Mayzent

siponimod · Tablet, Film Coated · Oral

Prescription (Rx) Sphingosine 1-phosphate Receptor Modulator

Uses

1 INDICATIONS AND USAGE MAYZENT is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. MAYZENT is a sphingosine 1-phosphate (S1P) receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Dosage and administration

Assessments are required prior to initiating MAYZENT. ( 2.1 ) Titration is required for treatment initiation. ( 2.2 , 2.3 ) The recommended maintenance dosage is 2 mg. ( 2.2 ) The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. ( 2.3 ) Administer tablets whole; do not split, crush, or chew. ( 2.2 , 2.3 ) First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of myocardial infarction or heart failure. ( 2.4 ) 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 Dosage and Administration (2.2, 2.3), Contraindications (4) and Use in Specific Populations (8.6)] . An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available. 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 Dosage and Administration (2.4) and Warnings and Precautions (5.4)] . Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Drug Interactions (7.2, 7.3)] . Complete Blood Count Review results of a recent complete blood count (CBC) [see Warnings and Precautions (5.1)] . Liver Function Tests Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.6)] . Ophthalmic Evaluation Obtain a baseline evaluation of the fundus, including the macula, near the start of the treatment with MAYZENT [see Warnings and Precautions (5.3)] . 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 Warnings and Precautions (5.7)] . Current or Prior Medications If patients are taking anti-neoplastic, 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 Warnings and Precautions (5.1) and Drug Interactions (7.1)] . 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 Warnings and Precautions (5.1)] . 2.2 Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2 Maintenance Dosage After treatment titration ( see 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 Dosage and Administration (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 Warnings and Precautions (5.4)] . A 12-tablet starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage [see How Supplied/Storage and Handling (16.1, 16.2)] . Table 1 Dose Titration Regimen to Reach MAYZENT 2 mg Maintenance Dosage Titration Titration dose Titration regimen Day 1 0.25 mg 1 x 0.25 mg Day 2 0.25 mg 1 x 0.25 mg Day 3 0.50 mg 2 x 0.25 mg Day 4 0.75 mg 3 x 0.25 mg Day 5 1.25 mg 5 x 0.25 mg If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen. 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 Warnings and Precautions (5.4) and Use in Specific Populations (8.6)] . A 7-tablet starter pack should be used for patients who will be titrated to the 1-mg maintenance dosage [see How Supplied/Storage and Handling (16.1, 16.2)] . Table 2 Dose Titration Regimen to Reach MAYZENT 1 mg Maintenance Dosage Titration Titration dose Titration regimen Day 1 0.25 mg 1 x 0.25 mg Day 2 0.25 mg 1 x 0.25 mg Day 3 0.50 mg 2 x 0.25 mg Day 4 0.75 mg 3 x 0.25 mg If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen. 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 [see Contraindications (4), Warnings and Precautions (5.4), and Clinical Pharmacology (12.2)] . 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.

Dosage forms and strengths

0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘T’ on other side. 1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side. 2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side. Tablets: 0.25 mg, 1 mg, and 2 mg Novartis logo

Contraindications

4 CONTRAINDICATIONS MAYZENT is contraindicated in patients who have: A CYP2C9*3/*3 genotype [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.5)] In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.4)] Known hypersensitivity to siponimod, or to any of the inactive ingredients in MAYZENT. Observed reactions include angioedema [see Warnings and Precautions (5.8)] . Patients with a CYP2C9*3/*3 genotype. ( 4 ) In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure. ( 4 ) Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker. ( 4 ) Known hypersensitivity to siponimod, or to any of the inactive ingredients in MAYZENT. ( 4 , 5.8 )

