MAYZENT 0.25mg tablets medication leaflet

Mayzent 0.25 mg film-coated tablets

Mayzent 1 mg film-coated tablets

Mayzent 2 mg film-coated tablets

Mayzent 0.25 mg film-coated tablets

Each film-coated tablet contains siponimod fumaric acid equivalent to 0.25 mg siponimod.

Each tablet contains 59.1 mg lactose (as monohydrate) and 0.092 mg soya lecithin.

Mayzent 1 mg film-coated tablets

Each film-coated tablet contains siponimod fumaric acid equivalent to 1 mg siponimod.

Each tablet contains 58.3 mg lactose (as monohydrate) and 0.092 mg soya lecithin.

Mayzent 2 mg film-coated tablets

Each film-coated tablet contains siponimod fumaric acid equivalent to 2 mg siponimod.

Each tablet contains 57.3 mg lactose (as monohydrate) and 0.092 mg soya lecithin.

For the full list of excipients, see section 6.1.

Film-coated tablet

Mayzent 0.25 mg film-coated tablets

Pale red, round, biconvex, bevelled-edged film-coated tablet of approximately 6.1 mm diameter withcompany logo on one side and “T” on the other side.

Mayzent 1 mg film-coated tablets

Violet white, round, biconvex, bevelled-edged film-coated tablet of approximately 6.1 mm diameterwith company logo on one side and “L” on the other side.

Mayzent 2 mg film-coated tablets

Pale yellow, round, biconvex, bevelled-edged film-coated tablet of approximately 6.1 mm diameterwith company logo on one side and “II” on the other side.

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 (seesection 5.1).

Treatment with siponimod should be initiated and supervised by a physician experienced in themanagement of multiple sclerosis.

Before initiation of treatment, patients must be genotyped for CYP2C9 to determine their CYP2C9metaboliser 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 pct. 4.3, pct. 4.4 and5.2).

Treatment initiation

Treatment has to be started with a titration pack that lasts for 5 days. Treatment starts with 0.25 mgonce daily on days 1 and 2, followed by once-daily doses of 0.5 mg on day 3, 0.75 mg on day 4, and1.25 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 dailyin the morning with or without food.

Table 1 Dose titration regimen to reach maintenance dose

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 TITRATION

Day 4 0.75 mg 3 x 0.25 mg

Day 5 1.25 mg 5 x 0.25 mg

Day 6 2 mg1 1 x 2 mg1 MAINTENANCE1 In patients with CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mgtaken once daily (1 x 1 mg or 4 x 0.25 mg) (see above and sections 4.4 and 5.2). Additionalexposure of 0.25 mg on day 5 does not compromise patient safety.

Treatment maintenance

In patients with a CYP2C9*2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg (seesections 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.

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 bere-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 doseshould 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 bere-initiated with a new titration pack.

Siponimod has not been studied in patients aged 65 years and above. Clinical studies included patientsup to the age of 61 years. Siponimod should be used with caution in the elderly due to insufficient dataon safety and efficacy (see section 5.2).

Based on clinical pharmacology studies, no dose adjustment is needed in patients with renalimpairment (see section 5.2).

Siponimod must not be used in patients with severe hepatic impairment (Child-Pugh class C) (seesection 4.3). Although no dose adjustment is needed in patients with mild or moderate hepaticimpairment, caution should be exercised when initiating treatment in these patients (see sections 4.4and 5.2).

The safety and efficacy of siponimod in children and adolescents aged 0 to 18 years have not yet beenestablished. No data are available.

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 insection 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 anginapectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiringinpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure (seesection 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 apacemaker (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 (seesections 4.4 and 4.6).

Risk of infections

A core pharmacodynamic effect of siponimod is a dose-dependent reduction of the peripherallymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration oflymphocytes 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 afterdiscontinuation of prior therapy) should be available. Assessments of CBC are also recommended 3 to4 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, becausein 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 receivingsiponimod 1 mg should lead to interruption of siponimod therapy until the level reaches 0.6 x 109/lwhen 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 continuedthroughout this period (see below section “Stopping siponimod therapy”).

Patients should be instructed to report symptoms of infection to their physician promptly. Effectivediagnostic and therapeutic strategies should be employed in patients with symptoms of infection whileon therapy. Suspension of treatment with siponimod should be considered if a patient develops aserious infection.

Cases of cryptococcal meningitis (CM) have been reported for siponimod. Patients with symptoms andsigns consistent with CM should undergo prompt diagnostic evaluation. Siponimod treatment shouldbe suspended until CM has been excluded. If CM is diagnosed, appropriate treatment should beinitiated.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported with siponimod (seesection 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 besuspended until PML has been excluded. If PML is confirmed, treatment with siponimod should bediscontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated withsphingosine 1-phosphate (S1P) receptor modulators, including siponimod, who developed PML andsubsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition thatmay be rapid, can lead to serious neurological complications or death, and is often associated withcharacteristic changes on MRI. The time to onset of IRIS in patients with PML was usually fromweeks to months after S1P receptor modulator discontinuation. Monitoring for development of IRISand appropriate treatment of the associated inflammation should be undertaken.

