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Drug Name: Omaveloxolone
Brand Name: SKYCLARYS
FDA Approval: 28th Feb 2023
Company Name: Reata Pharmaceuticals
Primary Indications: Friedreich's ataxia
Despite concerns regarding the potency of the substantiating efficacy information, the regulatory body unexpectedly granted clearance for the first-in-class NRF2 agonist.
SKYCLARYS (Omaveloxolone) Indication & Usage:
The medicine called SKYCLARYS is made for people aged 16 and above who have Friedreich's ataxia. This includes both grown-ups and teenagers.
Friedreich's ataxia is a rare inherited problem that slowly hurts the nervous system. SKYCLARYS is given to help treat this condition and is approved to potentially ease the symptoms linked to Friedreich's ataxia in the specific group of people it's meant for.
SKYCLARYS (Omaveloxolone) Dosage and administration:
Before starting treatment with SKYCLARYS, it's important to do specific tests and keep an eye on the medication's safety.
These tests include checking levels of LFTs (ALT, AST, bilirubin), BNP, and lipid profile before starting SKYCLARYS and regularly during the treatment.
The purpose of these tests is to be proactive in checking for any potential harmful effects on the liver or lipid levels. It helps evaluate how safe and effective SKYCLARYS is overall.
So, following the suggested testing and monitoring steps is crucial to make sure the drug is safe and works well.
Recommended Dosage:
The suggested way to take SKYCLARYS is to have 150 mg, which is equal to 3 capsules, once a day.
It's best to take SKYCLARYS on an empty stomach, at least one hour before eating any meal.
To make sure SKYCLARYS works well and is safe, it's crucial to swallow the capsules whole. Don't open, crush, or chew them.
Following these recommended instructions for how much to take and when, and making sure to take the capsules correctly, helps the body absorb and use the medication properly.
This also helps minimize any potential risks or side effects.
Missed Doses
If you forget to take a dose of SKYCLARYS, it's better not to take two doses at once.
Instead, take the missed dose at the next scheduled time on the following day.
This way of handling a missed dose helps you stick to the right dosage plan and ensures that you're using the medication as directed.
Recommended Dosage of Omaveloxolone with the combined use of CYP3A4 Inhibitors and Inducers
When using SKYCLARYS along with CYP3A4 inhibitors or inducers, it's advised to follow specific dosage recommendations based on the strength or potency of the drug class.
CYP3A4 Drug Class |
Recommendation |
| Strong inhibitor | It is recommended to avoid concurrent use. |
| If it is not possible to avoid coadministration: | |
| Take only 50 mg of SKYCLARYS once every day. | |
| Watch closely for any negative side effects. | |
| Discontinue coadministration if negative side effects occur | |
| Moderate inhibitor | It is recommended to avoid concurrent use |
| If it is not possible to avoid coadministration: | |
| Take only 100 mg of SKYCLARYS once every day. | |
| Watch closely for any negative side effects. | |
| If you experience side effects, the recommended action is to lower the dosage to 50 mg once per day. | |
| Strong or moderate inducer | Discontinue coadministration if negative side effects occur |
Recommended Dosage in Patients with Liver Disease:
Hepatic Impairment |
Dosage Recommendation |
| Severe (Child-Pugh Class C) | Do not use. |
| Moderate (Child-Pugh Class B) |
Take 100 mg once a day while closely watching for any side effects. If adverse reactions emerge, it is recommended to consider reducing the dosage of the medication to 50 mg once daily. |
| Mild (Child-Pugh Class A) | 150 mg once daily |
Contraindications to Skyclarys (Omaveloxolone):
No contraindication is given in the FDA prescribing information.
