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Subsections
Siponimod Fumarate

TOC

Siponimod Fumarate

Class: 90:04.16 Sphingosine 1-Phosphate (S1P) Agents

Introduction

Siponimod fumarate, a selective sphingosine 1-phosphate (S1P) receptor modulator, has immunomodulatory and disease-modifying activity in multiple sclerosis (MS).(1)(2)(4)

Uses

Multiple Sclerosis

Siponimod fumarate is used orally for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.(1)(2)(3)

Clinical Experience

Efficacy and safety of siponimod have been established in a multicenter, randomized, double-blind, placebo-controlled study (EXPAND) in 1651 adults with secondary progressive MS who had evidence of disability progression in the 2 years prior to study entry, no evidence of relapse in the prior 3 months, and moderate to severe disability as indicated by an Expanded Disability Status Scale (EDSS) score of 3–6.5.(1)(2) The median age of patients in the study was 49 years, median disease duration was 16 years, and median EDSS score at baseline was 6.(1) Patients were randomized in a 2:1 ratio to receive siponimod (titrated to a dosage of 2 mg daily) or placebo.(1)(2) Neurologic evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse; MRI evaluations were performed at baseline and every 12 months.(1)(2)

The primary efficacy end point in the EXPAND study was the time to 3-month confirmed disability progression (defined as an increase from baseline of at least 1 EDSS point [or 0.5 points for patients with baseline EDSS score of 5.5 or higher] sustained over 3 months).(1)(2) Siponimod substantially reduced the risk of 3-month confirmed disability progression compared with placebo.(1)(2) Over a median study duration of 21 months (range: 1 day to 37 months), confirmed disability progression occurred in 26% of patients who received siponimod compared with 32% of placebo recipients (relative risk reduction of 21%).(1)(2) With regard to secondary end points, a 55% relative reduction in annualized relapse rate (defined as the average number of confirmed relapses per year) was observed with siponimod compared with placebo.(1)(2) Siponimod also had a beneficial effect on T2 lesion volume, but did not substantially delay the time to 20% deterioration on the timed 25-foot walk compared with placebo.(1)

Approximately 64% of patients in the EXPAND study had not experienced a relapse in the 2 years prior to study entry and were considered to have nonactive (or nonrelapsing) secondary progressive MS.(1)(2)(3) In this subgroup of patients, the risk of 3-month confirmed disability progression was not substantially decreased with siponimod treatment compared with placebo.(1)(2)(3) Efficacy of siponimod in patients with progressive forms of MS who have nonactive (nonrelapsing) disease has not been established.(3)

Approximately 47% of patients in the EXPAND study had active secondary progressive MS prior to study entry.(23) In this subgroup of patients, the risk of 3-month and 6-month confirmed disability progression was reduced with siponimod treatment compared to placebo.(23)

Clinical Perspective

Siponimod is one of several disease-modifying therapies used in the management of relapsing forms of MS.(3)(36) Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing magnetic resonance imaging (MRI) lesions, and disability progression.(76)(78) The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity; these experts state that the benefits versus risks (e.g., adverse effects or burden of taking a long-term medication) of treatment in patients who have had no relapses in 2 or more years and who do not have active MRI lesions are not known.(76) Because CNS damage occurs early and continues throughout the course of MS, other clinicians recommend that disease-modifying therapy be initiated as soon as possible following diagnosis and continued indefinitely unless there is a clear lack of benefit, adverse effects are intolerable, the patient is unable to adhere to the recommended treatment regimen, or a more appropriate treatment becomes available.(77) Clinicians should consider the adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate disease-modifying therapy.(76)(77)

There are several S1P receptor modulators currently available for the treatment of MS (e.g., fingolimod, ozanimod, ponesimod, siponimod);(36)(37) studies directly comparing the effects of these drugs are not available.(37)

Dosage and Administration

Supplementary dosing info/calc

General

Pretreatment Screening

  • Perform a baseline ophthalmologic examination of the fundus, including the macula, near the start of treatment with siponimod.(1)

  • Obtain a baseline electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present.(1) Consultation with a cardiologist prior to initiation of therapy and first-dose monitoring are recommended in patients with certain preexisting cardiac conditions.(1)

  • Assess whether the patient is on any concomitant drugs that slow heart rate or atrioventricular (AV) conduction.(1)

  • Obtain recent (i.e., within last 6 months) aminotransferase and bilirubin concentrations, and review results of a recent complete blood count (CBC) prior to initiating siponimod therapy.(1) Do not initiate treatment in patients with an active infection until the infection is resolved.(1)

  • Test patients for antibodies to varicella zoster virus (VZV); VZV vaccination is recommended in antibody-negative patients.(1)

  • Assess current and prior medications.(1) Consider potential additive immunosuppressive effects in patients receiving or who previously received antineoplastic, immunosuppressive, or immunomodulating therapies.(1)

  • Verify pregnancy status before initiating siponimod therapy.(1)

  • Because patient selection and dosage of siponimod are based on cytochrome P-450 (CYP) 2C9 genotype, pharmacogenetic testing is recommended prior to initiation of siponimod therapy.(1) However, a specific FDA-approved CYP2C9 genotyping test for siponimod currently is not available.(1) Siponimod therapy is contraindicated in patients with the CYP2C9*3/*3 genotype; a reduced maintenance dosage is recommended in patients with CYP2C9*1/*3 or *2/*3 genotypes.(1)

  • Obtain a baseline skin examination prior to or shortly after initiating siponimod therapy.(1)

Patient Monitoring

  • First-dose monitoring is recommended in patients with baseline sinus bradycardia (heart rate <55 beats per minute), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction (MI) or heart failure whenever therapy is initiated or reinitiated (after discontinuance for more than 4 days).(1)  (See First-dose Monitoring in Patients with Cardiac Conditions under Dosage and Administration.)