Herpes viral infection

Cases of herpes viral infection (including cases of meningitis or meningoencephalitis caused byvaricella zoster viruses [VZV]) have occurred with siponimod at any time during treatment. If herpesmeningitis or meningoencephalitis occur, siponimod should be discontinued and appropriate treatmentfor the respective infection should be administered. Patients without a physician-confirmed history ofvaricella or without documentation of a full course of vaccination against VZV should be tested forantibodies to VZV before starting siponimod (see below section “Vaccination”).

A full course of vaccination with varicella vaccine is recommended for antibody-negative patientsprior to commencing treatment with siponimod, following which initiation of treatment should bepostponed 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 for4 weeks after stopping treatment (see section 4.5).

Other types of vaccines may be less effective if administered during siponimod treatment (seesection 4.5). Discontinuation of treatment 1 week prior to planned vaccination until 4 weeks after isrecommended. If stopping siponimod therapy for vaccination, the possible return of disease activityshould 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 suchtherapy (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 occurredwithin the first 3-4 months of therapy. An ophthalmological evaluation is therefore recommended3-4 months after treatment initiation. As cases of macular oedema have also occurred on longer-termtreatment, patients should report visual disturbances at any time while on siponimod therapy and anevaluation 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 orunderlying/co-existing retinal disease due to a potential increase in the risk of macular oedema (seesection 4.8). It is recommended that these patients should undergo an ophthalmological evaluationprior 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 isrecommended that siponimod be discontinued if a patient develops macular oedema. A decision onwhether or not siponimod should be re-initiated after resolution needs to take into account thepotential benefits and risks for the individual patient.

Bradyarrhythmia

Initiation of siponimod treatment results in a transient decrease in heart rate and may also beassociated with atrioventricular conduction delays (see sections 4.8 and 5.1). A titration scheme toreach 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 ismaximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases areseen on subsequent days, with maximal decrease from day 1 (baseline) reached on day 5 to 6. Thehighest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, with thepulse declining on average 5 to 6 beats per minute (bpm). Post-dose declines on the following days areless pronounced. With continued dosing heart rate starts increasing after day 6 and reaches placebolevels within 10 days after treatment initiation.

Heart rates below 40 bpm were rarely observed. The atrioventricular conduction delays manifested inmost of the cases as first-degree atrioventricular (AV) blocks (prolonged PR interval onelectrocardiogram). 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 clinicalmanagement should be initiated and monitoring should be continued until the symptoms haveresolved. If necessary, the decrease in heart rate induced by siponimod can be reversed by parenteraldoses 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 aperiod of 6 hours after the first dose of siponimod for signs and symptoms of bradycardia (see alsosection 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 atthe end of the observation period. If post-dose bradyarrhythmia or conduction-related symptoms occuror 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/findingshave resolved. If pharmacological treatment is required, monitoring should be continued overnight and6-hour monitoring should be repeated after the second dose.

Due to the risk of serious cardiac rhythm disturbances or significant bradycardia, siponimod shouldnot 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 benefitsoutweigh the potential risks, and advice from a cardiologist should be sought prior to initiation oftreatment in order to determine the most appropriate monitoring strategy.

A thorough QT study demonstrated no significant direct QT-prolonging effect and siponimod is notassociated with an arrhythmogenic potential related to QT prolongation. Initiation of treatment mayresult 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 whowere treated with QT-prolonging medicinal products. If treatment with siponimod is considered inpatients with pre-existing significant QT prolongation or who are already being treated with

QT-prolonging medicinal products with known arrhythmogenic properties, advice from a cardiologistshould be sought prior to initiation of treatment in order to determine the most appropriate monitoringstrategy 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 depointes 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 calciumchannel 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 receivingsiponimod in clinical studies. Concomitant use of these substances during treatment initiation may beassociated with severe bradycardia and heart block. Because of the potential additive effect on heartrate, treatment with siponimod should generally not be initiated in patients who are concurrentlytreated with these substances (see section 4.5). In such patients, treatment with siponimod should beconsidered only if the anticipated benefits outweigh the potential risks.

If concomitant treatment with one of the above substances is considered during initiation of treatmentwith siponimod, advice from a cardiologist should be sought regarding the switch to anon-heart-rate-lowering medicinal product or appropriate monitoring for treatment initiation.

Bradyarrhythmic effects are more pronounced when siponimod is added to beta-blocker therapy. Forpatients receiving a stable dose of beta blocker, the resting heart rate should be considered beforeintroducing 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 beinterrupted until the baseline heart rate is >50 bpm. Treatment with siponimod can then be initiatedand treatment with beta blocker can be re-initiated after siponimod has been up-titrated to the targetmaintenance dose (see section 4.5).

