Ponvory

— THERAPEUTIC DISORDERS TREATED —
  • Multiple sclerosis
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Ponvory Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Ponesimod 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 20mg; tabs.

    Pharmacological Class

    Sphingosine 1-phosphate receptor modulator.

    How Supplied

    Starter Pack (2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg)—14; Tabs (20mg)—30

    How Supplied

    Ponvory (ponesimod) tablet is available as round, biconvex, film-coated tablets supplied in the following dosage strengths and package configurations.

    Child-Resistant Starter Pack (14 tablets):

    • 2mg Strength (2 tablets)

    • 3mg Strength (2 tablets)

    • 4mg Strength (2 tablets)

    • 5mg Strength (1 tablet)

    • 6mg Strength (1 tablet)

    • 7mg Strength (1 tablet)

    • 8mg Strength (1 tablet)

    • 9mg Strength (1 tablet)

    • 10mg Strength (3 tablets)

    Maintenance Dose Bottle:

    • 20mg Strength. Bottle of 30 tablets.

    Storage

    Starter Pack & Maintenance Dose Bottle: Store at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). Store in the original package.

    Manufacturer

    Janssen Pharmaceuticals, Inc.

    Generic Availability

    NO

    Ponvory Indications

    Indications

    Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

    Ponvory Dosage and Administration

    Prior to Treatment Evaluations

    Complete Blood Count (CBC)

    • Obtain a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) before initiating treatment with Ponvory.

    Cardiac Evaluation 

    • Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, obtain advice from cardiologist and recommend first-dose monitoring. 

    Liver Function

    • Obtain recent (i.e., within the last 6 months) transaminases (ALT and AST) and bilirubin levels.

    Ophthalmic Evaluation

    • Obtain an evaluation of the fundus, including the macula.

    Current or Prior Medications with Immune System Effects

    • Consider possible unintended additive immunosuppressive effects prior to initiation if concomitant use with anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs.

    Vaccinations

    • Test patients for antibodies to varicella zoster virus (VZV) before initiating; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with Ponvory. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of Ponvory.

    Adult

    Swallow whole. Initially 2mg once daily on Days 1 and 2; 3mg once daily on Days 3 and 4; 4mg once daily on Days 5 and 6; 5mg once daily on Day 7; 6mg once daily on Day 8; 7mg once daily on Day 9; 8mg once daily on Day 10; 9mg once daily on Day 11; 10mg once daily on Days 12, 13, and 14. Maintenance: 20mg once daily on Day 15 and thereafter. First dose 4hr monitoring for bradycardia, other abnormalities: see full labeling. Re-initiation of therapy after interruption for ≥4 consecutive doses: start with Day 1 of titration regimen.

    Adult

    Treatment Initiation

    • Swallow whole.

    • Use 14-day starter pack when initiating treatment with Ponvory.

    • Initiate 2mg once daily on Days 1 and 2; 3mg once daily on Days 3 and 4; 4mg once daily on Days 5 and 6; 5mg once daily on Day 7; 6mg once daily on Day 8; 7mg once daily on Day 9; 8mg once daily on Day 10; 9mg once daily on Day 11; 10mg once daily on Days 12, 13, and 14.

    Maintenance Dosage

    • After dose titration is complete, 20mg once daily on Day 15 and thereafter.

    First-Dose Monitoring

    • Initiation of Ponvory treatment results in a decrease in heart rate, first-dose 4-hour monitoring is recommended for patients with sinus bradycardia (HR <55bpm), first- or second-degree (Mobitz type I) AV block, or a history of MI or HF occurring >6 months prior to treatment initiation and in stable condition. 

    First 4-Hour Monitoring

    • Administer the first dose of Ponvory in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 4 hours after the first dose for signs and symptoms of bradycardia with a minimum of hourly pulse and blood pressure measurements. Obtain ECG prior to dosing and at the end of the 4-hour observation period.

