Siponimod Fumarate (Monograph)

Brand name: Mayzent
Drug class: Sphingosine 1-Phosphate (S1P) Agents

Medically reviewed by Drugs.com on Oct 10, 2024. Written by ASHP.

Introduction

Selective sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Siponimod Fumarate

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Siponimod is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

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. 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 therapy.

Efficacy not established in patients with progressive forms of MS with nonactive (nonrelapsing) disease.

Siponimod Fumarate Dosage and Administration

General

Pretreatment Screening

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

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

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

• 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. Do not initiate treatment in patients with an active infection until the infection is resolved.

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

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

• Verify pregnancy status before initiating siponimod therapy.

• 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. However, a specific FDA-approved CYP2C9 genotyping test for siponimod currently is not available. 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.

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

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 MI or heart failure whenever therapy is initiated or reinitiated (after discontinuance for more than 4 days). (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.

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

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

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

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

• Closely monitor patients with severe hepatic impairment.

Administration

Oral Administration

Administer orally once daily without regard to meals. Administer tablets whole; do not split, crush, or chew.

First-dose Monitoring in Patients with Cardiac Conditions

First-dose monitoring is recommended in patients with baseline sinus bradycardia (heart rate <55 bpm), first- or second-degree (Mobitz type I) AV block, or a history of MI or heart failure.

Administer first dose in a setting with available resources to manage symptomatic bradycardia.

Observe patients for signs and symptoms of bradycardia for ≥6 hours after first dose; measure heart rate and BP every hour. Obtain ECG at the end of observation period.

Continue monitoring beyond 6 hours in the following situations until abnormal finding has resolved: heart rate 6 hours postdose <45 bpm, heart rate 6 hours postdose is at the lowest postdose value (suggesting that maximum pharmacodynamic effect on the heart may not have occurred), or ECG 6 hours postdose shows new-onset second-degree or higher AV block.

If postdose symptomatic bradycardia, bradyarrhythmia, or conduction-related symptoms occur, or if 6 hour postdose ECG shows new-onset second-degree or higher AV block or corrected QT (QT_c) interval ≥500 msec, initiate appropriate management, including continuous ECG monitoring; continue observation until symptoms resolve if no pharmacologic intervention is required. If pharmacologic intervention is required, institute continuous overnight ECG monitoring and repeat first-dose monitoring procedures with the second dose.

Consult a cardiologist to determine most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation if considering siponimod in patients with certain preexisting cardiovascular or cerebrovascular conditions, patients with prolonged QT_c interval prior to initiating therapy or during the 6-hour observation period, patients with additional risk factors for QT-interval prolongation (e.g., those receiving concomitant QT-prolonging drugs with known risk of torsades de pointes), or patients receiving concomitant drugs that decrease heart rate or AV conduction.

Reinitiation of Therapy Following Treatment Interruption

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

Dosage

Dosage of siponimod fumarate is expressed in terms of siponimod.

Dosage is based on CYP2C9 genotype.

Initiate therapy with low dosage and titrate gradually.

If a dose is missed for >24 hours during initial titration period, must reinitiate therapy with day 1 of the titration regimen. If ≥4 consecutive daily doses are missed during maintenance therapy (i.e., after initial titration is complete), must retitrate dosage and perform first-dose monitoring.

Adults

Multiple Sclerosis

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

Oral

Recommended maintenance dosage is 2 mg once daily after appropriate titration.

Initiate therapy 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. Begin maintenance dosage of 2 mg daily on day 6.

Manufacturer states to use the Mayzent 2-mg Starter Pack in patients who will be titrated to the 2-mg maintenance dosage.

Multiple Sclerosis

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

Oral

Recommended maintenance dosage is 1 mg once daily after appropriate titration.

Titrate 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. Begin maintenance dosage of 1 mg daily on Day 5.

Manufacturer states to use the Mayzent 1-mg Starter Pack in patients who will be titrated to the 1-mg maintenance dosage.

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.

Renal Impairment

Dosage adjustment not necessary.

Geriatric Patients

Use caution when selecting dosage in geriatric patients considering the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in these patients.

Cautions for Siponimod Fumarate

Contraindications

• CYP2C9*3/*3 genotype.

