anti-multiple sclerosis agents
Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Binds to sphingosine 1-phosphate receptors, resulting in ↓ migration of lymphocytes into peripheral blood and CNS.
Delayed disability progression and decreased frequency of relapses.
Absorption: Well absorbed (84%) following oral administration. Food may delay absorption.
Distribution: Extensively distributed to body tissues.
Protein Binding: >99.9%.
Metabolism and Excretion: Primarily metabolized in liver via CYP2C9 isoenzyme, with some metabolism through the CYP3A4 isoenzyme, to inactive metabolites; primarily excreted in bile/feces.
Half-life: 30 hr.
|PO||unknown||6 days*||3–4 wk†|
- 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 (may cause fetal harm).
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 vaccination;
- 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)
- Rep: 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.
Adverse Reactions/Side Effects
CNS: ISCHEMIC STROKE, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML), SEIZURES, headache, dizziness
CV: MI, hypertension, bradycardia, heart block, peripheral edema
EENT: macular edema
GI: diarrhea, nausea, ↑ liver enzymes
Resp: PULMONARY EMBOLISM, ↓ pulmonary function
Misc: INFECTION (including bacterial, viral and fungal)
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Class Ia or class III antiarrhythmics may ↑ risk of torsade de pointes; avoid concurrent use.
- Concurrent use of QT-interval prolonging medications may ↑ risk of QT interval prolongation and torsade 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 wks after discontinuation of therapy.
- Vaccines may have ↓ effectiveness if administered during therapy; if vaccination necessary, discontinue therapy 1 wk before and for 4 wks after planned vaccination.
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.
Tablets: 0.25 mg, 2 mg
- Assess ECG for preexisting conduction abnormalities before starting therapy. May cause transient decrease in HR and atrioventricular conduction delays. Determine whether patient is taking drugs that could slow heart rate or atrioventricular (AV) conduction.
- Perform ophthalmic exam to assess fundus, including the macula, before starting therapy.
- Review current and past medications. If patient is currently taking or has taken anti-neoplastic, immunosuppressive, or immune-modulating therapies, consider possible unintended additive immunosuppressive effects before initiating treatment.
- Monitor for signs and symptoms of infection (fever, tiredness, body aches, chills, nausea, vomiting, headache, sore throat) before starting, periodically during and for 3 mo after therapy. Delay start of therapy until infection resolved. Interrupt therapy if serious infection occurs.
- Monitor for respiratory effects (reductions in forced expiratory volume [FEV1 ] and forced vital capacity [FVC]) with spirometry periodically during therapy.
- Assess skin for suspicious skin lesions periodically during therapy. Promptly evaluate suspicious skin lesions. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking siponimod.
- Monitor for signs and symptoms of posterior reversible encephalopathy syndrome (PRES) (impaired consciousness, convulsions, visual disturbances including blindness, loss of motor function, movement disorders, psychiatric disturbances, papilledema, visual impairment). Discontinue therapy if PRES develops. Usually reversible with discontinuation of siponimod.
- Upon discontinuation of therapy, monitor patient for exacerbation of disease, including disease rebound. Assess for a severe increase in disability upon discontinuation and begin therapy, as required.
Lab Test Considerations:
Before starting therapy, test patient for CYP2C9 variants to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.
- Review CBC before starting therapy.
- Test for antibodies to varicella zoster virus (VZV) before starting therapy.
- Determine AST, ALT, and bilirubin levels before starting therapy.
- Administer varicella zoster virus vaccination of antibody-negative patients before starting therapy. If live attenuated vaccine immunizations are required, administer at least 1 mo before start of therapy. Avoid use of live attenuated vaccines during and for 3 mo after therapy.
- Initiate therapy with a 4– or 5– day titration based on genotype, then begin maintenance dosing. If one titration dose is missed for >24 hrs, reinitiate therapy with Day 1 of the titration regimen.
- PO Administer once each day without regard to food. DNC: Swallow tablets whole; do not split, crush, or chew. Tablets are stable at room temperature for 3 months; if storage is needed for >3 months, store in refrigerator until use.
- Administer 1st dose in a setting with resources to manage symptomatic bradycardia. Monitor patient for 6 hrs after 1st dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG at the end of the Day 1 observation period. If heart rate <45 bpm six hr postdose, heart rate 6 hr postdose is at lowest value postdose suggesting maximum pharmacodynamic effect on heart may not have occurred, or ECG 6 hr postdose shows new onset second-degree or higher AV block, continue monitoring until abnormality resolves. Consult cardiologist.
- If therapy is interrupted ≥4 consecutive daily doses, reinitiate therapy with Day 1 of titration regimen.
- Instruct patient to take siponimod as directed. Do not stop taking siponimod without talking with health care professional. 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.
- Caution patient to avoid exposure to sunlight and ultraviolet light, wear protective clothing, and use sunscreen with a high protection factor to minimize risk or cutaneous malignancies.
- Advise patient to notify health care professional immediately if signs and symptoms of infection (fever, cough, feeling very tired, painful and frequent urination, flu-like symptoms, rash, headache with fever, neck stiffness, sensitivity to light, nausea or confusion), PRES (sudden severe headache, sudden loss of vision or visual changes, sudden confusion, seizure), PML, or allergic reaction (rash, itchy hives, swelling of lips, tongue or face) occur.
- Advise patient to notify health care professional if signs and symptoms of slow HR (dizziness, shortness of breath, lightheadedness, confusion, feeling like heart is beating slowly or skipping beats, chest pain, tiredness), liver injury (unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine), respiratory effects (new or worsening shortness of breath), or changes in vision (blurriness or shadows in the center of vision, a blind spot in center of vision, sensitivity to light, unusually colored vision) occur.
- Inform patient that increase in disability and exacerbation of disease, including disease rebound, may occur after discontinuation of siponimod.
- 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.
- Rep: 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.
Delayed disability progression and decreased frequency of relapses.
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