omaveloxolone

Omaveloxolone is an oral medication used in the treatment of Friedreich’s ataxia, an inherited, genetic, neurodegenerative disorder that affects parts of the nervous system. Friedreich’s ataxia impairs movement, balance and speech and causes unsteady gait, slurred speech, and eventually, spinal and foot deformities, and cardiac muscle disease. Omaveloxolone is a novel drug, first of its class, approved by the FDA in February 2023 and expected to be commercially available in the second quarter of 2023.

Omaveloxolone belongs to a class of medications known as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators. The exact mechanism of action of omaveloxolone in the treatment of Friedreich’s ataxia is not fully clear, but it is believed to work by reducing inflammation and oxidative stress caused by free radicals. Free radicals, also known as reactive oxygen species (ROS), result from cellular metabolic processes and are normally neutralized by natural antioxidants in the body. Excessive ROS causes oxidative stress that damages tissues.

Omaveloxolone activates Nrf2, a transcription factor that is involved in the cellular response to oxidative stress. Nrf2 stimulates pathways that resolve inflammation by reducing oxidative stress, inhibiting pro-inflammatory signaling and restoring the function of mitochondria, the organelles in the cells that produce energy. Nrf2 signaling pathway and mitochondrial function are usually impaired in Friedreich’s ataxia.

• Omaveloxolone can cause elevation of liver enzymes ALT and AST in the blood. Use with caution in patients with pre-existing impairment of liver function.
  • Check the patient’s ALT, AST and bilirubin levels before initiating omaveloxolone, monitor every month for the first 3 months of treatment, and periodically thereafter.
  • If ALT and AST are higher than 5 times upper limit of normal (ULN) or higher than 3 times ULN with high bilirubin level, discontinue omaveloxolone, and monitor liver function. If levels resolve, resume treatment with increased frequency of liver function monitoring.
• Omaveloxolone can cause an increase in the levels of brain-type natriuretic peptide (BNP), a protein that is a marker of cardiac function. Elevation in BNP can indicate heart failure. If a patient develops signs of fluid overload, evaluate BNP and cardiac function, manage appropriately and discontinue omaveloxolone, if necessary.
• Omaveloxolone can increase LDL cholesterol and decrease HDL cholesterol levels. Monitor the patient’s cholesterol levels and manage appropriately.
• Omaveloxolone can reduce the effectiveness of hormonal contraceptives. Caution patients to use alternate or additional non-hormonal contraceptives.

Common side effects of omaveloxolone include:

• Elevated liver enzymes ALT and AST
• Headache
• Nausea
• Vomiting
• Abdominal pain
• Diarrhea
• Reduced appetite
• Fatigue
• Musculoskeletal pain
• Mouth and throat (oropharyngeal) pain
• Muscle spasms
• Back pain
• Influenza
• Rash
• Increase in LDL cholesterol
• Decrease in HDL cholesterol
• Elevation of brain-type natriuretic peptide (BNP), a protein

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 50 mg

Adult and Pediatric:

Friedreich Ataxia

• Indicated for treatment of Friedreich ataxia in adults and adolescents aged 16 years and above

Children below 16 years:

• Safety and efficacy not established

Adults and adolescents 16 years and above:

• 150 mg (3 capsules) orally every day

Dosage Modifications

Renal impairment

• Effect of renal impairment on the omaveloxolone pharmacokinetics is unknown

Hepatic impairment

• Mild (Child-Pugh A): No dosage adjustment required
• Moderate (Child-Pugh B): 100 mg orally every day; closely monitor for adverse effects; consider lowering dose to 50 mg/day if adverse effects emerge
• Severe (Child-Pugh C): Avoid use

CYP3A4 inhibitors

• Avoid coadministration
• If unavoidable
  • Strong inhibitors: Reduce omaveloxolone to 50 mg/day; discontinue if adverse effects emerge
  • Moderate inhibitors: Reduce omaveloxolone to 100 mg/day; if adverse effects emerge, further reduce to 50 mg/day

CYP3 inducers

• Strong or moderate inducers: Avoid coadministration

Dosing Considerations

Monitoring

• Obtain ALT, AST, and total bilirubin before initiating, monthly for first 3 months, and periodically thereafter
• Obtain B-type natriuretic peptide (BNP) before initiating and as clinically indicated thereafter
• Obtain lipid parameters before initiating and periodically thereafter

Overdose

• There is no information available on omaveloxolone overdose. Overdose is likely to increase the severity of adverse reactions including abnormalities in the levels of cholesterol, and elevation of liver enzymes AST and ALT, and B-Type natriuretic peptide (BNP). Treatment of overdose may be symptomatic and supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Omaveloxolone has no known severe interactions with other drugs.
• Omaveloxolone has serious interactions with at least 117 different drugs.
• Omaveloxolone has moderate interactions with at least 42 different drugs.
• Omaveloxolone has no known mild interactions with other drugs.

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• There are no adequate and well-controlled studies on the safety of omaveloxolone use in pregnant women, however, animal reproduction studies show evidence of fetal harm.
• Omaveloxolone may reduce the efficacy of hormonal contraceptives. Avoid concomitant use with combined hormonal contraceptives, implants and progestin-only pills. Women using hormonal contraceptives should use an alternative or additional non-hormonal contraceptive during omaveloxolone treatment and for 28 days after final dose.
• There are no data on the presence of omaveloxolone in breastmilk, or its effects on milk production and the breastfed infant. Decision to breastfeed should be based on the mother’s clinical need for omaveloxolone, benefits of breastfeeding to the infant, and potential risk to the infant from exposure to the drug or underlying maternal condition.

• Take omaveloxolone exactly as prescribed.
• You will need periodic blood tests, follow up with your physician and do not miss your appointments.
• Report immediately to your physician if you develop symptoms of fluid overload and heart failure including:
  • Sudden weight gain
  • Swelling of extremities (peripheral edema)
  • Shortness of breath
  • Palpitations
• Store omaveloxolone safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.