    Additional Monitoring After 4-Hour Monitoring

    • Continue monitoring until the abnormality resolves if any of the following is present (even in the absence of symptoms) after 4 hours:

      • the heart rate 4 hours post-dose is <45 beats per minute (bpm); 

      • the heart rate 4 hours post-dose is at the lowest value post-dose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; 

      • the ECG 4 hours post-dose shows new onset second degree or higher AV block. 

    • If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 4 hours post-dose shows new onset second degree or higher AV block or QTc ≥500msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 4-hour monitoring after the second dose.

    • If treatment with Ponvory is considered in the following patients, advice from a cardiologist should be sought to determine the most appropriate monitoring strategy during treatment initiation:

      • With some preexisting heart and cerebrovascular conditions

      • With a prolonged QTc interval before dosing or during the 4-hour observations, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes

      • Receiving concurrent therapy with drugs that slow heart rate or AV conduction 

    Reinitiation of Ponvory After Treatment Interruption

    • Interruption during treatment, especially during titration, is not recommended.

    • If less than 4 consecutive doses are missed:

      • during titration: resume treatment with the first missed titration dose and resume the titration schedule at that dose and titration day. 

      • during maintenance: resume treatment with the maintenance dosage.

    • If 4 or more consecutive doses are missed:

      • Reinitiate treatment with Day 1 of the titration regimen (new starter pack).

    Children

    Not established.

    Renal Impairment

     

     

    Hepatic Impairment

    Not recommended in patients with moderate or severe hepatic impairment.

    Other Modifications

    Contraception

    • Females: Advise females of reproductive potential to use effective contraception during and for 1 week after discontinuation.

     

    Ponvory Contraindications

    Contraindications

    Recent (within the last 6 months) occurrence of: MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, Class III/IV heart failure. Presence of Mobitz Type II 2nd- or 3rd degree AV block, sick sinus syndrome, or sino-atrial block, unless paced.

    Ponvory Boxed Warnings

    Not Applicable

    Ponvory Warnings/Precautions

    Warnings/Precautions

    Increased risk of infections (may be fatal). Obtain recent CBC including lymphocyte count prior to initiation. Consider treatment interruption if serious infection develops. Active infection: do not start until infection resolved. Test for antibodies to varicella zoster virus; if negative, consider immunization before starting ponesimod. Immunosuppressed. Withhold if progressive multifocal leukoencephalopathy (PML) is suspected; discontinue if PML is confirmed. Risk of bradyarrhythmia, AV conduction delays: titration is required for treatment initiation. Obtain ECG prior to initiation to determine if preexisting conduction abnormalities are present. History of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, severe untreated sleep apnea: not recommended; refer to cardiologist if treatment is considered. History of recurrent syncope or symptomatic bradycardia: do benefit/risk assessment; refer to cardiologist if treatment is considered. Monitor BP during treatment. Severe respiratory disease (eg, pulmonary fibrosis, asthma, COPD): perform spirometric evaluation during treatment if clinically indicated. Obtain recent LFTs (within the last 6 months) prior to initiation. Monitor for hepatic dysfunction; discontinue if significant liver injury is confirmed. Moderate or severe hepatic impairment (Child-Pugh class B and C): not recommended. Perform periodic skin exam (esp. with risk factors); monitor for suspicious skin lesions and evaluate if observed. Diabetes, history of uveitis: increased risk of macular edema. Perform ophthalmic exam of fundus, including the macula, prior to initiation, and if any change in vision occur during therapy. Monitor for severe increase in disability after treatment discontinuation. Elderly. Pregnancy. Advise females of reproductive potential to use effective contraception during and for 1 week after discontinuation. Nursing mothers.

    Warnings/Precautions

    Infections

    • Obtain a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) before initiating treatment with Ponvory. 

    • Consider interrupting treatment with Ponvory if a patient develops a serious infection. 

    • Do not initiate treatment in patients with active infection until resolved. Monitor for infection during and for 1 to 2 weeks after discontinuation.