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

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

Warnings/Precautions

Infectious Complications

Siponimod causes dose-dependent reductions in peripheral lymphocyte count to 20–30% of baseline values. May increase risk of infections; serious and sometimes fatal infections reported rarely.

Before initiating treatment, review a recent (i.e., within 6 months or after discontinuance of previous therapy) CBC. Delay initiation of therapy in patients with severe active infections until infection has resolved.

Monitor patients for signs and symptoms of infection during and for 3–4 weeks after discontinuing therapy. If a serious infection develops, consider interruption of therapy and manage infection as clinically indicated.

Concomitant use of siponimod with antineoplastic, immunosuppressive (including corticosteroids), or immunomodulating therapies may increase risk of immunosuppression.

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, reported with another S1P receptor modulator. Cryptococcal meningitis reported rarely with siponimod. If signs and symptoms consistent with cryptococcal meningitis occur, promptly evaluate and treat patient; interrupt siponimod therapy until infection excluded. If cryptococcal meningitis is diagnosed, initiate appropriate treatment.

Herpetic infections reported, including VZV reactivation leading to varicella zoster meningitis or meningoencephalitis. In patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV, test for antibodies to VZV before initiating siponimod. VZV vaccination of antibody-negative patients is recommended; postpone initiation of siponimod for 4 weeks following vaccination.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in MS patients treated with S1P receptor modulators, including siponimod. PML typically occurs in immunocompromised patients and usually leads to death or severe disability. Longer treatment duration increases PML risk. 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

Monitor patients closely for clinical symptoms or MRI findings that may be suggestive of PML. MRI signs of PML may be apparent before clinical manifestations develop. If PML suspected, perform appropriate diagnostic evaluation; if PML is confirmed, discontinue therapy.

Immune reconstitution inflammatory syndrome (IRIS) reported in MS patients treated with S1P receptor modulators whodeveloped PML and subsequently discontinued treatment. Time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitor for IRIS and initiate appropriate treatment.

Macular Edema

Macular edema reported, usually within first 4 months of treatment.

Perform an ophthalmologic evaluation of the fundus, including the macula, at baseline, periodically during therapy, and if there is any change in vision. Continued therapy in patients with macular edema not evaluated; macula edema over an extended period of time can lead to permanent vision loss; weigh potential benefits and risks for the individual patient. Risk of recurrence after rechallenge not evaluated.

Increased risk of macular edema in patients with diabetes mellitus or a history of uveitis; monitor such patients with regular ophthalmologic evaluations during therapy.

Bradyarrhythmia and AV Conduction Delays

Transient decreases in heart rate and AV conduction delays observed during initial dosing.

After first dose, heart rate decrease begins within 1 hour and peaks in approximately 3–4 hours. Heart rate continues to decrease with upward dosage titration; maximal decrease from baseline occurs on days 5–6. Largest postdose decline in hourly mean heart rate observed on day 1, decreasing an average of 5–6 bpm; declines on subsequent days less pronounced. With continued dosing, heart rate begins increasing after 6 days and reaches baseline levels within 10 days.

Bradycardia generally was asymptomatic; few patients experienced symptoms, including dizziness or fatigue. Heart rate <40 bpm observed rarely.

AV conduction delays follow a similar temporal pattern during dosage titration. Conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not result in discontinuance of siponimod therapy.

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

Not recommended in patients with a history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea; bradycardia may be poorly tolerated in such patients. Individualize use in patients with a history of recurrent syncope or symptomatic bradycardia based on assessment of potential risks versus benefits. If treatment is considered in any of these patients, consult a cardiologist for monitoring recommendations.

Consult a cardiologist if treatment is considered in patients with substantial QT-interval prolongation (i.e., corrected QT [QT_c] interval >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 taking concomitant drugs that decrease heart rate.

Contraindicated in patients with a recent cardiovascular event (e.g., MI, unstable angina, stroke, TIA, heart failure).

Respiratory Effects

May decrease pulmonary function tests. Dose-dependent reductions in FEV₁ observed as early as 3 months after initiating therapy. Not known whether these changes are reversible after discontinuing siponimod. In clinical studies, changes in FEV₁ were similar in patients with asthma or COPD and the overall population.

Assess pulmonary function (e.g., spirometry) during siponimod therapy if clinically indicated.

