4.1. Therapeutic indications

Skyclarys is indicated for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

4.2. Posology and method of administration

Omaveloxolone should be initiated and supervised by physicians with experience in the treatment of patients with Friedreich Ataxia.

Posology

The recommended dose is 150 mg omaveloxolone (3 hard capsules of 50 mg each) once daily.

Medicine lost through emesis should not be replaced with an additional dose.

If a dose is missed, the next dose should be taken as usual the following day. A double dose should not be taken to make up for a missed dose.

Dose modifications for concomitant therapy

The recommended dosages for concomitant use of omaveloxolone with strong or moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers are described in Table 1 (see sections 4.4 and 4.5).

Table 1: Recommended dosage modifications of omaveloxolone with concomitant use of CYP3A4 inhibitors

Concomitant Drug Class

Dosage Recommendation

Strong CYP3A4 inhibitor

Recommended to avoid concomitant use.

If coadministration cannot be avoided:

• Reduce the dosage of Skyclarys to 50 mg once daily with close monitoring for adverse reactions.

• If adverse reactions emerge, coadministration with strong CYP3A4 inhibitors should be discontinued.

Moderate CYP3A4 inhibitor

Recommended to avoid concomitant use.

If coadministration cannot be avoided:

• Reduce the dosage of Skyclarys to 100 mg once daily with close monitoring for adverse reactions.

• If adverse reactions emerge, further reduce the dosage of Skyclarys to 50 mg once daily.

Elderly

No dose adjustment is required based on age (see section 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh Class A).

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) (see section 5.2).

Renal impairment

The effect of moderate and severe renal impairment on the pharmacokinetics of omaveloxolone has not been studied (see section 5.2).

Paediatric population

The safety and efficacy of Skyclarys in children and adolescents aged less than 16 years have not yet been established. No data are available.

Method of administration

This medicinal product is for oral use.

Omaveloxolone should be taken on an empty stomach at least 1 hour before or 2 hours after eating (see sections 4.5 and 5.2).

Skyclarys capsules should be swallowed whole.

For patients who are unable to swallow whole capsules, Skyclarys capsules may be opened, and the entire contents sprinkled onto 2 tablespoons of apple puree. Patients should consume all the medicine/food mixture immediately on an empty stomach at least 1 hour before or 2 hours after eating. It should not be stored for future use (see section 5.2).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Elevation of aminotransferases

Treatment with omaveloxolone in clinical trials with patients with Friedreich's ataxia has been associated with elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (see section 4.8). On-treatment aminotransferase elevations of ≥ 3 × the upper limit of normal (ULN) were reported in 29.4% of patients, with maximal values occurring in the majority of patients within the first 12 weeks of treatment. Initial increases were followed by a trend toward normalization.

ALT, AST, and bilirubin should be monitored prior to initiation of omaveloxolone, monthly during the first 3 months of treatment, and periodically thereafter as clinically indicated. If ALT or AST increases to > 5 × the ULN, omaveloxolone should be immediately discontinued, and liver function tests should be repeated as soon as possible. If laboratory abnormalities stabilize or resolve, omaveloxolone can be reinitiated. If ALT or AST increases to > 3 × the ULN and bilirubin increases to > 2 × the ULN, omaveloxolone should be immediately discontinued and liver function tests should be repeated. Testing should be continued as appropriate. When laboratory abnormalities stabilize or resolve, Skyclarys may be reinitiated with an appropriate frequency of monitoring liver function.

Drug interactions

Omaveloxolone is primarily metabolised by CYP3A4 (see section 5.2). Concomitant use of strong or moderate CYP3A4 inhibitors may significantly increase the systemic exposure of omaveloxolone (see section 4.5). If concomitant use of strong or moderate CYP3A4 inhibitors is unavoidable, dose reduction of omaveloxolone with monitoring should be considered (see section 4.2).

Concomitant use of omaveloxolone with strong or moderate CYP3A4 inducers may significantly decrease the exposure of omaveloxolone (see section 4.5), which may reduce the effectiveness of omaveloxolone. Patients treated with omaveloxolone should be warned to avoid concomitant use of CYP3A4 inducers while taking omaveloxolone. Alternative medicinal products should be considered if possible (see sections 4.2 and 4.5).

