substrate) did not alter digoxin to clinically relevant extent.. In Vitro Studies. CYP Enzymes: voxelotor is reversible and time-dependent inhibitor as well as an inducer of CYP2B6.. Transporter Systems: voxelotor is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2-K, or BSEP. Voxelotor is not substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on OXBRYTA use in pregnant women to evaluate for 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 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 RiskWomen 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 DataIn embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 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 pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 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.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONOXBRYTA(R) (ox brye ta) (voxelotor) tablets OXBRYTA(R) (ox brye ta)(voxelotor) tablets for oral suspensionThis Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 12/2021 What is OXBRYTAOXBRYTA is prescription medicine used for the treatment of sickle cell disease in adults and children years of age and older. It is not known if OXBRYTA is safe and effective in children with sickle cell disease below years of age.Do not take OXBRYTA if you or your child have had an allergic reaction to voxelotor or any of the ingredients in OXBRYTA. See the end of this leaflet for list of the ingredients in OXBRYTA.Before taking OXBRYTA, tell your healthcare provider about all of your medical conditions, including if you or your child:have liver problemsare pregnant or plan to become pregnant. It is not known if OXBRYTA can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if OXBRYTA can pass into your breastmilk and if it can harm your baby. Do not breastfeed during treatment with OXBRYTA and for at least weeks after the last dose.Tell your healthcare provider about all the medicines you or your child take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines may affect how OXBRYTA works. OXBRYTA may also affect how other medicines work and may affect the results of certain blood tests. Keep list of all your medicines and show it to your healthcare provider.How should take OXBRYTATake OXBRYTA exactly as your healthcare provider tells you.Do not change your dose or stop taking OXBRYTA unless your healthcare provider tells you to. Your healthcare provider may change your dose if needed.Take your prescribed dose of OXBRYTA time each day.Take OXBRYTA with or without food.OXBRYTA comes in two different dosage forms, OXBRYTA tablets and OXBRYTA tablets for oral suspension. Your healthcare provider will decide which dosage form you take based on your age, weight, and ability to swallow tablets. If you take OXBRYTA tablets: Swallow each OXBRYTA tablet whole. Do not cut, crush, or chew the tablets.If you take OXBRYTA tablets for oral suspension: See the detailed Instructions for Use on how to prepare and take your dose. You must mix the OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water or clear soda, right before taking it. Do not swallow whole, cut, crush, or chew the tablets for oral suspension. Check to make sure you receive the correct dosage form of OXBRYTA each time your prescription is filled to avoid taking the wrong medicine.Your healthcare provider may also prescribe medicine called hydroxyurea during treatment with OXBRYTA.If you or your child miss dose of OXBRYTA or if the entire dose is not taken, skip that dose and return to your normal dosing schedule the next day.What should avoid while taking OXBRYTADo not take St. Johns wort during treatment with OXBRYTA.What are the possible side effects of OXBRYTA OXBRYTA can cause serious side effects, including:Serious allergic reactions. Tell your healthcare provider or get emergency medical help right away if you get:rashhivesshortness of breath (difficult breathing)swelling of the faceThe most common side effects of OXBRYTA include:headachediarrheastomach-area (abdominal) painnausearash or hivesfeverThe most common side effects of OXBRYTA in children ages to less than 12 years of age include: fevervomitingrashstomach-area (abdominal) paindiarrheaheadacheThese are not all the possible side effects of OXBRYTA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Global Blood Therapeutics, Inc. at 1-833-428-4968 (1-833-GBT-4YOU).How should store OXBRYTAStore OXBRYTA between 68F to 86F (20C to 30C).The OXBRYTA bottle comes with child-resistant closure.The OXBRYTA bottle may contain desiccant canister to help keep your medicine dry (protect it from moisture) and polyester coil. Do not eat the desiccant or polyester coil.Keep OXBRYTA and all medicines out of the reach of children.General information about the safe and effective use of