What Are Common Skyclarys Side Effects to Watch For?

Skyclarys (omaveloxolone) is the first FDA-approved medication for Friedreich ataxia. While many people tolerate the medication well ^[1], it can cause physical side effects and specific laboratory changes—most notably, elevations in liver enzymes ^[2]. Because these changes can happen without you feeling them, starting Skyclarys requires a strict schedule of blood tests and close communication with your care team.

Urgent Warning Signs

Some symptoms require immediate medical attention. Do not wait for your next scheduled blood test if you develop signs of severe liver problems, such as yellowing of your skin or eyes (jaundice), dark urine, pale stools, severe nausea or vomiting, or sharp pain in your upper right abdomen.

Because Friedreich ataxia can affect the heart, you should also seek emergency care if you experience severe chest pain, new or worsening shortness of breath, fainting, a rapid or irregular heartbeat, sudden swelling in your legs, or rapid weight gain.

Common Physical Side Effects

In clinical trials, the most commonly reported physical side effects included headache, nausea, fatigue, diarrhea, abdominal pain, and musculoskeletal pain (muscle and bone pain) ^[1]. Because side effects like fatigue and nausea can sometimes be difficult to distinguish from your typical daily symptoms, it is helpful to track how you feel when you first start the medication so you can easily spot changes. Always report severe or lingering discomfort to your care team.

Elevated Liver Enzymes and Required Monitoring

The most critical laboratory change to watch for involves the liver. Skyclarys frequently causes an increase in aminotransferases (ALT and AST), which are enzymes that can indicate liver stress ^[2]. In small, real-world observational studies tracking patients over 12 months, over half of patients experienced these elevations, usually within the first three months of treatment ^[3]. While severe liver injury is rare and these enzyme elevations often do not cause physical symptoms, they require careful monitoring ^[1][2].

To monitor your liver safely, prescribing guidelines require:

• Before starting: Baseline blood tests for ALT, AST, and total bilirubin (a yellowish substance made when red blood cells break down) ^[2].
• The first three months: Blood tests every single month ^[2].
• After three months: Periodic testing as directed by your doctor ^[2].

Your doctor will evaluate your results using the upper limit of normal (ULN), which is the highest number expected in a healthy person’s lab result. If your liver enzymes rise above 5 times the ULN—or above 3 times the ULN if you also have elevated bilirubin or signs of liver dysfunction—your doctor will instruct you to temporarily stop the medication ^[2]. Never stop, change your dose, or restart Skyclarys on your own. Once your levels return to normal, your doctor will decide if it is safe to restart treatment with closer monitoring ^[2].

Changes to Heart and Lipid Markers

Friedreich ataxia can affect the heart, often causing the heart muscle to thicken. Skyclarys can increase levels of BNP (B-type natriuretic peptide), a blood marker used to evaluate heart stress ^[1]. In clinical trials, BNP elevations occurred in about 14% of people on Skyclarys compared to 4% on placebo ^[1].

While small observational follow-up studies (lasting 6 to 12 months) noted that BNP and overall cardiac function generally remained stable ^[3][4], a BNP test alone is not a complete cardiac assessment. The official recommendation is to assess BNP before starting treatment and periodically during treatment as clinically indicated ^[2]. Your cardiologist will interpret these lab results alongside your physical symptoms, electrocardiograms (ECGs), and echocardiograms.

Skyclarys can also cause increases in cholesterol levels, including LDL (“bad” cholesterol) and ApoB (a protein attached to bad cholesterol) ^[5][3]. Baseline and periodic monitoring of your lipid profile is recommended so your clinician can appropriately manage any changes based on your overall cardiovascular risk ^[5].

Drug Interactions

Skyclarys is processed in the body by a specific liver enzyme called CYP3A4 ^[6]. Other medications and supplements can interfere with this process:

• CYP3A4 Inhibitors: Drugs like certain antifungal medications can block the enzyme, causing dangerously high levels of Skyclarys in your blood ^[6].
• CYP3A4 Inducers: Other medications can speed up the enzyme, making Skyclarys less effective ^[6].
• Grapefruit: Grapefruit and grapefruit juice can also act as inhibitors and should be avoided.
• Other Substrates: Skyclarys may alter the effectiveness of other medications you take, potentially including certain hormonal contraceptives ^[6].

Always check with your doctor or pharmacist before starting or stopping any prescription drug, over-the-counter medicine, or herbal supplement while taking Skyclarys ^[6].