siponimod

ROUTE	ONSET	PEAK	DURATION
PO	unknown	6 days*	3–4 wk‡

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);
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 in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

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)

Interactions ⬆ ⬇

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.

Route/Dosage ⬆ ⬇

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.

Availability ⬆ ⬇

Tablets: 0.25 mg; 1 mg; 2 mg

Assessment ⬆ ⬇

Perform first-dose monitoring for patients with preexisting HR <55 bpm, 1st- or 2nd- degree AV block, or history of MI or HF.
First-dose monitoring: Monitor pulse and BP hourly for ≥6 hr and periodically during therapy. Obtain ECG prior to starting therapy (determine preexisting conduction abnormalities) and at end of observation period. If the patient develops a HR <45 bpm, or lowest postdose heart rate is at the end of the 6-hr observation period; or postdose ECG shows new ≥ 2nd-degree AV block, monitor until abnormality resolves. If bradycardia is symptomatic or conduction-related symptoms occur,monitor with continuous ECG until resolved. If pharmacological intervention is required,repeat first-dose monitoring for second dose. If the patient has preexisting heart or cerebrovascular conditions, prolonged QTc interval prior to or during therapy, or uses drugs that may prolong QT interval or slow HR/AV conduction,monitor with continuous ECG overnight in an appropriate medical facility.
Monitor for signs of infection during and for 3–4 wk after discontinuation of therapy. Consider suspending therapy if serious infection develops. If clinical signs of PML (progressive unilateral body weakness; changes in vision, memory, orientation, personality) or MRI changes occur,immediately withhold therapy and perform appropriate diagnostics. If PML is confirmed,permanently discontinue siponimod and monitor for IRIS (rapid neurologic clinical decline, characteristic MRI changes). The time to onset of IRIS in patients with PML was generally within a few mo after receptor modulator discontinuation. If IRIS occurs,initiate appropriate medical treatment.
Perform baseline ophthalmologic exam of the fundus, including the macula, at start of therapy, then at 3–4 mo, periodically during therapy, and with any visual changes. If macular edema occurs,consider discontinuing siponimod based on benefits and risks for the individual patient.
Monitor for signs and symptoms of liver injury. If symptoms of liver injury occur,check liver enzymes and discontinue siponimod if significant injury confirmed.
Monitor for symptoms of PRES (sudden onset headache, altered metal status, visual changes, seizures). If symptoms occur,discontinue siponimod.
Evaluate pulmonary function with spirometry periodically during therapy when indicated clinically.
Perform baseline skin exam and periodically thereafter. Evaluate suspicious skin lesions promptly.
Monitor for severe ↑ in disability on discontinuation of therapy and institute appropriate treatment as needed.
Review current and past medications. If patient is currently taking or has taken antineoplastic, immunosuppressive, or immune-modulating therapies, consider possible unintended additive immunosuppressive effects before initiating treatment.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.Prior to initiation, assess patient for CYP2C9 variants to determine CYP2C9 genotype, if available.
- Obtain baseline AST, ALT, and total bilirubin, periodically during therapy, and for 2 mo after therapy discontinued.
- Obtain CBC within 6 mo of initiating or discontinuing therapy.
- Assess for VZV antibodies before starting therapy.

Implementation ⬆ ⬇

Before initiating therapy (≥ 1 mo), administer VZV vaccine to patients who are antibody negative.
Initiate therapy with a 4- or 5-day titration based on genotype; then begin maintenance dosing. If one titration dose is missed for >24 hr, reinitiate therapy with Day 1 of the titration regimen.
PO: Administer once daily without regard to food. DNC: Swallow tablets whole; do not split, crush, or chew.Tablets are stable at room temperature for 3 mo; if stored >3 mo, refrigerate until use.
- If therapy is interrupted ≥4 consecutive daily doses, reinitiate therapy with Day 1 of titration regimen.

Patient/Family Teaching ⬆ ⬇

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.
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. 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 www.mothertobaby.org/join-study.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇

Time/Action Profile ⬆ ⬇

Contraind./Precautions ⬆ ⬇