Warnings and precautions

Infections: MAYZENT may increase the risk. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment. Do not start in patients with active infection. ( 5.1 ) Progressive Multifocal Leukoencephalopathy (PML): Withhold MAYZENT at the first sign or symptom of PML. ( 5.2 ) Macular Edema: Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with MAYZENT. Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing MAYZENT if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.3 ) Bradyarrhythmia and Atrioventricular Conduction Delays: MAYZENT may result in a transient decrease in heart rate; titration is required for treatment initiation. Consider resting heart rate with concomitant beta-blocker use; obtain cardiologist consultation before concomitant use with other drugs that decrease heart rate. ( 5.4 , 7.2 , 7.3 ) Respiratory Effects: May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. ( 5.5 ) Liver Injury: Obtain liver enzyme results before initiation. Closely monitor patients with severe hepatic impairment. Discontinue if significant liver injury occurs. ( 5.6 ) Cutaneous Malignancies: Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. ( 5.7 ) Increased Blood Pressure: Monitor blood pressure during treatment. ( 5.9 ) Fetal Risk: Women of childbearing potential should use effective contraception during and for 10 days after stopping MAYZENT. ( 5.10 ) 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 (5.14)] . 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 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 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. 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 Drug Interactions (7.4)] .

Side effects

The following serious adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.2)] Macular Edema [see Warnings and Precautions (5.3)] Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.4)] Respiratory Effects [see Warnings and Precautions (5.5)] Liver Injury [see Warnings and Precautions (5.6)] Cutaneous Malignancies [see Warnings and Precautions (5.7)] Hypersensitivity [see Warnings and Precautions (5.8)] Increased Blood Pressure [see Warnings and Precautions (5.9)] Fetal Risk [see Warnings and Precautions (5.10)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.11)] Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions (5.12)] Severe Increase in Disability After Stopping MAYZENT [see Warnings and Precautions (5.13)] Immune System Effects After Stopping MAYZENT [see Warnings and Precautions (5.14)] Most common adverse reactions (incidence greater than 10%) are headache, hypertension, and transaminase increases. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction 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. Adverse reaction MAYZENT 2 mg (N = 1099) % Placebo (N = 546) % Headache a 15 14 Hypertension b 13 9 Transaminase increased c 11 3 Falls 11 10 Edema peripheral d 8 4 Nausea 7 4 Dizziness 7 5 Diarrhea 6 4 Bradycardia e 6 3 Pain in extremity f 6 4 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, 5.3, 5.4, 5.5)] . 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 (FEV 1 ) were observed in patients treated with MAYZENT [see Warnings and Precautions (5.5)] . 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 BCC, SCC, 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 receptor modulators. The risk of BCC and SCC is increased in MAYZENT-treated patients [see Warnings and Precautions (5.7)] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of MAYZENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: Hypersensitivity reactions, including angioedema, rash, and urticaria [see Contraindications (4) and Warnings and Precautions (5.8)] . Infections and Infestations: Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] .

Drug interactions

Vaccination: Avoid live-attenuated vaccines during and for up to 4 weeks after treatment with MAYZENT. ( 7.4 ) CYP2C9 and Dual CYP2C9/3A4 Inhibitors: Strong CYP2C9 inhibitors increase siponimod exposure; concomitant use with MAYZENT is not recommended. Monitor for adverse reactions during concomitant use of MAYZENT with moderate CYP2C9 inhibitors or moderate CYP2C9/CYP3A4 dual inhibitors. ( 7.5 ) CYP2C9 and CYP3A4 Inducers: Dual moderate CYP2C9/strong CYP3A4 inducers decrease siponimod exposure; concomitant use with MAYZENT is not recommended. Monitor for loss of efficacy with concomitant use of MAYZENT and moderate or strong CYP3A4 inducers in patients with CYP2C9*1/*3 or *2/*3 genotypes. ( 7.6 ) 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 (5.12)] . 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) antiarrhythmic 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 (5.4) 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 (5.4)] . 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 [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 Dual CYP2C9/CYP3A4 Inhibitors Concomitant use of MAYZENT and drugs that cause strong CYP2C9 inhibition is not recommended because a clinically relevant increase in exposure to siponimod is anticipated. Monitor for adverse reactions during concomitant use of MAYZENT with moderate CYP2C9 inhibitors or moderate CYP2C9/CYP3A4 dual inhibitors [see Clinical Pharmacology (12.3)] . 7.6 CYP2C9 and CYP3A4 Inducers Because of an expected significant reduction in siponimod exposure, concomitant use of MAYZENT and dual moderate CYP2C9/strong CYP3A4 inducers in patients with all CYP2C9 genotypes is not recommended. Monitor for loss of efficacy with concomitant use of MAYZENT and moderate or strong CYP3A4 inducers in patients with CYP2C9*1/*3 or *2/*3 genotype [see Clinical Pharmacology (12.3)] .

