BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR OXBRYTA ® ( voxelotor ) tablets , for oral use
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INDICATIONS AND USAGE
OXBRYTA is a hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease in adults and pediatric patients 12 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 ).
DOSAGE AND ADMINISTRATION
The recommended dosage of OXBRYTA for sickle cell disease is 1,500 mg taken orally once daily with or without food .
Recommended Dosage for Hepatic Impairment
The recommended dosage of OXBRYTA in patients with severe hepatic impairment ( Child Pugh C ) is 1,000 mg taken once daily with or without food . No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment .
Recommended Dosage with Concomitant Moderate or Strong Inducers , Strong Inhibitors of CYP3A4 , or Fluconazole
Avoid concomitant use of strong or moderate CYP3A4 inducers , strong CYP3A4 inhibitors , or fluconazole with OXBRYTA . If concomitant use of strong or moderate CYP3A4 inducers , strong CYP3A4 inhibitors , or fluconazole is unavoidable , adjust the OXBRYTA dosage as recommended in Table 1 .
Table 1 : OXBRYTA Recommended Dosage for Concomitant Medications Concomitant Medication Strong CYP3A4 inhibitors or fluconazole Strong or moderate CYP3A4 inducers
Recommended Dosage 1,000 mg once daily 2,500 mg once daily
CONTRAINDICATIONS
OXBRYTA is contraindicated in patients with a history of drug hypersensitivity reaction to voxelotor or excipients .
WARNINGS AND PRECAUTIONS 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 .
If hypersensitivity reactions occur , discontinue OXBRYTA and administer appropriate medical therapy . Do not reinitiate OXBRYTA in patients who experience these symptoms with previous use .
Laboratory Test Interference
OXBRYTA administration may interfere with measurement of Hb subtypes ( HbA , HbS , and HbF ) by HPLC . If precise quantitation of Hb species is required , chromatography should be performed when the patient is not receiving OXBRYTA therapy .
Clinical Trials Experience
The safety of OXBRYTA was evaluated in the HOPE trial based upon 88 patients who received OXBRYTA 1,500 mg and 91 patients who received placebo orally once daily . Seventy-four patients received OXBRYTA 1,500 mg once daily for ≥24 weeks and 65 patients for ≥48 weeks .
In patients who received OXBRYTA 1,500 mg once daily the median age was 24 years ( range : 12-59 ); 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 an adverse reaction occurred in 41 % [ 36 / 88 ] of patients who received OXBRYTA . Most frequent adverse reactions requiring dosage interruption occurring in more than one patient who received OXBRYTA 1,500 mg included diarrhea , headache , rash , and vomiting .
The safety profile observed in pediatric patients 12 to < 17 years of age treated with OXBRYTA 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 2 .
Table 2 : Adverse Reactions ( ≥10 %) in Patients Receiving OXBRYTA with a Difference Between Arms of > 3 % Compared to Placebo in HOPE
Adverse Reaction a OXBRYTA 1,500 mg ( N = 88 ) Placebo ( N = 91 ) a
Adverse reactions were Grades 1 or 2 except for Grade 3 diarrhea ( 1 ), nausea ( 1 ), rash ( 1 ) and rash generalized ( 3 )
Headache 23 ( 26 %) 20 ( 22 %) Diarrhea 18 ( 20 %) 9 ( 10 %)
Abdominal Pain b 17 ( 19 %) 12 ( 13 %) Nausea 15 ( 17 %) 9 ( 10 %) Fatigue 12 ( 14 %) 9 ( 10 %) Rash c 12 ( 14 %) 9 ( 10 %) Pyrexia 11 ( 12 %) 6 ( 7 %) b
Abdominal pain ( grouped PTs ) included the following PTs : abdominal pain and upper abdominal pain c
Rash ( grouped PTs ) includes the following PTs : rash , urticaria , generalized rash , maculo-papular rash , pruritic rash , papular rash , erythematous rash , and vesicular rash
Clinically relevant adverse reactions occurring in < 10 % of patients included :
• Drug hypersensitivity
DRUG INTERACTIONS Effect of Other Drugs on Voxelotor Sensitive CYP3A4 Substrates : Voxelotor increased the systemic exposure of midazolam ( a sensitive CYP3A4 substrate ). Avoid co-administration with sensitive CYP3A4 substrates with a narrow therapeutic index . If unavoidable , consider dose reduction of the CYP3A4 substrate ( s ).
Strong CYP3A4 Inhibitors or Fluconazole : Co-administration of strong CYP3A4 inhibitors or fluconazole may increase voxelotor plasma concentrations and may lead to increased toxicity .
Avoid co-administration of OXBRYTA with strong CYP3A4 inhibitors or fluconazole and replace these drugs with alternative drugs when possible . Decrease the OXBRYTA dosage when co-administration with a strong CYP3A4 inhibitor or fluconazole is unavoidable .
Strong or Moderate CYP3A4 Inducers : Co-administration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma concentrations and may lead to reduced efficacy .
Avoid co-administration of OXBRYTA with strong or moderate CYP3A4 inducers . Increase the OXBRYTA dosage when co-administration with a strong or moderate CYP3A4 inducer is unavoidable .
Effect of Voxelotor on Other Drugs Voxelotor increased the systemic exposure of midazolam ( a sensitive CYP3A4 substrate ). Avoid co-administration 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 ).
USE IN SPECIFIC POPULATIONS 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 . OXBRYTA should only be used during pregnancy if the benefit of the drug outweighs the potential risk .
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 .
Pediatric Use The safety and effectiveness of OXBRYTA for sickle cell disease have been established in pediatric patients aged 12 years and older . Use of OXBRYTA for sickle cell disease is supported by evidence from an adequate and well-controlled study in adults and pediatric patients ( HOPE trial ). The safety and efficacy of OXBRYTA in pediatric patients below the age of 12 years have not been established .
The adverse reactions observed in pediatric patients 12 to < 17 years treated with OXBRYTA were similar in type and frequency to those observed in adults .
Hepatic Impairment Severe hepatic impairment increases voxelotor exposures . Reduce OXBRYTA dose ( see Dosage and Administration ).
© Global Blood Therapeutics , Inc . Oxbryta is a registered trademark of Global Blood Therapeutics , Inc . All other trademarks referenced herein are the property of their individual owners . P-VOX-US-00311 v2