AHFS Class:

• Other Miscellaneous Therapeutic Agents 92:92

Generic Name(s):

• Omaveloxolone

Omaveloxolone is a potent activator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is involved in the cellular response to oxidative stress.1,2,5

Friedreich's Ataxia

Omaveloxolone is used for the treatment of Friedreich's ataxia in adults and adolescents ≥16 years of age.1 Omaveloxolone has been designated an orphan drug by FDA for treatment of this condition.2

The safety and efficacy of omaveloxolone in this use are based principally on the results of a randomized, double-blind, placebo-controlled trial (MOXIe) in patients 16—40 years of age with Friedreich's ataxia.1,3

Clinical Experience

The current indication for omaveloxolone is based principally on the results of a randomized, double-blind, placebo-controlled study (MOXIe) in patients 16—40 years of age with genetically confirmed Friedreich's ataxia.1,3 Eligible patients had stable baseline modified Friedreich's Ataxia Rating Scale (mFARS) scores between 20—80, could complete maximal exercise testing, and had a left ventricular ejection fraction of ≥40%.1,3 A total of 103 patients were randomized in a 1:1 ratio to treatment with either omaveloxolone 150 mg once daily or placebo.1 The primary outcome was change from baseline in mFARS at 48 weeks.1,3

Of the patients enrolled in the study, 53% were male, 97% were white, and the mean age was 24 years at study entry.1 The primary efficacy analysis was based on a full analysis set, which consisted of 82 patients without pes cavus (loss of lateral support, determined by visualization of light from a flashlight under the foot arch when barefoot and weight bearing).1

At 48 weeks, omaveloxolone resulted in substantially lower mFARS scores (less impairment) relative to placebo.1 In the full analysis set, the least squares mean change from baseline in mFARS scores at 48 weeks was -1.56 and 0.85 with omaveloxolone and placebo, respectively, with a treatment difference of -2.41.1 For all 103 randomized patients (patients with or without pes cavus), the results were similar to the full analysis population, with a mFARS least squares mean difference between treatment groups of ‑1.94.1

In an open-label extension study, 73 patients from the full analysis set of the MOXIe trial either continued on omaveloxolone, or switched to omaveloxolone from placebo (i.e., delayed-start).5 The difference in mFARS between omaveloxolone and placebo observed at the end of the MOXIe trial (week 48) was preserved at the end of the delayed-start period (extension week 72).5 Additionally, patients previously randomized to omaveloxolone in the MOXIe trial maintained mean mFARS values from extension baseline through 144 weeks.5

Clinical Perspective

Friedreich's ataxia is a rare, inherited, progressive, neurodegenerative disease, most commonly presenting in individuals 5—20 years of age.6 The disease manifests with neurological dysfunction, primarily as limb and gait ataxia, but patients may also develop diabetes, scoliosis, hearing/vision loss, and cardiomyopathy.6 There is no resolutive cure for Friedreich's ataxia to date; while not curative, omaveloxolone is the first FDA-approved treatment for the condition.7

An international consensus on the best practices for Friedreich's ataxia includes use of supportive care, gait aids, and physical rehabilitation for patients with limb dysfunction.4 Non-pharmacologic treatments are recommended first-line for management of spasticity prior to use of local (e.g., botulinum toxin injection) or systemic (e.g., baclofen, benzodiazepines) pharmacotherapy.4 Other pharmacological agents are recommended depending on associated clinical symptoms in patients with Friedreich's ataxia; for example, gabapentin and pregabalin are options for patients with restless leg syndrome, and antidepressants may be used to manage fatigue or depression.4 The guideline was published prior to the approval of omaveloxolone and does not address the specific place in therapy for this drug.4

General

Pretreatment Screening

• Obtain baseline ALT, AST, total bilirubin, B-type natriuretic peptide (BNP), and lipid parameters prior to treatment.1

Patient Monitoring

• Monitor ALT, AST, and total bilirubin every month for the first 3 months of treatment and periodically thereafter.1 Increase the frequency of monitoring if levels increase during treatment.1
• Monitor for signs and symptoms of fluid overload during treatment.1 If signs and symptoms of fluid overload develop, worsen, or require hospitalization, monitor BNP and assess cardiac function.1
• Monitor lipid parameters periodically during treatment.1

