MAYZENT is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease, and active secondary progressive disease, in adults.

4.2.1 Assessments Prior to First Dose of MAYZENT

Before initiation of treatment with MAYZENT, assess the following:

 CYP2C9 Genotype Determination

Test patients for CYP2C9 variants to determine CYP2C9 genotype [see section Posology and method of administration (4.2.2, 4.2.3), Contraindications (4.3), and specific populations-CYP2C9 Genotype)]. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.

Complete Blood Count

Review results of a recent complete blood count (CBC) [Special warnings and precautions for use (4.4.1)].

Ophthalmic Evaluation

Obtain an evaluation of the fundus, including the macula [Special warnings and precautions for use (4.4.2)].

Cardiac Evaluation

Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first-dose monitoring is recommended [see section Posology and method of administration (4.2.4), Posology, and Special warnings and precautions for use (4.4.3)].

Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see section Interaction with other medicinal products and other forms of interaction (4.5.2, 4.5.3)].

Current or Prior Medications

If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with MAYZENT [see section Special warnings and precautions for use (4.4.1) and Interaction with other medicinal products and other forms of interaction (4.5.1)].

Vaccinations

Test patients for antibodies to varicella zoster virus (VZV) before initiating MAYZENT; VZV vaccination of antibody- negative patients is recommended prior to commencing treatment with MAYZENT [see section Special warnings and precautions for use (4.4.1)].

Liver Function Tests

Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels [see section Special warnings and precautions for use (4.4.5)].

Skin Examination

Obtain a baseline skin examination prior to or shortly after initiation of MAYZENT. If a suspicious skin lesion is observed, it should be promptly evaluated [see section Special warnings and precautions for use].

4.2.2 Recommended Dosage in Patients with CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2

Maintenance Dosage

After treatment titration (see section Treatment Initiation), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9 *1/*3 or *2/*3 genotype [see section Posology and method of administration (4.2.3)].

Administer tablets whole; do not split, crush, or chew MAYZENT tablets.

Treatment Initiation

Initiate MAYZENT with a 5-day titration,  as shown in Table 1 [see section Special warnings and precautions for use (4.4.3)]. A 12-tablet starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage [see section Special precautions for storage / Nature and contents of container (6.4, 6.5)].

Table 1            Dose Titration Regimen to Reach MAYZENT 2 mg Maintenance Dosage

If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.

4.2.3 Recommended Dosage in Patients with CYP2C9 Genotypes *1/*3 or *2/*3

Maintenance Dosage

In patients with a CYP2C9 *1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally  once daily starting on Day 5.

Administer tablets whole; do not split, crush, or chew MAYZENT tablets

Treatment Initiation

Initiate MAYZENT with a 4-day titration, as shown in Table 2 [see section Special warnings and precautions for use (4.4.3) and specific populations-CYP2C9 Genotype]. 

A 7-tablet starter pack should be used for patients who will be titrated to the 1-mg maintenance dosage.

Table 2            Dose Titration Regimen to Reach MAYZENT 1 mg Maintenance Dosage

If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.

4.2.4 First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions

Because initiation of MAYZENT treatment results in a decrease in heart rate (HR), first-dose 6 hour monitoring is recommended for patients with sinus bradycardia [HR less than 55 beats per minute (bpm)], first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure [Special warnings and precautions for use (4.4.3) and Pharmacodynamics effects (5.2)].

First Dose 6-Hour Monitoring

Administer the first dose of MAYZENT in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG in these patients at the end of the Day 1 observation period.

Additional Monitoring After 6-Hour Monitoring

If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:

·         The heart rate 6 hours postdose is less than 45 bpm

·         The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred

·         The ECG 6 hours postdose shows new onset second-degree or higher AV block.

If postdose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post- dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.

Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with MAYZENT is considered in patients:

·            with some preexisting heart and cerebrovascular conditions  [see section Special warnings and precautions for use (4.4.3)]

·            with a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes [Special warnings and precautions for use(4.4.3) and Interaction with other medicinal products and other forms of interaction (4.5.2)]

·            Receiving concurrent therapy with drugs that slow heart rate or AV conduction [see section Interaction with other medicinal products and other forms of interaction (4.5.2, 4.5.3)].

4.2.5         Reinitiation of MAYZENT After Treatment Interruption

After the initial titration is complete, if MAYZENT treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen [see section Posology and method of administration (4.2.2, 4.2.3)]; also complete first- dose monitoring  in patients for whom it is recommended [see section Posology and method of administration (4.2.4)].

