Skyclarys

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. 5). 3 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.

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. 2). 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. 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. 2). 4

8%). 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 rasha 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 8 System Organ Class Preferred Term Frequency Category 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.

bBased on laboratory evaluations with values > 200 pg/mL. cBased 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.

8% of patients. 8% of the events occurred within the first 12 weeks of therapy. 9% of patients. 8% of all Skyclarys-treated patients. One patient (2%) was discontinued for aminotransferase elevation per protocol. 7% experiencing elevations ≥ 5 × the ULN.

8). 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.

2). 5). 2). 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. 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.

8% of patients who received placebo. 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.

1.