Administration

Omaveloxolone is administered orally.1

Administer omaveloxolone capsules on an empty stomach ≥1 hour before eating.1 Swallow the capsules whole; do not crush or chew.1

For patients who are unable to swallow whole capsules, open the capsule(s) and sprinkle the entire contents onto 2 tablespoons (30 mL) of applesauce.1 Stir the mixture until homogenous, and swallow the entire drug/applesauce mixture immediately.1 Do not store the mixture for future use.1 Do not mix contents of the capsule(s) with milk or orange juice.1 Do not administer via an enteral feeding tube.1

If a dose of omaveloxolone is missed, take the next dose at its scheduled time the following day.1 Do not take a double dose to make up for a missed dose.1

Store omaveloxolone capsules at 20-25ºC (excursions permitted between 15-30ºC).1

Dosage

Adult Dosage

Friedreich's Ataxia

The recommended dosage of omaveloxolone in adults is 150 mg (3 capsules) taken orally once daily.1

Pediatric Dosage

Friedreich's Ataxia

The recommended dosage of omaveloxolone in adolescents ≥16 years of age is 150 mg (3 capsules) taken orally once daily.1

Dosage Modification for Concomitant Use with Strong or Moderate CYP3A4 Inhibitors

If coadministration of omaveloxolone with a strong cytochrome P-450 (CYP) 3A4 inhibitor cannot be avoided, reduce omaveloxolone dosage to 50 mg once daily with close monitoring of adverse reactions.1 If adverse reactions emerge, discontinue coadministration with strong CYP3A4 inhibitors.1

If coadministration of omaveloxolone with a moderate CYP3A4 inhibitor cannot be avoided, reduce omaveloxolone dosage to 100 mg once daily with close monitoring of adverse reactions.1 If adverse reactions emerge, further reduce omaveloxolone dosage to 50 mg once daily.1

Special Populations

Hepatic Impairment

Avoid use of omaveloxolone in patients with severe hepatic impairment (Child-Pugh class C).1

In patients with moderate hepatic impairment (Child-Pugh class B), reduce omaveloxolone dosage to 100 mg once daily with close monitoring for adverse reactions.1 If adverse reactions emerge, consider lowering the dosage to 50 mg once daily.1

No dosage adjustments are necessary in patients with mild hepatic impairment (Child-Pugh class A).1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• None.1

Warnings/Precautions

Elevation of Aminotransferases

Elevation in hepatic transaminases (ALT and AST) may occur with omaveloxolone therapy.1

In the principal efficacy study of omaveloxolone, 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 who received omaveloxolone.1 No cases of concomitant elevation of transaminases and total bilirubin were observed.1 Maximum increases in ALT and AST occurred within 12 weeks after starting omaveloxolone.1 Increases in serum aminotransferases were generally asymptomatic and reversible following discontinuation of omaveloxolone.1 Patients with clinically significant liver disease were excluded from the study.1

Monitor ALT, AST, and total bilirubin prior to initiation of omaveloxolone, every month for the first 3 months of treatment, and periodically thereafter.1 If transaminases increase to levels >5 times the ULN, or >3 times the ULN with evidence of liver dysfunction (e.g., elevated bilirubin), discontinue omaveloxolone immediately and repeat liver function tests as soon as possible.1 If transaminase levels stabilize or resolve, omaveloxolone may be reinitiated with an appropriate increased frequency of monitoring of liver function.1

Elevation of B-Type Natriuretic Peptide

Treatment with omaveloxolone can cause an increase in B-type natriuretic peptide (BNP), a marker of cardiac function.1

In the principal efficacy study, an increase from baseline in BNP and a BNP above the ULN (100 pg/mL) was observed in 14 and 4% of patients who received omaveloxolone and placebo, respectively.1 The incidence of elevation of BNP >200 pg/mL was 4% in patients who received omaveloxolone.1 Cardiomyopathy and cardiac failure are common in patients with Friedreich's ataxia.1 The study excluded patients with 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.1 It is unclear whether the observed elevations in BNP in the study are related to omaveloxolone or cardiac disease associated with Friedreich's ataxia.1

