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 (AAN [Farez 2019]).
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.
Refer to adult dosing; use with caution.
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
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)
Ponvory: FDA approved March 2021; anticipated availability April 2021.
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/2021/213498s000lbl.pdf#page=30
Oral: Administer with or without food. Swallow tablets whole.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Ponesimod may cause teratogenicity, reproductive 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 2016; 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.
Multiple sclerosis, relapsing: Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.
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.
Mechanism: Unknown; ponesimod is extensively metabolized by multiple enzymes in the cytochrome P450 system, predominantly with CYP3A4, therefore, drug-drug interactions with medications that utilize these enzymes may occur (Ref).
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
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.
• Progressive multifocal leukoencephalopathy: 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.
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 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.
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 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
Alemtuzumab: Ponesimod may enhance the immunosuppressive effect of Alemtuzumab. Risk X: Avoid combination
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 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 diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy
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
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
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
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
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
Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect 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 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
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
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
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
Pneumococcal Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy
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
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
Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of 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 Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination
Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination
Siponimod: 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
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
UGT1A1 Inducers: May decrease the serum concentration of Ponesimod. Risk X: Avoid combination
Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination
Vaccines (Inactivated/Non-Replicating): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated/Non-Replicating). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification
Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). 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 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, and/or posterior reversible encephalopathy syndrome; skin examination and monitoring for suspicious skin lesions (periodically); severe increase in disability following discontinuation of therapy.
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.
Tablet Therapy Pack (Ponvory Starter Pack Oral)
2-3-4-5-6-7-8-9& 10 MG (per each): $340.80
Tablets (Ponvory Oral)
20 mg (per each): $340.80
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