Version May 2024
Note: Before initiating siponimod, determine CYP2C9 genotype and dose accordingly. First-dose 6-hour monitoring is recommended for patients with certain preexisting cardiac conditions, including sinus bradycardia (HR <55 bpm), first- or second-degree (Mobitz type 1) AV block, or a history of MI or heart failure. For these patients, administer the first dose and doses following therapy interruption (≥4 days) in a setting in which resources to appropriately manage symptomatic bradycardia and other conduction abnormalities are available. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other appropriate specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
Multiple sclerosis: Oral:
CYP2C9 Genotype *1/*1, *1/*2, or *2/*2:
Initial: 0.25 mg once daily on Days 1 and 2, then 0.5 mg once daily on Day 3, then 0.75 mg once daily on Day 4, then 1.25 mg once daily on Day 5.
Maintenance: 2 mg once daily, beginning on Day 6.
CYP2C9 Genotype *1/*3 or *2/*3:
Initial: 0.25 mg once daily on Days 1 and 2, then 0.5 mg once daily on Day 3, then 0.75 mg once daily on Day 4.
Maintenance: 1 mg once daily, beginning on Day 5.
Missed dose: If a dose is missed for more than 24 hours during the initial titration regimen, reinitiate with Day 1 of the titration regimen. If treatment with siponimod is interrupted for 4 or more consecutive daily doses after completion of initial titration, reinitiate treatment with Day 1 of the titration regimen, including first-dose monitoring when appropriate.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
No dosage adjustments necessary.
No dosage adjustments necessary.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
>10%:
Cardiovascular: Hypertension (13%)
Hepatic: Increased serum transaminases (11%; including increased gamma-glutamyl transferase, increased serum alanine aminotransferase [3 to 5 × ULN: 6%; 8 to 10 × ULN: <1%], increased serum alkaline phosphatase, and increased serum aspartate aminotransferase [3 to 5 × ULN: 1%; 8 to 10 × ULN: <1%])
Nervous system: Falling (11%), headache (15%)
1% to 10%:
Cardiovascular: Bradycardia (4% to 6%), first-degree atrioventricular block (5%), peripheral edema (8%), second-degree atrioventricular block (<2%)
Dermatologic: Basal cell carcinoma of skin (1%)
Gastrointestinal: Diarrhea (6%), nausea (7%)
Hematologic & oncologic: Lymphocytopenia (<5%)
Hepatic: Increased serum bilirubin (≤10%)
Infection: Herpes virus infection (5%), herpes zoster infection (3%)
Nervous system: Asthenia (<5%), dizziness (7%), seizure (2%), tremor (<5%)
Neuromuscular & skeletal: Limb pain (6%)
Ophthalmic: Macular edema (2%; history of uveitis or diabetes mellitus: 10%)
Respiratory: Reduced forced expiratory volume (<5%)
<1%:
Hematologic & oncologic: Squamous cell carcinoma
Infection: Varicella zoster infection (meningitis)
Frequency not defined:
Dermatologic: Fungal skin infection
Respiratory: Bronchitis, sinusitis, upper respiratory tract infection
Postmarketing:
Dermatologic: Malignant melanoma
Genitourinary: Testicular neoplasm (seminoma)
Nervous system: Meningitis (cryptococcal), progressive multifocal leukoencephalopathy
CYP2C9*3/*3 genotype; recent (in the past 6 months) myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure; Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, unless patient has a functioning pacemaker.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to siponimod, peanut, soya, or any component of the formulation; patients at increased risk for opportunistic infections, including those who are immunocompromised due to treatment (eg, antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation, bone marrow transplantation) or disease (eg, immunodeficiency syndrome); severe active infections including bacterial, fungal, or viral infections (eg, hepatitis, tuberculosis); known active malignancy (excluding basal cell carcinoma); pregnancy and women in childbearing years not using effective contraception.
Concerns related to adverse effects:
• Atrioventricular conduction delays: Initiation has been associated with transient and asymptomatic AV conduction delays, including first-degree atrioventricular (AV) block (most cases) and second-degree AV block, usually Mobitz type I. The conduction abnormalities typically occur concomitantly with bradycardia, resolve within 24 hours of treatment initiation, and do not require discontinuation of siponimod or treatment with atropine. No second-degree AV blocks of Mobitz type II or higher degree were observed, and most conduction abnormalities occurred at doses >2 mg or in situations when the siponimod dose was not titrated.
