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).

Treatment with siponimod should be initiated and supervised by a physician experienced in the management of multiple sclerosis. Before initiation of treatment, patients must be genotyped for CYP2C9 to determine their CYP2C9 metaboliser status (see sections 4.4, 4.5 and 5.2). In patients with a CYP2C9*3*3 genotype, siponimod should not be used (see sections 4.3, 4.4 and 5.2). In patients with a CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg taken once daily (four tablets of 0.25 mg) (see sections 4.4 and 5.2). The recommended maintenance dose of siponimod in all other CYP2C9 genotype patients is 2 mg. Mayzent is taken once daily. Posology Treatment initiation Treatment has to be started with a titration pack that lasts for 5 days. Treatment starts with 0.25 mg once daily on days 1 and 2, followed by once-daily doses of 0.5 mg on day 3, 0.75 mg on day 4, and 1.25 mg on day 5, to reach the patient’s prescribed maintenance dose of siponimod starting on day 6 (see Table 1). During the first 6 days of treatment initiation the recommended daily dose should be taken once daily in the morning with or without food. Table 1 Dose titration regimen to reach maintenance dosage Titration Titration dose Titration regimen Dose Day 1 0.25 mg 1 x 0.25 mg Day 2 0.25 mg 1 x 0.25 mg Day 3 0.5 mg 2 x 0.25 mg Day 4 0.75 mg 3 x 0.25 mg Day 5 1.25 mg 5 x 0.25 mg TITRATION Day 6 2 mg1 1 x 2 mg1 MAINTENANCE 1 In patients with CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg taken once daily (4 x 0.25 mg) (see above and sections 4.4 and 5.2). Additional exposure of 0.25 mg on day 5 does not compromise patient safety. Missed dose(s) during treatment initiation During the first 6 days of treatment, if a titration dose is missed on one day treatment needs to be re-initiated with a new titration pack. Missed dose after day 6 If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled. Re-initiation of maintenance therapy after treatment interruption If maintenance treatment is interrupted for 4 or more consecutive daily doses, siponimod needs to be re-initiated with a new titration pack. Special populations Elderly Siponimod has not been studied in patients aged 65 years and above. Clinical studies included patients up to the age of 61 years. Siponimod should be used with caution in the elderly due to insufficient data on safety and efficacy (see section 5.2). Renal impairment Based on clinical pharmacology studies, no dose adjustment is needed in patients with renal impairment (see section 5.2). Hepatic impairment Siponimod must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3). Although no dose adjustment is needed in patients with mild or moderate hepatic impairment, caution should be exercised when initiating treatment in these patients (see sections 4.4 and 5.2). Paediatric population The safety and efficacy of siponimod in children and adolescents aged 0 to 18 years have not yet been established. No data are available. Method of administration Oral use. Siponimod is taken with or without food. The film-coated tablets should be swallowed whole with water.

- 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).

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 for S1P receptor modulators, including siponimod, and other therapies for multiple sclerosis (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, treatment with siponimod should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with sphingosine 1-phosphate (S1P) receptor modulators, including siponimod, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was usually from weeks to months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. Herpes viral infection Cases of herpes viral infection (including cases of meningitis or meningoencephalitis caused by varicella zoster viruses [VZV]) have occurred with siponimod at any time during treatment. If herpes meningitis or meningoencephalitis occur, siponimod should be discontinued and appropriate treatment for the respective infection should be administered. Patients without a physician-confirmed history of varicella or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before starting siponimod (see below section “Vaccination”). Vaccination A full course of vaccination with varicella vaccine is recommended for antibody-negative patients prior to commencing treatment with siponimod, following which initiation of treatment should be postponed for 1 month to allow the full effect of vaccination to occur (see section 4.8). The use of live attenuated vaccines should be avoided while patients are taking siponimod and for 4 weeks after stopping treatment (see section 4.5). Other types of vaccines may be less effective if administered during siponimod treatment (see section 4.5). Discontinuation of treatment 1 week prior to planned vaccination until 4 weeks after is recommended. If stopping siponimod therapy for vaccination, the possible return of disease activity should be considered (see below section “Stopping siponimod therapy”). Concomitant treatment with anti-neoplastic, immune-modulating or immunosuppressive therapies Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids) should be co-administered with caution due to the risk of additive immune system effects during such therapy (see section 4.5). Macular oedema Macular oedema with or without visual symptoms was more frequently reported on siponimod (1.8%) than on placebo (0.2%) in the phase III clinical study (see section 4.8). The majority of cases occurred within the first 3-4 months of therapy. An ophthalmological evaluation is therefore recommended 3-4 months after treatment initiation. As cases of macular oedema have also occurred on longer-term treatment, patients should report visual disturbances at any time while on siponimod therapy and an evaluation of the fundus, including the macula, is recommended. Siponimod therapy should not be initiated in patients with macular oedema until resolution. Siponimod should be used with caution in patients with a history of diabetes mellitus, uveitis or underlying/co-existing retinal disease due to a potential