Miglustat Gen.Orph · 4.3 Contraindications · 1

HOS-217627 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most common adverse reactions reported in clinical studies with miglustat were diarrhoea, flatulence, abdominal pain, weight loss and tremor (see section 4.4). The most common serious adverse reaction reported with miglustat treatment in clinical studies was peripheral neuropathy (see section 4.4). In 11 clinical studies in different indications 247 patients were treated with miglustat at doses of 50-200 mg three times a day (t.i.d.) for an average duration of 2.1 years. Of these patients, 132 had type 1 Gaucher disease, and 40 had Niemann-Pick type C disease. Adverse reactions were generally of mild to moderate severity and occurred with similar frequency across indications and doses tested. Tabulated list of adverse reactions Adverse reactions from clinical studies and spontaneous reporting, occurring in > 1% of patients, are listed in the table below by system organ class and frequency (very common: ≥ 1/10, common: ≥ 1/100 to < 1/10, uncommon: ≥ 1/1,000 to < 1/100, rare: ≥ 1/10,000 to < 1/1,000, very rare: < 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2. - Tabulated list of adverse reactions System Organ Class (SOC) Frequency Adverse reaction Blood and lymphatic system Common Thrombocytopenia disorders Metabolism and nutrition Very common Weight loss, decreased appetite disorders Psychiatric disorders Common Depression, insomnia, libido decreased Nervous system disorders Very common Tremor Common Peripheral neuropathy, ataxia, amnesia, paraesthesia, hypoaesthesia, headache, dizziness Gastrointestinal disorders Very common Diarrhoea, flatulence, abdominal pain Common Nausea, vomiting, abdominal distension/discomfort, constipation, dyspepsia Musculoskeletal and connective Common Muscle spasms, muscle weakness tissue disorder General disorders and Common Fatigue, asthenia, chills and malaise administration site reactions

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HOS-217623 · has-contraindication-information · PDF-Seite 3

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

HOS-217622 · has-indication-information · PDF-Seite 2

Miglustat Gen.Orph is indicated for the oral treatment of adult patients with mild to moderate type 1 Gaucher disease. Miglustat Gen.Orph may be used only in the treatment of patients for whom enzyme replacement therapy is unsuitable (see sections 4.4 and 5.1). Miglustat Gen.Orph is indicated for the treatment of progressive neurological manifestations in adult patients and paediatric patients with Niemann-Pick type C disease (see sections 4.4, and 5.1).

HOS-217625 · has-interaction-information · PDF-Seite 5

Limited data suggest that co-administration of miglustat and enzyme replacement with imiglucerase in patients with type 1 Gaucher disease may result in decreased exposure to miglustat (approximate reductions of 22% in Cmax and 14% in AUC were observed in a small parallel-group study). This study also indicated that miglustat has no or limited effect on the pharmacokinetics of imiglucerase.

HOS-217626 · has-pregnancy-information · PDF-Seite 5

Pregnancy There are no adequate data from the use of miglustat in pregnant women. Studies in animals have shown maternal and embryo-foetal toxicity, including decreased embryo-foetal survival (see section 5.3). The potential risk for humans is unknown. Miglustat crosses the placenta and should not be used during pregnancy. Breast-feeding It is not known if miglustat is secreted in breast milk. Miglustat Gen.Orph should not be taken during breast-feeding. Fertility 5 Studies in the rat have shown that miglustat adversely affects sperm parameters (motility and morphology) thereby reducing fertility (see sections 4.4 and 5.3). Contraception in males and females Contraceptive measures should be used by women of childbearing potential. Reliable contraceptive methods should be maintained while male patients are taking Miglustat Gen.Orph and for 3 months following discontinuation (see sections 4.4 and 5.3).

HOS-217624 · has-warning-information · PDF-Seite 3

Tremor 3 Approximately 37% of patients in clinical studies in type 1 Gaucher disease, and 58% of patients in a clinical study in Niemann-Pick type C disease reported tremor on treatment. In type 1 Gaucher disease, these tremors were described as an exaggerated physiological tremor of the hands. Tremor usually began within the first month of treatment, and in many cases resolved after 1 to 3 months of continued treatment. Dose reduction may ameliorate the tremor, usually within days, but discontinuation of treatment may sometimes be required. Gastrointestinal disturbances Gastrointestinal events, mainly diarrhoea, have been observed in more than 80% of patients, either at the outset of treatment or intermittently during treatment (see section 4.8). The mechanism is most likely inhibition of intestinal disaccharidases such as sucrase-isomaltase in the gastrointestinal tract leading to reduced absorption of dietary disaccharides. In clinical practice, miglustat-induced gastrointestinal events have been observed to respond to individualised diet modification (for example reduction of sucrose, lactose and other carbohydrate intake), to taking miglustat between meals, and/or to anti-diarrhoeal medicinal products such as loperamide. In some patients, temporary dose reduction may be necessary. Patients with chronic diarrhoea or other persistent gastrointestinal events that do not respond to these interventions should be investigated according to clinical practice. Miglustat has not been evaluated in patients with a history of significant gastrointestinal disease, including inflammatory bowel disease. Cases of Crohn’s disease have been reported post-marketing in Niemann-Pick type C disease patients treated with Miglustat Gen.Orph. Gastrointestinal disturbances are common adverse events of Miglustat Gen.Orph. Therefore, in patients with chronic diarrhoea and/or abdominal pain that do not respond to interventions or in the event of clinical worsening, the possibility of Crohn’s disease should be considered. Effects on spermatogenesis Reliable contraceptive methods should be maintained while male patients are taking miglustat and for 3 months following discontinuation. Miglustat should be discontinued and reliable contraception be used for the next 3 months before attempting to conceive (see sections 4.6 and 5.3). Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameter

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