Omaveloxolone (Monograph)

Brand name: Skyclarys
Drug class: Other Miscellaneous Therapeutic Agents
Chemical name: N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicen-4a-yl]-2,2-difluoropropanamide
Molecular formula: C₃₃H₄₄F₂N₂O₃
CAS number: 1474034-05-3

Introduction

Omaveloxolone activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in the cellular response to oxidative stress.

Uses for Omaveloxolone

Omaveloxolone has the following uses:

Omaveloxolone is indicated for the treatment of Friedreich's ataxia in adults and adolescents 16 years of age and older.

Omaveloxolone Dosage and Administration

General

Omaveloxolone is available in the following dosage form(s) and strength(s):

Capsules containing 50 mg of omaveloxolone.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Administer omaveloxolone on an empty stomach at least one hour before eating. Swallow omaveloxolone capsules whole. Do not open, crush, or chew.

If a dose of omaveloxolone is missed, take the next dose at its scheduled time the following day. A double dose should not be taken to make up for a missed dose.

Obtain ALT, AST, bilirubin, BNP, and lipid parameters prior to initiating omaveloxolone and during treatment.

Pediatric Patients

The recommended dosage of omaveloxolone in adolescents ≥16 years of age is 150 mg (3 capsules) taken orally once daily.

Adults

The recommended dosage of omaveloxolone in adults is 150 mg (3 capsules) taken orally once daily.

Recommendations for Concomitant Use with CYP3A4 Inhibitors or Inducers

Avoid concomitant use with strong CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dosage of omaveloxolone to 50 mg once daily with close monitoring for adverse reactions. If adverse reactions emerge, coadministration with strong CYP3A4 inhibitors should be discontinued.

Avoid concomitant use with moderate CYP3A4 inhibitors. If coadministration cannot be avoided, reduce the dosage of omaveloxolone to 100 mg once daily with close monitoring for adverse reactions. If adverse reactions emerge, further reduce the dosage of omaveloxolone to 50 mg once daily.

Avoid concomitant use with strong or moderate CYP3A4 inducers.

Recommended Dosage in Patients with Moderate or Severe Hepatic Impairment

The recommended dosage of omaveloxolone is 100 mg once daily for patients with moderate hepatic impairment (Child-Pugh class B); closely monitor for adverse reactions and consider lowering to 50 mg once daily if adverse reaction emerge. Avoid use in patients with severe hepatic impairment (Child-Pugh class C).

Related/similar drugs

Skyclarys

Cautions for Omaveloxolone

Contraindications

• None.

Warnings/Precautions

Elevation of Aminotransferases

Treatment with omaveloxolone can cause an elevation in hepatic transaminases (ALT and AST). In the principal efficacy study, the incidence of elevations of ALT or AST above 5 times and 3 times the upper limit of normal (ULN) was 16% and 31%, respectively, in patients treated with omaveloxolone. There were no cases of concomitant elevation of transaminases and total bilirubin observed in the study. Maximum increases in ALT and AST occurred within 12 weeks after starting omaveloxolone. Increases in serum aminotransferases were generally asymptomatic and reversible following discontinuation of omaveloxolone. Patients with clinically significant liver disease were excluded from the study.

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

Elevation of B-Type Natriuretic Peptide

Treatment with omaveloxolone can cause an increase in BNP, a marker of cardiac function. In the principal efficacy study, a total of 14% of patients treated with omaveloxolone had an increase from baseline in BNP and a BNP above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of elevation of BNP above 200 pg/mL was 4% in patients treated with omaveloxolone. Cardiomyopathy and cardiac failure are common in patients with Friedreich’s ataxia. Patients were excluded from the study if they had BNP levels > 200 pg/mL prior to study entry, or a history of clinically significant left-sided heart disease and/or clinically significant cardiac disease, with the exception of mild to moderate cardiomyopathy associated with Friedreich’s ataxia. Whether the observed elevations in BNP are related to omaveloxolone or cardiac disease associated with Friedreich’s ataxia is unclear.

Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function. Check BNP prior to initiation of omaveloxolone. Monitor patients for the signs and symptoms of fluid overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or more of weight gain in a 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

Treatment with omaveloxolone can cause changes in cholesterol. In the principal efficacy study, 29% of patients treated with omaveloxolone reported elevated cholesterol above ULN at one or more time points. Mean increases were observed within 2 weeks of initiation of omaveloxolone and returned to baseline within 4 weeks of discontinuing treatment. A total of 16% of patients treated with omaveloxolone had an increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients who received placebo. The mean increase in LDL-C for all omaveloxolone-treated patients was 23.5 mg/dL at 48 weeks. A total of 6% of patients treated with omaveloxolone had decreases in high-density lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The mean decrease in HDL-C for all omaveloxolone-treated patients was 5.3 mg/dL at 48 weeks.

