Version May 2024
Friedreich ataxia: Oral: 150 mg once daily (Ref).
Missed dose: If a dose is missed, take the next dose at its scheduled time the next day; do not double the dose to make up for a missed dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling.
Hepatic impairment prior to treatment initiation:
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): 100 mg once daily; may decrease to 50 mg once daily if adverse reactions occur.
Severe impairment (Child-Pugh class C): Avoid use.
Hepatotoxicity during treatment:
ALT and/or AST >5 times ULN, or ALT and/or AST >3 times ULN with evidence of hepatic dysfunction (eg, elevated bilirubin): Immediately discontinue and repeat LFTs. If elevated transaminases stabilize or resolve, may reinitiate therapy with increased monitoring.
Fluid overload (new or worsening) and/or elevated B-type natriuretic peptide: Promptly evaluate cardiac function and B-type natriuretic peptide (if not already obtained) and manage appropriately; management of fluid overload and heart failure may require discontinuation of therapy.
Refer to adult dosing.
(For additional information see "Omaveloxolone: Pediatric drug information")
Friedreich ataxia: Adolescents ≥16 years: Oral: 150 mg once daily (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Dosing adjustment for toxicity:
Signs of decreasing cardiac function which may include new or worsening fluid overload (eg, ≥1.4 kg [3 lb] in 1 day or ≥2.3 kg [5 lb] in 1 week) and/or elevated B-type natriuretic peptide: Promptly evaluate cardiac function and B-type natriuretic peptide (if not already obtained) and manage appropriately; management of fluid overload and heart failure may require discontinuation of therapy.
There are no dosage adjustments provided in the manufacturer's labeling.
Adolescents ≥16 years: Oral:
Baseline hepatic impairment:
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): 100 mg once daily; may decrease to 50 mg once daily if adverse reactions occur.
Severe impairment (Child-Pugh class C): Avoid use.
Hepatotoxicity during treatment:
ALT and/or AST >5 times ULN, or ALT and/or AST >3 times ULN with evidence of hepatic dysfunction (eg, elevated bilirubin): Immediately discontinue and repeat LFTs. If elevated transaminases stabilize or resolve, may reinitiate therapy with increased monitoring.
Increased serum alanine aminotransferase (ALT) and increased serum aspartate aminotransferase (AST) have been reported with omaveloxolone. Transaminase elevation was asymptomatic and reversible with discontinuation of therapy (Ref).
Mechanism: Related to the pharmacologic action; activation of nuclear factor erythroid 2-related factor (Nrf2) induces aminotransferase genes and increases serum activity of ALT and AST (Ref).
Onset: Varied; maximum increases in ALT and AST typically occur within 12 weeks of initiation of therapy.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults.
>10%:
Endocrine & metabolic: Increased LDL cholesterol (16%), increased serum cholesterol (29%)
Gastrointestinal: Abdominal pain (29%), decreased appetite (12%), diarrhea (20%), nausea (33%), vomiting (16%)
Hepatic: Increased serum alanine aminotransferase (≤37%) (table 1), increased serum aspartate aminotransferase (≤37%) (table 2)
|
Drug (Omaveloxolone) |
Placebo |
Population |
Number of Patients (Omaveloxolone) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
37% |
2% |
Adolescents and adults |
51 |
52 |
Combined incidence with increased serum aspartate aminotransferase |
|
Drug (Omaveloxolone) |
Placebo |
Population |
Number of Patients (Omaveloxolone) |
Number of Patients (Placebo) |
Comments |
|---|---|---|---|---|---|
|
37% |
2% |
Adolescents and adults |
51 |
52 |
Combined incidence with increased serum alanine aminotransferase |
Infection: Influenza (16%)
Nervous system: Fatigue (24%), headache (37%)
Neuromuscular & skeletal: Back pain (13%), muscle spasm (14%), musculoskeletal pain (20%)
Respiratory: Oropharyngeal pain (18%)
1% to 10%:
Dermatologic: Skin rash (10%)
Endocrine & metabolic: Decreased HDL cholesterol (6%)
There are no contraindications listed in the manufacturer's labeling.
Concerns related to adverse effects:
• Cardiac effects: B-type natriuretic peptide increases may occur during therapy and may indicate cardiac failure. Cardiac failure and cardiomyopathy may also occur with Friedreich ataxia. Associated signs/symptoms of cardiac failure–associated fluid overload include sudden weight gain (eg, ≥1.4 kg [3 lb] in 1 day or ≥2.3 kg [5 lb] in 1 week), palpitations, peripheral edema, and shortness of breath.
