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Siponimod

Class: Immunomodulatory Agents
- Sphingosine 1-Phosphate (S1P) Receptor Modulators
- Immunomodulators
Chemical Name: 1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid
Molecular Formula: C29H35F3N2O3
CAS Number: 1220909-40-9
Brands: Mayzent

Medically reviewed by Drugs.com. Last updated on May 25, 2020.

Introduction

Selective sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).1 2 4

Uses for Siponimod

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.1 2 3

Siponimod is one of several disease-modifying therapies used in the management of relapsing forms of MS.3 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 77 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.76 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.76 77

Efficacy of siponimod not established in patients with progressive forms of MS with nonactive (nonrelapsing) disease.3

Siponimod Dosage and Administration

General

  • Perform baseline ophthalmologic examination of the fundus, including the macula, prior to initiating therapy.1 (See Macular Edema under Cautions.)

  • Obtain ECG prior to initiating therapy.1 (See Bradyarrhythmia and AV Conduction Delays under Cautions.)

  • Review recent (i.e., ≤6 months or after discontinuance of previous therapy) aminotransferase and bilirubin concentrations and CBC prior to initiating therapy.1 (See Liver Injury and also see Infectious Complications under Cautions.)

  • Test patients for antibodies to varicella zoster virus (VZV) prior to initiating therapy; VZV vaccination recommended in antibody-negative patients.1 (See Infectious Complications under Cautions.)

Pharmacogenetic Testing

  • Determine CYP2C9 genotype prior to initiating therapy (specific FDA-approved CYP2C9 genotyping test for siponimod therapy currently not available).1 (See Pharmacogenomics under Cautions.)

  • Do not initiate therapy in patients with CYP2C9*3/*3 genotype.1

  • Reduced dosage recommended in patients with CYP2C9*1/*3 or *2/*3 genotypes.1

Restricted Distribution

  • Obtain siponimod only through specialty pharmacies.17

  • Contact manufacturer at 877-629-9368 or consult Mayzent website ([Web]) for additional information.17

Administration

Oral Administration

Administer orally once daily without regard to meals.1

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.1 (See Bradyarrhythmia and AV Conduction Delays under Cautions.)

Administer first dose in a setting with available resources to manage symptomatic bradycardia.1

Observe patients for signs and symptoms of bradycardia for ≥6 hours after first dose; measure heart rate and BP every hour.1 Obtain ECG at the end of observation period.1

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.1

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 (QTc) interval ≥500 msec, initiate appropriate management, including continuous ECG monitoring; continue observation until symptoms resolve if no pharmacologic intervention is required.1 If pharmacologic intervention is required, institute continuous overnight ECG monitoring and repeat first-dose monitoring procedures with the second dose.1

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 QTc 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.1

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.1 21

Dosage

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

Dosage is based on CYP2C9 genotype.1 (See Pharmacogenetic Testing under Dosage and Administration.)

Initiate therapy with low dosage and titrate gradually.1 19 20

If a dose is missed for >24 hours during initial titration period, must reinitiate therapy with day 1 of the titration regimen.1 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.1 21 (See Reinitiation of Therapy Following Treatment Interruption under Dosage and Administration.)

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.1

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 5.1 Begin maintenance dosage of 2 mg daily on day 6.1

Manufacturer states to use Mayzent Starter Pack only in patients who will be titrated to the 2-mg maintenance dosage.1

Multiple Sclerosis
Patients with CYP2C9 Genotypes *1/*3 or *2/*3
Oral

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

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 4.1 Begin maintenance dosage of 1 mg daily on Day 5.1

Manufacturer states that Mayzent Starter Pack is not intended for use in patients who will be titrated to the 1-mg maintenance dosage.1

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.1

Renal Impairment

Dosage adjustment not necessary.1

Cautions for Siponimod

Contraindications

  • CYP2C9*3/*3 genotype.1

  • Recent (in the past 6 months) MI, unstable angina, stroke, 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 dose-dependent reductions in peripheral lymphocyte count to 20–30% of baseline values.1 May increase risk of infections; serious and sometimes fatal infections reported rarely.1 22

