Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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 MAY API MAR24 V7                              Page 3 of 23                            EU SmPC Jan.2024 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.

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.

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.

MAY API MAR24 V7                               Page 4 of 23                            EU SmPC Jan.2024 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,
MAY API MAR24 V7                               Page 5 of 23                             EU SmPC Jan.2024 -     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 MAY API MAR24 V7                               Page 6 of 23                             EU SmPC Jan.2024 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), 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 secondary progressive multiple sclerosis (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.

MAY API MAR24 V7                                Page 7 of 23                             EU SmPC Jan.2024 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.

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.

Effects on Driving

4.7    Effects on ability to drive and use machines

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).