increase in the risk of macular oedema (see section 4.8). It is recommended that these patients should undergo an ophthalmological evaluation prior to initiating therapy and regularly while receiving siponimod therapy to detect macular oedema. Continuation of siponimod therapy in patients with macular oedema has not been evaluated. It is recommended that siponimod be discontinued if a patient develops macular oedema. A decision on whether or not siponimod should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient. Bradyarrhythmia Initiation of siponimod treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays (see sections 4.8 and 5.1). A titration scheme to reach the maintenance dose on day 6 is therefore applied at the start of treatment (see section 4.2). After the first titration dose, the heart rate decrease starts within one hour and the day 1 decline is maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from day 1 (baseline) reached on day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, with the pulse declining on average 5 to 6 beats per minute (bpm). Post-dose declines on the following days are less pronounced. With continued dosing heart rate starts increasing after day 6 and reaches placebo levels within 10 days after treatment initiation. Heart rates below 40 bpm were rarely observed. The atrioventricular conduction delays manifested in most of the cases as first-degree atrioventricular (AV) blocks (prolonged PR interval on electrocardiogram). In clinical studies, second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed in less than 1.7% of patients at the time of treatment initiation. Most of the bradyarrhythmic events or atrioventricular conduction delays were asymptomatic, transient and resolved within 24 hours and did not require discontinuation of treatment. Should post-dose symptoms occur (dizziness, non- cardiac chest pain and headache), appropriate clinical management should be initiated and monitoring should be continued until the symptoms have resolved. If necessary, the decrease in heart rate induced by siponimod can be reversed by parenteral doses of atropine or isoprenaline. Treatment initiation recommendation in patients with certain pre-existing cardiac conditions As a precautionary measure, patients with the following cardiac conditions should be observed for a period of 6 hours after the first dose of siponimod for signs and symptoms of bradycardia (see also section 4.3): - sinus bradycardia (heart rate <55 bpm), - history of first- or second-degree [Mobitz type I] AV block, - history of myocardial infarction, - history of heart failure (patients with NYHA class I and II). In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occur or if ECG 6 hours post-dose shows new onset second-degree or higher AV block or QTc =500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose. Due to the risk of serious cardiac rhythm disturbances or significant bradycardia, siponimod should not be used in patients with: - history of symptomatic bradycardia or recurrent syncope, - uncontrolled hypertension, or - severe untreated sleep apnoea. In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. A thorough QT study demonstrated no significant direct QT-prolonging effect and siponimod is not associated with an arrhythmogenic potential related to QT prolongation. Initiation of treatment may result in decreased heart rate and indirect prolongation of the QT interval during the titration phase. Siponimod was not studied in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT-prolonging medicinal products. If treatment with siponimod is considered in patients with pre-existing significant QT prolongation or who are already being treated with QT-prolonging medicinal products with known arrhythmogenic properties, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy during treatment initiation. Siponimod has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of treatment results in decreased heart rate, siponimod should not be used concomitantly with these medicinal products during treatment initiation. Experience is limited in patients receiving concurrent therapy with heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) as these medicinal products were not studied in patients receiving siponimod in clinical studies. 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 4.5). In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks. If concomitant treatment with one of the above substances is considered during initiation of treatment with siponimod, advice from a cardiologist should be sought regarding the switch to a non-heart-rate-lowering medicinal product or appropriate monitoring for treatment initiation. Bradyarrhythmic effects are more pronounced when siponimod is added to beta-blocker therapy. For patients receiving a stable dose of beta blocker, the resting heart rate should be considered before introducing treatment. If the resting heart rate is >50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is =50 bpm, then beta-blocker treatment should be interrupted until the baseline heart rate is >50 bpm. Treatment with siponimod can then be initiated and treatment with beta blocker can be re-initiated after siponimod has been up-titrated to the target maintenance dose (see section 4.5). Liver function Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with siponimod. In the phase III clinical study, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times the upper limit of normal (ULN) was observed in 5.6% of patients treated with siponimod 2 mg compared to 1.5% of patients who received placebo (see section 4.8). In clinical studies treatment was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic function or if the elevation exceeded a 5-fold increase. In the phase III clinical study, 1% of all discontinuations met one of these criteria. Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checked and siponimod should be discontinued if significant liver injury is confirmed. Resumption of therapy will be dependent on whether or not another cause of liver injury is determined and on the benefits to the patient of resuming therapy versus the risks of recurrence of liver dysfunction. Although there are no data to establish that patients with pre-existing liver disease are at increased risk of developing elevated liver function test values when taking siponimod, caution should be exercised in patients with a history of significant liver disease. Cutaneous neoplasms Basal cell carcinoma (BCC) and other cutaneous neoplasms, including squamous cell carcinoma (SCC) and malignant melanoma, have been reported in patients receiving siponimod, especially in patients with longer treatment duration (see section 4.8). Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 months taking into consideration clinical judgement. Careful skin examinations should be maintained with longer treatment duration. Patients should be advised to promptly report any suspicious skin lesions to their physician. Patients treated with siponimod should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy. Unexpected neurological or psychiatric symptoms/signs Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported for another sphingosine-1-phosphate (S1P) receptor modulator. Such events have not been reported for siponimod in the development programme. However, should a patient on siponimod treatment develop any unexpected neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioural changes, cortical visual disturbances or any other neurological cortical symptoms/signs or any symptom/sign suggestive of an increase in intracranial pressure) or accelerated neurological deterioration, a complete physical and neurological examination should promptly be scheduled and MRI should be considered. Prior treatment with immunosuppressive or immune-modulating therapies When switching from other disease-modifying therapies, the half-life and mode of action of the other therapy must be considered to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. A peripheral lymphocyte count (CBC) is recommended prior to initiating siponimod to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved. Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with siponimod after alemtuzumab is not recommended. Siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. Blood pressure effects Patients with hypertension uncontrolled by medicinal products were excluded from participation in clinical studies and special care is indicated if patients with uncontrolled hypertension are treated with siponimod. Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given placebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation, reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment. Blood pressure should be regularly monitored during treatment with siponimod. CYP2C9 genotype Before initiation of treatment with siponimod, patients should be genotyped for CYP2C9 to determine their CYP2C9 metaboliser status (see section 4.2). Patients homozygous for CYP2C9*3 (CYP2C9*3*3 genotype: approximately 0.3 to 0.4% of the population) should not be treated with siponimod. Use of siponimod in these patients results in substantially elevated siponimod plasma levels. The recommended maintenance dose is 1 mg daily in patients with a CYP2C9*2*3 genotype (1.4-1.7% of the population) and in patients with a *1*3 genotype (9-12% of the population) to avoid increased exposure to siponimod (see sections 4.2 and 5.2). Women of childbearing potential Due to risk for the foetus, siponimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for at least 10 days after treatment discontinuation (see sections 4.3 and 4.6). Stopping siponimod therapy Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of another S1P receptor modulator. The possibility of severe exacerbation of disease after stopping siponimod treatment should be considered. Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon siponimod discontinuation and appropriate treatment should be instituted as required. After siponimod therapy has been stopped, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod. After stopping siponimod therapy in the setting of PML, it is recommended to monitor the patient for development of immune reconstitution inflammatory syndrome (PML-IRIS) (see above section “Progressive multifocal leukoencephalopathy”). In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system and therefore caution should be exercised for 3 to 4 weeks after the last dose. Interference with haematological testing Since siponimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with siponimod. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes. Excipients The tablets contain soya lecithin. Patients who are hypersensitive to peanut or soya should not take siponimod (see section 4.3). The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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). 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 steady state had less pronounced negative chronotropic effects (less than additive) in comparison to addition of siponimod on top of propranolol pharmacokinetic/pharmacodynamic steady state (additive HR effect). Vaccination The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during siponimod treatment and for 4 weeks after treatment (see section 4.4). During and for up to 4 weeks after treatment with siponimod vaccinations may be less effective. The efficacy of vaccination is not considered to be compromised if siponimod treatment is paused 1 week prior to vaccination until 4 weeks after vaccination. In a dedicated phase I healthy volunteer study, concomitant siponimod treatment with influenza vaccines or shorter treatment pause (from 10 days prior to 14 days after vaccination) showed inferior responder rates (approximately 15% to 30% lower) compared to placebo, while the efficacy of a PPV 23 vaccination was not compromised by concomitant siponimod treatment (see section 4.4). Potential of other medicinal products to affect siponimod pharmacokinetics Siponimod is metabolised primarily by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme and the drug-drug

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. 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.