  • Monitor patients for signs and symptoms of infection during and for 3–4 weeks after discontinuing therapy.(1)

  • Perform an examination of the fundus, including the macula, periodically during therapy and any time there is a change in vision.(1)

  • Periodic skin examinations are recommended, especially for those with risk factors for skin cancer.(1)

  • Monitor blood pressure during siponimod therapy and manage as clinically indicated.(1)

  • Perform spirometric evaluation of respiratory function during siponimod therapy if clinically indicated.(1)

  • Closely monitor patients with severe hepatic impairment.(1)

Administration

Siponimod is administered orally once daily without regard to meals.(1) Administer tablets whole; do not split, crush, or chew.(1)

Store siponimod tablets in the refrigerator at 2–8°C in their original unopened containers.(1) After the container is opened, the tablets may be stored at room temperature 20–25°C for up to 3 months; do not refrigerate the drug after the container is opened.(1)

First-dose Monitoring in Patients with Cardiac Conditions

First-dose monitoring is recommended in patients with baseline sinus bradycardia (heart rate less than 55 beats per minute), first- or second-degree (Mobitz type I) AV block, or a history of MI or heart failure.(1) In such patients, the first dose of siponimod should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available.(1) These patients should be observed for signs and symptoms of bradycardia for at least 6 hours after the first dose with hourly blood pressure and heart rate measurements.(1) An ECG should be obtained at the end of the observation period.(1)

Continued observation beyond 6 hours should be instituted in the following situations until the abnormal finding has resolved: heart rate 6 hours postdose is less than 45 beats per minute, heart rate 6 hours postdose is at the lowest postdose value (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred), or the ECG 6 hours postdose shows new-onset second-degree or higher AV block.(1) If postdose symptomatic bradycardia, bradyarrhythmia, or conduction-related symptoms occur, or if the 6-hour postdose ECG shows new-onset second-degree or higher AV block or a corrected QT (QTc) interval of 500 msec or greater, appropriate management should be initiated including continuous ECG monitoring; monitoring should be continued until symptoms have resolved if no pharmacologic intervention is required.(1) If pharmacologic intervention is required, continuous overnight ECG monitoring should be instituted and the same first-dose monitoring procedures should be repeated with the second dose of siponimod.(1)

Consultation with a cardiologist is recommended to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation if siponimod is considered in patients with certain preexisting cardiovascular or cerebrovascular conditions, patients with a prolonged QTc interval prior to initiating therapy or during the 6-hour observation period, patients with additional risk for QT-interval prolongation (e.g., those receiving concomitant therapy with drugs that prolong the QT interval and cause torsades de pointes), or patients receiving concomitant therapy with other drugs that decrease heart rate or AV conduction.(1)

Dosage

Dosage of siponimod fumarate is expressed in terms of siponimod.(1)

Dosage of siponimod is based on CYP2C9 genotype.(1) A reduced dosage is recommended in patients with CYP2C9 genotypes *1/*3 and *2/*3.(1)

Siponimod therapy must be initiated with a low dosage and gradually titrated to reduce the risk of adverse cardiac effects.(1)(19)(20)

Patients with CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2

For the treatment of relapsing forms of multiple sclerosis (MS) in adults with CYP2C9 genotypes *1/*1, *1/*2, or *2/*2, the recommended maintenance dosage of siponimod after appropriate titration is 2 mg once daily.(1) Siponimod therapy should be initiated according to the following 5-day titration schedule: 0.25 mg on day 1, 0.25 mg on day 2, 0.5 mg on day 3, 0.75 mg on day 4, and 1.25 mg on day 5; the maintenance dosage of 2 mg daily may then be started on day 6.(1)

The manufacturer recommends use of the Mayzent® 2-mg Starter Pack, which contains 12 siponimod 0.25 mg tablets, only for patients who will be titrated to a target maintenance dosage of 2 mg daily.(1)

Patients with CYP2C9 Genotypes *1/*3 or *2/*3

For the treatment of relapsing forms of MS in adults with CYP2C9 genotypes *1/*3 or *2/*3, the recommended maintenance dosage of siponimod after appropriate titration is 1 mg once daily.(1) Siponimod should be titrated according to the following 4-day schedule: 0.25 mg on day 1, 0.25 mg on day 2, 0.5 mg on day 3, and 0.75 mg on day 4; the maintenance dosage of 1 mg daily may then be started on day 5.(1)

The manufacturer recommends use of the Mayzent® 1-mg Starter Pack, which contains 7 siponimod 0.25 mg tablets in patients who will be titrated to a target maintenance dose of 1 mg daily.(1)

Missed Dose

If a dose of siponimod is missed for more than 24 hours during the initial titration period, therapy must be reinitiated with day 1 of the titration regimen.(1)

Reinitiation of Therapy Following Treatment Interruption

If siponimod therapy is interrupted for 4 or more consecutive days, heart rate effects similar to those observed upon treatment initiation may recur when the drug is reintroduced; therefore, the usual dosage titration and first-dose monitoring procedures should be performed.(1)(21)

Special Populations

Hepatic Impairment

Dosage adjustment of siponimod is not necessary in patients with hepatic impairment.(1)

