Ponesimod (Monograph)

Brand name: Ponvory
Drug class: Immunomodulatory Agents
- Sphingosine 1-Phosphate (S1P) Receptor Modulators
- Immunomodulators
Chemical name: (5Z)-5-[[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]phenyl]methylidene]-3-(2-methylphenyl)-2-propylimino-1,3-thiazolidin-4-one
Molecular formula: C₂₃H₂₅ClN₂O₄S
CAS number: 854107-55-4

Medically reviewed by Drugs.com on Aug 19, 2022. Written by ASHP.

Introduction

Selective sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).

Uses for Ponesimod

Multiple Sclerosis

Treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Ponesimod is one of several disease-modifying therapies used in the management of relapsing forms of MS. Although not curative, these therapies have all been shown to modify several measures of disease activity, including relapse rates, new or enhancing MRI lesions, and disability progression.

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing forms of MS who have had recent relapses and/or MRI activity. Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.

Ponesimod Dosage and Administration

General

Pretreatment Screening

• Obtain recent (i.e., ≤6 months or after discontinuance of previous therapy) CBC, including lymphocyte count. Delay initiation of therapy in patients with an active infection until infection is resolved.

• Obtain baseline ECG. If patient has any of the following preexisting cardiac conditions, consult a cardiologist: significant QT prolongation (QT interval corrected for rate [QT_c] >500 msec); presence of an arrhythmia requiring treatment with a Class Ia or Class III antiarrhythmic drug; unstable ischemic heart disease, decompensated heart failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension; history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block.

• Obtain recent (i.e., within the previous 6 months) transaminase and bilirubin levels.

• In patients with previous uveitis or macular edema, obtain an evaluation of the fundus, including the macula.

• Assess current or prior medications. Additive immunosuppressive effects can occur when taking concomitant antineoplastic, noncorticosteroid immunosuppressive, or immunomodulating treatments. Also assess whether patients are taking any medications that slow the heart rate or AV conduction.

• Test patients for varicella zoster antibodies; if the patient is antibody-negative, vaccination against varicella zoster is recommended.

Patient Monitoring

• First-dose monitoring is recommended in patients with sinus bradycardia, first- or second-degree (Mobitz type I) AV block, or history of MI or heart failure. (See First-dose Monitoring in Patients with Certain Cardiac Conditions under Dosage and Administration.)

• Monitor BP during treatment.

• Evaluate pulmonary function with spirometry if clinically indicated.

• Evaluate any changes in vision promptly with an ophthalmic exam of the fundus, including the macula.

• Monitor for signs and symptoms of infection during and for 1–2 weeks following discontinuance of therapy.

• Periodic skin evaluation is recommended in all patients, particularly those with increased risk of skin cancer.

Administration

Oral Administration

Administer orally once daily without regard to food. Swallow tablets whole; do not chew or crush.

First-dose Monitoring in Patients with Certain Cardiac Conditions

Initiation of ponesimod decreases heart rate and may cause transient AV conduction delays. First-dose 4-hour monitoring recommended in patients with heart rate <55 bpm, first- or second-degree AV block, or history of MI or heart failure occurring within the previous 6 months in stable condition.

Seek advice from a cardiologist to determine most appropriate monitoring strategy (which may include overnight monitoring) in patients with preexisting heart and cerebrovascular conditions; with prolonged significant QT_c before initiation of therapy or during the 4-hour first-dose monitoring period, or risk factors for QT_c prolongation; receiving concomitant therapy with QT_c prolonging drugs with a known risk of torsades des pointes; or receiving concomitant drugs that slow heart rate or AV conduction.

Administer first dose of ponesimod in a setting with available resources to manage symptomatic bradycardia. At minimum, observe patients for at least 4 hours for signs and symptoms of bradycardia with hourly pulse and BP measurements.

Obtain ECG prior to first dose and at the end of 4-hour observation period.

Extend monitoring if any of the following abnormalities are present after 4 hours (even in the absence of symptoms) until the finding resolves: heart rate <45 bpm; heart rate during the monitoring period is at lowest value, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; or ECG 4 hours post-dose shows new onset second-degree or higher AV block.

If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction abnormalities occur, or if the ECG 4-hours post-dose shows new onset second-degree or higher AV block or QT_c ≥500 msec, initiate appropriate treatment and start continuous ECG monitoring. Continue monitoring until symptoms resolve if no pharmacologic treatment is required. If pharmacologic treatment is required, continue monitoring the patient overnight and repeat first-dose monitoring after the second dose.

Dosage

Adults

Multiple Sclerosis

Oral

Titrate dosage over 14 days to maintenance dosage of 20 mg once daily. (See Table 1).

Use a starter pack for patients initiating treatment. The starter pack is administered over 14 days, with maintenance treatment starting on day 15. If dose titration is interrupted, missed dose instructions must be followed.

