Version July 2025
Note: Cardiac monitoring: First-dose 4-hour monitoring is recommended for patients with certain preexisting cardiac conditions, including sinus bradycardia (heart rate <55 bpm), first- or second-degree (Mobitz type 1) atrioventricular block, or a history of myocardial infarction or heart failure ≥6 months prior to initiation. 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. Infection: Delay initiation of therapy in patients with active infection. In high-risk populations or in countries with high tuberculosis (TB) burden, screen for latent infections (eg, hepatitis, TB) 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 (Ref).
Multiple sclerosis, relapsing: Oral:
Initial: Administer once daily according to the following 14-day dose titration:
|
Day of therapy |
Dose |
|---|---|
|
1 and 2 |
2 mg |
|
3 and 4 |
3 mg |
|
5 and 6 |
4 mg |
|
7 |
5 mg |
|
8 |
6 mg |
|
9 |
7 mg |
|
10 |
8 mg |
|
11 |
9 mg |
|
12, 13, and 14 |
10 mg |
|
15 and thereafter |
20 mg |
Maintenance: 20 mg once daily, beginning on day 15.
Missed dose:
≤3 consecutive doses missed: If during titration, resume with the first missed titration dose, and resume the titration schedule at that dose and titration day. If during maintenance, resume treatment with the maintenance dosage.
≥ 4 consecutive doses missed : Reinitiate treatment with day 1 of the initial 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 adjustment necessary.
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate or severe impairment (Child-Pugh class B or C): Avoid use.
Infection, serious: Consider interrupting ponesimod if serious infection occurs.
Macular edema: Consider discontinuing ponesimod if macular edema develops. Consider potential benefits and risks; risk of recurrence after rechallenge has not been evaluated.
Posterior reversible encephalopathy syndrome: Discontinue ponesimod if posterior reversible encephalopathy syndrome is suspected.
Progressive multifocal leukoencephalopathy: Discontinue ponesimod if progressive multifocal leukoencephalopathy is confirmed.
Refer to adult dosing; use with caution.
Transient, dose dependent decreases in heart rate, bradycardia, and sinus bradycardia (HR <50 bpm) have been observed primarily following the first dose of ponesimod and with dose titration. Transient atrioventricular (AV) conduction delays, manifesting as first-degree AV block, have also been observed with initiation of therapy. Second- and third-degree AV blocks have occurred with other sphingosine 1-phosphate (S1P) receptor modulators. In addition, hypertension has commonly been reported with ponesimod.
Mechanism: Ponesimod is a selective S1P receptor modulator; S1P receptors play a role in regulating vascular tone, heart rate, and cardiac repolarization (Ref).
Bradycardia/decreased heart rate: Dose-related; S1P modulators have been associated with negative chronotropic effects; however, these effects may attenuate over time secondary to S1P desensitization on atrial myocytes (Ref).
Onset:
Bradycardia/decreased heart rate: Rapid; following the first dose, onset typically begins within 1 hour postdose, with maximal decrease usually occurring ~2 to 4 hours postdose. Following day 1, decreases in heart rate are typically less pronounced.
Hypertension: Delayed; increased BP occurred ~1 month after initiation of therapy and persisted with continued treatment.
Risk factors:
• Bradycardia/AV conduction delays: Preexisting conditions that may increase the risk for bradycardia or AV block; concurrent therapy with medications that decrease heart rate. Of note, contraindications related to these risk factors exist.
Basal cell carcinoma and other skin malignancies (including malignant melanoma and squamous cell carcinoma of the skin) have occurred rarely with ponesimod.
Risk factors:
• Preexisting skin cancer (potential risk factor)
Increased serum transaminases have been observed with ponesimod therapy, primarily as increased serum alanine aminotransferase (ALT), including increases up to 5 x ULN. Most ALT increases ≥3 x ULN were single transient asymptomatic events that resolved spontaneously or resulted in discontinuation of therapy (per trial protocol) (Ref). The majority of patients with ALT increases ≥3 x ULN continued treatment, with values decreasing to ALT <3 x ULN within ~2 to 4 weeks.
Onset: Delayed; median time to development of ALT ≥3 x ULN was 3 months.