Liver Injury

May increase hepatic enzyme concentrations (ALT, AST, or γ-glutamyltransferase [GGT]). Most elevations occur within 6 months. In clinical studies, elevated ALT concentrations returned to normal within approximately 1 month after discontinuance of the drug; no cases of serious hepatotoxicity reported.

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

Cutaneous Malignancies

Associated with increased risk of basal cell carcinoma and squamous cell carcinoma. Other cutaneous malignancies reported.

Perform skin examinations prior to or shortly after starting treatment and periodically thereafter, especially in patients with risk factors for skin cancer.

Use protective clothing and sunscreen to avoid exposure to sunlight and ultraviolet (UV) light. Avoid use of UV-B radiation or psoralen and UV-A (PUVA)-photochemotherapy.

Blood Pressure Effects

May increase blood pressure. In clinical studies, average increases over placebo in SBP and DBP were approximately 3 and 1.2 mm Hg, respectively; increases were first detected approximately 1 month following treatment initiation and persisted with continued treatment.

Monitor blood pressure during therapy and manage as clinically indicated.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity observed in animals.

Avoid pregnancy during therapy. Females of childbearing potential should use effective contraception during and for 10 days after drug discontinuance.

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES reported in patients receiving another S1P receptor modulator.

Monitor for any unexpected neurological or psychiatric signs or symptoms (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, increased intracranial pressure, accelerated neurological deterioration). Promptly perform complete physical and neurological examination if such manifestations occur and consider MRI evaluation.

Although symptoms usually reversible, may evolve into ischemic stroke or cerebral hemorrhage; a delay in diagnosis and treatment of PRES may lead to permanent neurologic sequelae.

If PRES is suspected, discontinue siponimod.

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

When switching patients from drugs with prolonged immune effects to siponimod, consider the duration and mechanism of action of these drug to avoid unintended additive immunosuppressive effects while also minimizing risk of disease reactivation.

Severe Increase in Disability Following Discontinuance

Severe exacerbation of disease, including rebound disease, reported rarely after discontinuance of another S1P receptor modulator; consider possibility that this effect can also occur with siponimod. Observe patients for severe increase in disability following discontinuance of siponimod and institute appropriate treatment as clinically indicated.

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

Immunosuppression Following Discontinuance

Siponimod remains in the blood for up to 10 days following discontinuance. Initiating other drugs during this period warrants same considerations needed for concomitant administration (e.g., risk of additive immunosuppressive effects). Pharmacodynamic effects (e.g., decreased lymphocyte counts) may persist for up to 3–4 weeks.

Specific Populations

Pregnancy

No adequate data in pregnant women; may cause fetal harm.

A pregnancy registry has been established to monitor outcomes in women exposed to siponimod during pregnancy. 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.

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Potential effects on nursing infants or on milk production not known. Consider known benefits of breast-feeding along with mother's clinical need for siponimod and any potential adverse effects of the drug or disease on the infant.

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. Effective contraception is required for approximately 10 days after stopping treatment.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age. Use with caution.

Hepatic Impairment

Clinically important changes in pharmacokinetics not expected. Dosage adjustment not necessary.

Closely monitor patients with severe hepatic impairment for liver injury; discontinue therapy if liver injury occurs.

Renal Impairment

Clinically important changes in pharmacokinetics not expected. Dosage adjustment not necessary.

Not studied in patients with end-stage renal disease or those requiring hemodialysis; however, hemodialysis not expected to affect siponimod concentrations.

Pharmacogenomics

Genetic polymorphism of CYP2C9 has a substantial impact on metabolism of siponimod. The variant *2 and *3 alleles are associated with reduced CYP2C9 enzyme activity and impaired drug metabolism.

Determine CYP2C9 genotype prior to initiating therapy. Siponimod is contraindicated in patients with CYP2C9*3/*3 genotype because of possibility of substantially increased plasma drug concentrations. A reduced dosage of siponimod is recommended in patients with CYP2C9*1/*3 or *2/*3 genotypes.

Certain pharmacokinetic drug interactions also are dependent on CYP2C9 genotype.

Common Adverse Effects

Headache, hypertension, increased hepatic aminotransferase concentrations.

Drug Interactions

Metabolized principally by CYP2C9 and, to a lesser extent, by CYP3A4.

