Cerdelga · 4.1 Therapeutic indications · 1

HOS-096922 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most frequently reported adverse reaction with eliglustat is dyspepsia, reported in approximately 6% of the pooled adult clinical trial patients, and in 10.5% (for both cohorts) of paediatric patients from the ELIKIDS study. Overall, the safety profile of eliglustat in paediatric patients observed in clinical development setting was consistent with the established safety profile in adults. Tabulated list of adverse reactions Adverse reactions are ranked 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)]). Adverse reactions from long term clinical trial data reported in at least 4 patients are presented in Table 4. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4: Tabulated list of adverse reactions System organ class Common Nervous system disorders Headache*, dizziness*, dysgeusia Cardiac disorders Palpitations Respiratory, thoracic and Throat irritation, cough mediastinal disorders Dyspepsia, abdominal pain upper*, diarrhoea*, nausea, constipation, Gastrointestinal disorders abdominal pain*, gastroesophageal reflux disease, abdominal distension*, gastritis, dysphagia, vomiting*, dry mouth, flatulence Skin and subcutaneous tissue Dry skin, urticaria* disorders Musculoskeletal and Arthralgia, pain in extremity*, back pain* connective tissue disorders General disorders and Fatigue administration site conditions * The incidence of the adverse reaction was the same or higher with placebo than with eliglustat in the placebo-controlled pivotal study. Paediatric population In the ELIKIDS paediatric study Cohort 1 (eliglustat monotherapy), the most common adverse reactions were dyspepsia (9.8%) and dry skin (3.6%). In Cohort 2 (eliglustat/imiglucerase combination therapy), the most common adverse reactions were headache, dyspepsia, gastritis, and fatigue (each experienced by 16.7% (1/6) of the patients). Of 57 enrolled patients, 53 (93%, 48/51 in Cohort 1) experienced at least one treatment-emergent adverse event (TEAE) with no meaningful difference by age group, gender, o

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HOS-096918 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Cerdelga is contraindicated in patients who are CYP2D6 IMs or EMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, and patients who are CYP2D6 PMs taking a strong CYP3A inhibitor (see section 4.5). Cerdelga is contraindicated in CYP2D6 EMs with severe hepatic impairment and in CYP2D6 EMs with mild or moderate hepatic impairment taking a strong or moderate CYP2D6 inhibitor (see sections 4.2 and 5.2). 4

HOS-096917 · has-indication-information · PDF-Seite 2

Adults Cerdelga is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1), who are CYP2D6 poor metabolisers (PMs), intermediate metabolisers (IMs) or extensive metabolisers (EMs). Paediatric population (from 6 to < 18 years of age) weighing ≥ 15 kg Cerdelga is indicated for paediatric patients with GD1 who are 6 years and older with a minimum body weight of 15 kg, who are stable on enzyme replacement therapy (ERT), and who are CYP2D6 PMs, IMs or EMs. 2

HOS-096920 · has-interaction-information · PDF-Seite 5

Eliglustat is metabolised primarily by CYP2D6 and to a lesser extent by CYP3A4. Concomitant administration of substances affecting CYP2D6 or CYP3A4 activity may alter eliglustat plasma concentrations. Eliglustat is an inhibitor of P-gp and CYP2D6 in vitro; concomitant administration of eliglustat with P-gp or CYP2D6 substrate substances may increase the plasma concentration of those substances. The list of substances in section 4.5 is not an inclusive list and the prescriber is advised to consult the SmPC of all other prescribed medicinal products for potential drug-drug interactions with eliglustat. 5 Agents that may increase eliglustat exposure Cerdelga is contraindicated in patients who are CYP2D6 IMs or EMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor, and in patients who are CYP2D6 PMs taking a strong CYP3A inhibitor (see section 4.3). Use of eliglustat under these conditions results in substantially elevated eliglustat plasma concentrations. CYP2D6 inhibitors in IMs and EMs After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated 30 mg once daily doses of paroxetine, a strong inhibitor of CYP2D6, resulted in a 7.3- and 8.9-fold increase in eliglustat Cmax and AUC0-12, respectively. Once a day dosing of eliglustat for EMs and IMs is recommended when a strong CYP2D6 inhibitor (e.g. paroxetine, fluoxetine, quinidine, bupropion) is used concomitantly in IMs and EMs. At 84 mg twice daily dosing with eliglustat in non-PMs, it is predicted that concomitant use of moderate CYP2D6 inhibitors (e.g., duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone) would increase eliglustat exposure approximately up to 4-fold. Caution should be used with moderate CYP2D6 inhibitors in IMs and EMs. CYP2D6 inhibitors in EMs with mild or moderate hepatic impairment See sections 4.2, 4.3 and 4.4. CYP2D6 inhibitors in EMs with severe hepatic impairment See sections 4.2 and 4.3. CYP3A inhibitors in IMs and EMs After repeated 84 mg twice daily doses of eliglustat in non-PMs, concomitant administration with repeated 400 mg once daily doses of ketoconazole, a strong inhibitor of CYP3A, resulted in a 3.8 and 4.3-fold increase in eliglustat Cmax and AUC0-12, respectively; similar effects would be expected for other strong inhibitors of CYP3A (e.g. clarithromycin, ketoconazole, itraconazole, cobici

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HOS-096921 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no or limited amount of data from the use of eliglustat in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is recommended to avoid the use of Cerdelga during pregnancy. Breast-feeding It is unknown whether eliglustat/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of eliglustat in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Cerdelga therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. 7 Fertility Effects on testes and reversible inhibition of spermatogenesis were observed in rats (see section 5.3). The relevance of these findings for humans is not known.

HOS-096919 · has-warning-information · PDF-Seite 5

Patients with pre-existing cardiac conditions Use of eliglustat in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause mild increases in ECG intervals at substantially elevated plasma concentrations, use of eliglustat should be avoided in patients with cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g. quinidine) and Class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Patients with hepatic impairment and concomitant use with other medicinal products Concomitant use of eliglustat with CYP2D6 or CYP3A4 inhibitors in CYP2D6 EMs with mild hepatic impairment can result in further elevation of eliglustat plasma concentrations, with the magnitude of the effect depending on the enzyme inhibited and the potency of the inhibitor. In CYP2D6 EMs with mild hepatic impairment taking a weak CYP2D6 inhibitor or strong, moderate or weak CYP3A inhibitor, a once daily dose is recommended (e.g. if a dose of 84 mg eliglustat is taken twice daily, it should be adjusted to 84 mg eliglustat once daily) (see sections 4.2 and 5.2). Patients with renal impairment Limited or no data are available in CYP2D6 EMs, IMs or PMs with ESRD and in CYP2D6 IMs or PMs with mild, moderate, or severe renal impairment; use of eliglustat in these patients is not recommended (see sections 4.2 and 5.2). Monitoring of clinical response Some treatment-naïve patients showed less than 20% spleen volume reduction (sub-optimal results) after 9 months of treatment (see section 5.1). For these patients, monitoring for further improvement or an alternative treatment modality should be considered. For patients with stable disease who switch from enzyme replacement therapy to eliglustat, monitoring for disease progression (e.g. after 6 months with regular monitoring thereafter) should be performed for all disease domains to evaluate disease stability. Reinstitution of enzyme replacement therapy or an alternative treatment modality should be considered in individual patients who have a sub-optimal response. Lactose Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.