Reinitiating treatment after missed doses during titration period: If fewer than 4 consecutive doses are missed during the titration period, resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day. If 4 or more consecutive doses are missed, reinitiate treatment with day 1 of the titration schedule using a new starter pack. If treatment is reinitiated with day 1 of the titration regimen, perform first-dose monitoring for patients in whom this monitoring is recommended.

Reinitiating treatment after missed doses during maintenance therapy: If fewer than 4 consecutive doses are missed during maintenance therapy, resume treatment with the maintenance dose. If 4 or more consecutive doses are missed, reinitiate treatment with day 1 of the titration schedule using a new starter pack. If treatment is reinitiated with day 1 of the titration regimen, perform first-dose monitoring for patients in whom this monitoring is recommended.

Special Populations

Hepatic Impairment

Mild hepatic impairment (Child-Pugh Class A): No dosage adjustment needed.

Moderate or severe hepatic impairment (Child-Pugh Class B and C): Use not recommended.

Renal Impairment

No dosage adjustment necessary.

Geriatric Patients

No specific dosage recommendations.

Cautions for Ponesimod

Contraindications

• Patients with any of the following conditions within the previous 6 months: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or class III or IV heart failure.

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

Warnings/Precautions

Infectious Complications

Ponesimod can increase susceptibility to infection by decreasing peripheral blood lymphocytes. Rare and life-threatening infections have occurred.

Before initiating treatment, review a recent (i.e., within 6 months or after discontinuance of previous therapy) CBC, including lymphocyte count. Delay initiation of therapy in patients with severe active infections until infection has resolved.

Monitor patients for signs and symptoms of infection during and for 1–2 weeks after discontinuing therapy. Consider interruption of therapy if a serious infection develops.

Concomitant use with antineoplastic, immunosuppressive (including corticosteroids), or immunomodulating therapies may increase risk of immunosuppression.

Herpes viral infections reported. In patients without a professional-confirmed history of varicella (chickenpox) or without confirmed vaccination against varicella zoster virus (VZV), test for VZV antibodies before initiating ponesimod. VZV vaccination of antibody-negative patients is recommended; postpone initiation of ponesimod for 4 weeks following vaccination.

Cryptococcal infections, including cases of fatal cryptococcal meningitis and disseminated cryptococcal infections, reported with S1P receptor modulators and other MS therapies. If signs and symptoms of cryptococcal meningitis occur, promptly evaluate and treat patient; interrupt ponesimod therapy until infection excluded. If cryptococcal meningitis is diagnosed, initiate appropriate treatment.

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain caused by the JC virus, reported in patients receiving S1P receptor modulators and other MS therapies. Immunocompromised patients or patients receiving multiple immunosuppressant therapies are at increased risk. Monitor patients for clinical symptoms or MRI findings suggestive of PML. MRI signs may be apparent before clinical manifestations develop. If PML is suspected, interrupt ponesimod therapy until condition excluded.

Bradyarrhythmia and Atrioventricular Conduction Delays

Transient decreases in heart rate and AV conduction delays observed during initial dosing.

After first dose, heart rate effects typically occur in the first hour, peak within 2–4 hours, and recover within 4–5 hours. Heart rate decreases become less pronounced with upward dosage titration. Bradycardia reported but resolved without intervention.

AV conduction delays followed a similar pattern to observed heart rate decreases. First-degree AV block observed. Abnormalities were transient and resolved without intervention within 24 hours. No second- or third-degree AV blocks reported.

Consult a cardiologist if ponesimod treatment is considered in patients with significant QT prolongation (i.e., QT_c >500 msec), atrial flutter/fibrillation, or arrhythmias requiring treatment with class Ia or class III antiarrhythmic drugs; with unstable ischemic heart disease, decompensated heart failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension; with history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sinoatrial heart block; or receiving concomitant drugs that prolong the QT interval or decrease heart rate.

Contraindicated in patients with a recent cardiovascular event (e.g., MI, unstable angina, stroke, TIA, heart failure).

Prior to initiation of therapy, obtain baseline ECG. Do not use in patients with second-degree Mobitz type II or higher AV block or sick-sinus syndrome unless patient has a functioning pacemaker. (See Contraindications under Cautions.)

Titrate dosage when starting ponesimod in all patients. Perform first-dose monitoring in patients with a history of sinus bradycardia, Mobitz type II first- or second-degree block, or history of MI or heart failure.

