Leitlinien & Arzneimittelsicherheit

HOS-098585 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The safety profile of siponimod was based on data from the core clinical study. The most common adverse reactions identified in the core part of study A2304 were headache (15%) and hypertension (12.6%). The safety-related information from the extension part of the long-term study A2304 was consistent with that observed in the core part. Tabulated list of adverse reactions Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse reaction is based on the following convention: 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); not known (cannot be estimated from the available data). Table 2 Tabulated list of adverse reactions Infections and infestations Common Herpes zoster Rare Progressive multifocal leukoencephalopathy Not known Meningitis cryptococcal Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Common Melanocytic naevus Basal cell carcinoma Uncommon Squamous cell carcinoma Malignant melanoma Blood and lymphatic system disorders Common Lymphopenia Immune system disorders Rare Immune reconstitution inflammatory syndrome (IRIS) Not known Hypersensitivity reactions, including rash, urticaria and angioedema 13  Nervous system disorders Very common Headache Common Dizziness Seizure Tremor Eye disorders Common Macular oedema Cardiac disorders Common Bradycardia Atrioventricular block (first and second degree) Vascular disorders Very common Hypertension Gastrointestinal disorders Common Nausea Diarrhoea Musculoskeletal and connective tissue disorders Common Pain in extremity General disorders and administration site conditions Common Oedema peripheral Asthenia Investigations Ve

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HOS-098581 · has-contraindication-information · PDF-Seite 4

- Hypersensitivity to the active substance, or to peanut, soya or any of the excipients listed in section 6.1. - Immunodeficiency syndrome. - History of progressive multifocal leukoencephalopathy or cryptococcal meningitis. - Active malignancies. - Severe liver impairment (Child-Pugh class C). - Patients who in the previous 6 months had a myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure (see section 4.4). - Patients with a history of second-degree Mobitz type II atrioventricular (AV) block, third-degree AV block, sino-atrial heart block or sick-sinus syndrome, if they do not wear a pacemaker (see section 4.4). - Patients homozygous for CYP2C9*3 (CYP2C9*3*3) genotype (poor metaboliser). - During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6). 4

HOS-098580 · has-indication-information · PDF-Seite 3

Mayzent is indicated for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1).

HOS-098583 · has-interaction-information · PDF-Seite 10

Antineoplastic, immune-modulating or immunosuppressive therapies Siponimod has not been studied in combination with antineoplastic, immune-modulating or immunosuppressive therapies. Caution should be exercised during concomitant administration due to the risk of additive immune effects during such therapy and in the weeks after administration of any of these medicinal products is stopped (see section 4.4). Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with siponimod after alemtuzmab is not recommended unless the benefits of treatment clearly outweigh the risks for the individual patient (see section 4.4). 10 Anti-arrhythmic medicinal products, QT-prolonging medicinal products, medicinal products that may decrease heart rate During treatment initiation siponimod should not be concomitantly used in patients receiving class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) anti-arrhythmic medicinal products, QT-prolonging medicinal products with known arrhythmogenic properties, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart rate (see section 4.4). No data are available for concomitant use of these medicinal products with siponimod. Concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with siponimod should generally not be initiated in patients who are concurrently treated with these substances (see section 4.4). If treatment with siponimod is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate-lowering medicinal products or appropriate monitoring for treatment initiation. Beta blockers Caution should be exercised when siponimod is initiated in patients receiving beta blockers due to the additive effects on lowering heart rate (see section 4.4). Beta-blocker treatment can be initiated in patients receiving stable doses of siponimod. The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated in a dedicated pharmacodynamic/safety study. The addition of propranolol on top of siponimod pharmacokinetic/pharmacodynamic

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HOS-098584 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential/Contraception in females Siponimod is contraindicated in women of childbearing potential not using effective contraception (see section 4.3). Therefore, before initiation of treatment in women of childbearing potential a negative pregnancy test result must be available and counselling should be provided regarding serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment and for at least ten days following the last dose of siponimod (see section 4.4). Specific measures are also included in the Physician Education Pack. These measures must be implemented before siponimod is prescribed to female patients and during treatment. When stopping siponimod therapy for planning a pregnancy, the possible return of disease activity should be considered (see section 4.4). Pregnancy There are no or limited amount of data available from the use of siponimod in pregnant women. Animal studies have demonstrated siponimod-induced embryotoxicity and foetotoxicity in rats and rabbits and teratogenicity in rats, including embryo-foetal deaths and skeletal or visceral malformations at exposure levels comparable to the human exposure at the daily dose of 2 mg (see section 5.3). In addition, clinical experience with another sphingosine-1-phosphate receptor modulator indicated a 2-fold higher risk of major congenital malformations when administered during pregnancy compared with the rate observed in the general population. 12 Consequently, siponimod is contraindicated during pregnancy (see section 4.3). Siponimod should be stopped at least 10 days before a pregnancy is planned (see section 4.4). If a woman becomes pregnant while on treatment, siponimod must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed. Breast-feeding It is unknown whether siponimod or its major metabolites are excreted in human milk. Siponimod and its metabolites are excreted in the milk of rats. Siponimod should not be used during breast-feeding. Fertility The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on male reproductive organs in rats and monkeys or on fertility parameters in rats.

HOS-098582 · has-warning-information · PDF-Seite 5

Infections Risk of infections A core pharmacodynamic effect of siponimod is a dose-dependent reduction of the peripheral lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see section 5.1). The immune system effects of siponimod may increase the risk of infections (see section 4.8). Before initiating treatment, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended 3 to 4 months after treatment initiation and at least yearly thereafter, and in case of signs of infection. Absolute lymphocyte counts <0.2 x 109/l, if confirmed, should lead to dose reduction to 1 mg, because in clinical studies siponimod dose was reduced in patients with absolute lymphocyte counts <0.2 x 109/l. Confirmed absolute lymphocyte counts <0.2 x 109/l in a patient already receiving siponimod 1 mg should lead to interruption of siponimod therapy until the level reaches 0.6 x 109/l when re-initiation of siponimod can be considered. Initiation of treatment should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after discontinuation, vigilance for infection should be continued throughout this period (see below section “Stopping siponimod therapy”). Patients should be instructed to report symptoms of infection to their physician promptly. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with siponimod should be considered if a patient develops a serious infection. Cases of cryptococcal meningitis (CM) have been reported for siponimod. Patients with symptoms and signs consistent with CM should undergo prompt diagnostic evaluation. Siponimod treatment should be suspended until CM has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Progressive multifocal leukoencephalopathy Cases of progressive multifocal leukoencephalopathy (PML) have been reported with siponimod (see section 4.8). Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. If PML is suspected, siponimod treatment should be suspended until PML has been excluded. If PML is confirmed, trea

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