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available beforeinitiation 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 siponimod2 mg compared to 1.5% of patients who received placebo (see section 4.8). In clinical studiestreatment was discontinued if the elevation exceeded a 3-fold increase and the patient showedsymptoms related to hepatic function or if the elevation exceeded a 5-fold increase. In the phase IIIclinical study, 1% of all discontinuations met one of these criteria.

Patients who develop symptoms suggestive of hepatic dysfunction should have liver enzymes checkedand siponimod should be discontinued if significant liver injury is confirmed. Resumption of therapywill be dependent on whether or not another cause of liver injury is determined and on the benefits tothe 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 riskof developing elevated liver function test values when taking siponimod, caution should be exercisedin 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 inpatients with longer treatment duration (see section 4.8).

Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 monthstaking into consideration clinical judgement. Careful skin examinations should be maintained withlonger treatment duration. Patients should be advised to promptly report any suspicious skin lesions totheir physician. Patients treated with siponimod should be cautioned against exposure to sunlightwithout protection. These patients should not receive concomitant phototherapy with UV-B radiationor PUVA-photochemotherapy.

Unexpected neurological or psychiatric symptoms/signs

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported for anothersphingosine-1-phosphate (S1P) receptor modulator. Such events have not been reported for siponimodin the development programme. However, should a patient on siponimod treatment develop anyunexpected neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioural changes,cortical visual disturbances or any other neurological cortical symptoms/signs or any symptom/signsuggestive of an increase in intracranial pressure) or accelerated neurological deterioration, a completephysical 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 othertherapy must be considered to avoid an additive immune effect whilst at the same time minimising therisk of disease reactivation. A peripheral lymphocyte count (CBC) is recommended prior to initiatingsiponimod 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 itsproduct information, initiating treatment with siponimod after alemtuzumab is not recommended.

Siponimod can generally be started immediately after discontinuation of beta interferon or glatirameracetate.

Patients with hypertension uncontrolled by medicinal products were excluded from participation inclinical studies and special care is indicated if patients with uncontrolled hypertension are treated withsiponimod.

Hypertension was more frequently reported in patients on siponimod (12.6%) than in those givenplacebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimodresulted 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, diastolic1.2 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 determinetheir 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 withsiponimod. Use of siponimod in these patients results in substantially elevated siponimod plasmalevels. 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 avoidincreased exposure to siponimod (see sections 4.2 and 5.2).

Due to risk for the foetus, siponimod is contraindicated during pregnancy and in women ofchildbearing potential not using effective contraception. Before initiation of treatment, women ofchildbearing potential must be informed of this risk to the foetus, must have a negative pregnancy testand must use effective contraception during treatment and for at least 10 days after treatmentdiscontinuation (see sections 4.3 and 4.6).

Stopping siponimod therapy

Severe exacerbation of disease, including disease rebound, has been rarely reported afterdiscontinuation of another S1P receptor modulator. The possibility of severe exacerbation of diseaseafter stopping siponimod treatment should be considered. Patients should be observed for relevantsigns of possible severe exacerbation or return of high disease activity upon siponimod discontinuationand appropriate treatment should be instituted as required.

After siponimod therapy has been stopped, siponimod remains in the blood for up to 10 days. Startingother 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 fordevelopment 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 within10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects onperipheral lymphocyte count, may persist for up to 3-4 weeks after the last dose. Use ofimmunosuppressants within this period may lead to an additive effect on the immune system andtherefore 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 apatient treated with siponimod. Laboratory tests involving the use of circulating mononuclear cellsrequire larger blood volumes due to reduction in the number of circulating lymphocytes.

The tablets contain soya lecithin. Patients who are hypersensitive to peanut or soya should not takesiponimod (see section 4.3).

The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, totallactase 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 orimmunosuppressive therapies. Caution should be exercised during concomitant administration due tothe risk of additive immune effects during such therapy and in the weeks after administration of any ofthese medicinal products is stopped (see section 4.4).

Due to the characteristics and duration of alemtuzumab immune suppressive effects described in itsproduct information, initiating treatment with siponimod after alemtuzmab is not recommended unlessthe 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 maydecrease 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 medicinalproducts, QT-prolonging medicinal products with known arrhythmogenic properties,heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances thatmay decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heartrate (see section 4.4). No data are available for concomitant use of these medicinal products withsiponimod. Concomitant use of these substances during treatment initiation may be associated withsevere bradycardia and heart block. Because of the potential additive effect on heart rate, treatmentwith siponimod should generally not be initiated in patients who are concurrently treated with thesesubstances (see section 4.4). If treatment with siponimod is considered, advice from a cardiologistshould be sought regarding the switch to non-heart-rate-lowering medicinal products or appropriatemonitoring for treatment initiation.

Beta blockers

Caution should be exercised when siponimod is initiated in patients receiving beta blockers due to theadditive effects on lowering heart rate (see section 4.4). Beta-blocker treatment can be initiated inpatients receiving stable doses of siponimod.