If concomitant therapy with drugs that decrease heart rate (e.g., beta-blockers, nondihydropyridine calcium-channel blockers, digoxin) is considered, consult a cardiologist. For patients on stable dosages of a beta-blocker, may initiate treatment with ponesimod if resting heart rate >55 bpm. If resting heart rate ≤55 bpm, interrupt beta-blocker therapy until heart rate >55 bpm; can then initiate ponesimod and reintroduce treatment with the beta-blocker once ponesimod has been uptitrated to the maintenance dosage of 20 mg daily. Do not initiate ponesimod treatment if the patient is on any other heart rate-reducing drugs without first consulting a cardiologist.

If 4 or more consecutive daily doses are missed during treatment initiation or maintenance therapy, retitrate the dosage using a new starter pack, and follow first-dose monitoring recommendations.

Respiratory Effects

May cause a decline in respiratory function. Dose-dependent reductions in FEV₁ observed. Not known if these effects are reversible.

Assess pulmonary function (e.g., spirometry) if clinically indicated.

Liver Injury

May increase hepatic enzyme concentrations (e.g., ALT).

Review recent (i.e., within last 6 months) aminotransferase and bilirubin concentrations before initiating treatment. If patients develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and/or dark urine), check liver enzymes. Discontinue ponesimod if liver injury is confirmed.

BP Effects

Increased BP and hypertension reported. Hypertensive crises reported in a patient who had longstanding hypertensive heart disease.

Monitor BP during therapy and manage as clinically indicated.

Cutaneous Malignancies

Basal cell carcinoma and other skin malignancies reported. Periodic skin evaluation is recommended in all patients, particularly those with increased risk of skin cancer; in such patients, protective measures against sunlight and ultraviolet light also recommended. Promptly evaluate any suspicious skin lesions. Concurrent phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking ponesimod.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal toxicity and teratogenicity observed in animals.

Women of childbearing potential should use effective contraception during and for 1 week after drug discontinuance.

Macular Edema

Risk of macular edema with S1P receptor modulators. Increased risk in patients with diabetes mellitus or a history of uveitis.

Perform ophthalmologic evaluation of the fundus, including the macula, if there is any change in vision. In patients with diabetes mellitus or history of uveitis, perform ophthalmologic evaluation of the fundus, including the macula, at baseline and regularly during therapy. Continued therapy in patients with macular edema not evaluated; weigh potential benefits and risks for the individual patient.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) reported rarely with S1P receptor modulators. Not reported in clinical studies with ponesimod.

Monitor for any unexpected neurological or psychiatric signs or symptoms (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, increased intracranial pressure, accelerated neurological deterioration). Promptly perform complete physical and neurological examination if such manifestations occur and consider MRI evaluation.

A delay in diagnosis and treatment of PRES may lead to permanent neurologic sequelae.

If PRES is suspected, discontinue ponesimod.

Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immunomodulating Therapies

When switching patients from drugs with prolonged immune effects to ponesimod, consider the half-life and mechanism of action of the drugs to avoid unintended additive immunosuppression. Initiation of ponesimod not recommended after treatment with alemtuzumab.

Severe Increase in Disability Following Discontinuance of Therapy

MS exacerbation or disease rebound has been reported rarely after stopping treatment. Observe patients for increased disability after discontinuing treatment and appropriately treat with alternative agents if necessary.

Immunosuppression Following Discontinuance of Therapy

Ponesimod can lower the peripheral lymphocyte count for 1 week after discontinuation. Use of other immunosuppressants during this period can cause additive immunosuppressive effects and increase the risk of infection. Exercise caution if initiating treatment with other agents 1–2 weeks after the last dose of ponesimod.

Specific Populations

Pregnancy

No adequate data in pregnant women; may cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk. Potential effects on nursing infants or on milk production not known. Consider known benefits of breast-feeding along with mother's clinical need for ponesimod and any potential adverse effects of the drug or disease on the infant.

Females and Males of Reproductive Potential

Before initiating treatment, counsel women of childbearing potential on the risks of ponesimod to the developing fetus and need for effective contraception during treatment and for at least 1 week after the drug is discontinued.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger patients. Use with caution in geriatric patients.

Hepatic Impairment

Systemic exposure increased by 2–3 fold in patients with moderate to severe hepatic impairment.

No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). Use of ponesimod not recommended in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment.

Renal Impairment

Renal impairment does not substantially affect pharmacokinetics of ponesimod. The effects of dialysis not studied; however, not likely to affect plasma concentrations of ponesimod. No dosage adjustment is necessary in patients with renal impairment.

Other Special Populations

No clinically significant differences in pharmacokinetics of ponesimod observed based on gender, weight, or racial/ethnic group.

Common Adverse Effects

Most common adverse reactions (≥10%) include upper respiratory tract infection, elevated liver enzymes, and hypertension.

Drug Interactions

Metabolized by multiple enzyme systems including CYP isoenzymes CYP2JC, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12. Also undergoes direct glucuronidation principally by UGT1A1 and UGT2B7. Major contribution from any single metabolizing enzyme not observed.