Use in specific populations

8.1 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 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. There is a pregnancy safety study that monitors pregnancy and infant outcomes following exposure to MAYZENT. If MAYZENT is administered during pregnancy or within 10 days before the last menstrual period (LMP), pregnant women or healthcare providers should report the pregnancy to Novartis by emailing usdrugsafety.operations@novartis.com, calling 1-888-669-6682, or visiting the website at https://www.novartis.com/report . 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 than that 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. 8.2 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. 8.3 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 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 (5.10)] . 8.4 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. 8.5 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. 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) 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 Dosage and Administration (2.3) and Clinical Pharmacology (12.5)] .

Pregnancy

Pediatric use

8.4 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.

Geriatric use

8.5 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.

Overdosage

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 Warnings and Precautions (5.4, 5.9) and Clinical Pharmacology (12.2)] . 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.

Description

11 DESCRIPTION MAYZENT tablets contains siponimod, an S1P receptor modulator, as 2:1 co-crystal of siponimod and fumaric acid and has the following chemical name: 1-[[4-[(1 E )-1-[[[4-Cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-3-azetidinecarboxylic acid (2 E )-2-butenedioate (2:1). Its molecular formula is C 4 H 4 O 4
• 2C 29 H 35 F 3 N 2 O 3 , and its molecular weight is 1149.29 g/mol. Its structure is shown below: It is a white to almost white powder. MAYZENT is provided as 0.25 mg, 1 mg, and 2 mg film-coated tablets for oral use. Each tablet contains 0.25 mg, 1 mg, or 2 mg siponimod, equivalent to 0.28 mg, 1.11 mg, or 2.22 mg as 2:1 co-crystal of siponimod and fumaric acid, respectively. MAYZENT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, glyceryl dibehenate, lactose monohydrate, microcrystalline cellulose, with a film coating containing iron oxides (black and red iron oxides for the 0.25 mg and 1 mg strengths and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum. siponimod structural formula

Mechanism of action

12.1 Mechanism of Action Siponimod is an 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.

How supplied

16.1 How Supplied MAYZENT film-coated tablets are supplied as follows: 0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘T’ on other side. Starter Pack for 1-mg maintenance dosage – blister card of seven 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-89 Starter Pack for 2-mg maintenance dosage – blister card of twelve 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-12 Bottle of 28 tablets........................................................................................................................NDC 0078-0979-50 1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-1014-15 2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-0986-15 Bottle of 15 tablets.........................................................................................................................NDC 0078-0986-45 16.2 Storage and Handling Unopened Containers Store MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F). After dispensed by pharmacy to patient, MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Opened Containers Bottles MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not refrigerate after opening. Starter Pack/Blister Card MAYZENT 0.25 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not refrigerate after opening. Store in original calendarized blister wallet container. 16.1 How Supplied MAYZENT film-coated tablets are supplied as follows: 0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘T’ on other side. Starter Pack for 1-mg maintenance dosage – blister card of seven 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-89 Starter Pack for 2-mg maintenance dosage – blister card of twelve 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-12 Bottle of 28 tablets........................................................................................................................NDC 0078-0979-50 1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-1014-15 2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-0986-15 Bottle of 15 tablets.........................................................................................................................NDC 0078-0986-45 16.2 Storage and Handling Unopened Containers Store MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F). After dispensed by pharmacy to patient, MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Opened Containers Bottles MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not refrigerate after opening. Starter Pack/Blister Card MAYZENT 0.25 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not refrigerate after opening. Store in original calendarized blister wallet container.