Siponimod has no or negligible influence on the ability to drive and use machines. However, dizziness may occasionally occur when initiating therapy with siponimod. Therefore, patients should not drive or use machines during the first day of treatment initiation with siponimod (see section 4.4).

Summary of the safety profile The most common adverse drug reactions are headache (15%) and hypertension (12.6%). Tabulated list of adverse reactions Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug 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) 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 Very common Liver function test increased Common Pulmonary function test decreased Description of selected adverse reactions Infections In the phase III clinical study in patients with SPMS the overall rate of infections was comparable between the patients on siponimod and those on placebo (49.0% versus 49.1%, respectively). However, an increase in the rate of herpes zoster infections was reported on siponimod (2.5%) compared to placebo (0.7%). Cases of meningitis or meningoencephalitis caused by varicella zoster viruses have occurred with siponimod at any time during treatment. Cases of cryptococcal meningitis (CM) have also been reported for siponimod (see section 4.4). Macular oedema Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than in those given placebo (0.2%). Although the majority of cases occurred within 3 to 4 months of commencing siponimod, cases were also reported in patients treated with siponimod for more than 6 months (see section 4.4). Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmological examination. The macular oedema generally improved or resolved spontaneously after discontinuation of treatment. The risk of recurrence after re-challenge has not been evaluated. Bradyarrhythmia Initiation of siponimod treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays (see section 4.4). Bradycardia was reported in 6.2% of patients treated with siponimod compared to 3.1% on placebo and AV block in 1.7% of patients treated with siponimod compared to 0.7% on placebo (see section 4.4). The maximum decline in heart rate is seen in the first 6 hours post-dose. A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase and plateaued at doses =5 mg. Bradyarrhythmic events (AV blocks and sinus pauses) were detected with a higher incidence under siponimod treatment compared to placebo. Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions. The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline. Liver function tests Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated with siponimod. In the phase III study in patients with SPMS, liver function test increases were more frequently observed in patients on siponimod (11.3%) than in those on placebo (3.1%), mainly due to liver transaminase (ALT/AST) and GGT elevations. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of siponimod (see section 4.4). Blood pressure Hypertension was more frequently reported in patients on siponimod (12.6%) than in those given placebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation, reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment. Seizures Seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in the phase III clinical study in patients with SPMS. Respiratory effects Minor reductions in forced expiratory volume in 1 second (FEV1) and in the diffusing capacity of the lung for carbon monoxide (DLCO) values were observed with siponimod treatment. At months 3 and 6 of treatment in the phase III clinical study in patients with SPMS, mean changes from baseline in FEV1 in the siponimod group were -0.1 L at each time point, with no change in the placebo group. These observations were slightly higher (approximately 0.15 L mean change from baseline in FEV1) in patients with respiratory disorders such as chronic obstructive pulmonary disease (COPD) or asthma treated with siponimod. On chronic treatment, this reduction did not translate into clinically significant adverse events and was not associated with an increase in reports of cough or dyspnoea (see section 5.1). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In healthy subjects, the single maximum tolerated dose was determined to be 25 mg based upon the occurrence of symptomatic bradycardia after single doses of 75 mg. A few subjects received unintended doses of up to 200 mg daily for 3 to 4 days and experienced asymptomatic mild to moderate transient elevations of liver function tests. One patient (with a history of depression) who took 84 mg siponimod experienced a slight elevation in liver transaminases. If the constitutes first exposure to siponimod or occurs during the dose titration phase of siponimod it is important to observe for signs and symptoms of bradycardia, which could include overnight monitoring. Regular measurements