The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated ina dedicated pharmacodynamic/safety study. The addition of propranolol on top of siponimodpharmacokinetic/pharmacodynamic steady state had less pronounced negative chronotropic effects(less than additive) in comparison to addition of siponimod on top of propranololpharmacokinetic/pharmacodynamic steady state (additive HR effect).

The use of live attenuated vaccines may carry the risk of infection and should therefore be avoidedduring 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. Theefficacy of vaccination is not considered to be compromised if siponimod treatment is paused 1 weekprior 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 daysprior 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 byconcomitant 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 lesserextent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme and thedrug-drug interaction (DDI) effect in the presence of CYP3A or CYP2C9 inhibitors or inducers ispredicted to be dependent on the CYP2C9 genotype.

CYP2C9 and CYP3A4 inhibitors

Because of a significant increase in exposure to siponimod, concomitant use of siponimod andmedicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is notrecommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dualinhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderateor strong CYP3A4 inhibitor.

The co-administration of fluconazole (moderate CYP2C9/CYP3A4 dual inhibitor) 200 mg daily atsteady state and a single dose of siponimod 4 mg in healthy volunteers with a CYP2C9*1*1 genotypeled to a 2-fold increase in the area under the curve (AUC) of siponimod. According to evaluation ofthe drug interaction potential using physiologically based pharmacokinetic (PBPK) modelling, amaximum of a 2-fold increase in the AUC of siponimod is predicted across genotypes with any type of

CYP3A4 and CYP2C9 inhibitors except for patients with a CYP2C9*2*2 genotype. In CYP2C9*2*2patients, a 2.7-fold increase in the AUC of siponimod is expected in the presence of moderate

CYP2C9/CYP3A4 inhibitors.

CYP2C9 and CYP3A4 inducers

Siponimod may be combined with most types of CYP2C9 and CYP3A4 inducers. However, becauseof an expected reduction in siponimod exposure, the appropriateness and possible benefit of thetreatment should be considered when siponimod is combined:

- with strong CYP3A4/moderate CYP2C9 dual inducers (e.g. carbamazepine) or a moderate

CYP2C9 inducer in combination with a separate strong CYP3A4 inducer in all patientsregardless of genotype.

- with moderate CYP3A4 inducers (e.g. modafinil) or strong CYP3A4 inducers in patients with a

CYP2C9*1*3 or *2*3 genotype.

A significant reduction of siponimod exposure (by up to 76% and 51%, respectively) is expectedunder these conditions according to evaluation of the drug interaction potential using PBPKmodelling. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily doses ofrifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod AUCtau,ss and Cmax,ssby 57% and 45%, respectively, in CY2C9*1*1 subjects.

Co-administration with siponimod did not reveal clinically relevant effects on the pharmacokineticsand pharmacodynamics of the combined ethinylestradiol and levonorgestrel oral contraceptive.

Therefore the efficacy of the investigated oral contraceptive was maintained under siponimodtreatment.

No interaction studies have been performed with oral contraceptives containing other progestagens,however an effect of siponimod on the efficacy of oral contraceptives is not expected.

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 anegative pregnancy test result must be available and counselling should be provided regarding seriousrisk to the foetus. Women of childbearing potential must use effective contraception during treatmentand 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 beimplemented before siponimod is prescribed to female patients and during treatment.

When stopping siponimod therapy for planning a pregnancy, the possible return of disease activityshould be considered (see section 4.4).

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 andrabbits and teratogenicity in rats, including embryo-foetal deaths and skeletal or visceralmalformations at exposure levels comparable to the human exposure at the daily dose of 2 mg (seesection 5.3). In addition, clinical experience with another sphingosine-1-phosphate receptor modulatorindicated a 2-fold higher risk of major congenital malformations when administered during pregnancycompared with the rate observed in the general population.

Consequently, siponimod is contraindicated during pregnancy (see section 4.3). Siponimod should bestopped at least 10 days before a pregnancy is planned (see section 4.4). If a woman becomes pregnantwhile on treatment, siponimod must be discontinued. Medical advice should be given regarding therisk of harmful effects to the foetus associated with treatment and ultrasonography examinationsshould be performed.

It is unknown whether siponimod or its major metabolites are excreted in human milk. Siponimod andits metabolites are excreted in the milk of rats. Siponimod should not be used during breast-feeding.

The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on malereproductive 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, dizzinessmay occasionally occur when initiating therapy with siponimod. Therefore, patients should not driveor use machines during the first day of treatment initiation with siponimod (see section 4.4).

The safety profile of siponimod was based on data from the core clinical study. The most commonadverse 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 wasconsistent with that observed in the core part.

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequentreactions first. In addition, the corresponding frequency category for each adverse reaction is based onthe 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 theavailable data).