Before initiating treatment, review a recent (i.e., within 6 months or after discontinuance of previous therapy) CBC.1 Delay initiation of therapy in patients with severe active infections until infection has resolved.1

Monitor patients for signs and symptoms of infection during and for 3–4 weeks after discontinuing therapy.1 If a serious infection develops, consider interruption of therapy and manage infection as clinically indicated.1

Concomitant use of siponimod with antineoplastic, immunosuppressive (including corticosteroids), or immunomodulating therapies may increase risk of immunosuppression.1 (See Antineoplastic, Immunomodulatory, or Immunosuppressive Agents under Interactions.)

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, reported with another S1P receptor modulator.1 Cryptococcal meningitis reported rarely with siponimod.1 If signs and symptoms consistent with cryptococcal meningitis occur, promptly evaluate and treat patient; interrupt siponimod therapy until infection excluded.1 If cryptococcal meningitis is diagnosed, initiate appropriate treatment.1

Herpetic infections reported, including VZV reactivation leading to varicella zoster meningitis.1 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.1 VZV vaccination of antibody-negative patients is recommended; postpone initiation of siponimod for 4 weeks following vaccination.1

Although not reported with siponimod, progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in patients receiving another S1P receptor modulator.1 Immunocompromised patients or patients receiving multiple immunosuppressant therapies are at increased risk.1 Monitor patients for clinical symptoms or MRI findings suggestive of PML.1 MRI signs may be apparent before clinical manifestations develop.1 If PML is suspected, interrupt siponimod therapy until condition excluded.1

Macular Edema

Macular edema reported, usually within first 4 months of treatment.1

Perform an ophthalmologic evaluation of the fundus, including the macula, at baseline and during therapy if there is any change in vision.1 Continued therapy in patients with macular edema not evaluated; weigh potential benefits and risks for the individual patient.1

Increased risk of macular edema in patients with diabetes mellitus or a history of uveitis; monitor such patients with regular ophthalmologic evaluations during therapy.1

Bradyarrhythmia and AV Conduction Delays

Transient decreases in heart rate and AV conduction delays observed during initial dosing.1

After first dose, heart rate decrease begins within 1 hour and peaks in approximately 3–4 hours.1 Heart rate continues to decrease with upward dosage titration; maximal decrease from baseline occurs on days 5–6.1 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.1 With continued dosing, heart rate begins increasing after 6 days and reaches baseline levels within 10 days.1

Bradycardia generally was asymptomatic; few patients experienced symptoms, including dizziness or fatigue.1 Heart rate <40 bpm observed rarely.1

AV conduction delays follow a similar temporal pattern during dosage titration.1 Conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not result in discontinuance of siponimod therapy.1

Prior to initiation of therapy, obtain baseline ECG.1 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.1 (See Contraindications under Cautions.) 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.1 (See First-dose Monitoring in Patients with Cardiac Conditions under Dosage and Administration.)

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.1 Individualize use in patients with a history of recurrent syncope or symptomatic bradycardia based on assessment of potential risks versus benefits.1 If treatment is considered in any of these patients, consult a cardiologist for monitoring recommendations.1

Consult a cardiologist if treatment is considered in patients with substantial QT-interval prolongation (i.e., corrected QT [QTc] 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.1 (See Drugs that Decrease Heart Rate under Interactions.)

Contraindicated in patients with a recent cardiovascular event (e.g., MI, unstable angina, stroke, TIA, heart failure).1 (See Contraindications under Cautions.)