Not a substrate of p-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transport protein (OATP) 1B1, or OATP1B3.

Does not appear to have any clinically relevant drug interactions with CYP enzymes, UGT enzymes, or transporters.

Drugs Affecting Hepatic Microsomal Enzymes and Transporters

Strong CYP3A4 and UGT1A1 inducers (e.g., carbamazepine, phenytoin, rifampin): concomitant use can increase exposure to ponesimod and is not recommended.

Antineoplastic, Immunomodulatory, or Immunosuppressive Agents

Additive immune system effects may occur.

Specific Drugs

Ponesimod Pharmacokinetics

Absorption

Bioavailability

Plasma concentrations and AUC increase in a dose-proportional manner. Peak plasma concentrations are achieved within 2–4 hours.

Steady-state levels are achieved after 3 days of oral administration.

Absolute bioavailability following administration of a 10-mg dose is 84%.

Food

Food does not appear to have any relevant pharmacokinetic effects.

Distribution

Extent

Readily crosses the blood-brain barrier.

Distributed into milk in rats; not known whether distributes into human milk.

Plasma Protein Binding

99% bound to plasma proteins.

Elimination

Metabolism

Undergoes extensive metabolism prior to excretion, with unchanged ponesimod the main circulating component. The main inactive metabolites M12 and M13 comprise approximately 20 and 6% of total drug exposure, respectively.

Elimination Route

57–80% in feces (16% as unchanged drug), and 10–18% in urine (with no unchanged drug).

Half-life

Approximately 33 hours.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted to 15–30°C).

Actions

• A sphingosine 1-phosphate (S1P) receptor modulator; binds with high affinity to S1P receptor subtype 1 (S1P1).

• S1P receptors are expressed in multiple organs and systems, and are involved in regulating a variety of physiological processes including endocytosis, cardiac function, lymphocyte/hematopoietic cell trafficking, and vascular tone.

• S1P1 receptor regulates lymphocyte egress from peripheral lymphoid organs and is essential for lymphocyte recirculation. Activation of the S1P1 receptor causes rapid and sustained receptor internalization and degradation, blocking the capacity of lymphocytes to egress from lymph nodes and results in reduced number of lymphocytes in peripheral blood.

• Exact mechanism in MS not known, but may involve reduction of lymphocyte migration into the CNS.

• Causes dose-dependent reduction in peripheral lymphocyte counts. Following discontinuance, peripheral lymphocyte counts return to normal within 1–2 weeks.

Advice to Patients

• Importance of advising patients to read the manufacturer's patient information (medication guide).

• Instruct patients to swallow tablets whole and to not discontinue therapy without first consulting their clinician; advise patients to contact their clinician if they accidently take more than the prescribed dose.

• Risk of infection, which can be life-threatening, during ponesimod therapy and for 1–2 weeks after discontinuing treatment. Importance of advising patients to immediately contact their clinician if they develop any symptoms of infection (e.g., fever; flu-like symptoms; body aches; chills; nausea; or headache with fever, neck stiffness, sensitivity to light, nausea or confusion). Importance of informing patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

• Advise patients that if any immunizations are planned, they should be administered at least 1 month before starting ponesimod. Vaccines containing live viruses (live-attenuated vaccines) should not be administered during ponesimod therapy and for 1–2 weeks after the drug is discontinued.

• Risk of transient decreases in heart rate when starting treatment. To reduce this effect, dose titration is required. Importance of not missing doses. If 4 or more consecutive doses are missed, dose titration must be reinitiated.

• Risk of increased liver enzymes. Advise patients to contact their clinician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during ponesimod therapy.

• Risk of adverse respiratory effects. Importance of advising patients to contact their clinician if they experience new onset or worsening dyspnea.

• Risk of macular edema. Advise patients to contact their clinician if they experience any changes in their vision during ponesimod therapy. Inform patients that their risk of developing macular edema is higher if they have diabetes mellitus or a history of uveitis.

• Risk of posterior reversible encephalopathy syndrome (PRES). Advise patients to immediately inform their clinician if they experience sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae.

• Severe increase in disability following discontinuance of therapy. Advise patients to contact their physician if they develop worsening MS symptoms following discontinuance of ponesimod.

• Importance of informing patients that the immune system effects of ponesimod (decreased peripheral lymphocyte count) may last up to 1–2 weeks after the last dose.

• Risk of fetal harm. Importance of discussing possible fetal risk with women of childbearing potential and advising such women of the need for effective contraception during therapy and for 1 week after the drug is discontinued. Importance of women informing clinicians if they are or plan to become pregnant.

• Importance of women informing clinicians if they plan to breast-feed.

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ponesimod is available through a specialty pharmacy network. Clinicians may consult the Ponvory website at [Web] or call 877-CarePath (877-227-3728) for specific availability information.

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