Table 2 Tabulated list of adverse reactions

Common Herpes zoster

Rare Progressive multifocal leukoencephalopathy

Not known Meningitis cryptococcal

Common Melanocytic naevus

Basal cell carcinoma

Uncommon Squamous cell carcinoma

Malignant melanoma

Common Lymphopenia

Rare Immune reconstitution inflammatory syndrome (IRIS)

Very common Headache

Common Dizziness

Tremor

Common Macular oedema

Common Bradycardia

Atrioventricular block (first and second degree)

Very common Hypertension

Common Nausea

Common Pain in extremity

Common Oedema peripheral

Asthenia

Very common Liver function test increased

Common Pulmonary function test decreased

In the phase III clinical study in patients with SPMS the overall rate of infections was comparablebetween 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 withsiponimod at any time during treatment. Cases of cryptococcal meningitis (CM) have also beenreported for siponimod (see section 4.4).

Macular oedema

Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than in thosegiven placebo (0.2%). Although the majority of cases occurred within 3 to 4 months of commencingsiponimod, cases were also reported in patients treated with siponimod for more than 6 months (seesection 4.4). Some patients presented with blurred vision or decreased visual acuity, but others wereasymptomatic and diagnosed on routine ophthalmological examination. The macular oedemagenerally improved or resolved spontaneously after discontinuation of treatment. The risk ofrecurrence after re-challenge has not been evaluated.

Bradyarrhythmia

Initiation of siponimod treatment results in a transient decrease in heart rate and may also beassociated 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 patientstreated 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 andplateaued at doses ≥5 mg. Bradyarrhythmic events (AV blocks and sinus pauses) were detected with ahigher incidence under siponimod treatment compared to placebo.

Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg, with notably higherincidence under non-titrated conditions compared to dose titration conditions.

The decrease in heart rate induced by siponimod can be reversed by atropine or isoprenaline.

Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated withsiponimod. In the phase III study in patients with SPMS, liver function test increases were morefrequently observed in patients on siponimod (11.3%) than in those on placebo (3.1%), mainly due toliver transaminase (ALT/AST) and GGT elevations. The majority of elevations occurred within6 months of starting treatment. ALT levels returned to normal within approximately 1 month afterdiscontinuation of siponimod (see section 4.4).

Hypertension was more frequently reported in patients on siponimod (12.6%) than in those givenplacebo (9.0%) in the phase III clinical study in patients with SPMS. Treatment with siponimodresulted 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, diastolic1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment.

Seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in thephase 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 thelung for carbon monoxide (DLCO) values were observed with siponimod treatment. At months 3 and6 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) inpatients with respiratory disorders such as chronic obstructive pulmonary disease (COPD) or asthmatreated with siponimod. On chronic treatment, this reduction did not translate into clinically significantadverse events and was not associated with an increase in reports of cough or dyspnoea (seesection 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In healthy subjects, the single maximum tolerated dose was determined to be 25 mg based upon theoccurrence of symptomatic bradycardia after single doses of 75 mg. A few subjects receivedunintended doses of up to 200 mg daily for 3 to 4 days and experienced asymptomatic mild tomoderate transient elevations of liver function tests.

One patient (with a history of depression) who took 84 mg siponimod experienced a slight elevation inliver transaminases.

If the overdose constitutes first exposure to siponimod or occurs during the dose titration phase ofsiponimod it is important to observe for signs and symptoms of bradycardia, which could includeovernight monitoring. Regular measurements of pulse rate and blood pressure are required andelectrocardiograms should be performed (see sections 4.2 and 4.4).

There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange wouldresult in meaningful removal of siponimod from the body.

Pharmacotherapeutic group: Immunosuppressants, sphingosine-1-phosphate (S1P) receptormodulators, ATC code: L04AE03

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively totwo out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P1 and S1P5. By acting as afunctional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymphnodes. This reduces the recirculation of T cells into the central nervous system (CNS) to limit centralinflammation.

Reduction of the peripheral blood lymphocytes

Siponimod induces a dose-dependent reduction of the peripheral blood lymphocyte count within6 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 aremaintained with daily dosing.

In the vast majority (90%) of SPMS patients, lymphocyte counts return to the normal range within10 days of stopping therapy. After stopping siponimod treatment residual lowering effects onperipheral 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 treatmentinitiation (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 stimulationleading to cellular hyperpolarisation and reduced excitability. Due to its functional antagonism at S1P1receptors, initial titration of siponimod successively desensitises GIRK channels until the maintenancedose is reached.

Potential to prolong the QT interval

The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiacrepolarisation were investigated in a thorough QT study. The results did not suggest anarrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased theplacebo-corrected baseline-adjusted mean QTcF (ΔΔQTcF) by more than 5 ms, with a maximummean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound ofthe one-sided 95% CI for the ΔΔQTcF at all time points remained below 10 ms. Categorical analysisrevealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of morethan 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 clinicallyrelevant 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 ofincreased airway resistance.

The efficacy of siponimod has been investigated in a phase III study evaluating once-daily doses of2 mg in patients with SPMS.