Respiratory Effects

May decrease pulmonary function tests.1 Dose-dependent reductions in FEV1 observed as early as 3 months after initiating therapy.1 Not known whether these changes are reversible after discontinuing siponimod.1 In clinical studies, changes in FEV1 were similar in patients with asthma or COPD and the overall population.1

Assess pulmonary function (e.g., spirometry) during siponimod therapy if clinically indicated.1

Liver Injury

May increase hepatic enzyme concentrations (ALT, AST, or γ-glutamyltransferase [GGT]).1 19 22 Most elevations occur within 6 months.1 In clinical studies, elevated ALT concentrations returned to normal within approximately 1 month after discontinuance of the drug; no cases of serious hepatotoxicity reported.1 22

Review recent (i.e., within last 6 months) aminotransferase and bilirubin concentrations before initiating treatment.1 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).1 Discontinue siponimod if clinically important liver injury is confirmed.1

BP Effects

May increase BP.1 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.1

Monitor BP during therapy and manage as clinically indicated.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity observed in animals.1

Avoid pregnancy during therapy.1 Women of childbearing potential should use effective contraception during and for 10 days after drug discontinuance.1 (See Pregnancy under Cautions.)

Posterior Reversible Encephalopathy Syndrome (PRES)

PRES reported in patients receiving another S1P receptor modulator.1

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).1 Promptly perform complete physical and neurological examination if such manifestations occur and consider MRI evaluation.1

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.1

If PRES is suspected, discontinue siponimod.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, consider the duration and mechanism of action of these drug to avoid unintended additive immunosuppressive effects while also minimizing risk of disease reactivation.1 (See Specific Drugs under Interactions.)

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.1 Observe patients for severe increase in disability following discontinuance of siponimod and institute appropriate treatment as clinically indicated.1

Immunosuppression Following Discontinuance

Siponimod remains in the blood for up to 10 days following discontinuance.1 Initiating other drugs during this period warrants same considerations needed for concomitant administration (e.g., risk of additive immunosuppressive effects).1 (See Specific Drugs under Interactions.) Pharmacodynamic effects (e.g., decreased lymphocyte counts) may persist for up to 3–4 weeks.1

Specific Populations

Pregnancy

No adequate data in pregnant women;1 may cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Potential effects on nursing infants or on milk production not known.1 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.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Insufficient experience in patients ≥65 years of age.1 Use with caution.1

Hepatic Impairment

Clinically important changes in pharmacokinetics not expected.1 8 (See Special Populations under Pharmacokinetics: Absorption.) Dosage adjustment not necessary.1

Closely monitor patients with severe hepatic impairment for liver injury; discontinue therapy if liver injury occurs.1

Renal Impairment

Clinically important changes in pharmacokinetics not expected.1 7 (See Special Populations under Pharmacokinetics: Absorption.) Dosage adjustment not necessary.1

Not studied in patients with end-stage renal disease or those requiring hemodialysis; however, hemodialysis not expected to affect siponimod concentrations.1

Pharmacogenomics

Genetic polymorphism of CYP2C9 has a substantial impact on metabolism of siponimod.1 10 11 The variant *2 and *3 alleles are associated with reduced CYP2C9 enzyme activity and impaired drug metabolism.10 11 (See Special Populations under Pharmacokinetics: Absorption.)

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

Certain pharmacokinetic drug interactions also are dependent on CYP2C9 genotype.1 10 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Common Adverse Effects

Headache, hypertension, increased hepatic aminotransferase concentrations.1

Interactions for Siponimod

Metabolized principally by CYP2C9 and, to a lesser extent, by CYP3A4.1 9

Does not appear to inhibit or induce major CYP isoenzymes or transporters.1 3

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.1 10 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.1 (See Pharmacogenomics under Cautions.)

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 CYP3A4.1 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.1 Concomitant use not recommended.1

CYP2C9 inhibitors or inducers: Caution is advised if siponimod is used concomitantly with a moderate CYP2C9 inhibitor or inducer.1

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 CYP3A4.1 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.1 Concomitant use not recommended.1

Drugs that Decrease Heart Rate

Limited experience.1 Concomitant use during siponimod initiation may cause severe bradycardia or heart block.1

Concomitant use with drugs that decrease heart rate generally not recommended.1 If such concomitant therapy is being considered, consult a cardiologist.1

Drugs that Prolong QT Interval

Potential additive effects on heart rate with concomitant use of QT-prolonging drugs with arrhythmogenic potential.1

Siponimod generally should not be initiated in patients receiving QT-interval prolonging drugs with known arrhythmogenic activity.1 If such concomitant therapy is being considered, consult a cardiologist.1

Antineoplastic, Immunomodulatory, or Immunosuppressive Agents

Additive immune system effects may occur.1 Consider duration and mechanism of these drugs when initiating siponimod therapy.1 (See Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies under Cautions.)