Warnings and precautions
Elevation of Aminotransferases in clinical trials:
Elevated Liver enzymes |
Action |
| LFTs exceeding 5 times or 3 times the upper limit of normal | 16% and 31%, respectively |
| Concomitant elevation of transaminases and total bilirubin in Study 1 | None observed |
| Timing of maximum increases in ALT and AST | Within 12 weeks after starting SKYCLARYS |
| Symptoms associated with an increase in serum aminotransferases. | Most patients were asymptomatic and LFTs were reversibly abnormal |
| Exclusion Criteria for Study 1 | Clinically significant liver disease |
| Monitoring |
Before initiating SKYCLARYS, it is recommended to monitor LFTs. Monitor LFTs monthly for the first 3 months During the first three months of treatment, monitoring should be done every month, and periodically thereafter. In patients with LFTs exceeding 5 times the upper limit of normal or more than 3 times the ULN along with liver dysfunction, discontinue the treatment immediately and recheck liver function as soon as possible. After stabilization or resolution of transaminase levels, the treatment may be resumed but LFTs should be more frequently monitored. |
Elevation of B-Type Natriuretic Peptide
Parameter |
Action |
| BNP above the ULN (100 pg/mL) | 14% |
| BNP levels above 200 pg/mL | 4% |
| Exclusion Criteria for Study 1 |
Patients with B-type natriuretic peptide (BNP) levels exceeding 200 pg/mL before study enrollment or a medical history of significant left-sided heart disease and/or significant cardiac disease, except for mild to moderate cardiomyopathy related to Friedreich’s ataxia. |
| Monitoring |
Check BNP levels before treatment initiation. Monitored patients for signs and symptoms of fluid overload, such as sudden weight gain, peripheral edema, palpitations, and shortness of breath. If any signs and symptoms of fluid overload develop, worsen, or require hospitalization, BNP and cardiac function should be evaluated, and managed appropriately. It may be necessary to discontinue the treatment for the management of fluid overload and heart failure. |
Lipid Abnormalities
Parameter |
Action |
| Increase in cholesterol levels above the upper limit of normal | 29% |
| Increase in LDL cholesterol levels from the baseline | 16% |
| The mean increase in LDL-C at 48 weeks. | 23.5 mg/dL |
| Reductions in HDL-C levels from baseline | 6% |
| The average reduction in HDL-C levels at 48 weeks. | 5.3 mg/dL |
| Monitoring | Check lipid profile at baseline and subsequently at regular intervals throughout the course of treatment. |
Side Effects of SKYCLARYS (Omaveloxolone):
Adverse Reaction |
Frequency |
Severity |
Management |
Study/Source |
| Headache | Common | Mild to Moderate | Symptomatic treatment | Product label |
| Nausea | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Vomiting | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Abdominal Pain | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Diarrhea | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Fatigue | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Hyponatremia | Uncommon | Moderate to Severe | Medical intervention, Adjustment of dosage, or discontinuation of medication | Product label |
| Dehydration | Uncommon | Moderate to Severe | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Renal impairment | Uncommon | Moderate to Severe | Medical intervention, Adjustment of dosage, or discontinuation of medication | Product label |
| Hypokalemia | Uncommon | Moderate to Severe | Medical intervention, Adjustment of dosage, or discontinuation of medication | Product label |
| Peripheral edema | Rare | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
| Photosensitivity | Very rare | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Product label |
Side effects experienced in clinical trials:
Adverse Reaction |
Frequency |
Severity |
Management |
Study/Source |
| Elevated liver enzymes (AST/ALT) | Common | Mild to Moderate | Monitoring, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Headache | Common | Mild to Moderate | Symptomatic treatment | Study 1 |
| Nausea | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Abdominal Pain | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Fatigue | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Diarrhea | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Musculoskeletal pain | Common | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Pyrexia | Uncommon | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Dizziness | Uncommon | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Hypotension | Uncommon | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Vomiting | Uncommon | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
| Myalgia | Rare | Mild to Moderate | Symptomatic treatment, Adjustment of dosage, or discontinuation of medication | Study 1 |
The adverse reactions were reported in more than 10% of patients treated with SKYCLARYS and had a higher incidence than the placebo group.
Drug Interaction:
Interaction |
Drugs |
Effect |
Management |
| CYP3A4 Inhibitors | Moderate or strong inhibitors | Increased exposure of omaveloxolone | Avoid concomitant use, consider dosage modification |
| CYP3A4 Inducers | Moderate or strong inducers | Decreased exposure of omaveloxolone | Avoid concomitant use |
| Drug Interactions | CYP3A4 and CYP2C8 Substrates | Reduced exposure and activity of substrates | Refer to prescribing information for dosing instructions and monitor for lack of efficacy |
| Hormonal Contraceptives | Combined hormonal contraceptives, implants, progestin-only pills | Reduced efficacy of hormonal contraceptives | Avoid concomitant use |
Use in specific populations:
Population |
Risk Summary |
Recommendations |
| Pregnancy | Limited data | Consider benefits and risks |
| Lactation | Limited data | Consider the benefits of breastfeeding and the mother's clinical need for SKYCLARYS |
| Females and Males of Reproductive Potential | SKYCLARYS may reduce the effectiveness of hormonal contraceptives. |
Recommend effective non-hormonal contraception during the treatment and for 28 days after the last dose. |
| Children | Safety and efficacy established for ages 16 and above | Not established for ages less than 16 |
| Geriatric Use | Not studied older people, aged 65 and over | No data available |
| Hepatic Impairment | Increased plasma exposure in moderate or severe impairment |
Avoid in severe impairment; consider reduced dosage and close monitoring in moderate impairment; no dose adjustment is needed in mild impairment |
| Renal Impairment | Not significantly altered in mild or moderate impairment |
No dosage adjustment is needed in mild or moderate impairment; not studied in severe impairment or end-stage renal disease |
Mechanism of Action of Skyclarys (Omaveloxolone):
The precise mechanism is not known. Nevertheless, evidence has shown that Omaveloxolone activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways in vitro, in animals, and in humans. The Nrf2 pathway is involved in the cellular response to oxidative stress.