of pulse rate and blood pressure are required and electrocardiograms should be performed (see sections 4.2 and 4.4). There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA42 Mechanism of action Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively to two out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P1 and S1P5. By acting as a functional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymph nodes. This reduces the recirculation of T cells into the central nervous system (CNS) to limit central inflammation. Pharmacodynamic effects Reduction of the peripheral blood lymphocytes Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, due to the reversible sequestration of lymphocytes in lymphoid tissues. With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1*1 or *1*2 non-Japanese SPMS patient, corresponding to 20-30% of baseline. Low lymphocyte counts are maintained with daily dosing. In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. After stopping siponimod treatment residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose. Heart rate and rhythm Siponimod causes a transient reduction in heart rate and atrioventricular conduction on treatment initiation (see sections 4.4 and 4.8), which is mechanistically related to the activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P1 receptor stimulation leading to cellular hyperpolarisation and reduced excitability. Due to its functional antagonism at S1P1 receptors, initial titration of siponimod successively desensitises GIRK channels until the maintenance dose is reached. Potential to prolong the QT interval The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarisation were investigated in a thorough QT study. The results did not suggest an arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the placebo-corrected baseline-adjusted mean QTcF (??QTcF) by more than 5 ms, with a maximum mean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound of the one-sided 95% CI for the ??QTcF at all time points remained below 10 ms. Categorical analysis revealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of more than 60 ms and no corrected or uncorrected QT/QTc value exceeded 500 ms. Pulmonary function Siponimod treatment with single or multiple doses for 28 days is not associated with clinically relevant increases in airway resistance as measured by forced expiratory volume in 1 second (FEV1) and forced expiratory flow (FEF) during expiration of 25 to 75% of the forced vital capacity (FEF25-75%). A slight trend of reduced FEV1 was detected at non-therapeutic single doses (>10 mg). Multiple doses of siponimod were associated with mild to moderate changes in FEV1 and FEF25-75% which were not dose- and daytime-dependent and were not associated with any clinical signs of increased airway resistance. Clinical efficacy and safety The efficacy of siponimod has been investigated in a phase III study evaluating once-daily doses of 2 mg in patients with SPMS. Study A2304 (EXPAND) in SPMS Study A2304 was a randomised, double-blind, placebo-controlled, event and follow-up duration driven, phase III study in patients with SPMS who had documented evidence of progression in the prior 2 years in the absence or independent of relapses, no evidence of relapse in the 3 months prior to study enrolment and with a median Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry. The median EDSS was 6.0 at baseline. Patients above 61 years of age were not included. With regard to disease activity, features characteristic of inflammatory activity in SPMS can be relapse- or imaging-related (i.e. Gd-enhancing T1 lesions or active [new or enlarging] T2 lesions). Patients were randomised 2:1 to receive either once-daily siponimod 2 mg or placebo. Clinical evaluations were performed at screening and every 3 months and at the time of relapse. MRI evaluations were performed at screening and every 12 months. The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP) determined as at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5 or more) sustained for 3 months. Key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25W) and change from baseline in T2 lesion volume. Additional secondary endpoints included time to 6-month CDP, percent brain volume change and measures of inflammatory disease activity (annualised relapse rate, MRI lesions). Change in cognitive processing speed on Symbol Digit Modality Test score was an exploratory endpoint. Study duration was variable for individual patients (median study duration was 21 months, range: 1 day to 37 months). The study involved randomisation of 1 651 patients to either siponimod 2 mg (N=1 105) or placebo (N=546); 82% of patients treated with siponimod and 78% of placebo-treated patients completed the study. Median age was 49 years, median disease duration was 16 years and median EDSS score was 6.0 at baseline. 