 4.4.1 Infections

Risk of Infections

MAYZENT causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. MAYZENT may therefore increase the risk of infections, some serious in nature [see section Pharmacodynamics effects (5.1)]. Life-threatening and rare fatal infections have occurred in association with MAYZENT.

In Study 1 [see section Clinical Studies (5.1)], the overall rate of infections was comparable between the MAYZENT-treated patients and those on placebo (49.0% vs. 49.1% respectively). However, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin infection were more common in MAYZENT-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in MAYZENT-treated patients compared to 2.5% of patients receiving placebo.

Before initiating treatment with MAYZENT, results from a recent complete blood count (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed.

Initiation of treatment with MAYZENT 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 3-4 weeks after discontinuation of MAYZENT, vigilance for infection should be continued throughout this period [see section Special warnings and precautions for use (4.4.11)].

Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with MAYZENT should be considered if a patient develops a serious infection.

Cryptococcal Infections

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also occurred with MAYZENT. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. MAYZENT treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Herpes Viral Infections

Cases of herpes viral infection, including  cases of meningitis or meningoencephalitis caused by VZV reactivation, have been reported with MAYZENT. In Study 1, the rate of herpetic infections was 4.6% in MAYZENT-treated patients compared to 3.0% of patients receiving placebo. In Study 1, an increase in the rate of herpes zoster infections was reported in 2.5% of MAYZENT-treated patients compared to 0.7% of patients receiving placebo.

Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating MAYZENT (see section Vaccinations below).

 Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects during such therapy [see section Interaction with other medicinal products and other forms of interaction (4.5.2, 4.5.3)].

Vaccinations

Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating MAYZENT treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with MAYZENT, following which initiation of treatment with MAYZENT should be postponed for 4 weeks to allow the full effect of vaccination to occur.

Vaccinations may be less effective if administered during MAYZENT treatment.

The use of live-attenuated vaccines should be avoided while patients are taking MAYZENT and for 4 weeks after stopping treatment [see section Interaction with other medicinal products and other forms of interaction (4.5.2, 4.5.3)].

Progressive Multifocal Leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS treated with S1P receptor modulators, including MAYZENT. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in MAYZENT-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any other immunosuppressive or immunomodulatory medications concomitantly, and did not have any ongoing systemic medical conditions resulting in compromised immune system function. The majority of cases of PML associated with S1P receptor modulators, including MAYZENT, have occurred in patients treated for at least 2 years. The relationship between the risk of PML and the duration of treatment is unknown.

At the first sign or symptom suggestive of PML, withhold MAYZENT and perform an appropriate diagnostic evaluation.

Typical symptoms associated with PML are diverse, progress over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including S1P receptor modulators. Many of these patients subsequently became symptomatic with PML.

Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

If PML is confirmed, treatment with MAYZENT should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including MAYZENT, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

4.4.2 Macular Edema

Macular edema was reported in 1.8% of MAYZENT-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within  the first four months of therapy.

An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision  while taking  MAYZENT.

Continuation of MAYZENT therapy in patients with macular edema has not been evaluated. A decision on whether or not MAYZENT should be discontinued  needs to take into account the potential benefits and risks for the individual patient.

Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during MAYZENT therapy. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the clinical  trial experience  in adult patients with all doses of MAYZENT, the rate of macular edema was approximately  10%

in MS patients with a history of uveitis or diabetes mellitus versus 2% in those without a history of these diseases. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a history of uveitis  should have regular  follow-up examinations.

4.4.3 Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of MAYZENT treatment results in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of MAYZENT [see section Posology and method of administration (4.2.2,4. 2.3) and Pharmacodynamics effects (5.1)].

MAYZENT was not studied in patients who had:

·         In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, or decompensated heart failure requiring hospitalization

·         New York Heart Association  Class II-IV heart failure

·         Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz Type II second degree AV-block or higher grade AV-block  (either history or observed at screening),  unless patient has a functioning pacemaker

·         Significant  QT prolongation  (QTc greater than 500 msec)

·         Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic  drugs [see section Interaction with other medicinal products and other forms of interaction (4.5.2)].

Reduction in Heart Rate

After the first titration dose of MAYZENT, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 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.

In Study 1, bradycardia occurred in 4.4% of MAYZENT-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention [see section Undesirable effects (4.8.)].

Heart rates below 40 bpm were rarely observed.

Atrioventricular  Conduction Delays

Initiation of MAYZENT treatment has been associated with transient atrioventricular conduction delays that follow  a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of MAYZENT- treated patients and in 1.9 % of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with MAYZENT in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation  of MAYZENT treatment.