Potential to Prolong the QT Interval: Not known.
Parameter |
Value |
| Absorption | Median time to achieve peak plasma concentration: 7-14 hrs; total plasma exposure increases dose-dependently and proportionally over a dose range of 50-150 mg; Cmax increases less than dose proportionally |
| Effect of Food | A high-fat meal increases the maximum plasma concentration and the area under the plasma concentration-time curve of the drug. |
| Distribution | The mean apparent volume of distribution of the drug is 7361 L, which is equivalent to 105 L/kg for a person with a body weight of 70 kg. The drug is highly protein-bound, with 97% of the drug being bound to plasma proteins. |
| Elimination |
Mean terminal half-life: 57 hrs (range: 32-90 hrs); |
| Metabolism | Cytochrome P450 (CYP) 3A enzyme (to a lesser extent by the enzymes CYP2C8 and CYP2J2) |
| Excretion | Feces: 92% |
Clinical studies:
SKYCLARYS was evaluated for its efficacy in a 48-week, randomized, double-blind, placebo-controlled clinical trial in patients with Friedreich's Ataxia (Study 1; NCT02255435). The study details are presented in the following table.
| Criteria | Details |
| Study design | Randomized, double-blind, placebo-controlled trial |
| Duration of study | 48 weeks |
| Number of patients enrolled | 103 |
| Randomization | 1:1 |
| Dose | 150 mg once daily |
| Enrollment criteria | A stable modified Friedreich's Ataxia Rating Scale (mFARS) score ranging from 20 to 80, capability to perform maximal exercise testing, and a left ventricular ejection fraction of no less than 40%. |
| Patient characteristics | The mean age of 24 years, 53% male, 97% White |
| Inclusion of patients with pes cavus | Yes |
| Prespecified primary analysis | The Full Analysis Population of patients without pes cavus (n=82) were evaluated for change in modified Friedreich's Ataxia Rating Scale (mFARS) score from baseline compared to placebo at Week 48. |
| mFARS |
Consisted of four domains to assess bulbar function, upper limb coordination, lower limb coordination, and upright stability. The maximum score achievable on this tool is 99, with lower scores indicating greater physical impairment. |
| Efficacy outcome | At Week 48, statistically significantly lower modified Friedreich's Ataxia Rating Scale (mFARS) scores were observed in comparison to placebo. |
Patients Counseling Information:
| Topic | Information |
| Patient Labeling | Patients should read the FDA labeling. |
| Elevation of Aminotransferases | LFTs may be affected. Frequent monitoring is required. |
| Fluid Overload |
BNP, a marker of cardiac function, may rise with treatment. Testing before treatment initiation is recommended. Patients should also report signs of heart failure and fluid overload. These include sudden weight gain, peripheral edema, palpitations, and shortness of breath. |
| Lipid Abnormalities |
Lipid abnormalities are common with treatment. Patients should be tested for lipid derangements at baseline and periodically thereafter. In addition to guideline-guided therapy, a healthy diet and exercise regimen may help manage high cholesterol levels (Here is a meal plan for lowering cholesterol levels) |
| Drug Interactions |
Patients should inform their prescribers about any prescription and non-prescription medications they are currently on. |
| Pregnancy | Female patients should inform their healthcare provider if they are pregnant, planning to become pregnant or become pregnant during treatment. |
| Females of Reproductive Potential |
Recommend a non-hormonal intrauterine system or additional non-hormonal contraceptive (e.g. condoms) during the treatment and following the treatment for at least 28 days. |
| Administration |
Take the drug on an empty stomach, at least one hour before eating. Patients should swallow SKYCLARYS capsules whole and not open, crush, or chew them. If a dose is missed, patients should not double their dose or take more than the prescribed amount. |
| Grapefruit Juice | Advise patients to refrain from consuming grapefruit juice and grapefruit while taking SKYCLARYS. |
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