ponesimod (Rx)

Brand and Other Names:Ponvory
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Dosing & Uses


Dosage Forms & Strengths


  • 2mg
  • 3mg
  • 4mg
  • 5mg
  • 6mg
  • 7mg
  • 8mg
  • 9mg
  • 10mg
  • 20mg

Multiple Sclerosis

Indicated for relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease


  • Starter pack must be used for initiating treatment
  • 2 mg PO qDay initially; increase dose as per dose titration regimen (14-day titration)
  • Dose titration regimen
    • Days 1-2: 2 mg qDay
    • Days 3-4: 3 mg qDay
    • Days 5-6: 4 mg qDay
    • Day 7: 5 mg qDay
    • Day 8: 6 mg qDay
    • Day 9: 7 mg qDay
    • Day 10: 8 mg qDay
    • Day 11: 9 mg qDay
    • Days 12-14: 10 mg qDay


  • Day 15 and thereafter: 20 mg qDay

Dosage Modifications

Renal impairment

  • Mild-to-severe: No dosage adjustment necessary
  • Hemodialysis: No dose adjustment necessary; owing to high plasma protein binding (ie, >99%), dialysis not expected to alter concentration

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment necessary
  • Moderate-to-severe (Child-Pugh B or C): Not recommended

Dosing Considerations

Monitoring parameters

  • Before first dose
    • Recent CBC count, including lymphocyte count (eg, within the last 6 months or after discontinuing previous MS therapy)
    • ECG
    • Review medication history for drugs that may slow HR or AV conduction, antineoplastic agents, immunosuppressives, or immune-modulating therapies
    • Recent (eg, within last 6 months) AST/ALT and bilirubin levels
    • Evaluate fundus, including macula
    • Test for antibodies to varicella zoster virus (VZV); VZV vaccination for antibody-negative patients recommended; if vaccination required, administer at least 1 month before initiating ponesimod
  • First dose monitoring
    • Recommended for the following: Patients with sinus bradycardia (HR <55 beats per minute [bpm]), first- or second-degree (Mobitz type I) AV block, or a history of myocardial infarction (MI) or heart failure (HF) occurring >6 months before initiating treatment and in stable condition
    • Administer in setting where bradycardia can be appropriately managed
    • Monitor HR and BP at least hourly for 4 hr after first dose for signs and symptoms of bradycardia
    • Obtain an ECG before dosing and at the end of 4-hr observation period
  • After 4-hour monitoring
    • If symptomatic bradycardia, bradyarrhythmia, or conduction-related symptoms, or if new-onset second-degree or higher AV block or QTc ≥500 msec occur, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until resolution if no pharmacological treatment is required
    • If pharmacological treatment is required, continue monitoring overnight and repeat 4-hr monitoring after second dose
  • Possible abnormalities 4 hours post dose
    • If any of these abnormalities are present after 4 hr (even in absence of symptoms), continue monitoring until resolution
    • HR <45 bpm
    • HR is at lowest value post dose, suggesting that maximum pharmacodynamic effect on the heart may not have occurred
    • ECG shows new-onset second-degree or higher AV block
  • Consult cardiologist during treatment initiation for patients with the following
    • Preexisting heart and cerebrovascular conditions
    • Prolonged QTc interval before dosing or during 4-hr observation, or at additional risk for QT prolongation
    • Coadministration with drugs that slow HR or AV conduction, or that prolong QT with a known risk of torsades de pointes

Safety and efficacy not established



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            Adverse Effects


            Upper respiratory tract infection (37%)

            Elevated hepatic transaminases (23%)


            Hypertension (10%)

            Urinary tract infection (6%)

            Dyspnea (5%)

            Dizziness (5%)

            Cough (4%)

            Pain in extremity (4%)

            Somnolence (3%)

            Pyrexia (2%)

            C-reactive protein increased (2%)

            Hypercholesterolemia (2%)

            Vertigo (2%)

            Seizures (1.4%)


            Basal cell carcinoma (0.4%)

            Frequency Not Defined

            Dose-dependent reductions in FEV1




            In the past 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization, or Class III/IV HF

            Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has functioning pacemaker


            Elevated transaminases may occur; if symptoms (eg, unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, jaundice, dark urine) occur during therapy, check hepatic enzymes; if significant liver injury confirmed, discontinue therapy

            Hypertensive events reported; first detected ~1 month of treatment initiation and persisted with continued treatment; monitor BP and manage appropriately

