Skyclarys

SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

• 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 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 Elevation of Aminotransferases

  Treatment with SKYCLARYS can cause an elevation in hepatic transaminases (ALT and AST). In Study 1

  [see Clinical Studies ]

  , 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 and Use in Specific Populations ].
  ,
  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 ].

  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.
  )
• Recommended dosage is 150 mg (3 capsules) taken orally once daily. (
  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 ].
  • 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 ]
      .
    • 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.
  )
• Administer SKYCLARYS on an empty stomach, at least 1 hour before or 2 hours after eating. (
  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 ].
  • 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 ]
      .
    • 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.
  )
• 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 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 ].
  • 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 ]
      .
    • 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.
  )
• 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 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 ]

  .

  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
  ,
  8.6 Hepatic Impairment

  Omaveloxolone plasma exposure is increased in patients with moderate or severe hepatic impairment (Child-Pugh Class B and C)

  [see Clinical Pharmacology ]

  . Avoid treatment with SKYCLARYS in patients with severe hepatic impairment, including those who develop severe hepatic impairment. If hepatic function improves to moderate impairment, mild impairment, or normal function, initiation of SKYCLARYS treatment at the approved recommended dosage may be considered. For patients with moderate hepatic impairment, a reduced dosage is recommended with close monitoring for adverse reactions

  [see Dosage and Administration ]

  . For patients with mild hepatic impairment (Child-Pugh Class A), no dose adjustments are recommended.
  ,
  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_maxand AUC_0-infincreased 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 ]

  .

  Omaveloxolone C_maxand AUC_0-infwere similar when capsule contents were sprinkled on applesauce or when administered as intact capsules. The median T_maxof omaveloxolone was shortened from approximately 10 to 6 hours when sprinkled on applesauce

  [see Dosage and Administration ]

  .

  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 m²did not have a significant effect on the pharmacokinetics of omaveloxolone. Therefore, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²) 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/1.73m²) 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_maxincreased 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 ]

  .

  Drug Interaction Studies

  Clinical Studies

  Strong CYP3A Inhibitors:

  After single dose administration, omaveloxolone C_maxincreased 3-fold and AUC 4-fold following concomitant use with itraconazole (strong CYP3A inhibitor)

  [see Drug Interactions ]

  .

  Moderate CYP3A Inhibitors:

  After single dose administration, omaveloxolone C_maxand AUC increased approximately 1.25-fold following concomitant use with verapamil (moderate CYP3A4 and P-gp inhibitor)

  [see Drug Interactions ]

  .

  Moderate CYP3A Inducers:

  After single dose administration, omaveloxolone C_maxand AUC decreased 38% and 48%, respectively, following concomitant use with efavirenz (moderate CYP3A4 inducer)

  [see Drug Interactions ].

  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 ].

  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.
  )

SKYCLARYS capsules contain 50 mg of omaveloxolone, and are supplied as opaque hard capsules having a light green body and blue cap, imprinted with “RTA 408” in white ink on the body and “50” in white ink on the cap.

Pregnancy: Based on animal data, may cause fetal harm. (