Elevations in BNP may indicate cardiac failure and should prompt an assessment of cardiac function.1 Evaluate BNP prior to initiation of omaveloxolone.1 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.1 If signs and symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac function, and manage appropriately.1 Management of fluid overload and heart failure may require discontinuation of omaveloxolone.1

Lipid Abnormalities

Changes in cholesterol may occur with omaveloxolone therapy.1

In the principal efficacy study, 29% of patients treated with omaveloxolone reported elevated cholesterol above ULN at ≥1 time point.1 Mean increases were observed within 2 weeks of omaveloxolone initiation and returned to baseline within 4 weeks of discontinuing treatment.1 An increase in low-density lipoprotein cholesterol (LDL-C) from baseline was observed in 16 and 8% of patients who received omaveloxolone and placebo, respectively.1 The mean increase in LDL-C for all patients treated with omaveloxolone was 23.5 mg/dL at 48 weeks.1 Decreases in high-density lipoprotein cholesterol (HDL-C) from baseline were observed in 6 and 4% of patients who received omaveloxolone and placebo, respectively.1 The mean decrease in HDL-C for all patients treated with omaveloxolone was 5.3 mg/dL at 48 weeks.1

Assess lipid parameters prior to initiation of omaveloxolone, and monitor periodically during treatment.1 Manage lipid abnormalities in accordance with current clinical guideline recommendations.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of omaveloxolone in pregnant women.1 In animal studies, oral administration of omaveloxolone during pregnancy or throughout pregnancy and lactation resulted in 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.1

Lactation

No data are available on the presence of omaveloxolone or its metabolites in human milk.1 The effects of the drug on milk production or on breast-fed infants are unknown.1 Omaveloxolone was excreted in the milk of lactating rats following oral administration.1

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for omaveloxolone and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Females and Males of Reproductive Potential

Omaveloxolone may decrease the efficacy of hormonal contraceptives.1

Advise patients to avoid concomitant use of omaveloxolone with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills.1 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 with omaveloxolone, and for 28 days after discontinuation of omaveloxolone.1

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, based on adequate evidence from the principal efficacy study.1 The safety and effectiveness of omaveloxolone have not been established in pediatric patients <16 years of age.1

Geriatric Use

Clinical studies of omaveloxolone in Friedreich's ataxia did not include patients ≥65 years of age.1 No data are available to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

In patients with moderate and severe hepatic impairment (Child-Pugh class B and C), omaveloxolone clearance is reduced, resulting in increased plasma exposure of the drug.1 Peak plasma concentrations and AUC of omaveloxolone increased up to 1.83-fold and 1.65-fold, respectively, in patients with moderate hepatic impairment.1 Omaveloxolone AUC increased up to 2.17-fold in patients with severe hepatic impairment; however, this change was variable.1

Avoid omaveloxolone use in patients with severe hepatic impairment (Child-Pugh class C), including those who develop severe hepatic impairment.1 If hepatic function improves to moderate or mild impairment or to normal function, consider initiation of omaveloxolone at the approved recommended dosage.1

For patients with moderate hepatic impairment (Child-Pugh class B), a reduced dosage is recommended with close monitoring for adverse reactions.1

In patients with mild hepatic impairment (Child-Pugh class A), no clinically important differences in omaveloxolone pharmacokinetics were observed; no dosage adjustments are recommended in this population.1

Renal Impairment

The effects of renal impairment on omaveloxolone pharmacokinetics are unknown.1

Common Adverse Effects

The most common adverse reactions with omaveloxolone (incidence ≥20% and greater than placebo) are elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain.1

Omaveloxolone is substrate of cytochrome P-450 (CYP) isoenzyme 3A4, and a weak inducer of CYP3A4 and CYPC8.1

In vitro data indicate that omaveloxolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6, and not an inducer of CYP1A2 and CYP2B6.1

In vitro data indicate that omaveloxolone inhibits the renal transporter, organic anion transporter (OAT)1.1 Omaveloxolone is not an inhibitor of 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.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 Inhibitors