Renal Impairment

Dosage adjustment of siponimod is not necessary in patients with renal impairment.(1)

Geriatric Patients

Dosage selection for geriatric patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.(1)

Description

Siponimod fumarate is a sphingosine 1-phosphate (S1P) receptor modulator that binds selectively and with high affinity to S1P receptor subtypes 1 and 5.(1)(4)(5)(6)(9) S1P receptors are expressed in multiple organs and systems throughout the body and are involved in the regulation of a variety of physiological processes including immune, cardiac, and neurologic function.(4)(5)(6) Subtype 1 of the S1P receptor (S1P1) is expressed on the surface of lymphocytes and is involved in the regulation of lymphocyte egress from peripheral lymphoid organs.(4)(5)(6) Through modulation of S1P1, siponimod blocks the capacity of lymphocytes to egress from lymph nodes, causing a reversible sequestration of lymphocytes in lymphoid tissues and a reduction in peripheral blood lymphocytes.(1)(6) The exact mechanism by which siponimod exerts its therapeutic effects in multiple sclerosis (MS) is unknown, but may involve reduction of lymphocyte migration into the CNS.(1) Findings from preclinical studies suggest that siponimod readily crosses the blood-brain barrier and may have other effects on neuropathologic processes such as synaptic neurodegeneration and demyelination through direct modulation of neural cells (e.g., astrocytes, oligodendrocytes).(4)(9) Interaction of S1P receptor modulators with other S1P receptor subtypes (e.g., subtype 3, 4, and 5) is thought to mediate some of the adverse effects associated with these agents (e.g., cardiac effects, macular edema, pulmonary toxicity, possible hepatotoxicity).(3)(6)(18)

Siponimod causes a dose-dependent reduction in peripheral lymphocyte counts within 6 hours of the first dose.(1) Lymphocyte counts continue to decrease with continued daily dosing, reaching a nadir of 20–30% of baseline.(1) Lymphocyte counts remain low with continued daily dosing.(1) Following discontinuance of siponimod, lymphocyte counts return to the normal range within 10 days in 90% of patients; however, decreased peripheral lymphocyte counts may persist for up to 3–4 weeks after the last dose of siponimod.(1)

Siponimod is extensively absorbed following oral administration; peak plasma concentrations of the drug are achieved in about 4 hours (range: 3–8 hours).(1)(7)(8)(9) The absolute oral bioavailability of siponimod is approximately 84%.(1) Dose-proportional increases in siponimod concentrations are observed over the dosage range of 0.3–20 mg daily.(1) Following repeated daily dosing, steady-state concentrations of siponimod are attained after approximately 6 days; because dosage of siponimod is titrated over 6 days to the effective therapeutic dosage, 4 additional days of dosing are required to reach steady-state plasma concentrations.(1) Steady-state concentrations of the drug are approximately two- to threefold higher than the concentration achieved after the initial dose.(1) Administration with food delays time to peak plasma concentrations of siponimod by approximately 2–3 hours, but does not affect systemic exposure of the drug.(1) Siponimod exhibits high protein binding (exceeding 99.9%).(1) The drug is extensively metabolized, principally by cytochrome P-450 (CYP) isoenzyme 2C9 and, to a lesser extent, by CYP3A4.(1)(9) The fractional contributions of CYP2C9 and CYP3A4 are dependent on the patient's CYP2C9 genotype;(1)(10) in individuals with the CYP2C9*1/*1 genotype, CYP2C9 and CYP3A4 pathways generally account for 79.3 and 18.5%, respectively, of siponimod metabolism.(1)(9) Genetic polymorphism of CYP2C19 can substantially affect an individual's capacity to metabolize siponimod.(1)(10)(11) The major metabolites M3 and M17 are not expected to be pharmacologically active.(1) The apparent elimination half-life of siponimod is approximately 30 hours.(1) Siponimod is eliminated via biliary/fecal excretion, mainly as metabolites; only trace amounts of unchanged drug are detected in urine.(1)(9)

Cautions

Contraindications

  • Cytochrome P-450 (CYP) 2C9*3/*3 genotype.(1)

  • Recent (in the past 6 months) myocardial infarction (MI), unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or class III or IV heart failure.(1)

  • Mobitz type II second-degree or third-degree AV block or sick sinus syndrome unless patient has a functioning pacemaker.(1)

Warnings/Precautions

Infectious Complications

Siponimod causes a dose-dependent reduction in peripheral lymphocyte count to 20–30% of baseline values, and can therefore increase the risk of infections.(1)(22) Serious and sometimes fatal infections (including reactivation of latent infections) have occurred rarely in patients receiving siponimod.(1)(22) In the principal efficacy study in patients with multiple sclerosis (MS), the overall rate of infections (49%) with siponimod was similar to placebo; however, herpes viral infections, bronchitis, sinusitis, upper respiratory infections, and fungal skin infections occurred at a higher rate in siponimod-treated patients.(1) Serious infections occurred in 2.9% of patients receiving siponimod compared with 2.5% of those receiving placebo.(1)

Before initiating siponimod therapy, review a recent (i.e., within 6 months or after discontinuance of previous therapy) complete blood count (CBC).(1) Patients with severe active infections should not be initiated on siponimod therapy until the infection has resolved.(1) Monitor patients for infections during treatment with siponimod; if a serious infection develops, consider interruption of therapy and manage the infection as clinically indicated.(1) Because effects on peripheral lymphocyte count may persist for up to 3–4 weeks after discontinuance of siponimod therapy, continue monitoring for infections throughout this period.(1) Concomitant use of siponimod with antineoplastic, immunosuppressive (including corticosteroids), or immunomodulating therapies may increase the risk of immunosuppression.(1)