If treatment with MAYZENT is considered, advice from a cardiologist  should be sought:

·         In patients with significant  QT prolongation  (QTc greater than 500 msec),

·         In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs [see section Interaction with other medicinal products and other forms of interaction (4.5.2)].

·         In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension

·         In patients with a history of with second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino- atrial heart block [see section Contraindications (4.3)].

Treatment-Initiation   Recommendations

·         Obtain an ECG in all patients to determine whether preexisting conduction abnormalities  are present.

·         In all patients, a dose titration is recommended for initiation of MAYZENT treatment to help reduce cardiac effects [see section Posology and method of administration (4.2.2,4.2.3)].

·         In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure , if not contraindicated ECG testing and first- dose monitoring is recommended [see section Posology and method of administration (4.2.1,4. 2.4)].

·         Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, MAYZENT is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.

·         Use of MAYZENT in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation  of treatment in order to determine the most appropriate monitoring.

·         Experience with MAYZENT is limited in patients receiving concurrent therapy with drugs that decrease heart-rate (e.g., beta-blockers, calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate, such as ivabradine and digoxin). Concomitant use of these drugs during MAYZENT initiation may be associated with severe bradycardia and heart block.

o   For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing MAYZENT treatment. If the resting heart rate is greater than 50 bpm under chronic beta- blocker treatment, MAYZENT can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline  heart-rate is greater than 50 bpm.  Treatment with MAYZENT can then be initiated and treatment with a beta-blocker can be reinitiated after MAYZENT has been up-titrated to the target maintenance dosage [see section Interaction with other medicinal products and other forms of interaction (4.5.3)].

o   For patients taking other drugs that decrease heart rate, treatment with MAYZENT should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate [see section Posology and method of administration (4.2.4) and Interaction with other medicinal products and other forms of interaction (4.5.2)].

Missed Dose During Treatment Initiation  and Reinitiation  of Therapy Following Interruption

If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment,  reinitiate

Day 1 of the dose titration and follow titration monitoring recommendations see section Posology and method of administration (4.2.2),(4.2.3)].

4.4.4 Respiratory  Effects

Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MAYZENT- treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV1 from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference between MAYZENT-treated patients and patients receiving placebo in percent predicted FEV1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient  information  to determine the reversibility  of the decrease in FEV1 after drug discontinuation. In Study 1, five patients discontinued MAYZENT because of decreases in pulmonary function testing. MAYZENT has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV1 were similar in this subgroup compared with the overall population.  Spirometric  evaluation of respiratory function should be performed during therapy with MAYZENT if clinically  indicated.

4.4.5 Liver Injury

Elevations of transaminases may occur in MAYZENT-treated patients. Recent (i.e., within last 6 months) transaminase and bilirubin  levels should be reviewed before initiation  of MAYZENT therapy.

In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of MAYZENT-treated patients compared to 3.7% of patients receiving placebo, mainly because of transaminase

[alanine aminotransferase/aspartate aminotransferase/gamma-glutamyltransferase ALT/AST/GGT)] elevations.

In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% of MAYZENT-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALT  or AST increased eight and ten times ULN in MAYZENT-treated patients (0.5% and 0.2%, respectively) compared to no patients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels  returnedto normal within approximately 1 month after discontinuation of MAYZENT. In clinical trials, MAYZENT was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting,  abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have liver enzymes checked. MAYZENT should be discontinued  if significant  liver injury is  confirmed.

Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking MAYZENT, caution should be exercised when using MAYZENT in patients with a history of significant  liver disease.

4.4.6 Cutaneous Malignancies

The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P modulators.  Use of MAYZENT has been associated with an increased risk of BCC and SCC. In Study 1, the incidence of BCC and SCC was 1.1% and 0.2%, respectively, in MAYZENT-treated patients. Cases of other cutaneous malignancies, including melanoma, have also been reported in patients treated with MAYZENT and in patients treated with another S1P modulator [see Undesirable effects].

Skin examinations are recommended at the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking MAYZENT

4.4.7 Increased Blood Pressure

In Study 1, MAYZENT-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure, which was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. Hypertension was reported as an adverse reaction in 12.5% of MAYZENT-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with MAYZENT and managed appropriately.

4.4.8 Fetal Risk

Based on animal studies, MAYZENT may cause fetal harm [see section Fertility, Pregnancy and lactation (4.6.1)].

Because it takes approximately 10 days to eliminate MAYZENT from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping MAYZENT treatment.

4.4.9 Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible  encephalopathy syndrome (PRES) have been reported in patients receiving  a sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for MAYZENT-treated patients in the development program. However, should a MAYZENT-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, MAYZENT should be discontinued.