Concomitant use of omaveloxolone with a strong CYP3A4 inhibitor is expected to result in clinically important, increased exposure of omaveloxolone, which may increase the risk of adverse reactions.1

When omaveloxolone was used concomitantly with itraconazole (a strong CYP3A inhibitor), the peak plasma concentration and AUC of omaveloxolone increased 3-fold and 4-fold, respectively.1

Avoid concomitant use of omaveloxolone with strong CYP3A4 inhibitors.1 If concomitant use cannot be avoided, reduce omaveloxolone dosage to 50 mg once daily with close monitoring of adverse reactions; if adverse reactions emerge, discontinue coadministration with strong CYP3A4 inhibitors.1

Moderate CYP3A4 Inhibitors

Concomitant use of omaveloxolone with a moderate CYP3A4 inhibitor is expected to result in clinically important, increased exposure of omaveloxolone, which may increase the risk of adverse reactions.1

When omaveloxolone was used concomitantly with verapamil (a moderate CYP3A and P-glycoprotein [P-gp] inhibitor), the peak plasma concentration and AUC of omaveloxolone increased approximately 1.25-fold.1

Avoid concomitant use of omaveloxolone with moderate CYP3A4 inhibitors.1 If concomitant use cannot be avoided, 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.1

Weak CYP3A4 Inhibitors

No clinically important differences in omaveloxolone pharmacokinetics are expected following concomitant use with weak CYP3A4 inhibitors.1

Strong or Moderate CYP3A4 Inducers

Concomitant use of omaveloxolone with strong or moderate CYP3A4 inducers may significantly decrease exposure of omaveloxolone, which may reduce the effectiveness of omaveloxolone.1

Avoid concomitant use of omaveloxolone with strong or moderate CYP3A4 inducers.1

CYP3A4 Substrates

Concomitant use of omaveloxolone with CYP3A4 substrates can reduce the exposure of the substrates and thereby reduce their activity.1

When omaveloxolone was used concomitantly with midazolam (a CYP3A4 substrate), the AUC of midazolam decreased by approximately 45%.1

Refer to the prescribing information for CYP3A4 substrates for dosing instructions if used concomitantly with omaveloxolone, and monitor for lack of efficacy of the substrate.1

CYP2C8 Substrates

Concomitant use of omaveloxolone with CYP2C8 substrates can reduce the exposure of the substrates and thereby reduce their activity.1

When omaveloxolone was used concomitantly with repaglinide (a CYP2C8 substrate), the AUC of repaglinide decreased by approximately 35%.1

Refer to the prescribing information for CYP2C8 substrates for dosing instructions if used concomitantly with omaveloxolone, and monitor for lack of efficacy of the substrate.1

Strong CYP2C8 Inhibitors

No clinically important differences in omaveloxolone pharmacokinetics are expected following concomitant use with strong CYP2C8 inhibitors.1

Hormonal Contraceptives

Concomitant use with omaveloxolone may reduce the efficacy of hormonal contraceptives.1

Advise patients to avoid concomitant use of omaveloxolone with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills.1

Digoxin

No clinically important differences in the pharmacokinetics of digoxin (a P-gp substrate) were observed following concomitant use with omaveloxolone.1

Metformin

No clinically important differences in the pharmacokinetics of metformin (an OCT1 substrate) were observed following concomitant use with omaveloxolone.1

Rosuvastatin

When omaveloxolone was used concomitantly with rosuvastatin (a BCRP and OATP1B1 substrate), the AUC of rosuvastatin decreased by approximately 30%.1

Description

Omaveloxolone is a semi-synthetic triterpenoid drug that increases antioxidant activity.2 The exact mechanism by which omaveloxolone exerts its therapeutic effect in patients with Friedreich's ataxia is unknown.1 Omaveloxolone has been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans.1 The Nrf2 pathway is involved in the cellular response to oxidative stress.1 In individuals with Friedreich's ataxia, the Nrf2 pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction, and cell damage.2 Omaveloxolone may exert its effects by activating the Nrf2 pathway and blocking the degradation of Nrf2.2