• Lipid abnormalities: Increases in cholesterol and LDL and decreases in HDL may occur during therapy. Cholesterol increases typically occur within 2 weeks of initiation of therapy and return to baseline within 4 weeks of therapy discontinuation. At 48 weeks of therapy, a mean LDL increase of 23.5 mg/dL and a mean HDL decrease of 5.3 mg/dL have been measured.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with preexisting liver impairment.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Skyclarys: 50 mg [contains fd&c blue #1 (brilliant blue)]
No
Capsules (Skyclarys Oral)
50 mg (per each): $411.11
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Oral: Administer on an empty stomach ≥1 hour prior to eating. Swallow capsules whole; do not open, crush, or chew.
Oral: Administer on an empty stomach ≥1 hour before eating. Swallow capsules whole; do not open, crush, or chew.
Missed dose: If a dose is missed, administer the next dose at its scheduled time the next day; do not double the dose.
Friedreich ataxia: Treatment of Friedreich ataxia in adults and adolescents ≥16 years of age.
Omaveloxolone may be confused with oxandrolone.
Substrate of CYP2C8 (minor), CYP2J2 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces BCRP/ABCG2, CYP2C8 (weak), CYP3A4 (weak), OATP1B1/1B3 (SLCO1B1/1B3)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Atogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification
Cladribine: BCRP/ABCG2 Inducers may decrease the serum concentration of Cladribine. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Omaveloxolone. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Omaveloxolone. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Omaveloxolone. Management: Avoid this combination if possible. If coadministration is required, decrease the omaveloxolone dose to 100 mg daily and monitor closely for adverse reactions. If adverse reactions occur, decrease omaveloxolone to 50 mg daily. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Omaveloxolone. Management: Avoid this combination if possible. If coadministration is required, decrease the omaveloxolone dose to 50 mg daily and monitor closely for adverse reactions. Discontinue coadministration if adverse reactions occur. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Hormonal Contraceptives: Omaveloxolone may decrease the serum concentration of Hormonal Contraceptives. Risk X: Avoid combination
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inducers may decrease the serum concentration of Zavegepant. Risk X: Avoid combination
Cmax and AUC are increased (350% and 15%, respectively) with administration with a high-fat meal (800 to 1,000 calories; ~150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared to fasted conditions. Grapefruit and grapefruit juice increases exposure. Management: Administer on an empty stomach ≥1 hour prior to eating; avoid grapefruit and grapefruit juice during therapy.
Omaveloxolone may decrease the efficacy of hormonal contraceptives. Patients taking hormonal contraceptives should use an alternative method (eg, nonhormonal IUD) or a concomitant nonhormonal contraceptive (eg, condom) during treatment and for 28 days after the last dose of omaveloxolone. Consult drug interactions database for more detailed information specific to use of omaveloxolone and specific contraceptives.
Based on data from animal reproduction studies, in utero exposure to omaveloxolone may cause fetal harm.
It is not known if omaveloxolone is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Administer on an empty stomach ≥1 hour prior to eating. Avoid grapefruit and grapefruit juice.
ALT, AST, total bilirubin (prior to initiation, monthly for the first 3 months, and periodically during therapy; if therapy is interrupted due to elevated ALT, AST, and/or total bilirubin and reinitiated, increase frequency of monitoring as clinically appropriate), lipid panel (prior to initiation and during therapy as clinically appropriate), B-type natriuretic peptide (prior to initiation of therapy). Monitor for signs/symptoms of fluid overload (eg, sudden weight gain [eg, ≥3 lbs in 1 day or ≥5 lbs in 1 week], palpitations, peripheral edema, shortness of breath).
Omaveloxolone activates Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways, which are involved in the cellular response to oxidative stress; in vitro, omaveloxolone restores mitochondrial function in fibroblasts obtained from patients with Friedreich ataxia (Abeti 2018; Lynch 2021; manufacturer's labeling).
Absorption: Cmax and AUC are increased (350% and 15%, respectively) with administration with a high-fat meal (800 to 1,000 calories; ~150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) compared to fasted conditions.
Distribution: Vd: 7,361 L.
Protein binding: 97%.
Metabolism: Primarily metabolized via CYP3A with minor metabolism via CYP2C8 and CYP2J2.
Half-life elimination: 57 hours (range: 32 to 90 hours).
Time to peak: Median: 7 to 14 hours; range: 1 to 24 hours.
Excretion: Feces: 92%; urine: 0.1%.
Hepatic function: Moderate and severe hepatic impairment (Child-Pugh class B and C): Clearance is reduced, resulting in increased AUC and Cmax (increased by 1.65-fold and 1.83-fold, respectively, in moderate hepatic impairment; AUC variably increased by up to 2.17-fold in severe hepatic impairment). Dosage reduction is recommended.
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