Omaveloxolone

1 INDICATIONS AND USAGE SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Obtain alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, B-type natriuretic peptide (BNP), and lipid parameters prior to initiating SKYCLARYS and during treatment. ( 2.1 , 5.1 , 5.2 , 5.3 ) Recommended dosage is 150 mg (3 capsules) taken orally once daily. ( 2.2 ) Administer SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after eating. ( 2.2 ) Swallow SKYCLARYS capsules whole or open and sprinkle the entire contents of both halves of the capsule onto applesauce and mix. Do not crush or chew capsules. ( 2.2 ) Moderate and Severe Hepatic Impairment: The recommended dosage of SKYCLARYS is 100 mg once daily for patients with moderate hepatic impairment. If adverse reactions emerge, further reduce the dosage to 50 mg once daily. Avoid use in patients with severe hepatic impairment. ( 2.5 , 8.6 , 12.3 ) 2.1 Recommended Testing Before Initiating SKYCLARYS and Monitoring to Assess Safety Obtain ALT, AST, bilirubin, BNP, and lipid parameters prior to initiating SKYCLARYS and during treatment [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . 2.2 Recommended Dosage The recommended dosage of SKYCLARYS is 150 mg (3 capsules) taken orally once daily. Administer SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after eating [see Clinical Pharmacology ( 12.3 )]. Swallow SKYCLARYS capsules whole. Do not crush or chew. For patients who are unable to swallow whole capsules: SKYCLARYS capsules may be opened and the entire contents of both halves of the capsule sprinkled onto 2 tablespoons (30 mL) of applesauce [see Clinical Pharmacology ( 12.3 )] . Stir the mixture until homogenous. Swallow all the drug/applesauce mixture immediately. Do not store the mixture for future use. Contents of the SKYCLARYS capsules should not be mixed with milk or orange juice. Not for enteral feeding tube administration. 2.3 Missed Doses If a dose of SKYCLARYS 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. 2.4 Recommendations for Concomitant Use with Strong or Moderate CYP3A4 Inhibitors and Inducers The recommended dosage for concomitant use of SKYCLARYS with cytochrome P450 (CYP) 3A4 inhibitors and inducers are described in Table 1 [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]. Table 1: Recommended Dosage of SKYCLARYS with Concomitant Use of CYP3A4 Inhibitors and Inducers Concomitant Drug Class Dosage Strong CYP3A4 inhibitor Recommended to avoid concomitant use. If coadministration cannot be avoided: Reduce the dosage of SKYCLARYS to 50 mg once daily with close monitoring for adverse reactions. If adverse reactions emerge, coadministration with strong CYP3A4 inhibitors should be discontinued. Moderate CYP3A4 inhibitor Recommended to avoid concomitant use. If coadministration cannot be avoided: Reduce the dosage of SKYCLARYS to 100 mg once daily with close monitoring for adverse reactions. If adverse reactions emerge, further reduce the dosage of SKYCLARYS to 50 mg once daily. Strong or Moderate CYP3A4 inducer Recommended to avoid concomitant use. 2.5 Recommended Dosage for Patients with Hepatic Impairment The recommended dosage for patients with hepatic impairment are described in Table 2 [see Use in Specific Populations ( 8.6 )] . Table 2: Recommended Dosage in Patients with Hepatic Impairment Impairment Classification (Child-Pugh) Dosage Severe (Child-Pugh Class C) Avoid use Moderate (Child-Pugh Class B) 100 mg once daily with close monitoring for adverse reactions Consider lowering to 50 mg once daily if adverse reactions emerge Mild (Child-Pugh Class A) 150 mg once daily

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in other labeling sections: Elevation of aminotransferases [see Warnings and Precautions ( 5.1 )] Elevation of BNP [see Warnings and Precautions ( 5.2 )] Lipid abnormalities [see Warnings and Precautions ( 5.3 )] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-844-987-3224- or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of SKYCLARYS 150 mg once daily has been evaluated in 165 patients with Friedreich's ataxia, including 137 patients exposed for at least 48 weeks, and 125 patients exposed for at least 96 weeks. The most common adverse reactions in Study 1 (≥20% and greater than placebo) were elevated liver enzymes (AST/ALT), headache, nausea, abdominal pain, fatigue, diarrhea, and musculoskeletal pain. Table 3 shows the adverse reactions that occurred in 10% or more of patients treated with SKYCLARYS and greater than placebo. Table 3: Adverse Reactions Reported in 10% or More of Patients Treated with SKYCLARYS and Greater than Placebo (Study 1) Adverse Reactions SKYCLARYS 150 mg (N = 51) % Placebo (N = 52) % Elevated liver enzymes (AST/ALT) 37 2 Headache 37 25 Nausea 33 13 Abdominal pain 29 6 Fatigue 24 14 Diarrhea 20 10 Musculoskeletal pain 20 15 Oropharyngeal pain 18 6 Influenza 16 6 Vomiting 16 12 Muscle spasms 14 6 Back pain 13 8 Decreased appetite 12 4 Rash 10 4 Laboratory Abnormalities In addition to elevated liver enzymes, additional laboratory abnormalities include elevation of BNP and lipid abnormalities [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of SKYCLARYS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: hypersensitivity (urticaria, rash)