Specific Drugs

Drug

Interaction

Comments

Antiarrhythmic agents, class Ia (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol)

Torsades de pointes reported in patients with bradycardia receiving these antiarrhythmic agents1

Consult cardiologist before initiating siponimod1

Antifungal, azoles (e.g., fluconazole, itraconazole)

Fluconazole (a moderate CYP3A4 and CYP2C9 inhibitor): Increased AUC of siponimod by approximately twofold and increased peak plasma concentrations of the drug by approximately 10% in individuals with CYP2C9 *1/*1 genotype;1 11 a twofold to fourfold increase in siponimod AUC expected across different CYP2C9 genotypes1 10

Itraconazole (potent CYP3A4 inhibitor): Although increased siponimod exposure expected, slightly decreased siponimod exposures observed, indicating possible contribution of other metabolic pathways10 15

Fluconazole: Concomitant use not recommended1

Antineoplastic agents

Possible additive immunosuppressive effects1

Use concomitantly with caution1

Consider duration and mechanism of antineoplastic drugs when initiating siponimod therapy1

β-Adrenergic blocking agents

Possible additive effects on heart rate; may increase risk of severe bradycardia and heart block1

Initiation of siponimod in individuals receiving a β-Adrenergic blocking agent (propranolol) resulted in additive negative chronotropic effects; such effects were less pronounced when propranolol was initiated in individuals already receiving siponimod1 13

Initiate siponimod with caution1

Check resting heart rate prior to concomitant use1

If resting heart rate >50 bpm, may initiate siponimod in patients receiving stable dosages of a β-adrenergic blocking agent1

If resting heart rate ≤50 bpm, interrupt β-blocking therapy and initiate siponimod when baseline heart rate >50 bpm; may reinitiate β-adrenergic blocking agent after siponimod titrated up to target maintenance dosage1

May initiate β-adrenergic blocking agents in patients receiving stable dosages of siponimod1

Consult a cardiologist to determine most appropriate monitoring strategy1

Calcium-channel blocking agents (e.g., diltiazem, verapamil)

Experience limited with concurrent therapy; may increase risk of severe bradycardia and heart block1

Consult a cardiologist to determine most appropriate monitoring strategy1

Carbamazepine

Carbamazepine (moderate CYP2C9/potent CYP3A4 dual inducer) may substantially decrease systemic exposure of siponimod1

Concomitant use not recommended1

Contraceptives, oral

Clinically important effects on the pharmacokinetics and pharmacodynamics (e.g., follicle size and hormone levels) of an oral contraceptive containing ethinyl estradiol and levonorgestrel not observed1 16

Clinically important pharmacokinetic effects on oral contraceptives containing other progestins also not expected1

Digoxin

Experience limited with concurrent use; may increase risk of severe bradycardia and heart block1

Do not initiate concurrent therapy without consulting a cardiologist1

Efavirenz

Effect of efavirenz (moderate CYP3A4 inducer) on pharmacokinetics of siponimod dependent on CYP2C9 genotype; larger effect expected in patients with genotypes associated with reduced metabolism (e.g., CYP2C9 *1/*3, CYP2C9 *2/*3)1

Decreased AUC of siponimod by up to 52% expected1

Concomitant use not recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype1

Immunosuppressive or immunomodulating agents (e.g., alemtuzumab, glatiramer acetate, interferon beta, corticosteroids)

Possible additive immune system effects1

Use concomitantly with caution1

Consider duration and mechanism of immunosuppressive or immunomodulating drugs when initiating siponimod therapy1

Alemtuzumab: Initiating siponimod after alemtuzumab treatment not recommended because of the characteristics and duration of alemtuzumab's immunosuppressive effects1

Glatiramer acetate: Siponimod therapy generally can be started immediately after discontinuance of glatiramer acetate1

Interferon beta: Siponimod therapy generally can be started immediately after discontinuance of interferon beta1

