warnings and cautions
5 WARNINGS AND PRECAUTIONS Infections : Siponimod tablets 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 siponimod tablets 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 siponimod tablets. Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing siponimod tablets if macular edema develops. Diabetes mellitus and uveitis increase the risk. ( 5.3 ) Bradyarrhythmia and Atrioventricular Conduction Delays : Siponimod tablets 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 (BP) during treatment. ( 5.8 ) Fetal Risk : Women of childbearing potential should use effective contraception during and for 10 days after stopping siponimod tablets. ( 5.9 ) 5.1 Infections Risk of Infections Siponimod tablets 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. Siponimod tablets 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 siponimod tablets. In Study 1 [see Clinical Studies (14) ], the overall rate of infections was comparable between the siponimod tablets-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 siponimod tablets-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in siponimod tablets-treated patients compared to 2.5% of patients receiving placebo. Before initiating treatment with siponimod tablets, results from a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed. Initiation of treatment with siponimod tablets 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 siponimod tablets, vigilance for infection should be continued throughout this period [see Warnings and Precautions (5.13) ] . Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with siponimod tablets 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 siponimod tablets. 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. Siponimod tablets 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 siponimod tablets. In Study 1, the rate of herpetic infections was 4.6% in siponimod tablets-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 siponimod tablets-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 siponimod tablets (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 siponimod tablets treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with siponimod tablets, following which initiation of treatment with siponimod tablets should be postponed for 4 weeks to allow the full effect of vaccination to occur. Vaccinations may be less effective if administered during siponimod tablets treatment. The use of live-attenuated vaccines should be avoided while patients are taking siponimod tablets 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 siponimod tablets. 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 siponimod tablets -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 siponimod tablets, have occurred in patients treated for at least 18 months. At the first sign or symptom suggestive of PML, withhold siponimod tablets and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including S1P receptor modulators. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients. If PML is confirmed, treatment with siponimod tablets should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including siponimod tablets, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient's condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. 5.3 Macular Edema S1P receptor modulators, including siponimod tablets, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with siponimod tablets. Perform an examination of the fundus, including the macula, periodically while on therapy, and any time there is a change in vision. Macular edema was reported in 1.8% of siponimod tablets-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within the first four months of therapy. Continuation of siponimod tablets therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing siponimod tablets if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated. 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 siponimod tablets therapy. In the clinical trial experience in adult patients with all doses of siponimod tablets, the rate of macular edema was higher in MS patients with a history of uveitis or diabetes mellitus compared to those without a history of these diseases (10% vs. 2%, respectively). 5.4 Bradyarrhythmia and Atrioventricular Conduction Delays Since initiation of siponimod tablets 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 siponimod tablets [see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.2) ] . Siponimod tablets were 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 siponimod tablets, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5 to 6 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 siponimod tablets-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 siponimod tablets 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 siponimod tablets-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 siponimod tablets 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 siponimod tablets treatment. If treatment with siponimod tablets is considered, advice from a cardiologist should be sought in patients with: 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) ] Ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension 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 siponimod tablets 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, if not contraindicated, ECG testing and first-dose monitoring is recommended [see Dosage and Administration (2.1, 2.4) and Contraindications (4) ]. Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod tablets are 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 siponimod tablets 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 siponimod tablets 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 siponimod tablets 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 siponimod tablets treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod tablets 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 siponimod tablets can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod tablets 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 siponimod tablets 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) ] . 5.5 Respiratory Effects Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV 1 ) were observed in siponimod tablets-treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV 1 from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference between siponimod tablets-treated patients and patients receiving placebo in percent predicted FEV 1 at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV 1 after drug discontinuation. In Study 1, five patients discontinued siponimod tablets because of decreases in pulmonary function testing. Siponimod tablets have been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV 1 were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with siponimod tablets if clinically indicated. 5.6 Liver Injury Elevations of transaminases may occur in siponimod tablets-treated patients. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of siponimod tablets therapy. In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of siponimod tablets-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 siponimod tablets-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 siponimod tablets-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 siponimod tablets. In clinical trials, siponimod tablets were 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. Siponimod tablets 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 siponimod tablets, caution should be exercised when using siponimod tablets in patients with a history of significant liver disease. 5.7 Cutaneous Malignancies The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Use of siponimod tablets has been associated with an increased risk of BCC and SCC. In Study 1, the incidence of BCC and SCC was 1.1% and 0.2%, respectively, in siponimod tablets-treated patients [see Adverse Reactions (6.1) ] . Cases of other cutaneous malignancies, including melanoma, have also been reported in patients treated with siponimod tablets and in patients treated with other S1P receptor modulators. Kaposi's sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking siponimod tablets. 5.8 Increased Blood Pressure In Study 1, siponimod tablets-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 siponimod tablets-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with siponimod tablets and managed appropriately. 5.9 Fetal Risk Based on animal studies, siponimod tablets may cause fetal harm [see Use in Specific Populations (8.1) ] . Because it takes approximately 10 days to eliminate siponimod tablets from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping siponimod tablets treatment. 5.10 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 siponimod tablets-treated patients in the development program. However, should a siponimod tablets-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, siponimod tablets should be discontinued. 5.11 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 siponimod tablets. Initiating treatment with siponimod tablets after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1) ] . 5.12 Severe Increase in Disability After Stopping Siponimod Tablets 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 siponimod tablets treatment. Patients should be observed for a severe increase in disability upon siponimod tablets discontinuation and appropriate treatment should be instituted, as required. After stopping siponimod tablets in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [see Warnings and Precautions (5.2) ]. 5.13 Immune System Effects After Stopping Siponimod Tablets After stopping siponimod tablets 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 siponimod tablets [see Drug Interactions (7.1) ] .