64% of patients had no relapses in the 2 years prior to study entry and 76% had no gadolinium (Gd)-enhancing lesions on their baseline MRI scan. 78% of patients had been previously treated with a therapy for their MS. Time to onset of 3-month and 6-month CDP was significantly delayed for siponimod, with reduction in risk of 3-month CDP by 21% compared to placebo (hazard ratio [HR] 0.79, p=0.0134) and reduction in risk of 6-month CDP by 26% compared to placebo (HR 0.74, p=0.0058). Figure 1 Patients with 3- and 6-month CDP based on EDSS-Kaplan-Meier curves (full analysis set, study A2304) Number of patients at risk Placebo (N=546) Percentage of subjects with 3-month CDP Percentage of subjects with 6-month CDP Siponimod (N=1099) Study month Siponimod Placebo 0 10 20 30 40 50 0 10 20 30 40 50 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42 Hazard ratio: 0.79, p=0.0134; (95% Cl: 0.65, 0.95); risk reduction: 21% Hazard ratio: 0.74, p=0.0058; (95% Cl: 0.60, 0.92); risk reduction: 26% Study month 1099 947 781 499 289 101 4 0 546 463 352 223 124 35 0 0 Number of patients at risk Siponimod Placebo 1099 960 811 525 306 106 5 0 546 473 361 230 128 37 1 0 Time to 3-month CDP versus placebo (Primary endpoint) Time to 6-month CDP versus placebo Table 3 Clinical and MRI results of study A2304 A2304 (EXPAND) Endpoints Siponimod 2 mg (n=1 099) Placebo (n=546) Clinical endpoints Primary efficacy endpoint: Proportion of patients with 3-month confirmed disability progression (primary endpoint) 26.3% 31.7% Risk reduction1 21% (p=0.0134) Proportion of patients with 3-month confirmed 20% increase in timed 25-foot walk test 39.7% 41.4% Risk reduction1 6% (p=0.4398) Proportion of patients with 6-month confirmed disability progression 19.9% 25.5% Risk reduction1 26% [(p=0.0058)]6 Annualised relapse rate (ARR) 0.071 0.152 Rate reduction2 55% [(p<0.0001)]6 MRI endpoints Change from baseline in T2 lesion volume (mm3)3 +184 mm3 +879 mm3 Difference in T2 lesion volume change -695 mm3 (p<0.0001)7 Percentage brain volume change relative to baseline (95% CI)3 -0.497% -0.649% Difference in percentage brain volume change 0.152% [(p=0.0002)]6 Average cumulative number of Gd-enhancing T1 weighted lesions (95% CI)4 0.081 0.596 Rate reduction 86% [(p<0.0001)]6 Proportion of patients with 4-point worsening in Symbol Digit Modality Test5 16.0% 20.9% Risk reduction1 25% [(p=0.0163)]6 1 From Cox modelling for time to progression 2 From a model for recurrent events 3 Average over month 12 and month 24 4 Up to month 24 5 Confirmed at 6 months 6 [Nominal p-value for endpoints not included in the hierarchical testing and not adjusted for multiplicity] 7 Non-confirmatory p-value; hierarchical testing procedure terminated before reaching endpoint Results from the study showed a variable but consistent risk reduction in the time to 3- and 6-month CDP with siponimod compared to placebo in subgroups defined based on gender, age, pre-study relapse activity, baseline MRI disease activity, disease duration and disability levels at baseline. In the subgroup of patients (n=779) with active disease (defined as patients with relapse in the 2 years prior to the study and/or presence of Gd-enhancing T1 lesions at baseline) the baseline characteristics were similar to the overall population. Median age was 47 years, median disease duration was 15 years and median EDSS score at baseline was 6.0. Time to onset of 3-month and 6-month CDP was significantly delayed in siponimod-treated patients with active disease, by 31% compared to placebo (hazard ratio [HR] 0.69; 95% CI: 0.53, 0.91) and by 37% compared to placebo (HR 0.63; 95% CI: 0.47, 0.86), respectively. The ARR (confirmed relapses) was reduced by 46% (ARR ratio 0.54; 95% CI: 0.39, 0.77) compared to placebo. The relative rate reduction of cumulative number of Gd-enhancing T1 weighted lesions over 24 months was 85% (rate ratio 0.155; 95% CI: 0.104, 0.231) compared to placebo. The differences in T2 lesion volume change and in percentage of brain volume change (average over months 12 and 24) compared to placebo were -1163 mm3 (95% CI: -1 484, -843 mm3) and 0.141% (95% CI: 0.020, 0.261%), respectively. Figure 2 Patients with 3- and 6-month CDP based on EDSS-Kaplan-Meier curves – Subgroup with active SPMS (full analysis set, study A2304) In the subgroup of patients (n=827) without signs and symptoms of disease activity (defined as patients without relapse in the 2 years prior to the study and without presence of Gd-enhancing T1 lesions at baseline), effects on 3-month and 6-month CDP were small (risk reductions were 7% and 13%, respectively). Paediatric population The European Medicines Agency has deferred the obligation to submit the results of studies with siponimod in one or more subsets of the paediatric population in the treatment of multiple sclerosis (see section 4.2 for information on paediatric use).

