Nezglyal

HOS-101099 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The overall safety profile of leriglitazone is based on clinical studies and additional clinical experience in paediatric patients with ALD. In children (2 to 12 years of age), the most commonly reported adverse reactions during leriglitazone treatment were weight increased (8.7%), eyelid oedema (8.7%), leukopenia (8.7%) and neutropenia (8.7%) (see section 4.4). 7 Tabulated list of adverse reactions The safety of leriglitazone in paediatric patients with ALD was evaluated in an open label Phase II study MT-2-02, of 23 patients, aged 2 to 12 years of age. The mean (SD) treatment duration was of 76.2 (48.91) weeks and the median was 57.9 (Min, Max 5.4, 192.1) (see section 5.1). Adverse reactions in children (2 to 12 years of age) are listed in Table 4. Adverse reactions are classified according to MedDRA system organ class and frequency. Within each system organ class, adverse reactions are listed by frequency, based on the following frequency convention: 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. Table 4: Adverse reactions System organ class Adverse reaction Frequency Blood and lymphatic system Anaemia Common disorders Differential white blood cell count abnormal International normalised ratio increased Leukopenia Lymphopenia Neutropenia Prothrombin level increased Metabolism and nutrition disorders Weight increased Common Increased appetite Nervous system disorders Headache Common Cardiac disorders N-terminal prohormone brain natriuretic Common peptide increased Skin and subcutaneous tissue Night sweats Common disorders General disorders and administration Oedema*

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HOS-101095 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Hypersensitivity to thiazolidinediones. Cardiac failure or history of cardiac failure (NYHA stages I to IV) (see section 4.4).

HOS-101094 · has-indication-information · PDF-Seite 2

Nezglyal is indicated for the treatment of Cerebral Adrenoleukodystrophy (cALD) in males with Adrenoleukodystrophy (ALD) aged 2 to 12 years with non-Gadolinium (Gd) enhancing lesions (i.e. Gd negative) in brain Magnetic Resonance Imaging (MRI), with a Neurological Functional Score (NFS) of 0 or 1.

HOS-101097 · has-interaction-information · PDF-Seite 6

Interactions affecting leriglitazone No clinical drug-drug interaction studies have been completed with leriglitazone to date. Leriglitazone is predominantly metabolised by cytochrome P450 (CYP2C8 and CYP3A4) and it is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). CYP2C8 and CYP3A inhibitors Concomitant use of leriglitazone with strong and moderate CYP2C8 inhibitors (e.g. gemfibrozil) or strong and moderate CYP3A inhibitors (e.g. itraconazole, ketoconazole, clarithromycin, ritonavir, verapamil) is not recommended. Special care should be taken when inhibitors of both CYP2C8 and 3A4 are co-administered simultaneously with leriglitazone. CYP2C8 and CYP3A inducers Concomitant use of leriglitazone with CYP2C8 and/or CYP3A inducers (e.g. carbamazepine, rifampicin, phenytoin, phenobarbital) is not recommended. Transporter interactions No effect is expected on the absorption of leriglitazone when given concomitantly with P-gp or BCRP inhibitors, since the absolute oral bioavailability is high. P-gp and BCRP inhibitors are not expected to significantly increase the levels of leriglitazone in the brain. 6 Effect of leriglitazone on other medicinal products Transporter interactions The potential for inhibition of BCRP at the level of the intestine is unknown. Concomitant medicinal products being substrates of these transporters (including but not limited to lapatinib, methotrexate, rosuvastatin, topotecan, sulfasalazine) may increase their plasma concentrations and should be taken with caution. Interactions with glucose-lowering medicinal products No drug–drug interaction studies with antidiabetic medicinal products have been completed with leriglitazone to date. Leriglitazone increases insulin sensitivity, and therefore concomitant use with blood-glucose-lowering treatments (e.g. metformin, insulin, gliclazide, glimepiride or glibenclamide) may increase the risk of hypoglycaemia. Leriglitazone should not be used in patients receiving blood-glucose-lowering medicinal products. If concomitant use is considered unavoidable, patients must be closely monitored for signs and symptoms of hypoglycaemia.

HOS-101098 · has-pregnancy-information · PDF-Seite 7

Pregnancy Not applicable. Breast-feeding Not applicable. Fertility No human data on the effect of leriglitazone on fertility are available. In rats, there was no effect on fertility in males; however, an effect on fertility in females (reduced number of live embryos) was noted (see section 5.3)

HOS-101096 · has-warning-information · PDF-Seite 4

Oedema/fluid retention and cardiac failure Oedema events were observed very commonly in children (see section 4.8). Children had events typically of facial or periorbital oedema. Oedema can start within 4 weeks of treatment, with the majority of patients experiencing the event within 24 weeks. Diuretics are not recommended for management of oedema as they may decompensate electrolyte balance in patients receiving corticosteroid hormone replacement for ALD associated adrenal insufficiency. Oedema does not stabilise or resolve by dose reductions. In case of persisting or severe oedema, treatment withdrawal can be considered if the oedema is not tolerated. Patients should be informed to expect peripheral or facial oedema. 4 There are no data on the use of leriglitazone in patients with cardiac failure or a cardiac history and patients with risk factors for cardiac failure (see section 5.1). Use of leriglitazone in patients with cardiac failure or a cardiac history is contraindicated (see section 4.3). Patients should be observed for signs and symptoms of fluid retention (assessment of jugular venous pressure and examination for hepatomegaly are recommended after treatment initiation) and cardiac failure (NYHA stages I to IV) or weight increase related with fluid retention; particularly those patients with risk factors for cardiac failure (NYHA stages I to IV) e.g. hypertension, coronary disease, valve disease, family history (see section 4.8). Leriglitazone should be discontinued if clinically significant deterioration in cardiac status occurs. Patients undergoing HSCT (Haematopoietic Stem Cell Transplantation) Treatment with leriglitazone must be discontinued at least five days prior to initiating HSCT procedures, defined as the day of first administration of myeloablative conditioning medicinal products. The timing of discontinuation should be confirmed by the treating physician based on the planned conditioning regimen. Monitoring of hepatic function Hepatic enzymes should be checked prior to the initiation of therapy in all patients. Treatment should not be initiated in patients with increased baseline hepatic enzyme levels (Aspartate aminotransferase (AST) or ALT > 2 times the ULN), total bilirubin > 1.5 times ULN (unless due to Gilbert’s syndrome), or with any other evidence of liver disease. Following initiation of treatment, it is recommended that hepatic enzymes are monitored periodically

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