12.3 Pharmacokinetics Absorption The median (range) time to achieve peak plasma concentration (T max ) was 7 to 14 (1 to 24) hours. The total plasma omaveloxolone exposure based on area under the concentration-time curve (AUC) increased in a dose-dependent and dose proportional manner over a dose range of 50 mg (0.33 times the recommended dosage) to 150 mg, but maximum omaveloxolone plasma concentration (C max ) increased in a less than dose proportional manner over the dose range in healthy fasted subjects. Effect of Food Omaveloxolone C max and AUC 0-inf increased by approximately 350% and 15%, respectively, with a high-fat meal (800-1000 calories, approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared to fasted conditions [see Dosage and Administration ( 2.2 )] . Omaveloxolone C max and AUC 0-inf were similar when capsule contents were sprinkled on applesauce or when administered as intact capsules. The median T max of omaveloxolone was shortened from approximately 10 to 6 hours when sprinkled on applesauce [see Dosage and Administration ( 2.2 )] . Distribution The mean apparent volume of distribution of omaveloxolone is 7361 L (105 L/kg for a 70 kg person). Protein binding of omaveloxolone is 97%. Elimination The mean (range) terminal half-life of omaveloxolone is 57 hours (32 to 90 hours). The mean apparent plasma clearance of omaveloxolone is 109 L/hr. Metabolism Omaveloxolone is primarily metabolized by CYP3A with minor metabolism by CYP2C8 and CYP2J2. Excretion Following administration of a single oral dose of radiolabeled omaveloxolone 150 mg to healthy subjects, approximately 92% of the dose was recovered in feces (approximately 91% within 96 hours after administration) and 0.1% in urine. Specific Populations There were no clinically significant differences in the pharmacokinetics of omaveloxolone based on age (16 to 71 years of age), sex, race, or body weight (41 to 128 kg). Patients with Renal Impairment Population pharmacokinetic analysis demonstrated that estimated glomerular filtration rate (eGFR) values ≥ 63 mL/min/1.73 m 2 did not have a significant effect on the pharmacokinetics of omaveloxolone. Therefore, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m 2 ) is not expected to have a significant effect on the pharmacokinetics of omaveloxolone. The effect of moderate or severe renal impairment (eGFR ≤59 mL/min/1.73m 2 ) on the pharmacokinetics of omaveloxolone is unknown. Patients with Hepatic Impairment There were no clinically significant differences in the pharmacokinetics of omaveloxolone in subjects with mild hepatic impairment (Child-Pugh Class A). In subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C), omaveloxolone clearance was reduced, resulting in higher plasma exposure of omaveloxolone. The omaveloxolone AUC increased up to 1.65-fold and C max increased up to 1.83-fold in subjects with moderate hepatic impairment. The omaveloxolone AUC increased up to 2.17-fold in subjects with severe hepatic impairment; however, this change was variable [see Use in Specific Populations ( 8.6 )] . Drug Interaction Studies Clinical Studies Strong CYP3A Inhibitors: After single dose administration, omaveloxolone C max increased 3-fold and AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor) [see Drug Interactions ( 7.1 )] . Moderate CYP3A Inhibitors: After single dose administration, omaveloxolone C max and AUC increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and P-gp inhibitor) [see Drug Interactions ( 7.1 )] . Moderate CYP3A Inducers: After single dose administration, omaveloxolone C max and AUC decreased 38% and 48%, respectively, following concomitant use with efavirenz (moderate CYP3A4 inducer) [see Drug Interactions ( 7.1 )]. Certain CYP450 Enzymes or Transporter Substrates: Omaveloxolone decreased the AUC of midazolam (CYP3A4 substrate) by approximately 45%, AUC of repaglinide (CYP2C8 substrate) by approximately 35%, and AUC of rosuvastatin (BCRP and OATP1B1 substrate) by approximately 30% [see Drug Interactions ( 7.2 )]. There were no clinically significant differences in the pharmacokinetics of digoxin (P-gp substrate) or metformin [(organic cation transporter (OCT)1 substrate] when co-administered with omaveloxolone. Other Drugs: No clinically significant differences in the pharmacokinetics of omaveloxolone are expected following concomitant use with weak CYP3A4 inhibitors or strong CYP2C8 inhibitors. In Vitro Studies CYP Enzymes: Omaveloxolone is an inducer of CYP3A4 and CYP2C19. Omaveloxolone is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP2D6. Omaveloxolone is not an inducer of CYP1A2, CYP2B6, CYP2C8, and CYP2C9. Drug Transporters: Omaveloxolone is not an inhibitor of BCRP, BSEP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K. Omaveloxolone inhibited the renal transporter OAT1.