Study A2304 (EXPAND) in SPMS

The core part of study A2304 was a randomised, double-blind, placebo-controlled, event andfollow-up duration driven, phase III study in patients with SPMS who had documented evidence ofprogression in the prior 2 years in the absence or independent of relapses, no evidence of relapse in the3 months prior to study enrolment and with an Expanded Disability Status Scale (EDSS) score of 3.0to 6.5 at study entry. The median EDSS was 6.0 at baseline. Patients above 61 years of age were notincluded. With regard to disease activity, features characteristic of inflammatory activity in SPMS canbe 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. Clinicalevaluations were performed at screening and every 3 months and at the time of relapse. MRIevaluations 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 withbaseline EDSS of 5.5 or more) sustained for 3 months. Key secondary endpoints were time to 3-monthconfirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25W) and changefrom 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 anexploratory 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 thestudy. Median age was 49 years, median disease duration was 16 years and median EDSS score was6.0 at baseline. 64% of patients had no relapses in the 2 years prior to study entry and 76% had nogadolinium (Gd)-enhancing lesions on their baseline MRI scan. 78% of patients had been previouslytreated with a therapy for their MS.

Time to onset of 3-month and 6-month CDP was significantly delayed for siponimod, with reductionin risk of 3-month CDP by 21% compared to placebo (hazard ratio [HR] 0.79, p=0.0134) andreduction 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 (fullanalysis set, study A2304)

Time to 3-month CDP versus placebo Time to 6-month CDP versus placebo(Primary endpoint)50 5040 4030 3020 2010 10

Hazard ratio: 0.79, p=0.0134; (95% Cl: Hazard ratio: 0.74, p=0.0058; (95% Cl:0.65, 0.95); risk reduction: 21% 0.60, 0.92); risk reduction: 26%0 00 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42

Study month Study month

Number of patients at risk Number of patients at risk

Siponimod 1099 947 781 499 289 101 4 0 Siponimod 1099 960 811 525 306 106 5 0

Placebo 546 463 352 223 124 35 0 0 Placebo 546 473 361 230 128 37 1 0

Siponimod (N=1099) Placebo (N=546)

Percentage of subjects with 3-month CDP

Percentage of subjects with 6-month CDP

Table 3 Clinical and MRI results of study A2304

Endpoints A2304 (EXPAND)

Siponimod 2 mg Placebo(n=1 099) (n=546)

Clinical endpoints

Primary efficacy endpoint: 26.3% 31.7%

Proportion of patients with 3-month confirmeddisability progression (primary endpoint)

Risk reduction1 21% (p=0.0134)

Proportion of patients with 3-month confirmed 39.7% 41.4%20% increase in timed 25-foot walk test

Risk reduction1 6% (p=0.4398)

Proportion of patients with 6-month confirmed 19.9% 25.5%disability progression

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 +184 mm3 +879 mm3(mm3)3

Difference in T2 lesion volume change -695 mm3 (p<0.0001)7

Percentage brain volume change relative to -0.497% -0.649%baseline (95% CI)3

Difference in percentage brain volume change 0.152% [(p=0.0002)]6

Average cumulative number of Gd-enhancing T1 0.081 0.596weighted lesions (95% CI)4

Rate reduction 86% [(p<0.0001)]6

Proportion of patients with 4-point worsening in 16.0% 20.9%

Symbol Digit Modality Test5

Risk reduction1 25% [(p=0.0163)]61 From Cox modelling for time to progression2 From a model for recurrent events3 Average over month 12 and month 244 Up to month 245 Confirmed at 6 months6 [Nominal p-value for endpoints not included in the hierarchical testing and not adjusted formultiplicity]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-studyrelapse 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 yearsprior to the study and/or presence of Gd-enhancing T1 lesions at baseline) the baseline characteristicswere similar to the overall population. Median age was 47 years, median disease duration was 15 yearsand median EDSS score at baseline was 6.0.

Time to onset of 3-month and 6-month CDP was significantly delayed in siponimod-treated patientswith active disease, by 31% compared to placebo (hazard ratio [HR] 0.69; 95% CI: 0.53, 0.91) and by37% 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 ratereduction of cumulative number of Gd-enhancing T1 weighted lesions over 24 months was 85% (rateratio 0.155; 95% CI: 0.104, 0.231) compared to placebo. The differences in T2 lesion volume changeand in percentage of brain volume change (average over months 12 and 24) compared to placebowere -1 163 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)

Time to 3-month CDP versus placebo Time to 6-month CDP versus placebo(Primary endpoint)50 40

Hazard ratio: 0.69 (95% Cl: 0.53, Hazard ratio: 0.63 (95% Cl: 0.47,0.91); risk reduction: 31% 0.86); risk reduction: 37%0 00 6 12 18 24 30 36 42 0 6 12 18 24 30 36 42

Study month Study month

Number of patients at risk Number of patients at risk

Siponimod 516 439 376 245 149 48 1 0 Siponimod 516 447 391 258 156 51 1 0

Placebo 263 221 164 112 68 19 0 0 Placebo 263 225 171 115 68 20 0 0

Siponimod (N=516) Placebo (N=263)

In the subgroup of patients (n=827) without signs and symptoms of disease activity (defined aspatients without relapse in the 2 years prior to the study and without presence of Gd-enhancing T1lesions at baseline), effects on 3-month and 6-month CDP were small (risk reductions were 7% and13%, respectively).