4.4.10 Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies

When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating MAYZENT.

Initiating treatment with MAYZENT after treatment with alemtuzumab is not recommended [see section Interaction with other medicinal products and other forms of interaction (4.5.1)].

4.4.11 Severe Increase in Disability After Stopping MAYZENT

Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility  of severe exacerbation of disease should be considered after stopping MAYZENT treatment.

Patients should be observed for a severe increase in disability upon MAYZENT discontinuation and appropriate treatment should be instituted,  as required.

After stopping MAYZENT in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [ see section Special warnings and precautions for use (4.4.1)].

4.4.12 Immune System Effects After Stopping MAYZENT

After stopping MAYZENT therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy [see section Pharmacodynamics effects (5.1)]. However, residual pharmacodynamics 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 applied 3-4 weeks after the last dose of  MAYZENT [see section Interaction with other medicinal products and other forms of interaction (4.5.1)].

Lactose

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.

4.5.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies

MAYZENT has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see section Special warnings and precautions for use (4.4.1)].

When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see section Special warnings and precautions for use(4.4.9].

Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with MAYZENT after alemtuzumab is not recommended.

MAYZENT can generally  be started immediately  after discontinuation  of beta interferon or glatiramer acetate.

 4.5.2 Anti-Arrhythmic  Drugs, QT Prolonging Drugs, Drugs That may Decrease Heart Rate

MAYZENT has not been studied in patients taking QT prolonging drugs.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with MAYZENT is considered, advice from a cardiologist  should be sought.

Because of the potential additive effects on heart rate, treatment with MAYZENT should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin) [see section Special warnings and precautions for use(4.4.3) and Interaction with other medicinal products and other forms of interaction (4.5.3)]. If treatment with MAYZENT is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.

4.5.3         Beta-Blockers

Caution should be applied when MAYZENT is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of MAYZENT [see section Special warnings and precautions for use  for use (4.4.3)]. Beta-blocker treatment can be initiated  in patients receiving stable doses of MAYZENT [see section Pharmacodynamics effects (5.1)].

4.5.4         Vaccination

During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective; [see section Special warnings and precautions for use  (4.4.1)].

The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during MAYZENT treatment and for up to 4 weeks after discontinuation of treatment with MAYZENT [see section Special warnings and precautions for use(4.4.1)].

4.5.5         CYP2C9 and CYP3A4 Inhibitors

Because of a significant increase in exposure to siponimod, concomitant use of MAYZENT and drugs 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.

Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inhibitors.

4.5.6         CYP2C9 and CYP3A4 Inducers

Because of a significant decrease in siponimod exposure, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and strong CYP3A4 induction is not recommended for all patients. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.

Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inducers.

Concomitant use of MAYZENT and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 or *2/*3 genotype [see section Pharmacokinetic properties (5.2)].

4.5.7         Oral Contraceptives

         The effects of coadministration of siponimod 2 mg and 4 mg (twice the recommended dosage) once daily with a monophasic oral contraceptive (OC) containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were assessed in 24 healthy female subjects (18 to 40 years of age; CYP2C9*1/*1 genotype). There were no clinically relevant effects on the PK or PD of the OC. No interaction studies have been performed with OCs containing other progestagens; however, an effect of siponimod on their exposure is not expected.

4.6.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of MAYZENT in pregnant women. Based on animal data and its mechanism of action, MAYZENT can cause fetal harm when administered to a pregnant woman (see section Data). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated MAYZENT-induced embryotoxicity and fetotoxicity  in rats and rabbits and teratogenicity  in rats. Increased incidences  of post-implantation loss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryofetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest  recommended dose of 2 mg/day.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage  for the indicated population is unknown.

4.6.2       Lactation

Risk Summary

There are no data on the presence of siponimod in human milk, the effects of MAYZENT on the breastfed infant, or the effects of the drug on milk production. A study in lactating rats has shown excretion of siponimod  and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MAYZENT and any potential adverse effects on the breastfed infant from MAYZENT or from the underlying maternal condition.

4.6.3       Females and Males of Reproductive Potential

Contraception

Females

Before initiation of MAYZENT treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with MAYZENT [see section Fertility, Pregnancy and lactation (4.6.1)]. Since it takes approximately 10 days to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period [see section Special warnings and precautions for use  (4.4.7)].

