Voxelotor (Monograph)

Brand name: Oxbryta
Drug class: Blood Formation, Coagulation, and Thrombosis Agents; Miscellaneous

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

Introduction

Voxelotor is a hemoglobin S (HbS) polymerization inhibitor.

Uses for Voxelotor

Sickle Cell Disease

Treatment of sickle cell disease in adults and pediatric patients ≥4 years of age.

Approved under accelerated approval based on increase in hemoglobin. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Designated an orphan drug by FDA for treatment of sickle cell disease.

Hydroxyurea is first-line treatment for most patients with sickle cell disease. Although place of therapy for voxelotor remains to be determined, the drug may be considered in patients with low hemoglobin and more than 1 sickle cell pain crisis per year despite hydroxyurea therapy or for patients unable to tolerate hydroxyurea therapy. Effects of voxelotor on clinical outcomes such as pain crises or quality of life are currently not known.

Voxelotor Dosage and Administration

Administration

Oral Administration

Administer orally with or without food.

Voxelotor is commercially available as film-coated tablets, and as tablets for oral suspension. Tablets for oral suspension can be substituted for tablets in adults and pediatric patients ≥12 years of age who have difficulty swallowing. For pediatric patients 4 to <12 years of age, use of voxelotor tablets or voxelotor tablets for oral suspension is based on the patient’s weight and their ability to swallow tablets. If dose is missed or not entirely consumed, take again at the next scheduled time; an additional dose should not be administered to replace the missed dose.

May be given with or without hydroxyurea.

Tablets

Swallow film-coated tablets whole. Do not cut, crush, or chew.

Tablets for Oral Suspension

Do not swallow whole, cut, crush, or chew.

Disperse tablets for oral suspension immediately before administration in a cup containing room temperature clear liquid (e.g., water, clear soda, apple juice, clear electrolyte drink, clear flavored drink, clear sports drink). Disperse each 300-mg tablet for oral suspension in a minimum of 5 mL (1 teaspoonful) of clear drink (e.g., one 300-mg tablet is dispersed in ≥5 mL of clear drink, two 300-mg tablets are dispersed in ≥10 mL of clear drink, and so on). After tablets start to disintegrate, swirl contents and wait 1–5 minutes; swirl contents again and administer orally. Tablet(s) will not completely dissolve, and small tablet clumps will be left in mixture. If any residue is left, keep resuspending with the clear liquid until no tablet residue is remaining.

Dosage

Pediatric Patients

Sickle Cell Disease in Pediatric Patients 4 to <12 Years of Age

Oral

Recommended dosage is based on body weight:

10 kg to <20 kg: 600 mg once daily.

20 kg to <40 kg: 900 mg once daily.

≥40 kg: 1500 mg once daily.

Sickle Cell Disease in Pediatric Patients ≥12 Years of Age

Oral

1500 mg once daily.

Adults

Sickle Cell Disease

Oral

1500 mg once daily.

Dosage Modification for Hepatic Impairment

Pediatric Patients 4 to <12 Years of Age

Recommended dosage in pediatric patients 4 to <12 years of age with severe hepatic impairment (Child Pugh C) is based on body weight as shown in Table 1.

No dosage adjustment necessary for mild or moderate hepatic impairment (Child Pugh A or B).

Pediatric Patients ≥12 Years of Age

Severe hepatic impairment (Child Pugh C): 1000 mg once daily. No dosage adjustment necessary for mild or moderate hepatic impairment (Child Pugh A or B).

Adults

Severe hepatic impairment (Child Pugh C): 1000 mg once daily. No dosage adjustment necessary for mild to moderate hepatic impairment (Child Pugh A or B).

Dosage Modification for Concomitant Strong or Moderate CYP3A4 Inducers

Pediatric Patients 4 to <12 Years of Age

Avoid concomitant use of potent or moderate CYP3A4 inducers. If concomitant use is unavoidable, refer to Table 2 for dosage recommendations.

Pediatric Patients ≥12 Years of Age

Avoid concomitant use of potent or moderate CYP3A4 inducers. If concomitant use of potent CYP3A4 inducers is unavoidable, increase dosage to 2500 mg once daily. If concomitant use of moderate CYP3A4 inducers is unavoidable, increase dosage to 2000 mg once daily.

Adults

Avoid concomitant use of potent or moderate CYP3A4 inducers. If concomitant use of potent CYP3A4 inducers is unavoidable, increase dosage to 2500 mg once daily. If concomitant use of moderate CYP3A4 inducers is unavoidable, increase dosage to 2000 mg once daily.

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child Pugh C): dosage adjustment required.

Mild or moderate hepatic impairment (Child Pugh A or B): No dosage adjustment required.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Voxelotor

Contraindications

• Prior drug hypersensitivity to voxelotor or excipients.

Warnings/Precautions

Hypersensitivity Reactions

Serious hypersensitivity reactions have occurred in <1% of patients treated with voxelotor. Manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia.

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in postmarketing experience. Medically evaluate patients who develop a combination of skin rash, peripheral eosinophilia, and internal systemic organ involvement (e.g., hepatic, renal, pulmonary) while administered voxelotor.

Advise patients of signs and symptoms of severe hypersensitivity reactions, including DRESS. Discontinue if hypersensitivity reactions occur and administer appropriate medical therapy. Do not reinitiate.

Laboratory Test Interference

May interfere with measurement of hemoglobin (Hb) subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC). For precise measurement of Hb, perform chromatography after withholding voxelotor for 10 days.

Specific Populations

Pregnancy

No available data to evaluate for drug-associated risks in pregnancy. Animal studies have shown no adverse developmental effects to the fetus when administered during organogenesis. Adverse outcomes in pregnant females and in the developing fetus have been associated with sickle cell disease. Utilize during pregnancy only if the benefit of the drug outweighs potential risk.