            Based on animal studies, fetal harm may occur

            Consider possibility of severe exacerbation of disease after discontinuing therapy; monitor for severe increase in disability upon discontinuation and appropriately treat

            Risk of infections

            • May cause dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline; potentially increases susceptibility to infections
            • Life-threatening and rare fatal infections (herpes simplex encephalitis, varicella zoster meningitis, cryptococcal meningitis [CM], disseminated cryptococcal infections) reported with other sphingosine 1-phosphate (S1P) receptor modulators
            • Cases of herpes viral infection reported; confirm history of varicella (chicken pox) or full course of vaccination against VZV; if no proper documentation, test for antibodies against VZV
            • Monitor for clinical signs and symptoms of CM; if CM suspected, suspend therapy until CM is ruled out and undergo prompt diagnostic evaluation and treatment; if CM diagnosed, initiate appropriate treatment
            • Progressive multifocal leukoencephalopathy (PML) reported in patients treated with S1P receptor modulators and other MS therapies and is associated with some risk factors (eg, immunocompromised patients, polytherapy with immunosuppressants); monitor for clinical symptoms or MRI findings; if PML suspected, suspend treatment; if PML confirmed, discontinue treatment
            • Delay initiating treatment in patients with active infection until resolution
            • After discontinuation, lowering effect on peripheral lymphocyte count may persist for 1-2 weeks; continue vigilance for infection during these 1-2 weeks

            Bradyarrhythmias and AV conduction delays

            • Initiating treatment may result in transient decreases in HR and AV conduction delays
            • After first dose titration, decrease in HR typically begins with an hour and reaches its nadir within 2-4 hr; less pronounced with uptitration after Day 1
            • Conduction abnormalities typically were transient, asymptomatic, resolved without intervention within 24 hr and did not require discontinuing treatment
            • Not recommended for patients with the following
              • History of cardiac arrest
              • Cerebrovascular disease (eg, TIA, stroke occurring >6 months before initiating therapy)
              • Uncontrolled hypertension
              • Severe untreated sleep apnea
            • Consult cardiologist if considering treatment for patients with the following
              • Significant QT prolongation (QTc >500 msec)
              • Atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs
              • Unstable ischemic heart disease, cardiac decompensated failure occurring >6 months prior to initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring >6 months prior to initiation), or uncontrolled hypertension
              • History of Mobitz type II second-degree AV block or higher-grade AV block, sick sinus syndrome, or sinoatrial heart block

            Respiratory effects

            • Dose-dependent reductions in FEV1 and reductions in diffusion lung capacity for carbon monoxide were observed mostly occurring in the first month after initiating therapy
            • Data are insufficient on reversibility of the decrease in FEV1 or forced vital capacity after discontinuation
            • Use with caution in patients with severe respiratory disease (eg, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease)
            • Perform spirometric evaluation of respiratory function during therapy if clinically indicated

            Cutaneous malignancies

            • Basal cell carcinoma and other skin malignancies reported with S1P receptor modulators, including ponesimod
            • Perform skin examination for all patients, particularly those with risk factors for skin cancer
            • Advise to monitor suspicious skin lesions; if suspicious skin observed, promptly evaluate
            • Limit exposure to sunlight and UV light and use sunscreen with high protection factor in patients with increased risk of skin cancer
            • Concomitant phototherapy with UV-B radiation or psoralen plus UV A-photochemotherapy is not recommended

            Macular edema

            • S1P receptor modulators, including ponesimod, have been associated with an increased risk of macular edema
            • Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema; these patients should have regular follow-up examinations of the fundus, including the macula, during treatment
            • Continuation of therapy in patients with macular edema not evaluated; consider risks and benefits on whether to discontinue treatment

            Posterior reversible encephalopathy syndrome

            • Rare case of posterior reversible encephalopathy syndrome (PRES) reported with S1P receptor modulators
            • If unexpected neurological or psychiatric signs/symptoms develop, promptly schedule a complete physical and neurological examination and consider an MRI
            • Symptoms usually reversible, but may evolve into ischemic stroke or cerebral hemorrhage
            • Delayed diagnosis and treatment may lead to permanent neurological sequelae
            • If PRES suspected, discontinued treatment