:

Mayzent has no or negligible influence on the ability to drive and use machines.

 a. Summary of the safety profile

·         Infections [see section Special warnings and precautions for use(4.4.1) ]

·         Progressive Multifocal Leukoencephalopathy [see section Special warnings and precautions for use(4.4.1) ]

·         Macular Edema [see section Special warnings and precautions for use  (4.4.2)]

·         Bradyarrhytmia and Atrioventricular  (AV) Conduction Delays [see section Special warnings and precautions for use  (4.4.3)]

·         Respiratory Effects [see section Special warnings and precautions for use  (4.4.4)]

·         Liver Injury [see section Special warnings and precautions for use  (4.4.5)]

·         Cutaneous Malignancies [see section Special warnings and precautions for use (4.4.6)]

·         Increased Blood Pressure [see section Special warnings and precautions for use  (4.4.7)]

·         Fetal Risk [see section Special warnings and precautions for use  (4.4.8)]

·         Posterior Reversible Encephalopathy Syndrome [see section Special warnings and precautions for use  (4.4.9)]

·         Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune- Modulating Therapies [see section Special warnings and precautions for use  (4.4.10)]

·         Severe Increase in Disability  After Stopping MAYZENT [see section Special warnings and precautions for use  (4.4.11)]

·         Immune System Effects After Stopping MAYZENT [see section Special warnings and precautions for use  (4.4.12)]

b. Tabulated summary of adverse reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 1737 MS patients have received MAYZENT at doses of at least 2 mg daily. These patients were included in Study 1 [see section Clinical Studies (5.1)] and in a Phase 2 placebo-controlled study in patients with MS. In Study 1, 67% of MAYZENT-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of MAYZENT-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence  at least 10%) in MAYZENT-treated patients in Study 1 were headache, hypertension, and transaminase increases.

Terms were combined as follows:

a headache, tension headache, sinus headache, cervicogenic headache, drug withdrawal headache, and procedural headache

b hypertension, blood pressure increased, blood pressure systolic increased, essentialhypertension, blood pressure diastolic increased

c alanine aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, liver function test increased, hepatic function abnormal, liver function test abnormal, transaminases increased

d edema peripheral, joint swelling, fluid retention, swelling face

e bradycardia, sinus bradycardia, heart rate decreased

f pain in extremity  and limb  discomfort

The following adverse reactions have occurred in less than 5% of MAYZENT-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and pulmonary function test decreased [see section Special warnings and precautions for use  (4.4)].

Seizures

In Study 1, cases of seizures were reported in 1.7% of MAYZENT-treated patients, compared to 0.4% in patients receiving placebo. It is not known whether these events were related to the effects of MS, to MAYZENT, or to a combination of both.

Respiratory Effects

Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with MAYZENT [see section Special warnings and precautions for use  (4.4)].

Vascular Events

Vascular events, including ischemic strokes, pulmonary embolisms, and myocardial infarctions, were reported in 3.0% of MAYZENT-treated patients compared to 2.6% of patients receiving placebo. Some of these events were fatal. Physicians and patients should remain alert for the development of vascular events throughout treatment, even in the absence of previous vascular symptoms. Patients should be informed about the symptoms of cardiac or cerebral ischemia caused by vascular events and the steps to take if they occur.

Malignancies

Malignancies such as basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and seminoma were reported in MAYZENT-treated patients in Study 1 (in the core or extension parts). An increased risk of cutaneous malignancies has been reported in association with S1P modulators. The risk of basal cell carcinoma and squamous cell carcinoma is increased in MAYZENT-treated patients. [see Warnings and Precautions (5.6)].  [see section Special warnings and precautions for use (4.4)]. 

To report any side effect(s):

·         Saudi Arabia

-          National Pharmacovigilance Center (NPC):

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

In patients with overdosage of MAYZENT, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed [see section Special warnings and precautions for use (4.4.3, 4.4.6) and Pharmacodynamics effects (5.1)].

There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by MAYZENT can be reversed by atropine or isoprenaline..

5.1 Pharmacodynamics properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code:  L04AA42

-   Mechanism of action

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration  into the central nervous system.

 Pharmacodynamics effects:

Immune System

MAYZENT induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by 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 patient, corresponding to 20% to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing [see section Special warnings and precautions for use  (5.1)].

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. After stopping MAYZENT treatment, residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose [see section Special warnings and precautions for use  (5.1)].

Heart Rate and Rhythm

MAYZENT causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation [see section Special warnings and precautions for use  (4.4)]. The maximum decline in heart rate is see sectionn in the first 6 hours post dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by siponimod treatment.

A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of MAYZENT, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under MAYZENT treatment, compared to placebo.