OXBRYTA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use OXBRYTA for condition for which it was not prescribed. Do not give OXBRYTA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about OXBRYTA that is written for health professionals.What are the ingredients of OXBRYTAActive Ingredient: voxelotor Inactive Ingredients: OXBRYTA tablets: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.OXBRYTA tablets for oral suspension: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose. Manufactured for: Global Blood Therapeutics, Inc. South San Francisco, CA 94080, USA.OXBRYTA(R) (C) 2021 Global Blood Therapeutics, Inc. All rights reserved. For more information, call 1-833-428-4968 (1-833-GBT-4YOU) or go to www.OXBRYTA.com.. have liver problems. are pregnant or plan to become pregnant. It is not known if OXBRYTA can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if OXBRYTA can pass into your breastmilk and if it can harm your baby. Do not breastfeed during treatment with OXBRYTA and for at least weeks after the last dose.. Take OXBRYTA exactly as your healthcare provider tells you.. Do not change your dose or stop taking OXBRYTA unless your healthcare provider tells you to. Your healthcare provider may change your dose if needed.. Take your prescribed dose of OXBRYTA time each day.. Take OXBRYTA with or without food.. OXBRYTA comes in two different dosage forms, OXBRYTA tablets and OXBRYTA tablets for oral suspension. Your healthcare provider will decide which dosage form you take based on your age, weight, and ability to swallow tablets. If you take OXBRYTA tablets: Swallow each OXBRYTA tablet whole. Do not cut, crush, or chew the tablets.If you take OXBRYTA tablets for oral suspension: See the detailed Instructions for Use on how to prepare and take your dose. You must mix the OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water or clear soda, right before taking it. Do not swallow whole, cut, crush, or chew the tablets for oral suspension. If you take OXBRYTA tablets: Swallow each OXBRYTA tablet whole. Do not cut, crush, or chew the tablets.. If you take OXBRYTA tablets for oral suspension: See the detailed Instructions for Use on how to prepare and take your dose. You must mix the OXBRYTA tablets for oral suspension in room temperature clear drink, such as drinking water or clear soda, right before taking it. Do not swallow whole, cut, crush, or chew the tablets for oral suspension. Check to make sure you receive the correct dosage form of OXBRYTA each time your prescription is filled to avoid taking the wrong medicine.. Your healthcare provider may also prescribe medicine called hydroxyurea during treatment with OXBRYTA.. If you or your child miss dose of OXBRYTA or if the entire dose is not taken, skip that dose and return to your normal dosing schedule the next day.. Serious allergic reactions. Tell your healthcare provider or get emergency medical help right away if you get:. rash. hives. shortness of breath (difficult breathing). swelling of the face. headache. diarrhea. stomach-area (abdominal) pain. nausea. rash or hives. fever. fever. vomiting. rash. stomach-area (abdominal) pain. diarrhea. headache. Store OXBRYTA between 68F to 86F (20C to 30C).. The OXBRYTA bottle comes with child-resistant closure.. The OXBRYTA bottle may contain desiccant canister to help keep your medicine dry (protect it from moisture) and polyester coil. Do not eat the desiccant or polyester coil.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryThere are no available data on OXBRYTA use in pregnant women to evaluate for 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 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 RiskWomen 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 DataIn embryo-fetal development studies, voxelotor was administered orally to pregnant rats at 15, 50, and 250 mg/kg/day (gestation days through 17) and rabbits at 25, 75, and 150 mg/kg/day (gestation days 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 pre- and postnatal development study, voxelotor was administered orally to pregnant rats at 15, 50 and 250 mg/kg/day (gestation day 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 SummaryThere 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 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 weeks after the last dose.. 8.4 Pediatric Use. The safety and effectiveness of OXBRYTA for SCD have been established in pediatric patients aged years and older. The safety and efficacy of OXBRYTA in pediatric patients with SCD below the age of 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 to <12 years for SCD is supported by evidence from an open-label, Phase study. The study enrolled 45 pediatric patients aged 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 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)].