MAYZENT 0.25 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

Mayzent 0.25 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Mayzent 0.25 mg film-coated tablets

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

Excipient with known effect

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

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

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 with company logo on one side and “T” on the other side.

4.1 Therapeutic indications

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).

4.2 Posology and method of administration

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 CYP2C933 genotype, siponimod should not be used (see sections 4.3, 4.4 and 5.2).

In patients with a CYP2C923 or 13 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

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.

4.3 Contraindications

– 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 (CYP2C933) genotype (poor metaboliser).

– During pregnancy and in women of childbearing potential not using effective contraception (see sections 4.4 and 4.6).

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 periodically during treatment. Absolute lymphocyte counts <0.2 × 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 × 109/l. Confirmed absolute lymphocyte counts <0.2 × 109/l in a patient already receiving siponimod 1 mg should lead to interruption of siponimod therapy until the level reaches 0.6 × 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.

A case of cryptococcal meningitis (CM) has been reported for siponimod. Cases of CM have been reported for another sphingosine 1-phosphate (S1P) receptor modulator. 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.

No cases of progressive multifocal leukoencephalopathy (PML) have been reported for siponimod in the development programme; however, they have been reported for another S1P receptor modulator. 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.

Cases of herpes viral infection (including one case of reactivation of varicella zoster virus [VZV] infection leading to varicella zoster meningitis) have been reported in the siponimod development programme. 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).

Vaccinations may be less effective if administered during siponimod treatment. Discontinuation of treatment 1 week prior to planned vaccination until 4 weeks after is recommended. When 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

Reduction in heart rate

Initiation of siponimod treatment results in a transient decrease in heart rate (see sections 4.8 and 5.1), and 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. Patients who experienced bradycardia were generally asymptomatic. A few patients experienced mild to moderate symptoms including dizziness and non-cardiac chest pain, which resolved within 24 hours without intervention (see section 4.8). If necessary, the decrease in heart rate induced by siponimod can be reversed by parenteral doses of atropine or isoprenaline.

Atrioventricular conduction

Initiation of siponimod treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern to the observed decrease in heart rate during dose titration. 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. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours and did not require discontinuation of treatment.

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, or

– 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

In study A2304, basal cell carcinoma was the most common neoplasm and was reported with a similiar incidence in the siponimod 2 mg (1.01%, 12 patients) and placebo (1.23%, 7 patients) groups. However, additional cases in patients treated with siponimod have been reported with longer exposure (see section 4.8). Other skin malignancies, including melanoma, have also been reported in patients treated with siponimod and in patients on long-term therapy with another S1P modulator.

Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 months taking into consideration clinical judgement. 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 medication 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 (CYP2C933 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 CYP2C923 genotype (1.4–1.7% of the population) and in patients with a 13 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.

4.5 Interaction with other medicinal products and other forms of interaction

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 up to 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 (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 interaction (DDI) effect in the presence of CYP3A or CYP2C9 perpetrator drugs is predicted to be dependent on the CYP2C9 genotype.

CYP2C9 and CYP3A4 inhibitors

Because of a significant increase in exposure to siponimod, concomitant use of siponimod and medicinal products that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor.

The co-administration of fluconazole (moderate CYP2C9/strong CYP3A4 inhibitor) 200 mg daily at steady state and a single dose of siponimod 4 mg in healthy volunteers with a CYP2C911 genotype led to a 2-fold increase in the area under the curve (AUC) of siponimod. According to evaluation of the drug interaction potential using physiologically based pharmacokinetic (PBPK) modelling, a maximum 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 CYP2C922 genotype. In CYP2C922 patients, 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, because of an expected reduction in siponimod exposure, the appropriateness and possible benefit of the treatment should be considered when siponimod is combined:

– with strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine)

in all patients regardless of genotype

– with moderate CYP3A4 inducers (e.g. modafinil) in patients with a CYP2C913 or 23 genotype.

A significant reduction of siponimod exposure (by up to 76% and 51%, respectively) is expected under these conditions according to evaluation of the drug interaction potential using PBPK modelling. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively, in CY2C911 subjects.