No second-degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pauses occurred above the recommended dose of 2 mg, with notably higher incidence under non-titrated conditions compared to dose titration conditions [see section Posology and method of administration (4.2.2, 4.2.3)].

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

Beta-Blockers

The negative chronotropic effect of coadministration of siponimod and propranolol was evaluated in a dedicated pharmacodynamics (PD)/safety study. The addition of propranolol on top of siponimod at steady-state had less pronounced negative chronotropic effects (less than additive effect) than the addition of siponimod to propranolol at steady state (additive HR effect) [see section Interaction with other medicinal products and other forms of interaction (4.5.3)].

Cardiac Electrophysiology

In a thorough QT study with doses of 2 mg (recommended dose) and 10 mg (five times the recommended dose) siponimod at steady-state, siponimod treatment resulted in a prolongation of QTc , with the maximum mean (upper bound of the two-sided 90% CI) of 7.8 (9.93) ms at 2 mg dose and 7.2 (9.72) ms at 10 mg dose. There was an absence of dose- and exposure-response relationship for QTc effects with the 5-fold dose and exposures achieved by the supratherapeutic dose. No subject had absolute QTcF greater than 480 ms or ΔQTcF greater than 60 ms for siponimod treatment.

Pulmonary Function

Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in MAYZENT-treated patients and were greater than in patients taking placebo [see section Special warnings and precautions for use  (4.4)].

 Clinical efficacy and safety.

CLINICAL STUDIES

The efficacy of MAYZENT was demonstrated in Study 1, a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study in patients with secondary progressive multiple sclerosis (SPMS) who had evidence of disability progression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0-6.5 at study entry (NCT 01665144).

Patients were randomized to receive either once daily MAYZENT 2 mg or placebo, beginning with a dose titration [see section Posology and method of administration (4.2.2)]. Evaluations were performed at screening, every 3 months during the study, and at the time of a suspected 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), defined as at least a

1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher)  sustained for 3 months. A prespecified hierarchical analysis consisted of the primary endpoint and 2 secondary endpoints, the time to 3- month confirmed worsening of at least 20% from baseline on the timed 25-foot walk test and the change from baseline in T2 lesion volume. Additional endpoints included annualized  relapse rate (relapses/year)  and MRI measures of inflammatory disease activity.

Study duration was variable for individual  patients (median study duration was 21 months, range 1 day-37 months).

Study 1 randomized 1651 patients to either MAYZENT 2 mg (N = 1105) or placebo (N = 546); 82% of MAYZENT- treated patients and 78% of placebo-treated  patients completed the study. Median age was 49.0 years, 95% of patients  were white, and 60% female. The median disease duration was 16.0 years, and median EDSS score at baseline was 6.0 (56% of patients had ≥ 6.0 EDSS at baseline); 36% of patients had one or more relapses in the 2 years prior to study entry; 22% of those patients with available imaging had one or more gadolinium-enhancing lesions on their baseline MRI scan; 78% of patients had been previously treated with an MS therapy.

Results are presented in Table 4. MAYZENT was superior to placebo in reducing the risk of confirmed disability progression, based on a time-to-event analysis (hazard ratio 0.79, p < 0.0134; see section Figure 1). MAYZENT did not significantly delay the time to 20% deterioration in the timed 25-foot walk, compared to placebo. Patients treated with MAYZENT had a 55% relative reduction in annualized relapse rate, compared to patients on placebo (nominal p-value < 0.0001). The absolute reduction in the annualized relapse rate was 0.089. Although MAYZENT had a significant effect on disability progression compared to placebo in patients with active SPMS (e.g., SPMS patients with an MS relapse in the 2 years prior to the study), the effect of MAYZENT in patients with non-active SPMS was not statistically significant (see section Figure 2).

Table 4 Clinical and MRI Results From Study 1

Abbreviation: MRI, magnetic resonance imaging; NS, not statistically significant.

All analyses are based on the full analysis set (FAS), which includes  all randomized  subjects who took  at least one  dose of study  medication.  p-values are two-sided.

(1)  Defined as an increase of 1.0 point  or more from the baseline  Expanded  Disability   Status Scale (EDSS) score for patients  with baseline  score of

5.5 or less, or 0.5 or more when the baseline  score is  greater than 5.5.  Progression confirmed  at 3 months.  Cox proportional  hazard model

(2)  Defined as the average number of confirmed relapses per year (estimated from negative binomial  regression model   for recurrent events)

(3)  Adjusted  mean averaged over Months 12 and 24

* Statistically  significant

NS   Not statistically  significant

˄ Nominal  p value,  not corrected for multiple   comparisons

Figure 1  Time to Confirmed Disability Progression Based on EDSS (Study 1)

Figure 2  Time to Confirmed Disability Progression Based on EDSS (Study 1), Subgroup Analysis

* HR and 95% CI presented are model-based  estimates for a range of values of age andExpanded Disability Status Scale (EDSS).

. Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Juvenile Animal Toxicity Data
Oral administration of siponimod (0, 5, 15, or 50 mg/kg/day) to young rats from postnatal day 25 to day 70 resulted in mortality, lung histopathology (alveolar/interstitial edema, fibrin, interstitial mixed cell infiltration) and decrease in body weight gain at the mid and high doses. Neurobehavioral impairment (decreased acoustic startle response) was observed at the high dose but was reversible by the end of the recovery period. Decrease in immune function (T-cell dependent antibody response) was observed at all doses and had not fully recovered by 4 weeks after the end of dosing. A no-effect dose for adverse effects in juvenile animals was not identified.

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 2-3-fold greater than the initial dose. An up-titration regimen is used to reach the clinical therapeutic dose of siponimod of 2 mg after 6 days, and 4 additional days of dosing are required to reach the steady-state-plasma  concentrations.

Absorption

The time (Tmax) to reach maximum  plasma concentrations (Cmax) after oral administration  of immediate  release oral dosage forms of siponimod  was about 4 hours (range 3 - 8 hours). Siponimod  absorption is extensive  (greater than or equal to 70%, based on the amount of radioactivity  excreted in urine and the amount of metabolites  in feces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. After administration of siponimod 2 mg once-daily over 10 days, a mean Cmax of 30.4 ng/mL and mean area under plasma concentration-time curve over dosing interval (AUCtau) of 558 h*ng/mL were observed on day 10. Steady-state was reached after approximately 6 days of once- daily administration  of siponimod.

Food Effect

Food intake resulted in delayed absorption (the median Tmax increased by approximately 2-3 hours). Food intake had no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, MAYZENT may be taken without regard to meals.

Distribution

Siponimod distributes to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found in plasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding of siponimod is greater than 99.9% in healthy subjects and in hepatic and renal impaired  patients.

Elimination

Metabolism

Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by 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.

Excretion

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

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

Specific Populations

Data

Animal Data

When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dose with fetuses available for evaluation. A no-effect dose for adverse effects on embryofetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at the recommended human dose (RHD) of 2 mg/day.

When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis, embryolethality  and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested.

Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryofetal development in rabbits is less that than in humans at the RHD.

When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation, increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but the lowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on a mg/m2 basis.

Geriatric Use

Clinical studies of MAYZENT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection  for an elderly patient should be cautious, reflecting  the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

CYP2C9 Genotype

Before initiation of treatment with MAYZENT, test patients to determine CYP2C9 genotype.
MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype because of substantially elevated siponimod plasma levels.
The *3/*3 genotype is present in approximately 0.5% of white patients and 1% of Asian patients, and is less prevalent in other racial/ethnic groups.
MAYZENT dosage adjustment is recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype because of an increase in exposure to siponimod [see Posology and method of administration (4.2.3) and Preclinical safety data (5.3.1)].
The *1/*3 or *2/*3 genotypes are present in 2% to 20% of the population depending on ancestry.
There are other less frequently occurring polymorphisms in CYP2C9. Some polymorphisms, such as *5, *6, *8, and *11, are associated with decreased or loss of enzyme function. The impact of variants other than *2 and *3 on the pharmacokinetics of siponimod has not been evaluated. It is anticipated that variants that result in loss of CYP2C9 function (e.g., *6) will have similar effects on siponimod pharmacokinetics as the *3 variant [see Posology and method of administration (4.2.3) and Preclinical safety data (5.3.1)].

Male and Female Patients

Gender has no influence on siponimod pharmacokinetics (PK).

Racial or Ethnic Groups

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

Patients with Renal Impairment

No dose adjustments are needed in patients with renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects. Unbound AUCs were only slightly increased (by 33%), compared to healthy subjects, and it is not expected to be clinically significant. The effects of end- stage renal disease or hemodialysis on the PK of siponimod has not been studied. Due to the high plasma protein binding (greater than 99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod  concentration and no dose adjustments are anticipated based on these considerations.

Patients with Hepatic Impairment

No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod AUC parameters are 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 increased unbound siponimod AUC in subjects with moderate and severe hepatic impairment is not expected to be clinically significant. The mean half-life of siponimod was unchanged in hepatic impairment.

Drug Interaction Studies

Siponimod (and Metabolites M3, M17) as a Causative Agent of Interaction

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.

