Omaveloxolone (Monograph)

Drug class: Other Miscellaneous Therapeutic Agents

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

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Introduction

Potent activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2); Nrf2 pathway involved in cellular response to oxidative stress.

Uses for Omaveloxolone

Friedreich’s Ataxia

Used for treatment of Friedreich's ataxia in adults and adolescents ≥16 years of age (designated an orphan drug by FDA for this use).

​Current guidelines on treatment of Friedreich’s ataxia, a progressive neurogenerative disease, primarily focus on supportive care and treatment of associated clinical symptoms. Place in therapy for omaveloxolone not yet established.

Omaveloxolone Dosage and Administration

General

Pretreatment Screening

• Obtain baseline ALT, AST, total bilirubin, B-type natriuretic peptide (BNP), and lipid parameters prior to treatment.

Patient Monitoring

• Monitor ALT, AST, and total bilirubin every month for the first 3 months of treatment and periodically thereafter. Increase the frequency of monitoring if levels increase during treatment.

• Monitor for signs and symptoms of fluid overload during treatment. If signs and symptoms of fluid overload develop, worsen, or require hospitalization, monitor BNP and assess cardiac function.

• Monitor lipid parameters periodically during treatment.

Administration

Oral Administration

Administer orally on empty stomach at least 1 hour before eating. Swallow capsules whole; do not crush or chew.

For patients unable to swallow whole capsules, open capsule(s) and sprinkle entire contents onto 2 tablespoons (30 mL) of applesauce. Stir mixture until homogenous. Swallow entire drug/applesauce mixture immediately; do not store for future use. Do not mix contents of capsule(s) with milk or orange juice. Do not administer via an enteral feeding tube.

If a dose is missed, take next dose at scheduled time the following day. Do not take a double dose to make up for a missed dose.

Dosage

Pediatric Patients

Friedreich's Ataxia

Oral

Adolescents ≥16 years of age: 150 mg (3 capsules) once daily.

Adults

Friedreich's Ataxia

Oral

150 mg (3 capsules) once daily.

<C> Dosage Modification for Concomitant Use with Strong or Moderate CYP3A4 Inhibitors

Strong CYP3A4 inhibitor: If coadministration unavoidable, reduce omaveloxolone dosage to 50 mg once daily with close monitoring of adverse reactions. If adverse reactions emerge, discontinue coadministration with strong CYP3A4 inhibitor.

Moderate CYP3A4 inhibitor: If coadministration unavoidable, reduce omaveloxolone dosage to 100 mg once daily with close monitoring of adverse reactions. If adverse reactions emerge, further reduce omaveloxolone dosage to 50 mg once daily.

Special Populations

Hepatic Impairment

Severe hepatic impairment (Child-Pugh class C): Avoid use.

Moderate hepatic impairment (Child-Pugh class B): Reduce dosage to 100 mg once daily with close monitoring for adverse reactions. If adverse reactions emerge, consider lowering dosage to 50 mg once daily.

Mild hepatic impairment (Child-Pugh class A): No dosage adjustments necessary.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Related/similar drugs

Skyclarys

Cautions for Omaveloxolone

Contraindications

• None.

Warnings/Precautions

Elevation of Aminotransferases

Elevation in hepatic transaminases (ALT and AST) may occur.

Monitor ALT, AST, and total bilirubin prior to omaveloxolone initiation, every month for the first 3 months of treatment, and periodically thereafter. If transaminases increase to levels >5 times ULN, or >3 times ULN with evidence of liver dysfunction (e.g., elevated bilirubin), discontinue omaveloxolone immediately and repeat liver function tests as soon as possible. If transaminase levels stabilize or resolve, may reinitiate omaveloxolone with appropriate increased frequency of monitoring of liver function.

Elevation of B-Type Natriuretic Peptide

Increase in B-type natriuretic peptide (BNP), a marker of cardiac function, may occur. Elevations in BNP may indicate cardiac failure; should prompt assessment of cardiac function.

Evaluate BNP prior to omaveloxolone initiation. Monitor patients for signs and symptoms of fluid overload, such as sudden weight gain (≥3 pounds of weight gain in 1 day, or ≥5 pounds of weight gain in 1 week), peripheral edema, palpitations, and shortness of breath. If signs and symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac function, and manage appropriately. Management of fluid overload and heart failure may require discontinuation of omaveloxolone.