    • Herpes Viral Infections: 

      • Test for antibodies to varicella zoster virus; if negative, consider immunization before starting Ponvory.

    • Cryptococcal Infections: 

      • Evaluate for signs or symptoms consistent with a cryptococcal infection and undergo prompt diagnostic evaluation and treatment.

      • Suspend treatment until a cryptococcal infection has been excluded. If cryptococcal meningitis is diagnosed, initiate appropriate treatment.

    • Progressive Multifocal Leukoencephalopathy (PML):

      • MRI findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs that may be consistent with PML may be useful.

      • Suspend Ponvory treatment if PML is suspected until PML has been excluded. Discontinue Ponvory treatment if PML is confirmed.

    • Prior and Concomitant Treatment with Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies: 

      • Use caution when coadministering Ponvory with anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) due to the risk of additive immune system effects.

    • Vaccinations:

      • Test for antibodies to VZV before initiating Ponvory in patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV. 

      • VZV vaccination for antibody-negative patients is recommended prior to commencing treatment with Ponvory, following which initiation of treatment with Ponvory should be postponed for 4 weeks to allow the full effect of vaccination to occur.

      • If live attenuated vaccine immunizations are required, give at least 1 month prior to starting Ponvoy. 

      • Avoid using live attenuated vaccines during and for 1 to 2 weeks after treatment with Ponvoy.

    Bradyarrhythmia and Atrioventricular Conduction Delays

    • An up-titration scheme must be used to reach the maintenance dosage of Ponvory.

    • Reduction in heart rate 

      • Treatment initiation may result in a transient decrease in HR. 

    • Atrioventricular Conduction Delays 

      • Treatment initiation may result in transient AV conduction delays. 

      • The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours on treatment, but they occasionally required treatment with atropine or isoproterenol.

      • If treatment with Ponvory is considered, seek advice from a cardiologist for individual with: significant QT prolongation (QTc >500msec); or atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs; or unstable ischemic heart disease, cardiac decompensated failure occurring more than 6 months prior to treatment initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension; or a history of Mobitz Type II second degree AV block or higher-grade AV block, sick-sinus syndrome, or sino-atrial heart block.

    • Treatment Initiation Recommendations

      • For all patients, obtain an ECG to determine whether preexisting conduction abnormalities are present. Dose titration is recommended for initiation to reduce cardiac effects.

      • First-dose monitoring is recommended for patients with sinus bradycardia, first-or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset more than 6 months prior to initiation.

      • Not recommended for patients with history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea. If treatment is considered, seek advice from a cardiologist.

      • Assess the overall benefit-risk of Ponvory use in patients with a history of recurrent syncope or symptomatic bradycardia. If treatment is considered, seek advice from a cardiologist.

      • Concomitant use with drugs that decrease HR (e.g., beta-blockers, non-dihydropyridine calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate such as digoxin) may be associated with severe bradycardia and heart block. If treatment is considered, seek advice from a cardiologist.

        • If patients is receiving a stable dose of beta-blocker, consider resting HR prior to starting Ponvory. If HR is >55bpm, Ponvory can be initiated. If HR is ≤55bpm, interrupt beta-blocker until baseline HR is >55bpm.

        • Do not initiate Ponvory treatment in patients receiving other drugs that decrease HR without consulting a cardiologist.

    Respiratory Effects

    • Use caution in patients with severe respiratory disease (i.e., pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease). Perform spirometric evaluation of respiratory function during treatment if clinically indicated.

    Liver Injury

    • Obtain transaminase and bilirubin levels prior to starting treatment with Ponvory (within 6 months). 

    • Evaluate hepatic enzymes in patients who develop symptoms that may indicate hepatic dysfunction, including unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine. 

    • Discontinue Ponvory if significant liver injury is confirmed.

    • Not recommended to use in patients with moderate or severe hepatic impairment.