Ivabradine

Experience limited with concurrent use; may increase risk of severe bradycardia and heart block1

Do not initiate concurrent therapy without consulting a cardiologist1

Modafinil

Effect of modafinil (moderate CYP3A4 inducer) on pharmacokinetics of siponimod dependent on CYP2C9 genotype; larger effect expected in patients with genotypes associated with reduced metabolism (e.g., CYP2C9 *1/*3, CYP2C9 *2/*3)

Concomitant use not recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype1

Rifampin

Rifampin (dual moderate CYP2C9/potent CYP3A4 inducer) decreased AUC and peak plasma concentrations of siponimod by 57 and 45%, respectively, in patients with CYP2C9*1/*1 genotype; similar interaction expected with other CYP2C9 genotypes 1 10 12

Concomitant use not recommended1

Vaccines

Vaccinations may be less effective during and for up to 4 weeks following discontinuance of siponimod1

Live attenuated vaccines: Possible risk of infection1

Influenza and pneumococcal 23-valent vaccines: Limited effect on immune response observed14

Manufacturer recommends interruption of siponimod therapy 1 week prior to and for 4 weeks after administration of a planned vaccine1

Live attenuated vaccines: Avoid use during and for up to 4 weeks following discontinuance of siponimod1

VZV vaccine: Postpone treatment with siponimod for at least 1 month after vaccination1

Siponimod Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability is approximately 84%.1

Peak plasma concentrations attained about 4 hours following oral administration (range: 3–8 hours).1

Siponimod concentrations increase dose-proportionally over dosage range of 0.3–20 mg daily.1

Food

Food delays time to peak plasma concentrations by approximately 2–3 hours, but does not alter systemic exposure.1

Special Populations

Moderate hepatic impairment (Child-Pugh score 7–9): Systemic exposure of unbound siponimod is 15% higher; not expected to be clinically important.1 8

Severe hepatic impairment (Child-Pugh score 10–15): Systemic exposure of unbound siponimod is 50% higher; not expected to be clinically important.1 8

Severe renal impairment (eGFR 30–59 mL per minute): Systemic exposure of unbound siponimod is 33% higher; not expected to be clinically important.1 7

Systemic exposure of siponimod is increased in patients with variant CYP2C9 genotypes as follows:1

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

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

CYP2C9*2/*3 genotype: Systemic exposure is approximately twofold higher and peak plasma concentrations 21% higher compared with *1/*1 genotype.1 11

CYP2C9*3/*3 genotype: Systemic exposure is approximately fourfold higher and peak plasma concentrations 16% higher compared with *1/*1 genotype.1 11

Distribution

Extent

Crosses blood-brain barrier.1

Distributed into milk in rats; not known whether distributes into human milk.1

Plasma Protein Binding

>99.9%.1 7

Elimination

Metabolism

Extensively metabolized, principally by CYP2C9 and, to a lesser extent, by CYP3A4;1 9 fractional contributions of CYP2C9 and CYP3A4 are dependent on CYP2C9 genotype.1 10

Genetic polymorphism of CYP2C19 can substantially affect metabolism.1 10 11 (See Pharmacogenomics under Cautions.)

Major metabolites M3 and M17 not expected to be pharmacologically active.1

Elimination Route

Principally by biliary/fecal excretion, as metabolites.1

Unchanged drug not detected in urine.1

Half-life

Approximately 30 hours.1 10 11

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.1 10 11 (See Pharmacogenomics under Cautions.)

Stability

Storage

Oral

Tablets

Unopened containers: 2–8°C.1

Opened blister packs (i.e., Mayzent Starter Pack): 20–25°C for ≤1 week.1

Opened bottles: 20–25°C for ≤1 month.1

Actions

  • S1P receptor modulator; 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, and are involved in the regulation of a variety of physiological processes including immune, cardiac, and neurologic function.4 5 6

  • S1P1 receptor regulates lymphocyte egress from peripheral lymphoid organs and is essential for lymphocyte recirculation.4 5 6 Modulation of the S1P1 receptor blocks capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.1 6

  • Exact mechanism in MS not known, but may involve reduction of lymphocyte migration into the CNS.1

  • 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.1 Lymphocyte counts remain low with continued daily dosing.1 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.1

Advice to Patients

  • Importance of advising patients to read the manufacturer's patient information (medication guide).1

  • Importance of following instructions on proper storage of siponimod.1 (See Storage under Stability.)