Risk factors:
• History of significant liver disease (potential risk factor)
Reversible lymphocytopenia occurs during ponesimod therapy. Infection is commonly observed with use, typically upper respiratory tract infection and less commonly urinary tract infection; viral infections (eg, herpes virus infection) have also been observed. Infections may be serious, life-threatening, and potentially fatal. Fatal cryptococcal meningitis, disseminated cryptococcal infection, and progressive multifocal leukoencephalopathy have been reported with other sphingosine 1-phosphate (S1P) receptor modulators.
Mechanism: Dose-related; as an antagonist of the sphingosine 1-phosphate 1 receptor (S1P1R), ponesimod results in the blocking of S1P1R receptors on lymphocytes, a necessary signal for their release from peripheral lymphoid organs, causing a reduction in number of circulating lymphocytes. Sequestered lymphocytes remain in peripheral lymphoid organs preventing their movement to sites of inflammation where they would typically contribute to immune-mediated pathology (Ref).
Onset: Rapid; a single oral dose reduced circulating lymphocytes in a rapidly reversible manner; continued dosing results in a maximum effect within 7 to 14 days for each dose level (Ref).
Macular edema has occurred with ponesimod therapy. Though the incidence is rare, macular edema is also associated with other sphingosine 1-phosphate receptor modulators.
Risk factors:
• Diabetes
• Prior history of uveitis
Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients taking sphingosine 1-phosphate (S1P) receptor modulators. Symptoms may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients who discontinued S1P receptor modulator therapy due to developing PML and can result in a rapid decline in patient condition, including characteristic changes on MRI, neurological symptoms, and death.
Mechanism: An opportunistic viral infection of the brain caused by the John Cunningham (JC) virus.
Onset: PML: Symptoms progress over days to weeks. IRIS: Occurred within a few months after discontinuation in most cases.
Risk factors (general):
• Use in immunocompromised patients
• Polytherapy with immunosuppressants
Reduced forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide have occurred with ponesimod therapy. There is insufficient evidence to determine whether changes in FEV1 or decrease in forced vital capacity are reversible with drug discontinuation.
Mechanism: Dose-related; mechanism is unknown.
Onset: Varied; mostly occurred in the first month after therapy initiation.
Risk factors:
• Severe respiratory disease (eg, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Hepatic: Increased serum alanine aminotransferase (≥5 x ULN: 5%; ≥3 x ULN: 17%) (table 1), increased serum transaminases (23%) (table 2)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
Comments |
|---|---|---|---|---|
|
17% |
8% |
565 |
566 |
≥3 x ULN |
|
5% |
3% |
565 |
566 |
≥5 x ULN |
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
23% |
12% |
565 |
566 |
Infection: Infection (54%; serious or severe infection: 2%) (table 3)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
Comments |
|---|---|---|---|---|
|
54% |
52% |
565 |
566 |
N/A |
|
2% |
0.9% |
565 |
566 |
Serious or severe infection |
Respiratory: Upper respiratory tract infection (37%) (table 4)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
37% |
34% |
565 |
566 |
1% to 10%:
Cardiovascular: Bradycardia (≤6%) (table 5), chest discomfort (≥2%), first degree atrioventricular block (3%) (table 6), hypertension (10%) (table 7), peripheral edema (≥2%), sinus bradycardia (≤6%) (table 8)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
Comments |
|---|---|---|---|---|
|
6% |
2% |
565 |
566 |
Bradycardia at treatment initiation |
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
3% |
1% |
565 |
566 |
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
10% |
9% |
565 |
566 |
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
Comments |
|---|---|---|---|---|
|
6% |
2% |
565 |
566 |
Sinus bradycardia on ECG (defined as HR less than 50 bpm) |
Endocrine & metabolic: Hypercholesterolemia (2%), hyperkalemia (<2%)
Gastrointestinal: Dyspepsia (≥2%), xerostomia (≥2%)
Genitourinary: Urinary tract infection (6%) (table 9)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
6% |
5% |
565 |
566 |
Hematologic & oncologic: C-reactive protein increased (2%), lymphocytopenia (≤3%, including severe lymphocytopenia)
Infection: Herpes virus infection (5%) (table 10), herpes zoster infection (<2%), viral infection (<2%)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
5% |
5% |
565 |
566 |
Nervous system: Depression (≥2%), dizziness (5%), drowsiness (3%), fatigue (≥2%), insomnia (≥2%), migraine (≥2%), seizure (1%), vertigo (2%)