A post-hoc analysis of study A2304 (EXPAND) showed that siponimod delayed progression to

EDSS ≥7.0 (sustained until end of study, i.e. time to wheelchair), resulting in a risk reduction of 38%(HR from Cox model 0.62; 95% CI: 0.41, 0.92). The Kaplan-Meier estimate of percentage of patientsprogressed to EDSS ≥7.0 at month 24 was 6.97% in the siponimod group and 8.72% in the placebogroup. In the subgroup of patients with active SPMS, the risk reduction was 51% (HR 0.49; 95% CI:

0.27, 0.90) and the Kaplan-Meier estimates at month 24 were 6.51% in the siponimod group and8.69% in the placebo group. As these results were exploratory in nature, they should be interpretedwith caution.

Percentage of patients with 3-month CDP

Percentage of patients with 6-month CDP

The core part (CP) of study A2304 was followed by a single-arm, open-label extension part (EP). The

EP objective was exploratory in nature and in place to evaluate long-term efficacy and safety ofsiponimod for up to 7 additional years’ treatment. Of the total number of patients randomised, 68%(n=1 120) entered and 29% (n=485) completed the EP of study A2304. The Kaplan-Meier estimate ofpercentage of patients with 6-month CDP at month 108 was 64.7% in the continuous siponimod groupand 68.4% in the group of patients who switched from placebo to siponimod after CP. In patients withactive SPMS, the Kaplan-Meier estimate of percentage of patients with 6-month CDP at month 108was 62.9% in the continuous siponimod group and 68.1% in the group of patients who switched fromplacebo to siponimod after the CP.

The European Medicines Agency has deferred the obligation to submit the results of studies withsiponimod in one or more subsets of the paediatric population in the treatment of multiple sclerosis(see section 4.2 for information on paediatric use).

The time (Tmax) to reach maximum plasma concentrations (Cmax) after multiple oral administration ofsiponimod is about 4 hours (range: 2 to 12 hours). Siponimod absorption is extensive (≥70%, based onthe amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated toinfinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimodgiven once daily over 10 days, a mean Cmax of 30.4 ng/ml and mean AUCtau of 558 h*ng/ml wereobserved on day 10. Steady state was reached after approximately 6 days of multiple once-dailyadministration of siponimod.

Despite a delay in Tmax to 8 hours after a single dose, food intake had no effect on the systemicexposure of siponimod (Cmax and AUC), therefore siponimod may be taken without regard to meals(see section 4.2).

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-brainbarrier. Protein binding of siponimod is >99.9% in healthy subjects and in patients with hepatic orrenal impairment.

Siponimod is extensively metabolised, mainly by cytochrome P450 2C9 (CYP2C9) (79.3%), and to alesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%).

The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to theclinical effect and the safety of siponimod in humans.

In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 donot show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg oncedaily for all investigated CYP enzymes and transporters, and do not necessitate clinical investigation.

CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidativemetabolism pathways to overall elimination. PBPK modelling indicates a differential CYP2C9genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators onsiponimod exposure is anticipated (see section 4.5).

An apparent systemic clearance (CL/F) of 3.11 l/h was estimated in MS patients. The apparentelimination half-life of siponimod is approximately 30 hours.

Siponimod is eliminated from the systemic circulation mainly due to metabolism and subsequentbiliary/faecal excretion. Unchanged siponimod was not detected in urine.

Siponimod concentration increases in an apparent dose proportional manner after multiple once-dailydoses of siponimod 0.3 mg to 20 mg.

Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing andsteady-state levels are approximately 2- to 3-fold greater than after the initial dose. An up-titrationregimen is used to reach the clinically therapeutic dose of 2 mg siponimod after 6 days and4 additional days of dosing are required to reach the steady-state plasma concentrations.

Characteristics in specific groups or special populations

CYP2C9 genotype

The CYP2C9 genotype influences siponimod CL/F. Two population pharmacokinetic analysesindicated that CYP2C9*1*1 and *1*2 subjects behave as extensive metabolisers, *2*2 and *1*3subjects as intermediate metabolisers and *2*3 and *3*3 subjects as poor metabolisers. Compared to

CYP2C9*1*1 subjects, individuals with the CYP2C9*2*2, *1*3, *2*3 and *3*3 genotypes have 20%,35-38%, 45-48% and 74% smaller CL/F values, respectively. Siponimod exposure is thereforeapproximately 25%, 61%, 91% and 284% higher in CYP2C9*2*2, *1*3, *2*3 and *3*3 subjects,respectively, as compared to *1*1 subjects (see Table 4) (see sections 4.2 and 4.4).