Lipid Abnormalities

Changes in cholesterol may occur.

Assess lipid parameters prior to omaveloxolone initiation, and monitor periodically during treatment. Manage lipid abnormalities in accordance with current clinical guideline recommendations.

Specific Populations

Pregnancy

No adequate data on developmental risks associated with omaveloxolone use in pregnant women.

Lactation

No data available on presence of omaveloxolone or its metabolites in human milk. Effects on milk production or on breast-fed infants unknown.

Consider developmental and health benefits of breast-feeding along with mother’s clinical need for omaveloxolone and any potential adverse effects on breast-fed infant from drug or underlying maternal condition.

Females and Males of Reproductive Potential

May decrease efficacy of hormonal contraceptives.

Advise patients to avoid concomitant use of omaveloxolone with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills. Counsel females using hormonal contraceptives to use alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28 days after discontinuation of omaveloxolone.

Pediatric Use

Safety and effectiveness for treatment of Friedreich's ataxia established in pediatric patients ≥16 years of age. Safety and effectiveness not established in pediatric patients <16 years of age.

Geriatric Use

Clinical studies did not include patients ≥65 years of age. No data available to determine whether geriatric patients respond differently than younger adults.

Hepatic Impairment

Reduced drug clearance and increased plasma exposure in patients with moderate and severe hepatic impairment.

Severe hepatic impairment (Child-Pugh class C): AUC increased up to 2.17-fold; however, this change was variable. Avoid omaveloxolone in this population, including patients who develop severe hepatic impairment. If hepatic function improves to moderate or mild impairment or to normal function, consider omaveloxolone initiation at the approved recommended dosage.

Moderate hepatic impairment (Child-Pugh class B): Peak plasma concentrations and AUC increased up to 1.83-fold and 1.65-fold, respectively. Reduced dosage recommended in this population, with close monitoring for adverse reactions.

Mild hepatic impairment (Child-Pugh class A): No clinically important differences in omaveloxolone pharmacokinetics observed; no dosage adjustments recommended.

Renal Impairment

Effects on omaveloxolone pharmacokinetics unknown.

Common Adverse Effects

Most common adverse reactions (≥20%): Elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, musculoskeletal pain.

Drug Interactions

CYP3A4 substrate; weak inducer of CYP3A4 and CYPC8.

Does not inhibit CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6 in vitro. Does not induce CYP1A2 and CYP2B6 in vitro.

Inhibits the renal transporter, organic anion transporter (OAT)1, in vitro. Does not inhibit breast cancer resistance protein (BCRP), bile salt export pump, OAT3, organic anion transport polypeptide (OATP)1B1, OATP1B3, organic cation transport 2, multidrug and toxin extrusion (MATE)1, and MATE2K.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 Inhibitors

Concomitant use expected to result in clinically important, increased exposure of omaveloxolone; may increase risk of adverse reactions.

Avoid concomitant use. If concomitant use unavoidable, reduce omaveloxolone dosage to 50 mg once daily with close monitoring of adverse reactions; if adverse reactions emerge, discontinue coadministration.

Moderate CYP3A4 Inhibitors

Concomitant use expected to result in clinically important, increased exposure of omaveloxolone; may increase risk of adverse reactions.

Avoid concomitant use. If concomitant use unavoidable, reduce omaveloxolone dosage to 100 mg once daily with close monitoring of adverse reactions; if adverse reactions emerge, further reduce omaveloxolone dosage to 50 mg once daily.

Weak CYP3A4 Inhibitors

No clinically important differences in omaveloxolone pharmacokinetics expected following concomitant use.

Strong or Moderate CYP3A4 Inducers

Concomitant use may significantly decrease omaveloxolone exposure; may reduce effectiveness of omaveloxolone.

Avoid concomitant use.

CYP3A4 Substrates

Concomitant use can reduce exposure of substrates; can reduce activity of substrates.

Refer to prescribing information for CYP3A4 substrates for dosing instructions if used concomitantly with omaveloxolone; monitor for lack of efficacy of substrate.

CYP2C8 Substrates

Concomitant use can reduce exposure of substrates; can reduce activity of substrates.

