SKYCLARYS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SKYCLARYS (SKYCLARYS).
SKYCLARYS (omaveloxolone) is a nuclear factor erythroid 2-related factor 2 (Nrf2) activator. It binds to KEAP1, preventing Nrf2 degradation, leading to increased Nrf2 nuclear translocation and activation of antioxidant response elements (ARE) that upregulate antioxidant and mitochondrial protective proteins.
| Metabolism | Primarily metabolized by CYP3A4; minor contributions from CYP2C8 and CYP2C9. Also undergoes glucuronidation via UGT1A9 and UGT2B7. |
| Excretion | Approximately 70% of the dose is excreted in urine (mainly as unchanged drug and metabolites) and 30% in feces via biliary elimination. |
| Half-life | Median terminal elimination half-life is 32 hours (range 25–40 hours), supporting once-daily dosing. |
| Protein binding | >99% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd/F is approximately 12 L (0.15 L/kg), indicating limited extravascular distribution and high plasma protein binding. |
| Bioavailability | Oral bioavailability is approximately 94% (range 80–105%) when administered with food; food increases absorption. |
| Onset of Action | Oral: Therapeutic effects observed within 2–4 weeks; maximal benefit by 8–12 weeks. |
| Duration of Action | Duration of action is consistent with dosing interval (24 hours) due to half-life; sustained effect with daily administration. |
150 mg orally once daily with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not studied in severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease. |
| Liver impairment | Contraindicated in patients with Child-Pugh class B or C hepatic impairment. For Child-Pugh class A, no dose adjustment is recommended. |
| Pediatric use | Not established; safety and efficacy in pediatric patients have not been studied. |
| Geriatric use | No specific dose adjustment recommended based on age. Clinical studies included patients up to 80 years old; dosing should be individualized based on renal and hepatic function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SKYCLARYS (SKYCLARYS).
| Breastfeeding | No data on omaveloxolone in human milk; present in animal milk. M/P ratio unknown. Risk of serious adverse reactions (e.g., hepatotoxicity) in breastfed infants. Advise against breastfeeding during treatment and for at least 1 month after last dose. |
| Teratogenic Risk | SKYCLARYS (omaveloxolone) has no human pregnancy data; animal studies show fetal harm at exposures similar to human therapeutic doses. Based on mechanism (Nrf2 activation), potential for teratogenicity exists. First trimester: risk of structural anomalies cannot be excluded. Second and third trimesters: risk of fetal toxicity, including growth impairment. Avoid use in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Concomitant use with strong or moderate CYP3A4 inducers","Pregnancy"]
| Precautions | ["Elevations in liver enzymes (ALT/AST) – monitor hepatic function before and during treatment.","Increases in total cholesterol and low-density lipoprotein (LDL) – monitor lipid levels.","May cause increases in serum creatinine without affecting renal function.","Embryo-fetal toxicity – advise females of reproductive potential to use effective contraception."] |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) monthly during pregnancy. Perform fetal ultrasound for growth and anatomy. Monitor for maternal hepatic adverse events. Postnatal: monitor infant for hepatotoxicity if exposed in utero. |
| Fertility Effects | Animal studies: reduced fertility in males (sperm count, motility) and females (implantation loss) at clinically relevant doses. Human fertility effects unknown. May impair fertility in both sexes. |