Does not appear to inhibit or induce major CYP isoenzymes or transporters.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors or inducers: The effect on siponimod pharmacokinetics is dependent on CYP2C9 genotype; in patients with genotypes associated with reduced CYP2C9 activity (e.g., CYP2C9 *1/*3 or *2/*3), CYP3A4 inhibition or induction is expected to have a larger effect. Concomitant use of siponimod and a moderate (e.g., modafinil, efavirenz) or potent CYP3A4 inducer not recommended in patients with CYP2C9 *1/*3 or *2/*3 genotypes.

CYP2C9 and CYP3A4 inhibitors: Possible substantially increased systemic exposure of siponimod if used concomitantly with drugs that cause moderate inhibition of CYP2C9 and moderate or potent inhibition of CYP3A4. This dual inhibition of CYP2C9 and CYP3A4 can occur with 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. Concomitant use not recommended.

CYP2C9 inhibitors or inducers: Caution is advised if siponimod is used concomitantly with a moderate CYP2C9 inhibitor or inducer.

CYP2C9 and CYP3A4 inducers: Possible substantially decreased systemic exposure of siponimod if used concomitantly with drugs that cause moderate induction of CYP2C9 and potent induction of CYP3A4. This dual induction of CYP2C9 and CYP3A4 can occur with 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. Concomitant use not recommended.

Drugs that Decrease Heart Rate

Limited experience. Concomitant use during siponimod initiation may cause severe bradycardia or heart block.

Concomitant use with drugs that decrease heart rate generally not recommended. If such concomitant therapy is being considered, consult a cardiologist.

Drugs Associated with QT Prolongation

Potential additive effects on heart rate with concomitant use of QT-prolonging drugs with arrhythmogenic potential.

Siponimod generally should not be initiated in patients receiving QT-interval prolonging drugs with known arrhythmogenic activity. If such concomitant therapy is being considered, consult a cardiologist.

Antineoplastic, Immunomodulatory, or Immunosuppressive Agents

Additive immune system effects may occur. Consider duration and mechanism of these drugs when initiating siponimod therapy.

Specific Drugs

Siponimod Fumarate Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is approximately 84%.

Peak plasma concentrations attained about 4 hours following oral administration (range: 3–8 hours).

Siponimod concentrations increase dose-proportionally over dosage range of 0.3–20 mg daily.

Food

Food delays time to peak plasma concentrations by approximately 2–3 hours, but does not alter systemic exposure.

Special Populations

Moderate hepatic impairment (Child-Pugh score 7–9): Systemic exposure of unbound siponimod is 15% higher; not expected to be clinically important.

Severe hepatic impairment (Child-Pugh score 10–15): Systemic exposure of unbound siponimod is 50% higher; not expected to be clinically important.

Severe renal impairment (eGFR 30–59 mL per minute): Systemic exposure of unbound siponimod is 33% higher; not expected to be clinically important.

Systemic exposure of siponimod is increased in patients with variant CYP2C9 genotypes as follows:

CYP2C9*2/*2 genotype: Systemic exposure is expected to be 25% higher compared with *1/*1 (wild-type) genotype.

CYP2C9*1/*3 genotype: Systemic exposure is expected to be 61% higher compared with *1/*1 genotype.

CYP2C9*2/*3 genotype: Systemic exposure is approximately twofold higher and peak plasma concentrations 21% higher compared with *1/*1 genotype.

CYP2C9*3/*3 genotype: Systemic exposure is approximately fourfold higher and peak plasma concentrations 16% higher compared with *1/*1 genotype.

Distribution

Extent

Crosses blood-brain barrier.

Distributed into milk in rats; not known whether distributes into human milk.

Plasma Protein Binding

>99.9%.

Elimination

Metabolism

Extensively metabolized, principally by CYP2C9 and, to a lesser extent, by CYP3A4; fractional contributions of CYP2C9 and CYP3A4 are dependent on CYP2C9 genotype.

Genetic polymorphism of CYP2C19 can substantially affect metabolism.

Major metabolites M3 and M17 not expected to be pharmacologically active.

Elimination Route

Principally by biliary/fecal excretion, as metabolites.

Unchanged drug not detected in urine.

Half-life

Approximately 30 hours.

Special Populations

Mean half-life is prolonged to 51 hours in patients with CYP2C9*2/*3 and 126 hours in patients with CYP2C9*3/*3 genotypes.