Neuromuscular & skeletal: Back pain (≥2%), joint swelling (≥2%), limb pain (4%)
Ophthalmic: Macular edema (1%) (table 11)
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
1% |
0% |
565 |
566 |
Respiratory: Cough (4%), dyspnea (5%), rhinitis (≥2%), sinusitis (≥2%)
Miscellaneous: Fever (2%)
<1%: Hematologic & oncologic: Basal cell carcinoma of skin (table 12), malignant melanoma
|
Drug (Ponesimod) |
Comparator (Teriflunomide) |
Number of Patients (Ponesimod) |
Number of Patients (Teriflunomide) |
|---|---|---|---|
|
0.4% |
0.2% |
565 |
566 |
Frequency not defined: Respiratory: Reduced forced expiratory volume (dose dependent)
Postmarketing: Hematologic & oncologic: Squamous cell carcinoma of the skin
Myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure in the last 6 months; presence of Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome, or sinoatrial block, unless patient has a functioning pacemaker.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to ponesimod or any component of the formulation; patients at risk for opportunistic infections, including those immunocompromised due to treatment (eg, antineoplastic, immunosuppressive, or immunomodulating therapies; total lymphoid irradiation; bone marrow transplantation) or disease (eg, immunodeficiency syndrome); patients with active bacterial, fungal, or viral (eg, hepatitis, tuberculosis) infections; patients with active malignancy (except basal cell carcinoma of the skin); moderate or severe hepatic impairment; pregnancy; patients of childbearing potential not using highly effective birth control.
Concerns related to adverse effects:
• Neurotoxicity: Posterior reversible encephalopathy syndrome (PRES) has occurred with S1P receptor modulators. 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.
Disease-related concerns:
• Cardiovascular disease: Use is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (eg, transient ischemic attack, stroke occurring >6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, as bradycardia may be poorly tolerated; obtain cardiologist consultation prior to therapy initiation in these patients. Cardiologist consultation should also be obtained prior to initiation in patients with significant QT prolongation (≥500 msec), atrial flutter/fibrillation or arrhythmia treated with a class Ia or III antiarrhythmic, unstable ischemic heart disease, decompensated cardiac failure occurring ≥6 months prior to therapy initiation, history of Mobitz Type II second degree or higher AV block, sick sinus syndrome, sinoatrial heart block, recurrent syncope, or symptomatic bradycardia.
Concurrent drug therapy issues:
• Immunosuppressive or immune-modulating therapy: Initiating therapy following alemtuzumab treatment is not recommended. Treatment initiation following prior immunosuppressive or immune-modulating therapy may result in unintended additive immunosuppressive effects; half-life and mechanism of action of prior therapy should be taken into consideration.
Other warnings/precautions:
• Discontinuation of therapy: Severe exacerbation of disease and disease rebound has occurred following discontinuation of S1P receptor modulators. Monitor for development of immune reconstitution inflammatory syndrome in the setting of progressive multifocal leukoencephalopathy and severe increase in disability following discontinuation and begin appropriate treatment as needed.
• Immunizations: Vaccinations may be less effective if administered during treatment with ponesimod. Complete necessary live-attenuated vaccine immunization at least 1 month prior to initiation of therapy. Avoid live-attenuated vaccines in patients who currently receive or have discontinued ponesimod within the last 1 to 2 weeks; consider using live-attenuated vaccines only if risk of infection is high and killed vaccines are unavailable (AAN [Farez 2019]). Prior to initiation of therapy, test for VZV antibodies in patients without a health care professional–confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination. Provide a full course of VZV vaccination prior to initiation of therapy in VZV antibody–negative patients; delay initiation of therapy for 4 weeks following VZV vaccination.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Ponvory: 20 mg
Tablet Therapy Pack, Oral:
Ponvory Starter Pack: 2 mg, 3 mg, 4 mg (two each); 5 mg, 6 mg, 7 mg, 8 mg, 9 mg (one each); 10 mg (three each) (14 ea)
No
Tablet Therapy Pack (Ponvory Starter Pack Oral)
2-3-4-5-6-7-8-9& 10 MG (per each): $382.89
Tablets (Ponvory Oral)
20 mg (per each): $382.89
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:
Ponvory: 20 mg
Tablet Therapy Pack, Oral:
Ponvory Initiation Pack: 2 mg, 3 mg, 4 mg (two each); 5 mg, 6 mg, 7 mg, 8 mg, 9 mg (one each); 10 mg (three each) (14 ea)
Oral: Administer with or without food. Swallow tablets whole.
