Siponimod

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.

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

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 )

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)] .

5.2 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. Longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators: the majority of cases of PML associated with S1P receptor modulators, including MAYZENT, have occurred in patients treated for at least 18 months. 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. […]

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)] .

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)] .

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)] . 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 Dosage and Administration (2.3) and Clinical Pharmacology (12.5)] .

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.