Refer to prescribing information for CYP2C8 substrates for dosing instructions if used concomitantly with omaveloxolone; monitor for lack of efficacy of substrate.

Strong CYP2C8 Inhibitors

No clinically important differences in omaveloxolone pharmacokinetics expected following concomitant use.

Specific Drugs

Omaveloxolone Pharmacokinetics

Absorption

Bioavailability

Median time to peak plasma concentrations: 7–14 hours (range: 1–24 hours).

Peak plasma concentrations increased in a less than dose-proportional manner over dosage range of 50–150 mg in healthy fasted subjects; AUC increased in a dose-dependent and dose-proportional manner over dosage range of 50–150 mg.

Food

Peak plasma concentrations and AUC similar when capsule contents sprinkled on applesauce or when administered as intact capsules.

When sprinkled on applesauce, median time to peak plasma concentrations shortened from approximately 10 to 6 hours.

When administered with high-fat meal (800–1000 calories, approximately 150, 250, and 500–600 calories from protein, carbohydrate, and fat, respectively), peak plasma concentrations and AUC increased by approximately 350 and 15%, respectively, compared with fasted conditions.

Distribution

Extent

Not known whether omaveloxolone or metabolites distributed into human milk.

Plasma Protein Binding

97%.

Elimination

Metabolism

Primarily metabolized by CYP3A; minor metabolism by CYP2C8 and CYP2J2.

Elimination Route

Following administration of single oral dose of radiolabeled omaveloxolone 150 mg in healthy subjects, approximately 92% of dose recovered in feces (approximately 91% within 96 hours of administration), and 0.1% in urine.

Half-life

Mean terminal half-life: 57 hours (range: 32–90 hours).

Special Populations

No clinically important differences in pharmacokinetics based on age (16–71 years of age), sex, race, or body weight (41–128 kg).

Stability

Storage

Oral

Capsules

20–25ºC (excursions permitted between 15–30º C).

Actions

• Semi-synthetic triterpenoid drug that increases antioxidant activity.

• Activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans; Nrf2 pathway involved in cellular response to oxidative stress.

• May exert effects by activating Nrf2 pathway and blocking degradation of Nrf2; however, exact mechanism of therapeutic effect in Friedreich’s ataxia unknown.

Advice to Patients

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

• Advise patients to take omaveloxolone on an empty stomach ≥1 hour before eating.

• Inform patients to swallow omaveloxolone capsules whole, and to not crush or chew the capsules. For patients who are unable to swallow whole capsules, instruct the patient/caregiver to open the capsule(s), sprinkle the entire contents of both halves of the capsule(s) onto 2 tablespoons of applesauce, then stir the mixture. If sprinkled, advise patients to swallow the entire drug/applesauce mixture immediately, and to not store the mixture for future use. Instruct patients to not mix contents of the capsule(s) with milk or orange juice. Advise patients to not administer omaveloxolone via an enteral feeding tube.

• If a dose of omaveloxolone is missed, advise patients to not double their dose or take more than the prescribed dose.

• Advise patients that elevation in aminotransferases may occur with omaveloxolone therapy. Inform patients that liver function tests will be performed prior to initiating omaveloxolone, every month for the first 3 months of treatment, and periodically thereafter as needed.

• Advise patients that elevations in B-type natriuretic peptide (BNP), a marker of cardiac function, may occur with omaveloxolone therapy. Inform patients that BNP will be checked prior to initiating omaveloxolone and when signs and symptoms of fluid overload occur (e.g., sudden weight gain, peripheral edema, palpitations, shortness of breath). Advise patients to contact their clinician if they develop signs and symptoms of fluid overload.

• Advise patients that omaveloxolone therapy has been associated with increases in LDL cholesterol and decreases in HDL cholesterol. Inform patients that cholesterol will be assessed prior to starting omaveloxolone and monitored periodically during treatment.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.

• Advise patients to avoid grapefruit juice and grapefruit while they are taking omaveloxolone.

• Advise patients to notify their clinician if they become pregnant or intend to become pregnant during omaveloxolone therapy.

• Advise females using hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use with omaveloxolone, and for 28 days after discontinuation of omaveloxolone.

• Advise women to inform their clinician if they are or plan to breast-feed.

• Inform patients of other important precautionary information.

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.

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