Skyclarys Drug Information
Generic name: OMAVELOXOLONE
Uses of 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.
Dosage & Administration of Skyclarys
| Strong CYP3A4 inhibitor | Recommended to avoid concomitant use. If coadministration cannot be avoided:
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| Moderate CYP3A4 inhibitor | Recommended to avoid concomitant use. If coadministration cannot be avoided:
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| Strong or Moderate CYP3A4 inducer | Recommended to avoid concomitant use. |
Side Effects of Skyclarys
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.
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)
Warnings & Cautions for Skyclarys
Elevation of Aminotransferases Treatment with
SKYCLARYS can cause an elevation in hepatic transaminases (ALT and AST). In Study 1 , 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.
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. 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.
Drug Interactions with Skyclarys
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, 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. 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 , which may reduce the effectiveness of SKYCLARYS. Avoid concomitant use of SKYCLARYS with moderate or strong CYP3A4 inducers.
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 . 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 . 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 .
Pregnancy Safety for Skyclarys
Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to SKYCLARYS during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the program by calling 1-866-609-1785 or by sending an email to [email protected]. 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.
Pediatric Use 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 . Safety and effectiveness of SKYCLARYS have not been established in pediatric patients less than 16 years of age.
Clinical Studies of Skyclarys
The efficacy of SKYCLARYS was evaluated in a 48-week, randomized, double-blind, placebo-controlled study in patients 16 to 40 years of age with Friedreich's Ataxia (Study 1; NCT02255435). A total of 103 patients were randomized (1:1) to receive SKYCLARYS 150 mg once daily (n=51) or placebo (n=52). Enrolled patients had to have a stable modified Friedreich's Ataxia Rating Scale (mFARS) score between 20 and 80, be able to complete maximal exercise testing, and have a left ventricular ejection fraction of at least 40%. In Study 1, 53% of enrolled patients were male, 97% were White, and the mean age was 24 years at study entry. Patients with or without pes cavus were included in Study 1. Pes cavus was defined as having a loss of lateral support and was determined if light from a flashlight could be seen under the patient's arch when barefoot and weight bearing. The prespecified primary analysis was the change from baseline in the mFARS score compared to placebo at Week 48 in the Full Analysis Population of patients without pes cavus (n=82). The mFARS is a clinical assessment tool to assess patient function, which consists of 4 domains to evaluate bulbar function, upper limb coordination, lower limb coordination, and upright stability.
The mFARS has a maximum score of 99, with a lower score on the mFARS signifying lesser physical impairment. Treatment with SKYCLARYS resulted in statistically significant lower mFARS scores (less impairment) relative to placebo (see Table 4 ) at Week 48. Table 4: Primary Analysis in Full Analysis Population: mFARS Least Squares (LS) Mean Change from Baseline at Week 48 SD = Standard Deviation; LS = Least Squares; CI = Confidence Interval Mean (SD) Baseline mFARS Total Score LS Mean Change from Baseline at Week 48 Treatment difference SKYCLARYS-placebo (95% CI) p-value SKYCLARYS (n = 40) 40.95 -1.56 -2.41 (-4.32, -0.51) 0.0138 Placebo (n = 42) 38.78 0.85 The All Randomized Population (N=103), which included all patients regardless of pes cavus status, demonstrated similar results to the Full Analysis Population of lower mFARS scores in patients treated with SKYCLARYS compared to placebo, with a nominally significant least squares mean difference between treatment groups of ‑1.94 (95% CI: -3.71, -0.16, p=0.0331). In a post hoc, propensity-matched analysis, lower mFARS scores were observed in patients treated with SKYCLARYS after 3 years relative to a matched set of untreated patients from a natural history study. These exploratory analyses should be interpreted cautiously given the limitations of data collected outside of a controlled study, which may be subject to confounding.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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