Lipid abnormalities

Treatment with omaveloxolone has been associated with increases in low-density lipoprotein (LDL) cholesterol and decreases in high-density lipoprotein (HDL) cholesterol. Lipid parameters should be assessed prior to initiation of omaveloxolone and should be monitored periodically during treatment. Lipid abnormalities should be managed according to standard clinical guidelines.

Elevation of B-type natriuretic peptide (BNP)

Treatment with omaveloxolone has been associated with increases in BNP but without any concurrent increase in blood pressure or associated events of fluid overload or congestive heart failure. In Study 1, a total of 13.7% of patients treated with Skyclarys 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. The incidence of elevation of BNP above 200 pg/mL was 3.9% in patients treated with Skyclarys. Whether the elevations in BNP in Study 1 are related to Skyclarys or cardiac disease associated with Friedreich's ataxia is unclear.

In a study with a related compound in diabetic patients with chronic kidney disease (CKD), excess heart failure events due to fluid overload were observed among patients with stage IV CKD. Baseline BNP > 200 pg/mL and prior hospitalization for congestive heart failure were identified as risk factors for heart failure among patients who had stage IV CKD but not in patients who had stage 3b CKD.

Cardiomyopathy and diabetes mellitus are common in patients with Friedreich's ataxia. BNP should be monitored prior to and periodically during treatment. Patients should be advised of the signs and symptoms of congestive heart failure associated with fluid overload, such as sudden weight gain (≥ 1.4 kg in 1 day or ≥ 2.3 kg in 1 week), peripheral oedema, and shortness of breath. If signs and symptoms of fluid overload develop, BNP (or NT‑proBNP) should be monitored and managed according to standard clinical guidance. Treatment with Skyclarys should be interrupted during fluid overload management. If fluid overload cannot be appropriately managed, treatment with Skyclarys should be discontinued. Per clinical judgment, more frequent monitoring of patients with a recent hospitalization for fluid overload due to underlying cardiomyopathy, diabetic stage IV CKD, or other aetiologies is strongly recommended.

Body weight decrease

Treatment with Skyclarys has been associated with mild decreases in body weight. Advise patients to monitor their weight regularly. Further evaluate the patient if unexplained or clinically significant body weight decrease occurs.

Hypersensitivity reactions

Skyclarys is associated with a risk of hypersensitivity reactions including urticaria and rash (see section 4.8).

In the randomized, double-blind, placebo-controlled trial of 51 patients treated with Skyclarys 150 mg/day for 48 weeks, the frequency of hypersensitivity events was very common (≥ 1/10). All events were non-serious and all events reported in participants receiving omaveloxolone were mild in severity. The average time to onset for the omaveloxolone group was 135 days (minimum: 3 days, maximum: 360 days, median: 95 days). Hypersensitivity reactions including urticaria and rash have also been reported in the post-marketing setting and other clinical trials. In the post-marketing setting, one serious case of drug hypersensitivity has been reported, all events reported in other clinical trials were mild to moderate in severity. If a hypersensitivity reaction occurs, appropriate measures should be initiated if needed. Patients should be informed of the signs and symptoms of hypersensitivity.

Skyclarys contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free.'

4.5. Interaction with other medicinal products and other forms of interaction

Omaveloxolone is a substrate of CYP3A4. Co-administration of strong or moderate CYP3A4 inhibitors or CYP3A4 inducers will affect the pharmacokinetics of omaveloxolone.