  • Importance of advising patients to not discontinue siponimod without first consulting a clinician.1 Severe increase in disability reported after discontinuation of another S1P receptor modulator.1 Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuance of siponimod.1

  • Increased risk of infections.1 Importance of advising 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.1 Importance of informing patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.1

  • 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.1

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

  • Risk of macular edema.1 Importance of advising patients to contact their clinician if they experience any changes in their vision during siponimod therapy.1 Inform patients that their risk of developing macular edema is higher if they have diabetes mellitus or a history of uveitis.1

  • Importance of informing patients that initiation of siponimod results in a transient decrease in heart rate and that dosage titration is required to minimize this effect.1 Retitration of the dosage also is required if a dose is missed for >24 hours during the titration period or if ≥4 consecutive daily maintenance doses are missed.1 Importance of informing patients with certain preexisting cardiac conditions that they will need to be observed in their clinician's office or other medical facility for ≥6 hours after the first dose and that such monitoring is also required after reinitiation if treatment is interrupted or discontinued for certain periods.1

  • Risk of breathing problems.1 Importance of advising patients to contact their clinician if they experience any trouble breathing such as new onset or worsening dyspnea.1

  • Risk of increased liver enzymes.1 Importance of advising 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.1

  • Risk of posterior reversible encephalopathy syndrome (PRES).1 Importance of advising patients to immediately inform their clinician if they experience sudden onset of severe headache, altered mental status, visual disturbances, or seizure.1 Inform patients that delayed treatment could lead to permanent neurological sequelae.1

  • Risk of fetal harm.1 Importance of discussing possible fetal risk with women of childbearing potential and advising such women of the need for effective contraception during and for 10 days after discontinuance of siponimod.1 Importance of women informing clinicians if they are or plan to become pregnant.1

  • Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., antiarrhythmic or antihypertensive agents, β-adrenergic blocking agents, other immunosuppressive or immunomodulatory agents), as well as any concomitant illnesses (e.g., cardiovascular or cerebrovascular disease, cardiac arrhythmias, breathing problems including during sleep, liver disease, diabetes mellitus, history of uveitis).1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Distribution of siponimod is restricted.17 (See Restricted Distribution under Dosage and Administration.)

Siponimod Fumarate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

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

Mayzent 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

2 mg (of siponimod)

Mayzent

Novartis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 25, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Novartis Pharmaceuticals Corporation. Mayzent (siponimod) tablets prescribing information. East Hanover, NJ; 2019 Mar.

2. Kappos L, Bar-Or A, Cree BAC et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018; 391:1263-1273. http://www.ncbi.nlm.nih.gov/pubmed/29576505?dopt=AbstractPlus

3. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209884Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000SumR.pdf

4. Behrangi N, Fischbach F, Kipp M. Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action. Cells. 2019; 8 http://www.ncbi.nlm.nih.gov/pubmed/30621015?dopt=AbstractPlus

5. Subei AM, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis. CNS Drugs. 2015; 29:565-75. http://www.ncbi.nlm.nih.gov/pubmed/26239599?dopt=AbstractPlus

6. Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics. 2017; 14:859-873. http://www.ncbi.nlm.nih.gov/pubmed/28812220?dopt=AbstractPlus

7. Gardin A, Dodman A, Kalluri S et al. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther. 2017; 55:54-65. http://www.ncbi.nlm.nih.gov/pubmed/27841151?dopt=AbstractPlus

8. Shakeri-Nejad K, Aslanis V, Veldandi UK et al. Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study. Int J Clin Pharmacol Ther. 2017; 55:41-53. http://www.ncbi.nlm.nih.gov/pubmed/27443658?dopt=AbstractPlus

