Skyclarys
(omaveloxolone)Dosage & Administration
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Skyclarys Prescribing Information
SKYCLARYS is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.
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 ].
Recommended Dosage
The recommended dosage of SKYCLARYS is 150 mg (3 capsules) taken orally once daily.
- Administer SKYCLARYS on an empty stomach at least one hour before 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.
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.
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 and Clinical Pharmacology ].
| Concomitant Drug Class | Dosage |
| Strong CYP3A4 inhibitor | Recommended to avoid concomitant use. If coadministration cannot be avoided:
|
| Moderate CYP3A4 inhibitor | Recommended to avoid concomitant use. If coadministration cannot be avoided:
|
| Strong or Moderate CYP3A4 inducer | Recommended to avoid concomitant use. |
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 ].
| Impairment Classification (Child-Pugh) | Dosage |
| Severe (Child-Pugh Class C) | Avoid use |
| Moderate (Child-Pugh Class B) |
|
| Mild (Child-Pugh Class A) | 150 mg once daily |
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
Risk Summary
There are no adequate data on the developmental risks associated with the use of SKYCLARYS in pregnant women. In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans (see Animal Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in no adverse effects on embryofetal development; however, in a dose range-finding study, oral administration of omaveloxolone at doses up to 30 mg/kg/day to pregnant rats throughout organogenesis produced increases in post-implantation loss and resorptions, resulting in a decrease in viable fetuses, and reduced fetal weight at the highest dose tested. At the highest dose tested in the pivotal study (10 mg/kg/day), plasma exposure (AUC) was approximately 5 times that in humans at the recommended human dose (RHD) of 150 mg/day.
Oral administration of omaveloxolone (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in increased embryofetal mortality and skeletal variations and reduced fetal weight at the highest dose tested, which was associated with maternal toxicity. At the no-effect dose for adverse effects on embryofetal development (10 mg/kg/day), plasma exposure was less than that in humans at the RHD.
Oral administration of omaveloxolone (0, 1, 3, or 10 mg/kg/day) to rats throughout pregnancy and lactation resulted in an increase in stillbirths and impaired neurobehavioral function (increased locomotor activity and learning and memory deficits) in offspring at all doses, reduced body weight in offspring at all but the lowest dose tested, and delayed sexual maturation (males), increased postnatal mortality, and impaired reproductive performance in offspring at the highest dose tested. A no-effect dose for adverse effects on pre- and postnatal development was not identified. Plasma exposure (AUC) at the lowest dose tested was less than that in humans at the RHD.
Lactation
Risk Summary
There are no data on the presence of omaveloxolone or its metabolites in human milk. The effects on milk production and the breastfed infant are unknown. Omaveloxolone was excreted in the milk of lactating rats following oral administration. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SKYCLARYS and any potential adverse effects on the breastfed infant from SKYCLARYS or from the underlying maternal condition.
Females and Males of Reproductive Potential
SKYCLARYS may decrease the efficacy of hormonal contraceptives [see Drug Interactions and Clinical Pharmacology ]. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring), implants, and progestin only pills. Counsel females using hormonal contraceptives to use an alternative contraceptive method (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during concomitant use and for 28 days after discontinuation of SKYCLARYS.
Pediatric Use
The safety and effectiveness of SKYCLARYS for the treatment of Friedreich's ataxia have been established in pediatric patients aged 16 years and older. Use of SKYCLARYS for this indication is supported by evidence from one adequate and well-controlled study (Study 1) in adults and in pediatric patients aged 16 years and older [see Clinical Studies ].
Safety and effectiveness of SKYCLARYS have not been established in pediatric patients less than 16 years of age.
Geriatric Use
Clinical studies of SKYCLARYS in Friedreich's ataxia did not include patients aged 65 and over. No data are available to determine whether they respond differently than younger adult patients.
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.
None.
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 ].
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.
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.