Review the patient's immunization status prior to initiation of siponimod; avoid use of live attenuated vaccines during and for 4 weeks after siponimod therapy.(1) Vaccinations may be less effective if given during siponimod treatment.(1)

Cryptococcal Infections

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, have been reported with another sphingosine 1-phosphate (S1P) receptor modulator.(1) Cryptococcal meningitis has occurred rarely with siponimod.(1) Monitor patients closely for manifestations of cryptococcal meningitis.(1) Patients with signs or symptoms of cryptococcal infection should be promptly evaluated and treated; interrupt siponimod therapy until cryptococcal infection has been excluded.(1) If cryptococcal meningitis is diagnosed, initiate appropriate treatment.(1)

Herpes Virus Infection

Herpetic infections have been reported during premarketing studies with siponimod, including cases of varicella zoster virus (VZV) reactivation leading to varicella zoster meningitis or meningoencephalitis.(1) In the principal efficacy study in patients with MS, herpetic infections occurred more frequently in siponimod-treated patients (4.6%) than in patients who received placebo (3%); herpes zoster infections were reported in 2.5% of siponimod-treated patients compared with 0.7% of placebo recipients.(1)

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 therapy.(1) VZV vaccination is recommended in antibody-negative patients prior to starting siponimod therapy; initiation of siponimod should then be postponed for 4 weeks to allow the full effect of vaccination to occur.(1)

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, has been reported in MS patients treated with S1P receptor modulators, including siponimod.(1) PML typically occurs in immunocompromised patients and usually leads to death or severe disability.(1) PML has occurred in siponimod-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.(1) Longer treatment duration increases PML risk; majority of PML cases associated with S1P receptor modulators occurred in patients treated for at least 18 months.(1) Symptoms typically associated with PML are diverse, progress over a period of days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, confusion, and changes in cognition, memory, orientation, or personality.(1)

Monitor patients closely for clinical symptoms or MRI findings that may be suggestive of PML(1) MRI signs of PML may be apparent before clinical manifestations develop.(1) At the first sign or symptom suggestive of PML, withhold siponimod and perform appropriate diagnostic evaluation; if PML is confirmed, discontinue therapy.(1)

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment.(1) 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.(1) The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation.(1) Monitor for the development of IRIS and initiate appropriate treatment of the associated inflammation.(1)

Macular Edema

Macular edema was reported more frequently in siponimod-treated patients (1.8%) compared with patients receiving placebo (0.2%) in clinical trials and usually occurred within the first 4 months of therapy.(1) Obtain a baseline evaluation of the fundus, including the macula, near the start of siponimod treatment.(1) Perform an ophthalmologic examination of the fundus, including the macula, periodically during therapy and if there is any change in vision.(1) Continuation of siponimod 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 vision loss and the decision whether to discontinue therapy should be individualized based on an assessment of the potential benefits and risks.(1) The risk of recurrence after rechallenge has not been evaluated.(1)

Patients with diabetes mellitus or a history of uveitis are at increased risk of macular edema during siponimod therapy.(1) In the combined clinical trial experience with siponimod, the incidence of macular edema was approximately 10% in MS patients with a history of uveitis or diabetes mellitus compared with 2% in those without such a history.(1)

Bradyarrhythmia and Atrioventricular Conduction Delays

S1P modulators can cause adverse cardiac events because of their effects on S1P receptors expressed in cardiac tissue.(1)(3) Transient decreases in heart rate and AV conduction delays have been reported with these drugs, with the highest risk occurring during the initial dosing period.(1)(19) Following the first dose of siponimod, declines in heart rate begin within 1 hour and peak at approximately 3–4 hours.(1) Heart rate continues to decrease with upward dosage titration, with maximal decrease from baseline occurring on days 5–6.(1) The largest postdose decline in hourly mean heart rate is observed on day 1, decreasing an average of 5–6 beats per minute; declines on subsequent days are less pronounced.(1) With continued dosing of siponimod, heart rate begins increasing after 6 days and reaches levels similar to placebo within 10 days after treatment initiation.(1) AV conduction delays follow a similar temporal pattern.(1)

In the principal efficacy study, bradycardia occurred in 4.4% of siponimod-treated patients compared with 2.9% of patients receiving placebo.(1) Heart rates below 40 beats per minute were rarely observed.(1) Bradycardia generally was asymptomatic, but a few patients experienced symptoms, including dizziness or fatigue.(1) AV conduction delays generally manifested as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of siponimod-treated patients compared with 1.9% of patients receiving placebo.(1) Second-degree AV block, usually Mobitz type I (Wenckebach), was observed at the time of treatment initiation in less than 1.7% of patients receiving siponimod in clinical trials.(1) Conduction abnormalities typically were transient, asymptomatic, and resolved within 24 hours without the need for discontinuance of siponimod therapy; treatment with atropine was rarely required.(1)

Prior to initiation of siponimod therapy, obtain a baseline ECG should.(1) Do not use the drug in patients with second-degree Mobitz type II or higher AV block or sick-sinus syndrome unless the patient has a functioning pacemaker.(1) First-dose monitoring is recommended in patients with sinus bradycardia (heart rate <55 beats per minute), first- or second-degree (Mobitz type I) AV block, or a history (>6 months ago) of MI or heart failure.(1)