• Bradycardia: Initiation results in transient decreases in heart rate; gradual titration will minimize this effect. Following the first titration dose, heart rate may decrease as soon as 1 hour postdose, with the maximal decrease usually occurring ~3 to 4 hours postdose. Although postdose bradycardia will likely continue to occur during the dose titration period, it will not be as pronounced as day 1. Heart rate begins to increase after day 6 of therapy and typically returns to baseline after 10 days of therapy. Most patients are asymptomatic; however, dizziness and fatigue may occur; symptoms usually resolve within 24 hours.
• Hepatic effects: Elevated liver enzymes may occur; most elevations occurred within 6 months of treatment initiation. Obtain baseline liver enzymes and bilirubin in all patients prior to therapy initiation (within 6 months); monitor liver enzymes in patients who develop symptoms of hepatic dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine). Discontinue treatment with confirmation of liver injury; transaminases tend to return to normal within 1 month of discontinuation.
• Hypertension: Increased blood pressure may occur ~1 month after initiation of therapy; monitor blood pressure throughout treatment.
• Infections: Dose-dependent reduction of peripheral lymphocyte counts may increase risk of infections; life-threatening and rare fatal infections have occurred. Review CBC before treatment initiation. Delay treatment initiation in patients with severe active infections. Peripheral lymphocyte counts may also be lowered for 3 to 4 weeks after treatment discontinuation; therefore, continue to monitor for signs of infection during this period. Consider suspension of treatment if a serious infection develops. Rare cases of cryptococcal meningitis have occurred with siponimod; disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate receptor modulator. In patients with signs and symptoms of cryptococcal infection, treatment with siponimod should be interrupted until cryptococcal infection has been ruled out. Herpes viral infections, including cases of meningitis or meningoencephalitis caused by reactivation of varicella zoster virus (VZV) infection, have also occurred. In high-risk populations or in countries with high tuberculosis burden, screen for latent infections (eg, hepatitis, tuberculosis) prior to initiating therapy. For patients who screen positive for latent infections, consult infectious disease or other specialists (eg, liver specialists) regarding treatment options before initiating therapy (AAN [Farez 2019]).
• Macular edema: Macular edema has been reported, typically within the first 4 months of treatment. Patients may present with blurred vision, decreased visual acuity, or without symptoms. Patients with a history of diabetes mellitus or uveitis are at increased risk; use with caution. Perform ophthalmologic exams (including the fundus and macula) at baseline and if vision changes; more frequent examination is warranted in patients with diabetes or a history of uveitis.
• Malignancy: Cutaneous malignancies (eg, basal cell carcinoma, squamous cell carcinoma, melanoma) may occur with sphingosine 1-phosphate receptor modulators, including siponimod. Exposure to sunlight and UV light should be minimized (wear protective clothing and use high SPF sunscreen) and use of concomitant phototherapy (eg, UV-B radiation) not recommended. Additionally, cases of lymphoma have been reported with another sphingosine 1-phosphate receptor modulator (Manouchehri 2018).
• Neurotoxicity: Posterior reversible encephalopathy syndrome (PRES) has been observed with another sphingosine 1-phosphate receptor modulator. Monitor for signs/symptoms of PRES (eg, behavioral changes, cognitive deficits, cortical visual disturbances, any other neurological cortical symptom/sign, or symptoms/signs suggestive of increased intracranial pressure); symptoms are usually reversible, but may evolve into ischemic stroke or cerebral hemorrhage. Delayed diagnosis and treatment may result in permanent neurological sequelae. Discontinue use if PRES is suspected.
• Progressive multifocal leukoencephalopathy and associated sequelae: Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients taking S1P receptor modulators; associated risk factors include use in immunocompromised patients and polytherapy with immunosuppressants. Symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Discontinue treatment if PML is confirmed. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients who discontinued S1P receptor modulator therapy due to developing PML. In most cases, IRIS occurred within a few months after discontinuation. IRIS can result in a decline in patient condition, including characteristic changes on MRI, neurological symptoms, and death; initiate appropriate treatment of inflammation.
• QT prolongation: May cause QT prolongation; patients with a prolonged QT interval (>500 msec) at baseline or during the first 6 hours of treatment initiation, at an increased risk of QT prolongation, or on concomitant QT-prolonging drugs may require continuous overnight ECG monitoring in a medical facility after the initial dose.