Effect of other medicines on pharmacokinetics of omaveloxolone

Strong or moderate CYP3A4 inhibitors

In a clinical study, co-administration of Skyclarys with itraconazole, a strong CYP3A4 inhibitor, increased the area under the curve (AUC0‑inf) and maximal plasma concentration (Cmax) by approximately 4-fold and 3-fold, respectively. In a clinical study with healthy subjects, co-administration of verapamil (120 mg once daily) increased the AUC and Cmax by 1.24-fold and 1.28-fold, respectively. Verapamil is a known moderate CYP3A4 inhibitor and inhibitor of the P‑gp transporter. If concomitant use of strong or moderate CYP3A4 inhibitors is unavoidable, dosage reduction of Skyclarys should be considered with monitoring (see sections 4.2 and 4.4). Some examples of strong and moderate CYP3A4 inhibitors are clarithromycin, itraconazole, ketoconazole, ciprofloxacin, cyclosporine, fluconazole, and fluvoxamine.

As grapefruit and grapefruit juice are inhibitors of CYP3A4, patients should be warned to avoid these while taking Skyclarys (see section 4.4).

Strong or moderate CYP3A4 inducers

In a clinical study, co-administration of omaveloxolone with efavirenz, a moderate CYP3A4 inducer, decreased the area under the curve (AUC0-inf) and maximal plasma concentration (Cmax) by approximately 49% and 38%, respectively. Due to potential loss of efficacy, patients treated with Skyclarys should be warned to avoid use of strong or moderate CYP3A4 inducers while taking Skyclarys 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.

Effect of omaveloxolone on other medicinal products

The following were evaluated in clinical studies with omaveloxolone 150 mg in healthy subjects:

CYP3A4 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 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 (see section 4.6).

CYP2C8 substrates

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.

BCRP 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of omaveloxolone in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Skyclarys 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 Skyclarys, during treatment, and for 28 days following discontinuation of treatment.

Skyclarys may decrease the efficacy of hormonal contraceptives (see section 4.5). 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 Skyclarys.

Breast-feeding

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 (see section 5.3). A risk to the newborn infant cannot be excluded. Skyclarys 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 (see section 5.3).

4.7. Effects on ability to drive and use machines

Omaveloxolone may have a minor influence on the ability to drive and use machines. Fatigue may occur following administration of omaveloxolone (see section 4.8).

4.8. Undesirable effects

Summary of safety profile

The most frequently occurring adverse reactions observed with Skyclarys 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 Skyclarys 150 mg/day for 48 weeks (median exposure 0.92 patient years) are listed in Table 2 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 following Table 2.

Table 2 Adverse reactions

System Organ Class

Preferred Term

Frequency Category

Infections and infestations

Influenza

Very common

Urinary tract infection

Common

Immune system disorders

Hypersensitivity including urticaria and rash a

Very common

Metabolism and nutrition disorders

Decreased appetite

Very common

Hypertriglyceridemia

Common

Very low density lipoprotein increased

Common

Nervous system disorders

Headache

Very common

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain

Very common

Gastrointestinal disorders

Nausea

Very common

Diarrhoea

Very common

Vomiting

Very common

Abdominal upper pain

Common

Abdominal pain

Common

Hepatobiliary disorders

ALT increased

Very common

AST increased

Very common

GGT increased

Common

Musculoskeletal and connective tissue disorders

Back pain

Very common

Muscle spasms

Very common

Reproductive system and breast disorders

Dysmenorrhoea

Common

General disorders and administration site conditions

Fatigue

Very common

Investigations

BNP increasedb

Common

Weight decreasedc

Very common

a Cases have been reported in the post-marketing setting with unknown frequency

b Based on laboratory evaluations with values > 200 pg/mL.

c 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 Skyclarys 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 Skyclarys 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 Skyclarys-treated patients. One patient (2%) was discontinued for aminotransferase elevation per protocol.

In patients treated with Skyclarys, 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 Skyclarys. 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 Skyclarys 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 Skyclarys 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 Skyclarys treatment group, mean LDL increased by approximately 25 mg/dL and mean HDL decreased by approximately 5 mg/dL. After withdrawal of Skyclarys, 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 Skyclarys 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 Skyclarys 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 (Skyclarys, n=37; placebo, n=37), weight loss of at least 5% from baseline was observed in 32.4% of Skyclarys-treated patients versus 2.7% of placebo-treated patients.

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no specific antidote for Skyclarys. For patients who experience overdose, closely monitor and provide appropriate supportive treatment.