Siponimod is not recommended in patients with a history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea since significant bradycardia may be poorly tolerated in these patients.(1) Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be individualized based on an assessment of the potential risks versus benefits.(1) If siponimod therapy is considered in any of these patients, consult a cardiologist prior to initiation of treatment in order to determine the most appropriate monitoring strategy.(1)

Consult a cardiologist if siponimod treatment is considered in patients with substantial QT-interval prolongation (i.e., corrected QT [QTc] interval greater than 500 msec), arrhythmias requiring treatment with class Ia or class III antiarrhythmic drugs, ischemic heart disease, heart failure, history of cardiac arrest or MI, history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block, and in patients receiving concomitant drugs that decrease heart rate.(1)

Siponimod is contraindicated in patients with a recent cardiac event (e.g., MI, unstable angina, stroke, TIA, heart failure).(1)

Respiratory Effects

Siponimod may cause a decline in pulmonary function.(1) Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) have been observed as early as 3 months after initiation of siponimod therapy.(1) In a placebo-controlled trial in adults, baseline absolute FEV1 decreased by 88 mL and the percent predicted FEV1 was 2.8% lower in siponimod-treated patients compared with placebo recipients at 2 years.(1) It is not known whether the decrease in FEV1 is reversible after drug discontinuance.(1) In the principal efficacy study in patients with MS, 5 patients discontinued siponimod because of abnormal pulmonary function tests.(1) Clinical studies included MS patients with mild to moderate asthma or chronic obstructive pulmonary disease (COPD); changes in FEV1 in these patients were similar to those observed in the overall population.(1)

Perform spirometric evaluation of respiratory function during siponimod therapy if clinically indicated.(1)

Liver Injury

Elevations in hepatic enzyme concentrations have been reported in patients receiving siponimod.(1)(19)(22) In the principal efficacy study, increased hepatic aminotransferase and bilirubin concentrations were observed in 10.1% of siponimod-treated patients compared with 3.7% of placebo recipients; these abnormalities were mainly due to elevations in ALT, AST, or γ-glutamyltransferase (GGT) and generally occurred within 6 months of treatment initiation.(1)(22) Aminotransferase (ALT or AST) elevations exceeding 3 or 5 times the upper limit of normal (ULN) occurred in 5.6 or 1.4%, respectively, of siponimod-treated patients compared with 1.5 or 0.5%, respectively, of patients receiving placebo.(1) Aminotransferase elevations exceeding 8 or 10 times the ULN occurred in 0.5 or 0.2%, respectively, of siponimod-treated patients compared with none of the patients receiving placebo.(1) ALT concentrations returned to normal within approximately 1 month following discontinuance of the drug.(1) In clinical trials, siponimod was discontinued in patients with concurrent elevations of hepatic enzyme concentrations exceeding 3 times the ULN and manifestations of hepatic dysfunction; no cases of serious hepatotoxicity were reported.(1)(22)

Review recent (i.e., within last 6 months) aminotransferase and bilirubin concentrations prior to initiating siponimod therapy.(1) Check liver enzymes in patients who develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, jaundice and/or dark urine) and discontinue siponimod if clinically important liver injury is confirmed.(1)

Use siponimod with caution in patients with a history of clinically important liver disease; the risk of elevated hepatic enzyme concentrations in such patients is not known.(1)

Cutaneous Malignancies

Use of S1P receptor modulators, including siponimod, for long-term use has been associated with increased risk of cutaneous malignancies.(1) The incidence of basal cell carcinoma and squamous cell carcinoma was 1.1% and 0.2%, respectively, in the principal efficacy study, and other cutaneous malignancies, such as melanoma, Kaposi's sarcoma, and Merkel cell carcinoma have been reported in patients treated with S1P receptor modulators in the postmarketing setting.(1)

Perform skin examinations prior to or shortly after starting treatment and periodically thereafter, especially in patients with risk factors for skin cancer.(1) Monitor for and examine suspicious skin lesions.(1) Use protective clothing and sunscreen to avoid exposure to sunlight and ultraviolet (UV) light.(1) Avoid use of UV-B radiation or psoralen and UV-A (PUVA)-photochemotherapy while taking siponimod.(1)

Blood Pressure Effects

In the principal efficacy study, siponimod-treated patients experienced an average increase in systolic and diastolic blood pressure of approximately 3 and 1.2 mm Hg, respectively, compared with placebo.(1) These increases were first detected approximately 1 month following treatment initiation and persisted with continued treatment.(1) Treatment-related hypertension was reported in 12.5% of siponimod-treated patients compared with 9.2% of patients receiving placebo.(1)

Monitor blood pressure during siponimod therapy and manage as clinically indicated.(1)

Fetal/Neonatal Morbidity and Mortality

Siponimod may cause fetal harm based on its mechanism of action and animal findings.(1) Embryofetal toxicity and teratogenicity have been demonstrated in animals at dose exposures as low as 2 times those achieved with the maximum recommended human dosage of 2 mg daily.(1)

Women of childbearing potential should avoid pregnancy and use effective contraception during siponimod therapy and for 10 days after the drug is discontinued.(1)

Posterior Reversible Encephalopathy Syndrome

Although not reported in premarketing studies with siponimod, cases of posterior reversible encephalopathy syndrome (PRES) have occurred rarely in patients receiving another S1P receptor modulator.(1) If a patient develops any unexpected neurological or psychiatric signs or symptoms (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, increased intracranial pressure, accelerated neurological deterioration), a complete physical and neurological examination should be performed promptly; MRI evaluation also should be considered.(1)