• Respiratory effects: Reductions of forced expiratory volume in the first second of expiration (FEV1) are dose dependent and may occur within the first 3 months of therapy. It is unknown whether these changes are reversible with drug discontinuation. If clinically necessary, spirometric evaluation of respiratory function should be performed during therapy.
Disease-related concerns:
• Cardiovascular disease: For patients with sinus bradycardia (HR <55 bpm), first- or second-degree (Mobitz type 1) AV block, or a history of MI or heart failure (HF), initiation must occur in a setting with resources and personnel capable of appropriately managing symptomatic bradycardia. Patients may also require overnight monitoring during treatment initiation if they have prolonged QTc interval at baseline or at 6-hour postdose, ECG, additional risks for QT prolongation, concurrent therapy with QT prolonging agents with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction, or some preexisting heart and cerebrovascular conditions. Consult with a cardiologist before initiating siponimod in patients with QTc >500 msec, arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs, ischemic heart disease, HF, history of cardiac arrest or MI, cerebrovascular disease, uncontrolled hypertension, history of second degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block.
• Hepatic impairment: Use with caution and closely monitor patients with significant hepatic disease; may be at increased risk of increased liver enzymes.
Other warnings/precautions:
• Discontinuation of therapy: Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported with discontinuation of another sphingosine 1-phosphate receptor modulator. Monitor for development of IRIS in the setting of PML and severe increase in disability following discontinuation and begin appropriate treatment as needed. Due to residual pharmacodynamic effects following treatment discontinuation (eg, decreased peripheral lymphocyte counts), use caution for 3 to 4 weeks after the last dose of therapy.
• Immunizations: Vaccines may not be as effective if administered during therapy. Avoid immunization with live-attenuated vaccines during and for 4 weeks after treatment; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]; manufacturer's labeling). Testing for antibodies to varicella zoster virus (VZV) is recommended prior to initiation of treatment if history of chickenpox or VZV vaccination status is unknown. Complete full course of immunization for antibody-negative patients with varicella vaccine at least 4 weeks prior to initiating treatment.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as fumarate:
Mayzent: 0.25 mg, 1 mg, 2 mg [contains soybean lecithin]
Tablet Therapy Pack, Oral, as fumarate:
Mayzent Starter Pack: 7 x 0.25 MG (7 ea); 12 x 0.25 MG (12 ea) [contains soybean lecithin]
No
Tablet Therapy Pack (Mayzent Starter Pack Oral)
7 x 0.25 mg (per each): $96.03
12 x 0.25 mg (per each): $96.03
Tablets (Mayzent Oral)
0.25 mg (per each): $96.03
1 mg (per each): $384.13
2 mg (per each): $384.13
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as fumarate:
Mayzent: 0.25 mg, 2 mg [contains soybean lecithin]
Oral: Administer with or without food. Swallow tablets whole; do not chew, crush, or split.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Siponimod may cause carcinogenicity, teratogenicity, and has a structural or toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Mayzent: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209884s016s018lbl.pdf#page=23
Multiple sclerosis: Treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Substrate of CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Adagrasib: May increase the serum concentration of Siponimod. Risk X: Avoid combination
Alemtuzumab: May enhance the immunosuppressive effect of Siponimod. Risk X: Avoid combination
Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination
Bradycardia-Causing Agents: May enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Calcimimetic Agents: May increase the serum concentration of Siponimod. Management: Coadministration of siponimod with drugs which are both moderate inhibitors of CYP2C9 and moderate or strong inhibitors of CYP3A4 is not recommended. Risk D: Consider therapy modification
CarBAMazepine: May decrease the serum concentration of Siponimod. Risk X: Avoid combination
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Chikungunya Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination
Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification
Corticosteroids (Systemic): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Corticosteroids (Systemic). Risk C: Monitor therapy
COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification
COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy
COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Siponimod. Risk C: Monitor therapy
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification
Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Enzalutamide: May decrease the serum concentration of Siponimod. Risk X: Avoid combination
Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Fluconazole: May increase the serum concentration of Siponimod. Risk X: Avoid combination
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy
Immunosuppressants (Cytotoxic Chemotherapy): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor therapy
Immunosuppressants (Miscellaneous Oncologic Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy
Immunosuppressants (Therapeutic Immunosuppressant Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulator may enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Methotrexate: May enhance the immunosuppressive effect of Sphingosine 1-Phosphate (S1P) Receptor Modulator. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
MiFEPRIStone: May increase the serum concentration of Siponimod. Risk X: Avoid combination
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification
RifAMPin: May decrease the serum concentration of Siponimod. Risk X: Avoid combination
Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Siponimod may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Risk D: Consider therapy modification
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination
Patients who could become pregnant should use effective contraception during therapy and for 10 days after the last siponimod dose.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to siponimod may cause fetal harm. Disease modifying therapies are generally not initiated during pregnancy (AAN [Rae-Grant 2018]).