This medication is not on the NIOSH (2024) list; however, it may meet the criteria for a hazardous drug. Ponesimod may cause developmental toxicity and has a structural or toxicity profile similar to an existing hazardous agent.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Ponvory: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213498s004lbl.pdf#page=30
Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.
Substrate of CYP2J2 (Minor), CYP3A4 (Minor), UGT1A1, UGT2B7; 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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Abrocitinib: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Alemtuzumab: Ponesimod may increase immunosuppressive effects of Alemtuzumab. Risk X: Avoid
Antithymocyte Globulin (Equine): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor
Atazanavir: May increase serum concentration of UGT1A1 Substrates. Management: Do not use UGT1A1 substrates for which small increases in exposure can cause serious adverse effects together with atazanavir, and use caution with any UGT1A1 substrate, even when small changes in exposure are less likely to cause serious adverse effects. Risk D: Consider Therapy Modification
Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Baricitinib. Risk X: Avoid
BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of BCG Products. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Belumosudil: May increase serum concentration of UGT1A1 Substrates. Management: Avoid coadministration of belumosudil with substrates of UGT1A1 for which minimal concentration increases can cause serious adverse effects. If coadministration is required, dose reductions of the UGT1A1 substrate may be required. Risk D: Consider Therapy Modification
Bradycardia-Causing Agents: May increase bradycardic effects 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
Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Brincidofovir. Risk C: Monitor
Brivudine: May increase adverse/toxic effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Ceritinib: Bradycardia-Causing Agents may increase bradycardic effects 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 increase adverse/toxic effects of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Chikungunya Vaccine (Live). Risk X: Avoid
Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Cladribine. Risk X: Avoid
Coccidioides immitis Skin Test: Coadministration of Immunosuppressants (Therapeutic Immunosuppressant Agents) and Coccidioides immitis Skin Test may alter diagnostic results. 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 Modulators may increase immunosuppressive effects of Corticosteroids (Systemic). Risk C: Monitor
COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor
COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects 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 decrease therapeutic effects of COVID-19 Vaccine (Subunit). Risk C: Monitor
Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Dengue Tetravalent Vaccine (Live). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects 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 increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Etrasimod: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Fexinidazole: Bradycardia-Causing Agents may increase arrhythmogenic effects of Fexinidazole. Risk X: Avoid
Filgotinib: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid
Fingolimod: Bradycardia-Causing Agents may increase bradycardic effects 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
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor
Immunosuppressants (Cytotoxic Chemotherapy): Sphingosine 1-Phosphate (S1P) Receptor Modulators may increase immunosuppressive effects of Immunosuppressants (Cytotoxic Chemotherapy). Risk C: Monitor
Immunosuppressants (Miscellaneous Oncologic Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulators may increase immunosuppressive effects of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor
Immunosuppressants (Therapeutic Immunosuppressant Agents): Sphingosine 1-Phosphate (S1P) Receptor Modulators may increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor
Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Inebilizumab. Risk C: Monitor
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider Therapy Modification
Lacosamide: Bradycardia-Causing Agents may increase AV-blocking effects of Lacosamide. Risk C: Monitor
Landiolol: Bradycardia-Causing Agents may increase bradycardic effects of Landiolol. Risk X: Avoid
Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects 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
Methotrexate: May increase immunosuppressive effects of Sphingosine 1-Phosphate (S1P) Receptor Modulators. Risk C: Monitor
Midodrine: May increase bradycardic effects of Bradycardia-Causing Agents. Risk C: Monitor
Mitapivat: May decrease serum concentration of UGT1A1 Substrates. Risk C: Monitor
Mumps- Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Mumps- Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Nadofaragene Firadenovec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid
Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Natalizumab. Risk X: Avoid
Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ocrelizumab. Risk C: Monitor
Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ofatumumab. Risk C: Monitor
Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Pidotimod. Risk C: Monitor
Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Pimecrolimus. Risk X: Avoid
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Pneumococcal Vaccines. Risk C: Monitor
Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase hypersensitivity effects of 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
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects 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
Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects 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
Ritlecitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ritlecitinib. Risk X: Avoid
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ruxolitinib (Topical). Risk X: Avoid
Siponimod: Bradycardia-Causing Agents may increase bradycardic effects 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
Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects 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
Sphingosine 1-Phosphate (S1P) Receptor Modulators: May increase immunosuppressive effects of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor
Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Tacrolimus (Topical). Risk X: Avoid
Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects 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
Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Tertomotide. Risk X: Avoid
Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects 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
Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Typhoid Vaccine. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Ublituximab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Ublituximab. Risk C: Monitor
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase immunosuppressive effects of Upadacitinib. Risk X: Avoid
Vaccines (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Vaccines (Live). Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to starting immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider Therapy Modification
Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Yellow Fever Vaccine. Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Risk X: Avoid
Zoster Vaccine (Live/Attenuated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may increase adverse/toxic effects of Zoster Vaccine (Live/Attenuated). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may decrease therapeutic effects of Zoster Vaccine (Live/Attenuated). Risk X: Avoid
Patients who may become pregnant should use effective contraception during therapy and for 1 week after the last ponesimod dose.