Although symptoms of PRES usually are reversible, they may evolve into ischemic stroke or cerebral hemorrhage.(1) Therefore, a delay in diagnosis and treatment of PRES may lead to permanent neurological sequelae.(1) If PRES is suspected, discontinue siponimod therapy.(1)

Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies

When switching patients from drugs with prolonged immune effects to siponimod, the duration and mechanism of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while also minimizing the risk of disease reactivation.(1)

Initiating siponimod therapy after treatment with alemtuzumab is not recommended.(1)

Severe Increase in Disability Following Discontinuance of Therapy

Severe exacerbation of disease, including rebound disease, has been reported rarely after discontinuance of another S1P receptor modulator.(1) The possibility that this effect can also occur with siponimod should be considered.(1) Following discontinuance of siponimod therapy, observe patients for a severe increase in disability and initiate appropriate treatment as clinically indicated.(1)

Monitor for the development of immune reconstitution inflammatory syndrome (PML-IRIS) after discontinuing sipomimod in patients diagnosed with PML.(1)

Immunosuppression Following Discontinuance of Therapy

Siponimod remains in the blood for up to 10 days following the last dose of the drug.(1) Initiating other drugs during this period may result in concomitant exposure to siponimod.(1) Although lymphocyte counts return to the normal range in 90% of patients within 10 days following discontinuance of siponimod, pharmacodynamic effects (e.g., decreased peripheral lymphocyte count) may persist for up to 3–4 weeks.(1) Use of immunosuppressants within this period may result in additive immunosuppressive effects.(1)

Specific Populations

Pregnancy

Based on animal data and its mechanism of action, siponimod can cause fetal harm.(1) A pregnancy registry has been established to monitor outcomes in women exposed to siponimod during pregnancy.(1) Healthcare providers can enroll pregnant patients in the MotherToBaby Pregnancy Study in Multiple Sclerosis by calling 1-877-311-8972, visiting ([Web], or by emailing MotherToBaby@health.ucsd.edu.1)

Lactation

It is not known whether siponimod is distributed into human milk; the drug is distributed into milk in rats.(1) The effects of siponimod on nursing infants or on milk production are not known.(1) Consider the benefits of breast-feeding along with the importance of siponimod to the woman and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.(1)

Females and Males of Reproductive Potential

Prior to starting treatment, counsel females of childbearing potential on the potential for serious risk to the fetus and the need for effective contraception during treatment with siponimod.(1) The potential risk to the fetus may persist for approximately 10 days after stopping treatment; therefore, effective contraception is required during this time.(1) Animal studies found increased mortality, abnormal lung histopathology, and reduced body weight gain at mid and high doses.(1) Neurobehavioral impairment and reduced immune function were also observed.(1)

Pediatric Use

Safety and efficacy of siponimod have not been established in pediatric patients.(1) Siponimod has been associated with juvenile toxicity in animal studies.(1)

Geriatric Use

Clinical studies of siponimod did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently than younger patients.(1) Other clinical experience has not identified differences in response between geriatric patients and younger adults.(1)

Siponimod should be used with caution in geriatric patients.(1)

Hepatic Impairment

Results of a study in healthy individuals indicate that the pharmacokinetics of siponimod are not substantially altered by hepatic impairment.(1)(8) Following oral administration of a single 0.25-mg dose of siponimod in patients with moderate (Child-Pugh score 7–9) or severe (Child-Pugh score 10–15) hepatic impairment, systemic exposure of unbound siponimod was increased by 15 or 50%, respectively, compared with individuals without hepatic impairment; these differences were not considered to be clinically important.(1)(8) Hepatic impairment had no effect on mean half-life of siponimod.(1) Dosage adjustment is therefore not necessary in patients with hepatic impairment.(1)

Because siponimod can cause liver injury, patients with severe hepatic impairment should be closely monitored during therapy.(1)

Renal Impairment

Results of a study in healthy individuals indicate that the pharmacokinetics of siponimod are not substantially altered by renal impairment.(1)(7) Following oral administration of a single 0.25-mg dose of siponimod, systemic exposure of unbound siponimod was increased slightly by 33% in individuals with severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/minute) compared with individuals without renal impairment; however, this difference was not considered to be clinically important.(1)(7) Renal impairment had no effect on peak plasma concentrations and mean half-life of siponimod.(1) Dosage adjustment is therefore not necessary in patients with renal impairment.(1)

Siponimod has not been studied in patients with end-stage renal disease or those requiring hemodialysis; however, hemodialysis is not expected to affect siponimod concentrations because the drug is highly bound to plasma proteins.(1)

Pharmacogenomics

Genetic polymorphism of cytochrome P-450 (CYP) isoenzyme 2C9 has a substantial impact on metabolism of siponimod.(1)(10)(11) The variant *2 and *3 alleles are associated with reduced CYP2C9 activity and impaired drug metabolism.(10)(11)

Based on pharmacokinetic simulations, systemic exposure of siponimod is expected to be increased by 25, 61, 91, or 285% in individuals with CYP2C9*2/*2, *1/*3, *2/*3, or *3/*3 genotypes, respectively, compared with individuals with the *1/*1 (wild-type) genotype; systemic exposure of siponimod is expected to be similar between CYP2C9*1/*2 and CYP2C9*1/*1 genotypes.(1)(10) Following administration of a single 0.25-mg dose of siponimod in individuals with CYP2C9*2/*3 or *3/*3 genotypes, systemic exposure of siponimod was approximately twofold or fourfold higher, respectively, and peak plasma concentrations were 21 or 16% higher, respectively, than in individuals with the *1/*1 genotype.(1)(10)(11) In addition, mean half-life was prolonged in individuals with CYP2C9*2/*3 or *3/*3 genotypes (51 or 126 hours, respectively) compared with individuals with the *1/*1 genotype (28 hours).(1)(10)(11)