Absorption The time (Tmax) to reach maximum plasma concentrations (Cmax) after multiple oral administration of siponimod is about 4 hours (range: 2 to 12 hours). Siponimod absorption is extensive (=70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimod given once daily over 10 days, a mean Cmax of 30.4 ng/ml and mean AUCtau of 558 h*ng/ml were Number of patients at risk Placebo (N=263) Pe rc en ta ge of pa tie nt s wi th 3- m on th C D P Pe rc en ta ge of pa tie nt s wi th 6- m on th C D P Siponimod (N=516) Study month Siponimod Placebo 0 1 0 2 0 3 0 4 0 0 1 0 2 0 3 0 4 0 0 6 12 18 24 30 36 42 0 6 12 18 24 30 36 Study month 516 439 376 245 149 48 1 0 263 221 164 112 68 19 0 0 Number of patients at risk Siponimod Placebo Time to 3-month CDP versus placebo (Primary endpoint) Time to 6-month CDP versus placebo 42 516 447 391 258 156 51 1 0 263 225 171 115 68 20 0 0 5 0 Hazard ratio: 0.69 (95% Cl: 0.53, 0.91); risk reduction: 31% Hazard ratio: 0.63 (95% Cl: 0.47, 0.86); risk reduction: 37% observed on day 10. Steady state was reached after approximately 6 days of multiple once-daily administration of siponimod. Despite a delay in Tmax to 8 hours after a single dose, food intake had no effect on the systemic exposure of siponimod (Cmax and AUC), therefore siponimod may be taken without regard to meals (see section 4.2). Distribution Siponimod is distributed to body tissues with a moderate mean volume of distribution of 124 litres. The siponimod fraction found in plasma is 68% in humans. Siponimod readily crosses the blood-brain barrier. Protein binding of siponimod is >99.9% in healthy subjects and in patients with hepatic or renal impairment. Biotransformation Siponimod is extensively metabolised, mainly by cytochrome P450 2C9 (CYP2C9) (79.3%), and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans. In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug

In repeat-dose toxicity studies in mice, rats and monkeys, siponimod markedly affected the lymphoid system (lymphopenia, lymphoid atrophy and reduced antibody response), which is consistent with its primary pharmacological activity at S1P1 receptors (see section 5.1). Dose-limiting toxicities in animal species were nephrotoxicity in mice, body weight development in rats and adverse CNS and gastrointestinal effects in monkeys. The main target organs of toxicity in rodents included the lung, liver, thyroid, kidney and uterus/vagina. In monkeys, effects on muscle and skin were additionally observed. These toxicities developed at more than 30-fold higher systemic siponimod levels than the AUC-based human exposure at the maintenance dose of 2 mg/day. Siponimod did not exert any phototoxic or dependence potential and was not genotoxic in vitro and in vivo. Carcinogenicity In carcinogenicity investigations, siponimod induced lymphoma, haemangioma and haemangiosarcoma in mice, whereas follicular adenoma and carcinoma of the thyroid gland were identified in male rats. These tumour findings were either regarded as mouse-specific or attributable to metabolic liver adaptations in the particularly sensitive rat species and are of questionable human relevance. Fertility and reproductive toxicity Siponimod did not affect male and female fertility in rats up to the highest dose tested, representing an approximate 19-fold safety margin based on human systemic exposure (AUC) at a daily dose of 2 mg. The receptor affected by siponimod (sphinosine-1-phosphate receptor) is known to be involved in vascular formation during embryogenesis. In embryofoetal development studies conducted in rats and rabbits, siponimod induced embryotoxic effects in the absence of maternal toxicity. In both species, prenatal mortality was increased. While in rats a higher number of foetuses with external, skeletal and visceral malformations (e.g. cleft palate and misshapen clavicles, cardiomegaly and oedema) were noted, in rabbit foetuses skeletal and visceral variations were predominantly observed. In the prenatal and postnatal development study performed in rats, there was in increased number of dead (stillborn or found dead before postnatal day 4) and malformed pups (male pups with urogenital malformations and/or decreased anogenital distance; pups of both sexes with oedema, swollen soft cranium, or flexed hindlimbs). The exposure levels (AUC) at the respective NOAELs for embryofoetal (rats and rabbits) and pre/postnatal (rats) development were below the human systemic exposure (AUC) at a daily dose of 2 mg and consequently no safety margin exists.

Mayzent 2 mg film-coated tablets Tablet core Lactose monohydrate Microcrystalline cellulose Crospovidone Glycerol dibehenate Colloidal anhydrous silica Tablet coating Polyvinyl alcohol Titanium dioxide (E171) Yellow iron oxide (E172) Red iron oxide (E172) Talc Soya lecithin Xanthan gum

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Feb. 16, 2026

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