In general, disease-modifying therapies for multiple sclerosis (MS) are stopped prior to a planned pregnancy, except in patients at high risk of MS activity (AAN [Rae-Grant 2018]).
Consider use other agents in patients at high risk of disease reactivation who are planning to become pregnant. Delaying pregnancy is recommended for patients with persistent high disease activity; when disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).
Based on data from animal reproduction studies, in utero exposure to ponesimod may cause fetal harm. Ponesimod acts on the sphingosine 1-phosphate receptor, a receptor involved in embryogenesis, including vascular and neural development.
In general, disease-modifying therapies for multiple sclerosis (MS) are not initiated during pregnancy, except in patients at high risk of MS activity (AAN [Rae-Grant 2018]). When disease-modifying therapy is needed in these patients, other agents are preferred (ECTRIMS/EAN [Montalban 2018]).
It is not known if ponesimod 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 the benefits of treatment to the mother.
All patients:
CBC including lymphocyte count (baseline [within 6 months or after discontinuation of previous multiple sclerosis therapy]).
Hepatic monitoring: Bilirubin and transaminase levels (baseline [within 6 months]); transaminases in patients who develop symptoms of hepatic dysfunction (as clinically necessary).
ECG (baseline) and BP (as clinically indicated); 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) (as clinically indicated), latent infection screening (eg, hepatitis, tuberculosis [TB]) in high-risk populations or in countries with high TB burden (baseline); varicella-zoster virus (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), signs and symptoms of infection (during treatment and at least 1 to 2 weeks after discontinuation), signs/symptoms of progressive multifocal leukoencephalopathy, immune reconstitution inflammatory syndrome (IRIS), and/or posterior reversible encephalopathy syndrome; severe increase in disability following discontinuation of therapy.
Skin exam: Baseline or shortly after initiation of treatment, then periodically as clinically indicated; promptly evaluate suspicious lesions.
Additional required monitoring for patients with sinus bradycardia (heart rate <55 bpm), first- or second-degree (Mobitz type 1) atrioventricular block, or a history of myocardial infarction or heart failure ≥ 6 months prior to treatment initiation and in stable condition:
First-dose 4-hour monitoring: Monitor patient for 4 hours following the first dose for signs and symptoms of bradycardia; assess heart rate and BP measurements every 1 hour. Obtain ECG prior to dosing and after initial 4-hour dose observation period. After the initial 4-hour monitoring, monitor until resolution (even if asymptomatic) if 4-hour postdose heart rate is <45 bpm, 4-hour postdose heart rate is lowest postbaseline measurement, or 4-hour postdose ECG shows new-onset second-degree or higher atrioventricular (AV) block. Start continuous ECG monitoring if postdose symptomatic bradycardia, bradyarrhythmia, or conduction-related symptoms occur or if 4-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 during 4-hour monitoring, 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, BP) must be repeated for treatment interruption of ≥4 consecutive doses during the titration or maintenance period.
Ponesimod, a sphingosine 1-phosphate (S1P) receptor 1 modulator, binds with high affinity to S1P receptor 1. Ponesimod blocks lymphocytes’ ability to emerge from lymph nodes, reducing the number of lymphocytes available to the CNS, which reduces inflammation (Chaudhry 2017).
Distribution: Vd: 160 L.
Protein binding: >99%.
Metabolism: Extensively metabolized via CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12), non-CYP450 oxidation, and direct glucuronidation (primarily UGT1A1 and UGT2B7).
Bioavailability: 84%.
Half-life elimination: ~33 hours.
Time to peak: 2 to 4 hours.
Excretion: Feces: 57% to 80% (16% as unchanged drug); urine: 10% to 18% as metabolites.
