MAYZENT Film-coated tablet Ref.[9922] Active ingredients: Siponimod

5.1 Infections

Risk of Infections

MAYZENT causes a dose-dependent reduction in peripheral lymphocyte count to 20% to 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 Clinical Pharmacology (12.2)]. Life-threatening and rare fatal infections have occurred in association with MAYZENT.

In Study 1 [see Clinical Studies (14)], 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 CBC (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 to 4 weeks after discontinuation of MAYZENT, vigilance for infection should be continued throughout this period [see Warnings and Precautions (5.11)].

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 one case of reactivation of VZV infection leading to varicella zoster meningitis, have been reported in the development program of 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 Vaccinations below).

Progressive Multifocal Leukoencephalopathy:

Progressive multifocal leukoencephalopathy (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. 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.

No cases of PML have been reported in MAYZENT-treated patients in the development program; however, PML has been reported in patients treated with an S1P receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with MAYZENT should be suspended until PML has been excluded.

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 Drug Interactions (7.1)].

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.

The use of live attenuated vaccines should be avoided while patients are taking MAYZENT and for 4 weeks after stopping treatment [see Drug Interactions (7.1)].

Vaccinations may be less effective if administered during MAYZENT treatment. MAYZENT treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.

5.2 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.

5.3 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 Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.2)].

MAYZENT was not studied in patients who had:

• In the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (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 Drug Interactions (7.2)]

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 Adverse Reactions (6.1)]. 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 Drug Interactions (7.2)]
• 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 second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block [see Contraindications (4)]

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 Dosage and Administration (2.2, 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 with onset > 6 months prior to initiation, ECG testing and first-dose monitoring is recommended [see Dosage and Administration (2.1, 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.
  • 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 Drug Interactions (7.3)].
  • 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 Dosage and Administration (2.4) and Drug Interactions (7.2)].

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 Dosage and Administration (2.2, 2.3)].

5.4 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.

5.5 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 returned to 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.

5.6 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.

5.7 Fetal Risk

Based on animal studies, MAYZENT may cause fetal harm [see Use in Specific Populations (8.1)]. 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.

5.8 Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving an 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 an 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.

5.9 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 Drug Interactions (7.1)].

5.10 Severe Increase in Disability After Stopping MAYZENT

Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of an 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.

5.11 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 Clinical Pharmacology (12.2)]. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 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 to 4 weeks after the last dose of MAYZENT [see Drug Interactions (7.1)].

The following serious adverse reactions are described elsewhere in labeling:

• Infections [see Warnings and Precautions (5.1)]
• Macular Edema [see Warnings and Precautions (5.2)]
• Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.3)]
• Respiratory Effects [see Warnings and Precautions (5.4)]
• Liver Injury [see Warnings and Precautions (5.5)]
• Increased Blood Pressure [see Warnings and Precautions (5.6)]
• Fetal Risk [see Warnings and Precautions (5.7)]
• Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.8)]
• Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions (5.9)]
• Severe Increase in Disability After Stopping MAYZENT [see Warnings and Precautions (5.10)]
• Immune System Effects After Stopping MAYZENT [see Warnings and Precautions (5.11)]

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 Clinical Studies (14)] 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.

Table 3 lists adverse reactions that occurred in at least 5% of MAYZENT-treated patients and at a rate at least 1% higher than in patients receiving placebo.

Table 3. Adverse Reactions Reported in Study 1 (Occurring in at Least 5% of MAYZENT-Treated Patients and at a Rate at Least 1% Higher Than in Patients Receiving Placebo):

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, essential hypertension, 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 (1^st and 2^nd degree), asthenia, and pulmonary function test decreased [see Warnings and Precautions (5.1, 5.2, 5.3, 5.4)].

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 Warnings and Precautions (5.4)].

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 malignant melanoma in situ and seminoma were reported in MAYZENT-treated patients in Study 1. An increased risk of cutaneous malignancies has been reported in association with another S1P modulator.

7.1 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 Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.9)].

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.

7.2 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 Warnings and Precautions (5.3) and Drug Interactions (7.3)]. 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.

7.3 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 Warnings and Precautions (5.3)]. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT [see Clinical Pharmacology (12.2)].

7.4 Vaccination

During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective; therefore MAYZENT treatment should be paused 1 week prior and for 4 weeks after vaccination [see Warnings and Precautions (5.1)].

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 Warnings and Precautions (5.1)].

7.5 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.

7.6 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 and *2/*3 genotype [see Clinical Pharmacology (12.3)].

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 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 embryo-fetal 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% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

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 embryo-fetal 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 embryo-fetal 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/m ² basis.

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.

Contraception

Females

Before initiation of MAYZENT treatment, women of childbearing potential should be counselled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with MAYZENT [see Use in Specific Populations (8.1)]. 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 Warnings and Precautions (5.7)].

Safety and effectiveness in pediatric patients have not been established.

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.

8.6 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), which is approximately 0.4% to 0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod [see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)].