Oral contraceptives

Co-administration with siponimod did not reveal clinically relevant effects on the pharmacokinetics and pharmacodynamics of the combined ethinylestradiol and levonorgestrel oral contraceptive. Therefore the efficacy of the investigated oral contraceptive was maintained under siponimod treatment.

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.

4.6 Fertility, pregnancy and lactation

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.

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).

4.8 Undesirable effects

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).

Table 2 Tabulated list of adverse reactions

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%). In the extension part of the phase III clinical study, a case of cryptococcal meningitis (CM) has been reported (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.

4.9 Overdose

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 overdose 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 CYP2C911 or 12 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 (AAQTcF) 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 AAQTcF 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).

(Primary endpoint)

50

40

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30

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20

10

0

0

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Hazard ratio: 0.79, p=0.0134; (95% Cl: 0.65, 0.95); risk reduction: 21%

Figure 1 Patients with 3– and 6-month CDP based on EDSS-Kaplan-Meier curves (full analysis set, study A2304)

Time to 6-month CDP versus placebo

Study month

42

Number of patients at risk

Study month

Number of patients at risk

Siponimod     1099     947

Placebo 546     463

781

352

499

223

289

124

101

35

Siponimod Placebo

1099     960

546     473

811

361

525

230

306

128

106

37

I i i Siponimod (N=1099)

-!-----1-----1– Placebo (N=546)

Table 3 Clinical and MRI results of study A2304

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: –1484, –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

rc en ta ge of pa tie nt s wi th 3m on th C D P

2 0

1 0

(Primary endpoint)

Hazard ratio: 0.69 (95% Cl: 0.91); risk reduction: 31%

0.53,

0   6                              2

Time to 6-month CDP versus placebo Pe

Number of patients at risk

Siponimod   516    447    391

Placebo    263    225    171

Study month

Number of patients at

Sriipskonimod   516    439    376

Placebo    263    221     164

Study month

245    149     48     1      0

112     68      19     0      0

258     156      51      1       0

115     68      20     0      0

I ।     । Siponimod (N=516)

Placebo (N=263)

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).

5.2 Pharmacokinetic properties

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 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 interaction potential at the therapeutic dose of 2 mg once daily 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 oxidative metabolism pathways to overall elimination. PBPK modelling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated (see section 4.5).

Elimination

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

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

Linearity

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

Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing and steady-state levels are approximately 2– to 3-fold greater than after the initial dose. An up-titration regimen is used to reach the clinically therapeutic dose of 2 mg siponimod after 6 days and 4 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 analyses indicated that CYP2C911 and 12 subjects behave as extensive metabolisers, 22 and 13 subjects as intermediate metabolisers and 23 and 33 subjects as poor metabolisers. Compared to CYP2C911 subjects, individuals with the CYP2C922, 13, 23 and 33 genotypes have 20%, 35–38%, 45–48% and 74% smaller CL/F values, respectively. Siponimod exposure is therefore approximately 25%, 61%, 91% and 284% higher in CYP2C922, 13, 23 and 33 subjects, respectively, as compared to 11 subjects (see Table 4) (see sections 4.2 and 4.4).

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

Elderly

Results from population pharmacokinetics suggest that dose adjustment is not necessary in elderly patients (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).

Gender

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

Race/Ethnicity

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

Renal impairment

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

Hepatic impairment

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

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mayzent 0.25 mg film-coated tablets

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Crospovidone

Glycerol dibehenate

Colloidal anhydrous silica

Tablet coating

Polyvinyl alcohol

Titanium dioxide (E171)

Red iron oxide (E172)

Black iron oxide (E172)

Talc

Soya lecithin

Xanthan gum

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

Mayzent 0.25 mg film-coated tablets

Titration packs of 12 film-coated tablets in PA/alu/PVC/alu blister in wallet.

Packs of 84 or 120 film-coated tablets in PA/alu/PVC/alu blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Novartis Pharmaceuticals UK Limited

2nd Floor, The WestWorks Building, White City Place

195 Wood Lane

London

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United Kingdom