CYP2C9 genotype should be determined in all patients prior to initiation of siponimod therapy.(1) Siponimod is contraindicated in patients with the CYP2C9*3/*3 genotype because of the possibility of substantially increased plasma concentrations of the drug.(1) The *2 and *3 variants are more prevalent in patients of European or Asian ancestry, while *5, *6, *8, and *11 are more prevalent in people of African ancestry.(1) The CYP2C9*3/*3 genotype is present in approximately 0.5% of white patients and 1% of Asian patients; it is less prevalent in other racial/ethnic groups.(1) A reduced dosage of siponimod is recommended in patients with CYP2C9*1/*3 or *2/*3 genotypes.(1) The *1/*3 and *2/*3 genotypes are present in approximately 2% to 20% of patients depending on their ancestry.(1)

The effects of certain pharmacokinetic drug interactions also are dependent on CYP2C9 genotype.(1)(10) In patients with reduced CYP2C9 metabolic activity (e.g., CYP2C9 genotypes *1/*3 and *2/*3), CYP3A4 inhibition or induction is expected to have a larger effect on siponimod exposure.(1)

Less frequently occurring CYP2C9 polymorphisms (e.g., *5, *6, *8, and *11) may result in reduced or loss of enzyme function.(1) However, the pharmacokinetic impact of variants other than *2 and *3 has not been studied.(1) Variants that result in a loss of CYP2C9 function (e.g., *6) are expected to have similar pharmacokinetic effects as the *3 variant.(1)

Common Adverse Effects

Adverse effects reported in >10% of patients receiving siponimod in clinical studies include headache, hypertension, and increased hepatic aminotransferase concentrations.(1)

Go to Drug Interactions [DI]

Drug Interactions

Siponimod is metabolized principally by cytochrome P-450 (CYP) isoenzyme 2C9 and, to a lesser extent, by CYP3A4.(1)(9)

Siponimod does not appear to exhibit clinically important inhibition or induction of CYP isoenzymes or major transporters (e.g., breast cancer resistance protein [BCRP], P-glycoprotein).(1)(3)

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or Inducers of CYP3A4

The effect of CYP3A4 inhibition or induction on siponimod pharmacokinetics is dependent on CYP2C9 genotype; in patients with genotypes associated with reduced CYP2C9 metabolic activity (e.g., CYP2C9*1/*3, CYP2C9*2/*3), CYP3A4 inhibition or induction is expected to have a larger effect.(1)(10)

Concomitant use of siponimod and a moderate (e.g., modafinil, efavirenz) or potent CYP3A4 inducer is not recommended in patients with the CYP2C9*1/*3 or *2/*3 genotype.(1)

Inhibitors or Inducers of CYP2C9

Caution is advised if siponimod is used concomitantly with a moderate CYP2C9 inhibitor or inducer.(1)

Inhibitors of CYP2C9 and CYP3A4

Systemic exposure of siponimod may be substantially increased if used concomitantly with drugs that cause moderate inhibition of CYP2C9 and moderate or potent inhibition of CYP3A4.(1) This dual inhibition of CYP2C9 and CYP3A4 can occur with the use of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a combination of a moderate CYP2C9 inhibitor and a moderate or potent CYP3A4 inhibitor.(1) Concomitant use of siponimod under such conditions is not recommended.(1)

Inducers of CYP2C9 and CYP3A4

Systemic exposure of siponimod may be substantially decreased if used concomitantly with drugs that cause moderate induction of CYP2C9 and potent induction of CYP3A4.(1) This dual induction of CYP2C9 and CYP3A4 can occur with the use of a moderate CYP2C9/potent CYP3A4 dual inducer (e.g., rifampin, carbamazepine) or a combination of a moderate CYP2C9 inducer and a potent CYP3A4 inducer.(1) Concomitant use of siponimod under such conditions is not recommended.(1)

Drugs that Decrease Heart Rate

Severe bradycardia and heart block may occur during initiation of siponimod therapy in patients receiving drugs that decrease heart rate (e.g., β-adrenergic blocking agents, digoxin, diltiazem, ivabradine, verapamil).(1) Clinical experience with siponimod in such patients is limited; if treatment with siponimod is considered in patients receiving heart rate-lowering drugs, consultation with a cardiologist is recommended.(1)

β-Adrenergic Blocking Agents

Because of the potential for additive bradycardic effects, siponimod should be initiated with caution in patients receiving β-adrenergic blocking agents.(1) In an interaction study in healthy individuals, initiation of siponimod in individuals receiving propranolol resulted in additive negative chronotropic effects; such effects were less pronounced when propranolol was initiated in individuals receiving siponimod.(1)(13)

Patients receiving β-adrenergic blocking therapy should have their resting heart rate checked prior to initiating concomitant siponimod therapy.(1) Siponimod may be initiated in patients receiving stable dosages of a β-adrenergic blocking agent if their resting heart rate is greater than 50 beats per minute.(1) In patients with a resting heart rate of 50 beats per minute or less, β-adrenergic blocking therapy should be interrupted and siponimod therapy may be initiated when baseline heart rate exceeds 50 beats per minute; treatment with the β-adrenergic blocking agent can be reinitiated after siponimod has been titrated up to the target maintenance dosage.(1)