The median time to peak omaveloxolone plasma concentrations was 7-14 hours (range: 1-24 hours).1 In healthy fasted subjects, the omaveloxolone peak plasma concentrations increased in a less than dose-proportional manner over a dosage range of 50 mg (0.33 times the recommended dosage) to 150 mg.1 However, the total plasma drug exposure (AUC) increased in a dose-dependent and dose-proportional manner over the dosage range of 50-150 mg.1

Omaveloxolone peak plasma concentrations and AUC were similar when capsule contents were sprinkled on applesauce or when administered as intact capsules.1 When sprinkled on applesauce, the median time to peak omaveloxolone plasma concentrations was shortened from approximately 10 to 6 hours.1 When administered with a high-fat meal (800-1000 calories, approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively), omaveloxolone peak plasma concentrations and AUC increased by approximately 350 and 15%, respectively, compared with fasted conditions.1

Omaveloxolone is 97% protein bound.1 Omaveloxolone is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A, with minor metabolism by CYP2C8 and CYP2J2.1 The mean terminal half-life is 57 hours (range: 32-90 hours).1 Following oral administration of a single dose of radiolabeled omaveloxolone 150 mg in healthy subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours of administration), and 0.1% was recovered in urine.1 There are no clinically important differences in omaveloxolone pharmacokinetics based on age (16-71 years of age), sex, race, or body weight (41-128 kg).1

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).1
• Advise patients to take omaveloxolone on an empty stomach ≥1 hour before eating.1
• Inform patients to swallow omaveloxolone capsules whole, and to not crush or chew the capsules.1 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.1 If sprinkled, advise patients to swallow the entire drug/applesauce mixture immediately, and to not store the mixture for future use.1 Instruct patients to not mix contents of the capsule(s) with milk or orange juice.1 Advise patients to not administer omaveloxolone via an enteral feeding tube.1
• If a dose of omaveloxolone is missed, advise patients to not double their dose or take more than the prescribed dose.1
• Advise patients that elevation in aminotransferases may occur with omaveloxolone therapy.1 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.1
• Advise patients that elevations in B-type natriuretic peptide (BNP), a marker of cardiac function, may occur with omaveloxolone therapy.1 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).1 Advise patients to contact their clinician if they develop signs and symptoms of fluid overload.1
• Advise patients that omaveloxolone therapy has been associated with increases in low-density lipoprotein (LDL) cholesterol and decreases in high-density lipoprotein (HDL) cholesterol.1 Inform patients that cholesterol will be assessed prior to starting omaveloxolone and monitored periodically during treatment.1
• 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.1
• Advise patients to avoid grapefruit juice and grapefruit while they are taking omaveloxolone.1
• Advise patients to notify their clinician if they become pregnant or intend to become pregnant during omaveloxolone therapy.1
• 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.1
• Advise women to inform their clinician if they are or plan to breast-feed.1
• Inform patients of other important precautionary information.1

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.

Only references cited for selected revisions after 1984 are available electronically.

1. Reata Pharmaceuticals, Inc. SKYCLARYS^®(omaveloxolone) ORAL prescribing information. 2024 Jan. [Web]

2. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2024 March 29. [Web]

3. Lynch D, Chin M, Delatycki M, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89:212-225.

4. Corben L, Collins V, Milne S, et al. Clinical management guidelines for Friedreich ataxia: best practice in rare diseases. Orphanet J Rare Dis. 2022;17(1):415.

5. Lynch D, Chin M, Boesch S, et al. Efficacy of omaveloxolone in Friedreich's ataxia: delayed-start analysis of the MOXIe extension. Mov Disord. 2023;38(2):313-320.

6. Keita M, McIntyre K, Rodden L, Schadt K, Lynch D. Friedreich ataxia: clinical features of new developments. Neurodegener Dis Manag. 2022;12(5):267-283.

7. Pilotto F, Chellapandi DM, Puccio H. Omaveloxolone: a groundbreaking milestone as the first FDA-approved drug for Friedreich ataxia. Trends Mol Med . 2024;30(2):117-125.

8. Lee A. Omaveloxolone: first approval. Drugs . 2023;83(8):725-729.

9. Get Skyclarys: start your Friedreich ataxia treatment journey with Skyclarys. From Skyclarys website. Accessed March 28, 2024. [Web]