Lactation

Not known whether voxelotor or its metabolites distribute into milk, affect milk production, or affect breast-fed infants. The drug has been detected in milk of lactating rats; therefore, likely to be present in human milk.

Patients should not breast-feed during therapy and for 2 weeks after the last dose of the drug.

Pediatric Use

Safety and efficacy established in pediatric patients ≥4 years of age. Observed safety in pediatric patients 4 years to <12 years similar to that observed in patients ≥12 years of age and adults.

Safety and efficacy in patients <4 years of age not established.

Geriatric Use

Not studied in sufficient numbers of patients aged ≥65 years to determine if they respond differently from younger patients.

Hepatic Impairment

AUC increased by 14, 15, and 90%, respectively, in patients with mild (Child Pugh A), moderate (Child Pugh B), and severe (Child Pugh C) hepatic impairment compared to healthy subjects. Reduce dosage in patients with severe hepatic impairment.

Renal Impairment

Does not substantially affect voxelotor pharmacokinetics. Not studied in dialysis.

Common Adverse Effects

Adults (≥10%): headache, diarrhea, abdominal pain, nausea, rash, pyrexia.

Pediatric patients (>10%): pyrexia, vomiting, rash, abdominal pain, diarrhea, headache.

Drug Interactions

Primarily metabolized by CYP3A4, 3A5, 2B6, 2C19, and 2C9, and UGT1A1 and 1A9. In vivo, inhibits CYP isoenzyme 3A4, but not 1A2, 2C9, 2C19, 2C8, or 2D6. In vitro, voxelotor is a reversible and time-dependent inhibitor and inducer of CYP2B6. Does not inhibit P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1 protein, MATE2-K, or the bile sale export pump (BSEP). Not a substrate of P-gp, BCRP, OATP1A2, OATP1B1, OATP1B3, or BSEP.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: AUC of voxelotor increased to a small extent when administered concomitantly with a potent CYP3A4 inhibitor (itraconazole).

Inducers of CYP3A4: Concomitant use with potent or moderate inducers of CYP3A4 may result in decreased plasma and whole blood concentrations of voxelotor, leading to reduced efficacy.

Avoid co-administration with potent or moderate CYP3A4 inducers. If concomitant use is unavoidable, increase dosage of voxelotor.

Substrates of CYP3A4: Concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices may result in increased systemic exposure of the substrate. Avoid concomitant use; if unavoidable, consider reducing dosage of the sensitive CYP3A4 substrate.

Specific Drugs

Voxelotor Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained in a median of 2 hours following oral administration. Peak concentrations in whole blood and RBCs occur after a mean of 6–18 hours.

Food

Administration of a high-fat, high-calorie meal increases AUC and maximum serum concentrations in whole blood by 42 and 45%, respectively, relative to the fasted state. In plasma, AUC and maximum serum concentrations increased by 42 and 95%, respectively.

Special Populations

Mild and moderate hepatic impairment (Child Pugh A and B): Whole blood AUC 14 and 15% higher, respectively.

Severe hepatic impairment (Child Pugh C): Whole blood AUC 90% higher.

Age (12–59 years), sex, body weight (28–135 kg), or mild to severe renal impairment (Cl_cr 15–89 mL/minute) do not affect pharmacokinetics of voxelotor. Pharmacokinetics in whole blood and plasma similar between patients 4 to <17 years of age and adults at recommended doses.

Distribution

Extent

Not known whether voxelotor or its metabolites distribute into milk.

Plasma Protein Binding

99.8%.

Elimination

Metabolism

Metabolized by CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UGT1A1, and UGT1A9.

Elimination Route

Eliminated in feces (62.6% [33.3% as unchanged drug]), and urine (35.5% [0.08% as unchanged drug]).

Half-life

38.7 hours.

Stability

Storage

Oral

Tablets, Film-Coated

20–30°C.

Tablets, For Suspension

20–30°C.

Actions

• A hemoglobin S (HbS) polymerization inhibitor; binds to HbS with a 1:1 stoichiometry and distributes primarily in RBCs due to preferential binding to Hb.

• Demonstrates dose-dependent increases in Hb oxygen affinity.

• Dose-dependent reductions in hemolysis observed, as measured by indirect bilirubin and the percentage of reticulocytes.

• May also inhibit RBC sickling, improve RBC deformability, and reduce whole blood viscosity.

Advice to Patients

• Advise the patient to read the FDA-approved patient labeling (Patient Information).

• Advise patients that serious hypersensitivity reactions may occur, and to notify their healthcare providers if they develop generalized rash, fever, urticaria, shortness of breath, facial swelling, and eosinophilia.

• Advise patients and caregivers to visually inspect the tablets received each time the prescription is filled to verify that the correct formulation was filled and avoid dosing errors.

• Advise patients to continue taking voxelotor every day for as long as their physician tells them, since this is a long-term treatment.

• Inform patients that voxelotor film-coated tablets must be swallowed whole. Do not cut, crush, or chew voxelotor film-coated tablets. Inform patients that voxelotor tablets for oral suspension must be dispersed in a clear drink prior to administration, and must not be swallowed whole, cut, crushed, or chewed. The volume of drink necessary to disperse the tablets will vary based on the patient’s dosage.

• Inform patients that voxelotor can be taken with or without food. If a dose is missed or not entirely consumed, continue dosing on the day following the missed dose.

• Advise patients not to take St. John’s wort while taking voxelotor.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise female patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise females not to breast-feed while they are taking voxelotor and for at least 2 weeks after the last dose.

• Advise patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Voxelotor is obtained through designated specialty pharmacies. Contact manufacturer at 833-428-4968 or consult the Oxbryta website [Web] for specific availability information.

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