Patient information

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Administration Tell patients not to discontinue MAYZENT without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidentally take more MAYZENT than prescribed. Instruct patients to administer tablets whole; do not split, crush, or chew MAYZENT tablets. Risk of Infections Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking MAYZENT, and that they should contact their physician if they develop symptoms of infection [see Warnings and Precautions (5.1)] . Advise patients that the use of some vaccines containing live virus (live-attenuated vaccines) should be avoided during treatment with MAYZENT and MAYZENT should be paused 1 week prior and until 4 weeks after a planned vaccination. Recommend that patients postpone treatment with MAYZENT for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Progressive Multifocal Leukoencephalopathy Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients who received MAYZENT. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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 [see Warnings and Precautions (5.2)] . Macular Edema Advise patients that MAYZENT may cause macular edema, and that they should obtain an eye exam near the start of treatment with MAYZENT, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking MAYZENT [see Warnings and Precautions (5.3)] . Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased. Cardiac Effects Advise patients that initiation of MAYZENT treatment results in transient decrease in heart rate [see Warnings and Precautions (5.4)] . Inform patients that to reduce this effect, dosage titration is required. Advise patients that dosage titration is also required if a dose is missed for more than 24 hours during the titration or if 4 or more consecutive daily maintenance doses are missed [see Dosage and Administration (2.2, 2.3, 2.5) and Warnings and Precautions (5.4)] . Inform certain patients with certain preexisting cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods [see Dosage and Administration (2.4)] . Respiratory Effects Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea [see Warnings and Precautions (5.5)] . Liver Injury Inform patients that MAYZENT may increase liver enzymes. Advise patients that they should contact their physician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment [see Warnings and Precautions (5.6)] . Cutaneous Malignancies Inform patients that the risk of BCC and SCC is increased with the use of MAYZENT and that cases of melanoma have been reported. Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor [see Warnings and Precautions (5.7)] . Hypersensitivity Reactions Advise patients that MAYZENT may cause hypersensitivity reactions, including angioedema, rash, and urticaria. Advise patients to contact their healthcare provider if they have any symptoms associated with hypersensitivity [see Warnings and Precautions (5.8)] . Pregnancy and Fetal Risk Inform patients that, based on animal studies, MAYZENT may cause fetal harm [see Warnings and Precautions (5.10)] . Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with MAYZENT and for 10 days after stopping MAYZENT. Advise a female patient to immediately inform her prescriber if she is pregnant or planning to become pregnant. Advise patients that there is a pregnancy safety study that monitors pregnancy outcomes in women exposed to MAYZENT during pregnancy or within 10 days before last menstrual period (LMP). Encourage pregnant women to report the pregnancy to Novartis by emailing usdrugsafety.operations@novartis.com, calling 1-888-669-6682 or visiting the website at https://www.novartis.com/report [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1, 8.3)] . Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae [see Warnings and Precautions (5.11)] . Severe Increase in Disability After Stopping MAYZENT Inform patients that severe increase in disability has been reported after discontinuation of another S1P receptor modulator like MAYZENT.

Label text from the FDA structured product label by Novartis Pharmaceuticals Corporation (revised Jun 30, 2026). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Siponimod in 3 products

Mayzent NDC products (3)

NDC	Strength & form	Labeler	Type
0078-0979	Siponimod .25 mg/1 Tablet, Film Coated	Novartis Pharmaceuticals Corporation	NDA
0078-0986	Siponimod 2 mg/1 Tablet, Film Coated	Novartis Pharmaceuticals Corporation	NDA
0078-1014	Siponimod 1 mg/1 Tablet, Film Coated	Novartis Pharmaceuticals Corporation	NDA

Frequently asked questions

What is Mayzent used for?

What are the side effects of Mayzent?

Who makes Mayzent?

Mayzent is listed by 1 labeler in the FDA NDC directory, including Novartis Pharmaceuticals Corporation.