9. Glaenzel U, Jin Y, Nufer R et al. Metabolism and Disposition of Siponimod, a Novel Selective S1P/S1P Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018; 46:1001-1013. http://www.ncbi.nlm.nih.gov/pubmed/29735753?dopt=AbstractPlus

10. Huth F, Gardin A, Umehara K et al. Prediction of the Impact of Cytochrome P450 2C9 Genotypes on the Drug-Drug Interaction Potential of Siponimod With Physiologically-Based Pharmacokinetic Modeling: A Comprehensive Approach for Drug Label Recommendations. Clin Pharmacol Ther. 2019; 106:1113-1124. http://www.ncbi.nlm.nih.gov/pubmed/31199498?dopt=AbstractPlus

11. Gardin A, Ufer M, Legangneux E et al. Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects. Clin Pharmacokinet. 2019; 58:349-361. http://www.ncbi.nlm.nih.gov/pubmed/30088221?dopt=AbstractPlus

12. Gardin A, Gray C, Neelakantham S et al. Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects. Eur J Clin Pharmacol. 2018; 74:1593-1604. http://www.ncbi.nlm.nih.gov/pubmed/30105453?dopt=AbstractPlus

13. Biswal S, Polus F, Pal P et al. Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects. Int J Clin Pharmacol Ther. 2015; 53:855-65. http://www.ncbi.nlm.nih.gov/pubmed/26308174?dopt=AbstractPlus

14. Ufer M, Shakeri-Nejad K, Gardin A et al. Impact of siponimod on vaccination response in a randomized, placebo-controlled study. Neurol Neuroimmunol Neuroinflamm. 2017; 4:e398. http://www.ncbi.nlm.nih.gov/pubmed/28955715?dopt=AbstractPlus

15. Gardin A, Shakeri-Nejad K, Feller A et al. Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes. Eur J Clin Pharmacol. 2019; 75:1565-1574. http://www.ncbi.nlm.nih.gov/pubmed/31392364?dopt=AbstractPlus

16. Biswal S, Veldandi UK, Derne C et al. Effect of oral siponimod (BAF312) on the pharmacokinetics and pharmacodynamics of a monophasic oral contraceptive in healthy female subjects. Int J Clin Pharmacol Ther. 2014; 52:996-1004. http://www.ncbi.nlm.nih.gov/pubmed/25161159?dopt=AbstractPlus

17. Novartis Pharmaceuticals Corporation. Mayzent Prescription Start Form. From Mayzent website. Accessed 2019 Sep 18. https://www.mayzent.com/index.jsp

18. . Siponimod (Mayzent)--a new drug for multiple sclerosis. Med Lett Drugs Ther. 2019; 61:70-72. http://www.ncbi.nlm.nih.gov/pubmed/31169805?dopt=AbstractPlus

19. Selmaj K, Li DK, Hartung HP et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013; 12:756-67. http://www.ncbi.nlm.nih.gov/pubmed/23764350?dopt=AbstractPlus

20. Legangneux E, Gardin A, Johns D. Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects. Br J Clin Pharmacol. 2013; 75:831-41. http://www.ncbi.nlm.nih.gov/pubmed/22845008?dopt=AbstractPlus

21. Legangneux E, Shakeri-Nejad K, Aslanis V et al. Cardiac Effects of Siponimod (BAF312) Re-initiation After Variable Periods of Drug Discontinuation in Healthy Subjects. Clin Ther. 2016; 38:631-45.e1. http://www.ncbi.nlm.nih.gov/pubmed/26916566?dopt=AbstractPlus

22. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209884Orig1s000: Clinical review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000MedR.pdf

76. Rae-Grant A, Day GS, Marrie RA et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 90:777-788. http://www.ncbi.nlm.nih.gov/pubmed/29686116?dopt=AbstractPlus

77. Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence summary. Available from National MS Society website. http://www.nationalmssociety.org/getmedia/1e64b96c-9e55-400e-9a64-0cdf5e2d60fe/summaryDMTpaper_-final

78. National MS Society. Disease-modifying therapies for MS. Available from National MS Society website. http://stage.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease-Modifying-Medications.pdf

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