            Drug interaction overview

            • Antineoplastic, immune-modulating, or immunosuppressive therapies
              • Use with caution
              • May increase risk of additive immune effects during therapy and in weeks following administration
              • When switching from drugs with prolonged immune effects, consider half-life and mode of action of such drugs to avoid unintended additive effects
              • Initiating ponesimod after alemtuzumab is not recommended
              • May be started immediately after discontinuing beta interferon or glatiramer acetate
            • Vaccinations
              • Avoid use of live attenuated vaccines at least 1 month before initiating, during, and for 1-2 weeks after treatment
              • If tested negative for VZV antibodies, a full course of the varicella vaccine is recommended before initiating ponesimod
              • Vaccinations may be less effective if administered during treatment
            • Antiarrhythmic drugs, QT prolonging drugs, drugs that may decrease HR
              • Consult cardiologist if considering treatment
              • Class Ia (eg, quinidine, procainamide) and Class III (eg, amiodarone, sotalol) anti-arrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia
              • Generally, should not be initiated in patients who are concurrently taking QT prolonging drugs with known arrhythmogenic properties, HR-lowering calcium channel blockers (eg, verapamil, diltiazem), or other drugs that may decrease HR (eg, digoxin)
            • Beta-blockers
              • Use with caution
              • Beta-blockers may have additive effects on lowering HR
              • Patients on stable dose of beta-blocker; consider resting HR before initiating ponesimod
              • If resting HR >55 bpm under long-term beta-blocker treatment, therapy may be introduced
              • If resting HR ≤55 bpm, interrupt beta-blocker until baseline HR >55 bpm; ponesimod can then be initiated; restart beta-blocker once ponesimod is uptitrated to maintenance dose
            • Strong CYP3A4 and UGT1A1 inducers
              • Not recommended
              • In vitro assessments and limited clinical data indicated that concomitant use of strong CYP3A4 and UGT1A1 inducers (eg, rifampin, phenytoin, carbamazepine) may decrease systemic exposure of ponesimod; clinical relevance is unclear

            Pregnancy & Lactation


            There are no adequate and well-controlled studies in pregnant females

            Animal data

            • Administration during pregnancy produced adverse effects on development (eg, embryolethality, fetal malformations), in absence of maternal toxicity
            • In rats and rabbits, visceral and skeletal malformations occurred at clinically relevant maternal ponesimod exposures
            • Receptor affected by ponesimod (sphingosine-1-phosphate receptor 1) has demonstrated to have an important role in embryogenesis, including vascular and neural development


            Females of childbearing potential
            • Before initiating: Counsel on potential for risks to the fetus
            • During treatment: Use effective contraception
            • Discontinuation: Elimination of ponesimod from body may take ~1 week, potential risk to the fetus may persist; use effective contraception during this period


            No data are available on presence in human milk, effects on breastfed infants, or effects on milk production

            When orally administered to female rats during pregnancy and lactation, drug was detected in plasma of offspring, suggesting excretion in milk

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.



            Mechanism of Action

            Sphingosine 1-phosphate (S1P) receptor 1 modulator that binds with high affinity to S1P receptor 1

            Blocks capacity of lymphocytes to regress from lymph nodes, reducing number of lymphocytes in peripheral blood

            Mechanism of action in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into CNS


            Peak plasma time: 2-4 hr

            Absolute oral bioavailability: 84% (10-mg dose)

            Steady-state achieved following 3 days on maintenance dose


            Vd (steady-state): 160 L

            Protein-bound: >99%

            Readily crosses blood-brain-barrier as per animal studies


            Extensively metabolized before excretion in humans, although unchanged ponesimod was the main circulating component in plasma

            Inactive circulating metabolites: M12, M13

            Metabolism to M13 occurs primarily through a combination of non-CYP450 enzymatic activities

            Multiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12) and nonCYP450 enzymes catalyze oxidation to M12

            Also undergoes direct glucuronidation (mainly UGT1A1 and UGT2B7)


            Half-life: ~33 hr

            Clearance: 3.8 L/hr

            Excretion: Feces (57-80% [16% unchanged]); urine (10-18%)



            Oral Administration

            Take with or without food

            Swallow tablets whole

            Reinitiation after interruption

            • Interruption during treatment, especially during titration, is not recommended
            • <4 consecutive doses missed
              • During titration: Resume with first missed titration dose and resume titration schedule at that dose and titration day
              • During maintenance: Resume maintenance dose
            • ≥4 consecutive doses missed
              • During titration or maintenance: Reinitiate with Day 1 of titration regimen (new starter pack); complete first-dose monitoring if recommended


            Starter pack and maintenance dose bottle

            • Store at 20-25ºC (68-77ºF); excursions permitted from 15-30ºC (59-86ºF)
            • Store in the original package
            • Do not discard desiccant; protect from moisture
            • Keep out of reach of children




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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
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