Data collection to monitor pregnancy and infant outcomes following exposure to siponimod is ongoing. Health care providers are encouraged to enroll patients exposed to siponimod during pregnancy in the MotherToBaby Pregnancy Study in Multiple Sclerosis (1-877-311-8972); patients may also enroll themselves.
It is not known if siponimod is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
All patients:
CBC including lymphocyte counts (baseline [within 6 months or after discontinuation of previous therapy]).
Hepatic monitoring: Baseline bilirubin and transaminase levels in all patients prior to therapy initiation (within 6 months); monitor transaminases in patients who develop symptoms of hepatic dysfunction.
ECG (baseline); ophthalmologic exam of fundus, including macula (at baseline and if vision changes, more frequent in patients with diabetes or a history of uveitis), respiratory function (FEV1) if clinically indicated, latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline); VZV antibodies (prior to starting treatment in patients with no health care professional-confirmed history of chickenpox or without documented previous full series VZV vaccination), blood pressure, signs and symptoms of infection (during treatment and at least 3 to 4 weeks after discontinuation), signs/symptoms of progressive multifocal leukoencephalopathy, immune reconstitution inflammatory syndrome, and/or posterior reversible encephalopathy syndrome; monitor for suspicious skin lesions (periodically); severe increase in disability following discontinuation of therapy.
Skin exam: Baseline or shortly after initiation of therapy, then periodically as clinically indicated.
Additional required monitoring for patients with sinus bradycardia (HR <55 bpm), first- or second-degree (Mobitz type 1) AV block, or a history of MI or heart failure:
First-dose 6-hour monitoring: Monitor patient for 6 hours following the first dose for signs and symptoms of bradycardia; assess heart rate and blood pressure measurements every 1 hour. Repeat ECG after initial 6-hour dose observation period. After the initial 6-hour monitoring, continue to monitor (until resolution) if 6-hour postdose heart rate is <45 bpm, 6-hour postdose heart rate is lowest postbaseline measurement, or 6-hour postdose ECG shows new-onset second-degree or higher AV block. Start continuous ECG monitoring 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 QTc ≥500 msec. Monitor until symptom resolution if no pharmacologic treatment is necessary. Monitor overnight with continuous ECG in a medical facility and repeat observation period for second dose if pharmacologic intervention is necessary.
Patients may also require overnight monitoring during treatment initiation if they have prolonged QTc interval at baseline or at 6-hour postdose ECG, additional risks for QT prolongation, concurrent therapy with QT prolonging agents with a known risk of torsades de pointes, concurrent therapy with drugs that slow heart rate or AV conduction, or some preexisting heart and cerebrovascular conditions.
Initial monitoring procedures (ECG, heart rate, blood pressure) must be repeated for:
- treatment interruption of 24 hours during the initial titration regimen, or
- treatment interruption of ≥4 consecutive days during the maintenance period
Siponimod, a sphingosine-1-phosphate (S1P) receptor modulator, binds to sphingosine 1-phosphate receptors 1 and 5. Siponimod blocks the lymphocytes' ability to emerge from lymph nodes; therefore, the amount of lymphocytes available to the CNS is decreased, which reduces central inflammation (Behrangi 2019).
Absorption: Extensive.
Distribution: Vd: 124 L.
Protein binding: >99.9%.
Metabolism: Extensively metabolized, via CYP2C9 (79.3%) and CYP3A4 (18.5%) to inactive metabolites, M3 and M17.
Bioavailability: ~84%.
Half-life elimination: ~30 hours.
Time to peak: ~4 hours (range 3 to 8 hours).
Excretion: Biliary/fecal (as inactive metabolites).
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