Treatment with β-adrenergic blocking agents may be initiated in patients receiving stable dosages of siponimod.(1)

Drugs Associated with QT Prolongation

Additive effects on heart rate may occur with concomitant use of siponimod and QT-prolonging drugs with arrhythmogenic potential.(1) Siponimod has not been studied in patients concurrently treated with drugs that prolong the QT interval.(1)

Siponimod generally should not be initiated in patients receiving QT-prolonging drugs with known arrhythmogenic activity.(1) If treatment with siponimod is considered in patients receiving such QT-prolonging drugs, consultation with a cardiologist is recommended.(1)

Antiarrhythmic Agents

Cases of torsades de pointes have occurred in patients with bradycardia receiving class Ia (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.(1) A cardiologist should be consulted before initiating siponimod in patients receiving these antiarrhythmic agents.(1)

Antifungal Agents

Fluconazole

In healthy individuals with the CYP2C9*1/*1 genotype, concomitant administration of siponimod and fluconazole (a dual moderate CYP3A4/CYP2C9 inhibitor) increased area under the concentration-time curve (AUC) of siponimod by approximately twofold and increased peak plasma concentrations of the drug by approximately 10%; mean terminal half-life of siponimod was prolonged by 50%.(1)(11)

Based on pharmacokinetic modeling, coadministration of siponimod and fluconazole is expected to result in a twofold to fourfold increase in the AUC of siponimod across different CYP2C9 genotypes.(1)(10) Concomitant use of siponimod and fluconazole is not recommended.(1)

Itraconazole

Although increased systemic exposure of siponimod is expected when the drug is used concomitantly with itraconazole (a potent CYP3A4 inhibitor), slightly decreased siponimod exposures were observed when these drugs were coadministered in individuals with CYP2C9*1/*2 or *1/*3 genotypes, indicating possible contribution of other metabolic pathways.(10)(15)

Antineoplastic, Immunomodulatory, or Immunosuppressive Agents

Siponimod has not been studied in combination with antineoplastic, immunomodulatory, or immunosuppressive therapies; however, caution is advised and the potential for additive immunosuppressive effects should be considered during and in the weeks following administration of such concomitant therapy.(1) Because some drugs have prolonged immune effects, the half-lives and mechanisms of action of these drugs must be considered to avoid unintended additive immunosuppressive effects.(1)

Alemtuzumab

Because of the characteristics and duration of alemtuzumab's immunosuppressive effects, initiation of siponimod therapy after alemtuzumab treatment is not recommended.(1)

Glatiramer Acetate and Interferon Beta

The manufacturer states that siponimod therapy generally can be started immediately after discontinuance of glatiramer acetate or interferon beta therapy.(1)

Efavirenz

Based on pharmacokinetic modeling, coadministration of siponimod and efavirenz (a moderate CYP3A4 inducer) is expected to decrease AUC of siponimod by up to 52% across CYP2C9 genotypes.(1) Concomitant use of siponimod and efavirenz is not recommended in patients with CYP2C9*1/*3 or *2/*3 genotypes.(1)

Hormonal Contraceptives

Siponimod did not have any clinically important effects on the pharmacokinetics or pharmacodynamics (e.g., effect on follicle size and hormone levels) of an oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women with the CYP2C9*1/*1 genotype.(1)(16)

Siponimod is not expected to have clinically important pharmacokinetic effects on oral contraceptives containing other progestins.(1)

Rifampin

In healthy individuals with the CYP2C9*1/*1 genotype, concomitant administration of siponimod and rifampin (a dual moderate CYP2C9/potent CYP3A4 inducer) decreased AUC and peak plasma concentrations of siponimod by 57 and 45%, respectively.(1)(12) A similar interaction is expected in individuals with other CYP2C9 genotypes.(10) Concomitant use of siponimod and rifampin is not recommended.(1)

Vaccines

Vaccinations may be less effective during and for up to 4 weeks after discontinuance of siponimod therapy; therefore, the manufacturer recommends interruption of siponimod therapy 1 week prior to and for 4 weeks after administration of a planned vaccine.(1)

In a placebo-controlled study in healthy individuals, siponimod had limited effect on the immune response to influenza and pneumococcal 23-valent vaccines.(14)

Because of the risk of infection, administration of live attenuated vaccines should be avoided during siponimod therapy and for up to 4 weeks following discontinuance of the drug.(1)

Initiation of siponimod therapy should be delayed for at least 1 month after vaccination with varicella zoster virus (VZV).(1)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Siponimod can only be obtained through designated specialty pharmacies.(17) Clinicians may contact the manufacturer at 877-629-9368 or consult the Mayzent® website for additional information.(17)

Siponimod Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

7 tablets, film-coated, 0.25 mg (of siponimod)

Mayzent® 1-mg Starter Pack (available as blister pack intended only for patients who will receive the 1-mg maintenance dosage)

Novartis

12 tablets, film-coated, 0.25 mg (of siponimod)

Mayzent® 2-mg Starter Pack (available as blister pack intended only for patients who will receive the 2-mg maintenance dosage)

Novartis

Tablets, film-coated

0.25 mg (of siponimod)

Mayzent®

Novartis

1 mg (of siponimod)

Mayzent®

Novartis

2 mg (of siponimod)

Mayzent®

Novartis

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions October 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.