OMAVELOXOLONE Drug Interactions: What You Need to Know

INTERACTIONS Moderate or Strong CYP3A4 Inhibitors: Avoid concomitant use. Consider SKYCLARYS dosage reduction with monitoring if use is unavoidable. ( 2.4 , 7.1 ) Moderate or Strong CYP3A4 Inducers: Avoid concomitant use. ( 7.1 )

7.1 Effect of Other Drugs on SKYCLARYS CYP3A4 Inhibitors Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors is expected to result in clinically significant increased exposure of omaveloxolone <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span>, which may increase the risk of adverse reactions. Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inhibitors. If use cannot be avoided, dosage modifications are recommended <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. CYP3A4 Inducers Omaveloxolone is a CYP3A4 substrate. Concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers is expected to result in clinically significant decreased exposure of omaveloxolone <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> , which may reduce the effectiveness of SKYCLARYS. Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers.

7.2 Effect of SKYCLARYS on Other Drugs CYP3A4 and CYP2C8 Substrates Omaveloxolone is a weak inducer of CYP3A4 and CYP2C8. Concomitant use with SKYCLARYS can reduce the exposure of CYP3A4 and CYP2C8 substrates which may reduce the activity of these substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Refer to the prescribing information of substrates of CYP3A4 and CYP2C8 for dosing instructions if used concomitantly with SKYCLARYS and monitor for lack of efficacy of the concomitant treatment.

Hormonal Contraceptives

Omaveloxolone is a weak CYP3A4 inducer [see Clinical Pharmacology ( 12.3 )] . Concomitant use with SKYCLARYS may reduce the efficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills [see Use in Specific Populations ( 8.3 )] .

None. None. ( 4 )

AND PRECAUTIONS Elevation of Aminotransferases: Monitor ALT, AST, and total bilirubin prior to initiation, every month for the first 3 months of treatment, and periodically thereafter. ( 2.1 , 5.1 ) Elevation of B-type Natriuretic Peptide (BNP): Advise patients of signs and symptoms of fluid overload. ( 2.1 , 5.2 )

Lipid

Abnormalities: Monitor cholesterol periodically during treatment. ( 2.1 , 5.3 )

5.1 Elevation of Aminotransferases Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (ALT and AST).

In Study

1 [see Clinical Studies ( 14 )] , 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 treated with SKYCLARYS. There were no cases of concomitant elevation of transaminases and total bilirubin observed in Study 1. Maximum increases in ALT and AST occurred within 12 weeks after starting SKYCLARYS. Increases in serum aminotransferases were generally asymptomatic and reversible following discontinuation of SKYCLARYS. Patients with clinically significant liver disease were excluded from Study 1. Monitor ALT, AST, and total bilirubin prior to initiation of SKYCLARYS, every month for the first 3 months of treatment, and periodically thereafter. If transaminases increase to levels greater than 5 times the ULN, or greater than 3 times the ULN with evidence of liver dysfunction (e.g., elevated bilirubin), immediately discontinue SKYCLARYS and repeat liver function tests as soon as possible. If transaminase levels stabilize or resolve, SKYCLARYS may be reinitiated with an appropriate increased frequency of monitoring of liver function [see Adverse Reactions ( 6.1 ) and Use in Specific Populations ( 8.6 )].

5.2 Elevation of B-Type Natriuretic Peptide Treatment with SKYCLARYS can cause an increase in BNP, a marker of cardiac function.

In Study

1, a total of 14% of patients treated with SKYCLARYS had an increase from baseline in BNP and a BNP above the ULN (100 pg/mL), compared to 4% of patients who received placebo. The incidence of elevation of BNP above 200 pg/mL was 4% in patients treated with SKYCLARYS. Cardiomyopathy and cardiac failure are common in patients with Friedreich's ataxia. Patients were excluded from Study 1 if they had 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 [see Adverse Reactions ( 6.1 )]. Whether the elevations in BNP in Study 1 are related to SKYCLARYS or cardiac disease associated with Friedreich's ataxia is unclear. Elevations in BNP may indicate cardiac failure and should prompt an evaluation of cardiac function. Check BNP prior to initiation of SKYCLARYS. Monitor patients for the signs and symptoms of fluid overload, such as sudden weight gain (3 pounds or more of weight gain in one day, or 5 pounds or more of weight gain in a week), peripheral edema, palpitations, and shortness of breath. If signs and symptoms of fluid overload develop, worsen, or require hospitalization, evaluate BNP and cardiac function, and manage appropriately. Management of fluid overload and heart failure may require discontinuation of SKYCLARYS.

5.3 Lipid Abnormalities Treatment with SKYCLARYS can cause changes in cholesterol.

In Study

1, 29% of patients treated with SKYCLARYS reported elevated cholesterol above ULN at one or more time points. Mean increases were observed within 2 weeks of initiation of SKYCLARYS and returned to baseline within 4 weeks of discontinuing treatment. A total of 16% of patients treated with SKYCLARYS had an increase in low-density lipoprotein cholesterol (LDL-C) from baseline, compared to 8% of patients who received placebo. The mean increase in LDL-C for all SKYCLARYS-treated patients was 23.5 mg/dL at 48 weeks. A total of 6% of patients treated with SKYCLARYS had decreases in high-density lipoprotein cholesterol (HDL-C) from baseline compared to 4% of patients who received placebo. The mean decrease in HDL-C for all SKYCLARYS-treated patients was 5.3 mg/dL at 48 weeks. Assess lipid parameters prior to initiation of SKYCLARYS and monitor periodically during treatment. Manage lipid abnormalities according to clinical guidelines.