Stability

Storage

Oral

Tablets

Unopened containers: Store in the refrigerator at 2–8°C; after container is opened, may store at room temperature (20–25°C) for up to 3 months.

Opened blister packs (i.e., Mayzent 1-mg Starter Pack and Mayzent 2-mg Starter Pack): 20–25°C for up to 3 months; do not refrigerate after opening.

Opened bottles: 20–25°C for up to 3 months; do not refrigerate after opening.

Actions

• S1P receptor modulator; binds selectively and with high affinity to S1P receptor subtypes 1 and 5.

• S1P receptors are expressed in multiple organs and systems, and are involved in the regulation of a variety of physiological processes including immune, cardiac, and neurologic function.

• S1P1 receptor regulates lymphocyte egress from peripheral lymphoid organs and is essential for lymphocyte recirculation. Modulation of the S1P1 receptor blocks capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.

• Exact mechanism in MS not known, but may involve reduction of lymphocyte migration into the CNS.

• Dose-dependent reduction in peripheral blood lymphocyte counts occurs within 6 hours of first dose and continues with daily dosing, reaching a nadir of 20–30% of baseline. Lymphocyte counts remain low with continued daily dosing. Following discontinuance, lymphocyte counts generally return to normal within 10 days; however, decreased levels may persist for up to 3–4 weeks after last dose.

Advice to Patients

• Advise patients to not discontinue siponimod without first consulting a clinician. Advise patients to inform their physician if they accidently take more than the prescribed dose.

• Increased risk of infections. Advise patients to immediately contact their clinician if they develop any symptoms of infection (e.g., fever, chills, fatigue, body aches, nausea, vomiting) during therapy and the 3–4 weeks following discontinuance of the drug. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

• Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred with siponimod; PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Inform patients that typical symptoms associated with PML are diverse and progress over days to weeks. Advise patients to contact their clinician if they develop any symptoms suggestive of PML including 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.

• Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during siponimod therapy. Siponimod therapy should be interrupted 1 week prior to and until 4 weeks after a planned vaccination. Advise patients to delay siponimod therapy for at least 1 month after varicella zoster virus (VZV) vaccination.

• Risk of macular edema. Advise patients to contact their clinician if they experience any changes in their vision during siponimod therapy. Inform patients that their risk of developing macular edema is higher if they have diabetes mellitus or a history of uveitis.

• Inform patients that a transient decrease in heart rate can occur when siponimod is initiated and that dosage titration is required to minimize this effect. Retitration of the dosage also is required if a dose is missed for more than 24 hours during the titration period or if 4 or more consecutive daily maintenance doses are missed. Inform patients with certain preexisting cardiac conditions that they will need to be observed in their clinician's office or other medical facility for at least 6 hours after the first dose and that such monitoring is also required after reinitiation of therapy if treatment is interrupted or discontinued for certain periods.

• Siponimod can cause adverse respiratory effects. Advise patients to contact their clinician if they experience any trouble breathing such as new onset or worsening dyspnea.

• Risk of increased liver enzymes. Advise patients to contact their clinician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during siponimod therapy.

• Risk of basal cell carcinoma and reports of melanoma and squamous cell carcinoma. Advise patients that any new suspicious skin lesion should be evaluated. Advise patients to limit sunlight and ultraviolet (UV) light exposure by wearing protective clothing and sunscreen.

• Risk of fetal harm. Discuss possible fetal risk with females of childbearing potential and advise such females of the need for effective contraception during and for 10 days after discontinuance of siponimod.

• Risk of posterior reversible encephalopathy syndrome (PRES). Advise patients to immediately inform their clinician if they experience sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.

• Severe increase in disability has been reported after discontinuation of another sphingosine 1-phosphate (S1P) receptor modulator. Advise patients to contact their physician if they develop worsening symptoms of multiple sclerosis (MS) following discontinuance of siponimod.

• Advise patients that immunosuppressive effects of siponimod (e.g., decreased peripheral lymphocyte count) may last up to 3–4 weeks after discontinuance of the drug.

• Inform patients that siponimod may be stored at room temperature for up to 3 months. If storage beyond 3 months is required, containers should remain unopened and stored in the refrigerator until use.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

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. Clinicians may contact the manufacturer at 877-629-9368 or consult the Mayzent website for additional information.

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