Omaveloxolone

The AUC of repaglinide, a CYP2C8 substrate, was reduced by approximately 35% when co-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of CYP2C8 and can reduce the exposure of CYP2C8 substrates.

The AUC of rosuvastatin, a BCRP and OATP1B1 substrate, was reduced by approximately 30% when co-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of BCRP and can reduce the exposure of BCRP substrates.

The AUC of midazolam, a CYP3A4 substrate, was reduced by approximately 45% when co-administered with omaveloxolone, indicating that omaveloxolone is a weak inducer of CYP3A4 and can reduce the exposure of CYP3A4 substrates. Concomitant use with omaveloxolone 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.

Omaveloxolone is a CYP3A4 substrate. Concomitant use of omaveloxolone with 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 omaveloxolone with strong CYP3A4 inhibitors.

If coadministration cannot be avoided:

• Reduce the dosage of omaveloxolone to 50 mg once daily with close monitoring for adverse reactions.
• If adverse reactions emerge, coadministration with strong CYP3A4 inhibitors should be discontinued.

Omaveloxolone is a CYP3A4 substrate. Concomitant use of omaveloxolone with strong or moderate CYP3A4 inducers may significantly decrease the exposure of omaveloxolone, which may reduce the effectiveness of omaveloxolone. Due to potential loss of efficacy, patients treated with omaveloxolone should be warned to avoid use of strong or moderate CYP3A4 inducers while taking omaveloxolone and alternatives should be considered if possible. Some examples of strong or moderate CYP3A4 inducers are carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St. John’s wort, and efavirenz.

The dose should be reduced to 100 mg once daily with close monitoring for adverse reactions in patients with moderate hepatic impairment (Child-Pugh Class B). Lowering to 50 mg once daily should be considered if adverse reactions emerge.

The use of the medicinal product should be avoided in patients with severe hepatic impairment (Child-Pugh Class C).

There are no data from the use of omaveloxolone in pregnant women. Studies in animals have shown reproductive toxicity.

Omaveloxolone should not be used during pregnancy or in women of childbearing potential not using contraception. Patients should use effective contraception prior to starting treatment with omaveloxolone, during treatment, and for 28 days following discontinuation of treatment.

Omaveloxolone may decrease the efficacy of hormonal contraceptives. Advise patients to avoid concomitant use with combined hormonal contraceptives (e.g., pill, patch, ring). 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 omaveloxolone.

There are no data on the presence of omaveloxolone in human milk. Omaveloxolone is present in the milk of lactating rats and resulted in treatment-related effects in offspring. A risk to the newborn infant cannot be excluded. Omaveloxolone should not be used during breast-feeding.

Fertility

There are no data on the effects of Skyclarys on human fertility. Animal data did not indicate impairment of parent male or female fertility.

Omaveloxolone may have a minor influence on the ability to drive and use machines. Fatigue may occur following administration of omaveloxolone.

Summary of safety profile

The most frequently occurring adverse reactions observed with omaveloxolone are ALT increased and headache (37.3% each); weight decreased (34.0%); nausea (33.3%); AST increased and fatigue (21.6% each); diarrhoea (19.6%); oropharyngeal pain (17.6%); vomiting (15.7%), back pain, muscle spasms, and influenza (13.7% each); and decreased appetite (11.8%).

Tabulated list of adverse reactions

The adverse reactions observed in the randomized, double-blind, placebo-controlled trial in 51 patients treated with omaveloxolone 150 mg/day for 48 weeks (median exposure 0.92 patient years) are listed in the table below by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1 000 to <1/100). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Selected adverse reactions are further decribed in the following table.

Adverse reactions:

^a Based on laboratory evaluations with values >200 pg/mL.
^b Based on weight measured in the clinic with on-treatment weight loss ≥5%.
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; GGT=gamma glutamyltransferase.

Description of selected adverse reactions

Gastrointestinal disorders

Among patients treated with omaveloxolone in the randomized, double-blind, placebo-controlled study, nausea occurred in 33.3% of patients, diarrhoea in 19.6% of patients, vomiting in 15.7% of patients, abdominal upper pain in 9.8% of patients, and abdominal pain in 7.8% of patients. All events were assessed as either mild or moderate in severity, and 75.8% of the events occurred within the first 12 weeks of therapy.

Aminotransferase elevations

Among patients treated with omaveloxolone in the randomized, double-blind, placebo-controlled study, adverse reactions of aminotransferase elevations included: ALT increased in 37.3% of patients, AST increased in 21.6% of patients, and gamma glutamyltransferase (GGT) increased in 5.9% of patients. Treatment interruptions due to aminotransferase elevations occurred in 11.8% of all omaveloxolone-treated patients. One patient (2%) was discontinued for aminotransferase elevation per protocol.

In patients treated with omaveloxolone, the incidence of on-treatment elevations of ALT or AST ≥3 × the ULN was 29.4%, with 15.7% experiencing elevations ≥5 × the ULN. Elevations of ≥3 × the ULN were generally transient and reversible, with 80% of these patients experiencing maximal levels within the first 12 weeks of treatment. None of these patients had ALT or AST levels ≥3 × the ULN at the withdrawal visit. Mean values generally decreased towards baseline with continued treatment or after interruption in therapy. No patient had concomitant elevation of total bilirubin >1.5 × the ULN.

Elevation of BNP

In the randomized, double-blind, placebo-controlled study, increases in laboratory evaluations of BNP were observed in patients treated with omaveloxolone. Mean BNP values were elevated at Week 4, and remained elevated through Week 48, with peak mean elevations at Week 24. Mean BNP values remained below the ULN (<100 pg/mL). A total of 13.7% of patients treated with omaveloxolone had an increase from baseline in BNP and a BNP above the ULN (100 pg/mL), compared to 3.8% of patients who received placebo; 3.9% of patients had BNP values that exceeded 200 pg/mL while on treatment. There were no discontinuations due to BNP elevation.

Lipid abnormalities

Among patients treated with omaveloxolone in the randomized, double-blind, placebo-controlled study, hypertriglyceridaemia was reported in 3.9% of patients, very low-density lipoprotein increased was reported in 3.9% of patients, and hypercholesterolaemia was reported in 2.0% of patients. At Week 48 in the omaveloxolone treatment group, mean LDL increased by approximately 25 mg/dL and mean HDL decreased by approximately 5 mg/dL. After withdrawal of omaveloxolone, mean LDL and HDL levels returned to baseline.

Weight decreased

In the randomized, double-blind, placebo-controlled study, weight decrease was reported for 2.0% of patients treated with omaveloxolone and 1.9% of patients treated with placebo. No serious adverse reactions or discontinuations due to decreased appetite or weight decrease were reported in either treatment group.

Decrease in body weight was observed after Week 24. The mean weight decrease relative to baseline was 1.35 kg (SD 3.585 kg) in the omaveloxolone group and the mean weight increase relative to baseline was 1.17 kg (SD 4.108 kg) in the placebo group after 48 weeks of treatment. Among all patients with baseline BMI <25 kg/m² across both treatment groups (omaveloxolone, n=37; placebo, n=37), weight loss of at least 5% from baseline was observed in 32.4% of omaveloxolone-treated patients versus 2.7% of placebo-treated patients.

Paediatric population

Based on evaluation of omaveloxolone in randomized, placebo-controlled trials, the safety profile of omaveloxolone in paediatric patients aged 16 to less than 18 years (n=24) was consistent with the safety profile in adult patients.