Assess lipid parameters prior to initiation of omaveloxolone and monitor periodically during treatment. Manage lipid abnormalities according to clinical guidelines.

Specific Populations

Lactation

There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on milk production and the breastfed infant are unknown. Omaveloxolone was excreted in the milk of lactating rats following oral administration. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for omaveloxolone and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.

Pregnancy

There are no adequate data on the developmental risks associated with the use of omaveloxolone in pregnant women. In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Females and Males of Reproductive Potential

Omaveloxolone may decrease the efficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills. Counsel 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 and for 28 days after discontinuation of omaveloxolone.

Pediatric Use

The safety and effectiveness of omaveloxolone for the treatment of Friedreich's ataxia have been established in pediatric patients 16 years of age and older. Use of omaveloxolone for this indication is supported by evidence from one adequate and well-controlled study in adults and in pediatric patients 16 years of age and older.

Safety and effectiveness of omaveloxolone have not been established in pediatric patients less than 16 years of age.

Geriatric Use

Clinical studies of omaveloxolone in Friedreich’s ataxia did not include patients 65 years of age and older. No data are available to determine whether they respond differently than younger adult patients.

Hepatic Impairment

Omaveloxolone plasma exposure is increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B and C). Avoid treatment with omaveloxolone in patients with severe hepatic impairment, including those who develop severe hepatic impairment. If hepatic function improves to moderate impairment, mild impairment, or normal function, initiation of omaveloxolone treatment at the approved recommended dosage may be considered. For patients with moderate hepatic impairment, a reduced dosage is recommended with close monitoring for adverse reactions. For patients with mild hepatic impairment (Child-Pugh Class A), no dose adjustments are recommended.

Common Adverse Effects

Most common adverse reactions (incidence ≥20% and greater than placebo) are elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Omaveloxolone is a CYP3A4 substrate. Concomitant use of the drug with moderate or strong CYP3A4 inhibitors is expected to result in clinically significant increased exposure of omaveloxolone, which may increase the risk of adverse reactions. Avoid concomitant use of omaveloxolone with moderate or strong CYP3A4 inhibitors. If use cannot be avoided, dosage modifications are recommended.

Omaveloxolone is a CYP3A4 substrate. Concomitant use of the drug with moderate or strong CYP3A4 inducers may significantly decrease exposure of omaveloxolone, which may reduce the effectiveness of omaveloxolone. Avoid concomitant use of omaveloxolone with moderate or strong CYP3A4 inducers.

Omaveloxolone is a weak inducer of CYP3A4 and CYP2C8. Concomitant use with omaveloxolone can reduce the exposure of CYP3A4 and CYP2C8 substrates which may reduce the activity of these substrates. Refer to the prescribing information for CYP3A4 and CYP2C8 substrates for dosing instructions if used concomitantly with omaveloxolone and monitor for lack of efficacy of the concomitant drug.

Omaveloxolone is a weak CYP3A4 inducer. Concomitant use with omaveloxolone may reduce the efficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills.

Actions

Mechanism of Action

The precise mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich’s ataxia is unknown. Omaveloxolone have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress.

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

• Inform patients that elevation in aminotransferases have occurred in patients treated with omaveloxolone. Liver function tests will be performed prior to initiating omaveloxolone, every month for the first 3 months of treatment, and periodically thereafter as needed.

• Inform patients that elevations in BNP, a marker of cardiac function, have occurred in patients treated with omaveloxolone. BNP will be performed prior to initiating omaveloxolone and if signs and symptoms of fluid overload occur, such as sudden weight gain, peripheral edema, palpitations, and shortness of breath. Advise patients to contact their healthcare provider if signs and symptoms of fluid overload develop.

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

• Advise patients to discuss all medications they are taking, including other prescription medications, non-prescription medications, or herbal products (e.g., St. John’s Wort) with their healthcare provider.

• Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during omaveloxolone therapy.

• Counsel 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 and for 28 days after discontinuation of omaveloxolone.

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

• Swallow omaveloxolone capsules whole. Do not open, crush, or chew.

• Advise patients that if a dose of omaveloxolone is missed to not to double their dose or take more than the prescribed dose.

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

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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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