There are other less frequent occurring polymorphisms for CYP2C9. The pharmacokinetics ofsiponimod have not been evaluated in such subjects. Some polymorphisms such as *5, *6, *8 and *11are associated with decreased or loss of enzyme function. It is estimated that CYP2C9 *5, *6, *8 and

*11 alleles have a combined frequency of approximately 10% in populations with African ancestry,2% in Latinos/Hispanics and <0.4% in Caucasians and Asians.

Table 4 CYP2C9 genotype effect on siponimod CL/F and systemic exposure% of % exposure

CYP2C9 Frequency in Estimated CL/F

CYP2C9*1*1 increase versusgenotype Caucasians (L/h)

CL/F CYP2C9*1*1

Extensive metabolisers

CYP2C9*1*1 62-65 3.1-3.3 100 -

CYP2C9*1*2 20-24 3.1-3.3 99-100 -

Intermediate metabolisers

CYP2C9*2*2 1-2 2.5-2.6 80 25

CYP2C9*1*3 9-12 1.9-2.1 62-65 61

Poor metabolisers

CYP2C9*2*3 1.4-1.7 1.6-1.8 52-55 91

CYP2C9*3*3 0.3-0.4 0.9 26 284

Results from population pharmacokinetics suggest that dose adjustment is not necessary in elderlypatients (age 65 years and above). No patients over 61 years of age were enrolled in clinical studies.

Siponimod should be used with caution in the elderly (see section 4.2).

Results from population pharmacokinetics suggest that gender-based dose adjustment is not necessary.

The single-dose pharmacokinetic parameters were not different between Japanese and Caucasianhealthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of siponimod.

No siponimod dose adjustments are needed in patients with mild, moderate or severe renalimpairment. Mean siponimod half-life and Cmax (total and unbound) were comparable betweensubjects with severe renal impairment and healthy subjects. Total and unbound AUCs were onlyslightly increased (by 23 to 33%) compared to healthy subjects. The effects of end-stage renal diseaseor haemodialysis on the pharmacokinetics of siponimod have not been studied. Due to the high plasmaprotein binding (>99.9%) of siponimod, haemodialysis is not expected to alter the total and unboundsiponimod concentration and no dose adjustments are anticipated based on these considerations.

Siponimod must not be used in patients with severe hepatic impairment (see section 4.3). No doseadjustments for siponimod are needed in patients with mild or moderate hepatic impairment. Theunbound siponimod pharmacokinetics AUC is 15% and 50% higher in subjects with moderate andsevere hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg singledose studied. The mean half-life of siponimod was unchanged in hepatic impairment.

In repeat-dose toxicity studies in mice, rats and monkeys, siponimod markedly affected the lymphoidsystem (lymphopenia, lymphoid atrophy and reduced antibody response), which is consistent with itsprimary pharmacological activity at S1P1 receptors (see section 5.1).

Dose-limiting toxicities in animal species were nephrotoxicity in mice, body weight development inrats and adverse CNS and gastrointestinal effects in monkeys. The main target organs of toxicity inrodents included the lung, liver, thyroid, kidney and uterus/vagina. In monkeys, effects on muscle andskin were additionally observed. These toxicities developed at more than 30-fold higher systemicsiponimod 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 invivo.

In carcinogenicity investigations, siponimod induced lymphoma, haemangioma andhaemangiosarcoma in mice, whereas follicular adenoma and carcinoma of the thyroid gland wereidentified in male rats. These tumour findings were either regarded as mouse-specific or attributable tometabolic liver adaptations in the particularly sensitive rat species and are of questionable humanrelevance.

Fertility and reproductive toxicity

Siponimod did not affect male and female fertility in rats up to the highest dose tested, representing anapproximate 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 invascular formation during embryogenesis.

In embryofoetal development studies conducted in rats and rabbits, siponimod induced embryotoxiceffects in the absence of maternal toxicity. In both species, prenatal mortality was increased. While inrats a higher number of foetuses with external, skeletal and visceral malformations (e.g. cleft palateand misshapen clavicles, cardiomegaly and oedema) were noted, in rabbit foetuses skeletal andvisceral variations were predominantly observed.

In the prenatal and postnatal development study performed in rats, there was in increased number ofdead (stillborn or found dead before postnatal day 4) and malformed pups (male pups with urogenitalmalformations and/or decreased anogenital distance; pups of both sexes with oedema, swollen softcranium, or flexed hindlimbs).

The exposure levels (AUC) at the respective NOAELs for embryofoetal (rats and rabbits) andpre/postnatal (rats) development were below the human systemic exposure (AUC) at a daily dose of2 mg and consequently no safety margin exists.

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Date of first authorisation: 13 January 2020

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