Siponimod as an Object of Interaction

CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative  metabolism pathways to overall elimination. Physiologically based PK modeling 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.

Coadministration of Siponimod with CYP2C9 and CYP3A4 Inhibitors

The coadministration of fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor) 200 mg daily at steady-state and a single  dose of siponimod  4 mg in CYP2C9*1/*1 healthy volunteers led to a 2-fold increase in the AUC of siponimod.

Mean siponimod terminal half-life was increased by 50%. Fluconazole led to a 2-to 4-fold increase in the AUCtau,ss of siponimod across different CYP2C9 genotypes, according to in silico  evaluation  [see section Interaction with other medicinal products and other forms of interaction (4.5.5)].

Coadministration of Siponimod with CYP2C9 and CYP3A4 Inducers

The coadministration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively in CY2C9*1/*1 subjects. Rifampin and efavirenz (moderate CYP3A4 inducer) reduced the AUCtau,ss of siponimod by up to 78% and up to 52%, respectively, across CYP2C9 genotypes, according to in silico  evaluation [see section Interaction with other medicinal products and other forms of interaction (4.5.6)].

5.3.1 Pharmacogenomics

The CYP2C9 genotype has a significant impact on siponimod metabolism. After a single dose of 0.25 mg siponimod, AUCinf and AUClast were approximately 2- and 4-fold higher in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, respectively, while there was only a minor increase of Cmax by 21% and 16%, respectively, compared to extensive metabolizers (CYP2C9*1/*1). Mean half-life is prolonged in CYP2C9*2/*3 and CYP2C9*3/*3 carriers (51 hours and 126 hours, respectively).
An apparent systemic clearance (CL/F) of about 3.11 L/h was estimated in CYP2C9 extensive metabolizer
(CYP2C9*1/*1 and CYP2C9*1/*2) MS patients after multiple oral administrations of siponimod. Cl/F is 2.5, 1.9, 1.6, and
0.9 L/h in subjects with the CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes respectively. The resultant increase in siponimod AUC was approximately 25%, 61%, 91%, and 285% higher in CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 subjects, respectively, as compared to CYP2C9*1/*1 subjects [see section Posology and method of administration (4.2.1, 4.2.3) and Contraindications (4)]. As the apparent clearance estimated for CYP2C9*1*2 subjects is comparable to that of CYP2C9*1/*1 subjects, similar siponimod exposure is expected for both genotypes.
Variants other than *2 and *3 may also lead to decreased or loss of CYP2C9 function (e.g., *5, *6, *8, *11) and may have substrate-specific effects. The frequency of certain CYP2C9 variants differs based on ancestry. The *2 and *3 variants are more prevalent in patients of European or Asian ancestry, while *5, *6, *8, and *11 are more prevalent in individuals of African ancestry [see Use in Specific Populations].

5.3.2 NONCLINICAL   TOXICOLOGY

 Carcinogenesis, Mutagenesis, Impairment of  Fertility

Carcinogenesis

Oral carcinogenicity studies of spinomod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately  5 times the recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m2) basis.In rats, administration of siponimod (0, 10, 30, or 90 mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to 104 weeks, there was an increase in thyroid follicular cell adenoma and combined thyroid follicular cell adenoma and carcinoma in males at the highest dose tested. These findings are considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Plasma siponimod exposure (AUC) at the highest dose tested is approximately 200 times that in humans at the RHD.

Mutagenesis

Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and  in vivo

(micronucleus in mouse and rat) assays. Impairment of Fertility

When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) prior to and throughout the mating period, there was a dose-related  increase in precoital interval at all doses. A decrease in  implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were observed at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg)  is approximately  100 times the RHD on a mg/m2 basis.

When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were observed up to the highest dose tested (1 mg/kg). Plasma siponimod  exposure (AUC) at the highest dose tested is approximately  16 times that in humans at the RHD.

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Crospovidone

Glyceryl dibehenate

Silica colloidal anhydrous

Tablet coating

Polyvinyl alcohol

Titanium dioxide

Iron oxide (E172)

Talc

Lecithin

Xanthan gum

Not applicable.

Store in a refrigerator (2°C to 8°C).

Mayzent 0.25 mg film-coated tablets

Starter packs of 12 film-coated tablets in aluminium/aluminium blister in wallet.

Packs of 120 film-coated tablets in aluminium/aluminium blisters.

Mayzent 2 mg film-coated tablets

Packs of 28 film-coated tablets in aluminium/aluminium blisters.

Not all pack sizes may be marketed.

No special requirements for disposal.