• Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Contraindicated in:

• CYP2C9*3/*3 genotype (may have significantly ↑ siponimod levels)
• MI, unstable angina, stroke, TIA, decompensated HF requiring hospitalization, or class III or IV HF within previous 6 mo
• 2nd- or 3rd-degree heart block or sick sinus syndrome (in the absence of a pacemaker)
• Severe active infections
• OB: Pregnancy.

Use Cautiously in:

• History of ischemic heart disease, MI, HF, cerebrovascular disease, uncontrolled hypertension, 1st-degree heart block, symptomatic bradycardia, recurrent syncope, cardiac arrest, or severe untreated sleep apnea (↑ risk of bradycardia/heart block)
• CYP2C9 *1/*3 or *2/*3 genotype (dose ↓ recommended)
• Negative history for chickenpox or vaccination against varicella zoster virus (VZV)
• Diabetes mellitus/history of uveitis (↑ risk of macular edema)
• QT interval 500 msec
• Cardiac arrhythmias requiring use of class Ia or III antiarrhythmics
• Severe hepatic impairment
• QT interval prolongation before dosing or during observation period, hypokalemia, hypomagnesemia, congenital long QT syndrome, or concurrent use of QT interval prolonging medications (↑ risk of QT interval prolongation)
• Women of reproductive potential
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant
• Pedi: Safety and effectiveness not established in children
• Geri: Consider age-related ↓ in cardiac/renal/hepatic function, chronic illnesses, and concurrent drug therapy in older adults.

CV: hypertension, MI, bradycardia, heart block, peripheral edema.

Derm: BASAL/SQUAMOUS CELL CARCINOMA, MELANOMA.

EENT: macular edema.

GI: ↑liver enzymes, diarrhea, nausea.

Hemat: lymphopenia.

MS: pain.

Neuro: headache, posterior reversible encephalopathy syndrome (pres), progressive multifocal leukoencephalopathy (pml), seizures, stroke, dizziness, tremor.

Resp: pulmonary embolism, ↓ pulmonary function.
Misc: IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS), infection (including bacterial, viral and fungal).

Drug-Drug:

• Class Ia or class III antiarrhythmics may ↑ risk of torsades de pointes; avoid concurrent use.
• Concurrent use of QT-interval prolonging medications may ↑ risk of QT interval prolongation and torsades de pointes; avoid concurrent use.
• Concurrent use of beta blockers, diltiazem, verapamil, ivabradine, clonidine, or digoxin may ↑ risk of bradycardia; avoid concurrent use.
• ↑risk of immunosuppression with antineoplastics, immunosuppressants, or immune-modulating therapies; careful monitoring recommended.
• Concurrent use of both moderate CYP2C9 inhibitors and moderate or strong CYP3A4 inhibitors, including fluconazole, may significantly ↑ levels and risk of toxicity; concurrent use not recommended.
• Concurrent use of a moderate CYP2C9 inhibitor may ↑ levels and risk of toxicity; use with caution.
• Concurrent use of both moderate CYP2C9 inducers and moderate or strong CYP3A4 inducers, including rifampin or carbamazepine, may significantly ↓ levels and effectiveness; avoid concurrent use.
• Concurrent use of a moderate CYP2C9 inducer may ↓ levels and effectiveness; use with caution.
• Concurrent use of a moderate or strong CYP3A4 inducer, including modafinil or efavirenz in patients with the CYP2C9 *1/*3 or *2/*3 genotype, may significantly ↓ levels and effectiveness; use with caution.
• Live-attenuated vaccines↑ risk of infection; avoid use during therapy and for 4 wk after discontinuation of therapy.
• Vaccines may have ↓ effectiveness if administered during therapy.

• Tablets: 0.25 mg; 1 mg; 2 mg;

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

• PO (Adults): 0.25 mg once daily for 2 days (Days 1 and 2), then 0.5 mg once daily for 1 day (Day 3), then 0.75 mg once daily for 1 day (Day 4), then 1.25 mg once daily for 1 day (Day 5), then continue maintenance dose of 2 mg once daily starting on Day 6.

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

• PO (Adults): 0.25 mg once daily for 2 days (Days 1 and 2), then 0.5 mg once daily for 1 day (Day 3), then 0.75 mg once daily for 1 day (Day 4), then continue maintenance dose of 1 mg once daily starting on Day 5.

Mayzent

• Binds to sphingosine 1-phosphate receptors, resulting in ↓ migration of lymphocytes into peripheral blood and CNS.

• Delayed disability progression and decreased frequency of relapses.

Therapeutic Classification: anti-multiple sclerosis agents

Pharmacologic Classification:

Absorption: Well absorbed (84%) following oral administration. Food may delay absorption.

Distribution: Extensively distributed to body tissues.

Protein Binding: >99.9%.

Metabolism/Excretion: Primarily metabolized in liver via the CYP2C9 isoenzyme, with some metabolism through the CYP3A4 isoenzyme, to inactive metabolites; primarily excreted in bile/feces.

Half-life: 30 hr.

*Time to steady state plasma concentrations; peak plasma concentrations after a single dose at 3–8 hr.

†Time for complete elimination.

• Instruct patient to take siponimod as directed. Do not discontinue therapy without consulting health care professional; may cause severe ↑ in disability. If one or more doses are missed during initial dose titration, medication must be restarted. If dose is missed after initial dose titration, take as soon as remembered. If 4 or more days are missed, siponimod must be restarted with initial titration. Advise patient to read Medication Guide before starting therapy and with each Rx refill in case of changes.
• Advise patient to notify health care professional if they develop signs and symptoms of liver dysfunction, infection, PML, new onset dyspnea, PRES (sudden headache, confusion, seizures, loss of vision, weakness), hypersensitivity reactions (rash or itchy hives; swelling of lips, tongue, or face), skin lesions, nodules (shiny pearly nodules), patches or open sores that do not heal within wks, or changes in vision.
• Advise patient to notify health care professional if they develop signs and symptoms of slow HR (dizziness, shortness of breath, confusion, feeling of skipped heart beats, chest pain).
• Instruct patient not to receive live-attenuated vaccines during and for 2 mo after treatment due to risk of life-threatening infection. Advise patients who have not had a health care professional confirmed history of chickenpox or a full course vaccination should be tested for antibodies to VZV before starting therapy.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Caution patient to avoid exposure to sunlight and ultraviolet light, wear protective clothing, and use sunscreen with a high protection factor to minimize risk of cutaneous malignancies.
• May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 10 days after last dose. Advise patient to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Inform pregnant patients of registry that monitors outcomes in women exposed to siponimod during pregnancy. To enroll patient in the pregnancy registry, call 1-877-311-8972 or visit join-study.

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