    Increased Blood Pressure

    • Monitor blood pressure (BP) during treatment with Ponvory.

    Cutaneous Malignancies

    • Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. 

    • Monitor for suspicious skin lesions. Promptly evaluate if a suspicious skin lesion is observed. Limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor due to an increased risk for skin cancer.

    • Ponvory is not recommended in patients receiving phototherapy with UV-B radiation or PUVA-photochemotherapy.

    Fetal Risk 

    • Advise females of reproductive potential to use effective contraception during and for 1 week after discontinuation.

    Macular Edema

    • Perform an examination of the fundus, including the macula in all patients before starting treatment, and again at any time if a patient reports vision changes while on Ponvory therapy.  

    • Assess potential benefits and risks on whether or not to discontinue Ponvory therapy. Continuation of Ponvory therapy in patients with macular edema has not been evaluated.

    • Increased risk of macular edema in patients with a history of uveitis and patients with diabetes mellitus. Obtain regular follow-up examinations of the fundus in these patients.

    Posterior Reversible Encephalopathy Syndrome (PRES)

    • Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. 

    • Discontinue treatment if PRES is suspected.

    Severe Increase in Disability After Stopping Ponvory

    • Monitor for development of severe increase in disability following discontinuation of Ponvory and begin appropriate treatment as needed.

    Immune System Effects After Stopping Ponvory

    • When using immunosuppressants after stopping Ponvory therapy, apply caution 1 to 2 weeks after the last dose of Ponvory due to an additive effect on the immune system.

    Pregnancy Considerations

    Risk Summary

    • No adequate and well-controlled studies of Ponvory in pregnant women.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding and the mother’s clinical need for Ponvory and any potential adverse effects on the breastfed infant or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established.

    Geriatric Considerations

    Use caution in patients 65 years of age and older.

    Renal Impairment Considerations

     

     

    Hepatic Impairment Considerations

    Not recommended in patients with moderate or severe hepatic impairment.

    Other Considerations for Specific Populations

    Contraception

    • Females: Advise females of reproductive potential to use effective contraception during and for 1 week after discontinuation.

     

    Ponvory Pharmacokinetics

    Absorption

    The time to reach maximum plasma concentration of ponesimod is 2-4 hours post-dose. The absolute oral bioavailability of a 10 mg dose is 84%. 

    Distribution

    Following IV administration in healthy subjects, the steady-state volume of distribution of ponesimod is 160 L. Ponesimod is highly bound to plasma proteins (> 99%) and is mainly (78.5%) distributed in the plasma fraction of whole blood. Animal studies show that ponesimod readily crosses the blood-brain-barrier.

    Metabolism

    Multiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12) and non-CYP450 enzymes catalyze the oxidation of ponesimod to M12. Ponesimod also undergoes direct glucuronidation (mainly UGT1A1 and UGT2B7).

     

    Elimination

    After a single IV administration, the total clearance of ponesimod is 3.8 L/hour. The elimination half-life after oral administration is approximately 33 hours. Following a single oral administration of 14C-ponesimod, 57% to 80% of the dose was recovered in feces (16% as unchanged ponesimod), and 10% to 18% in urine (no unchanged ponesimod).

    Ponvory Interactions

    Interactions

    Concomitant antineoplastic, immunosuppressant or immune-modulating therapies may increase risk of immunosuppression; use caution when switching from long-acting immunotherapies; caution for 1–2 weeks after discontinuing ponesimod. Initiation after treatment with alemtuzumab: not recommended. Concomitant QT prolonging drugs (eg, quinidine, procainamide, amiodarone, sotalol): risk of torsades de pointes; refer to cardiologist if treatment is considered. Concomitant β-blockers, digoxin, diltiazem, verapamil during initiation may be associated with severe bradycardia or heart block; refer to cardiologist if treatment is considered. Avoid live attenuated vaccines during and for 1–2 weeks after discontinuing ponesimod; may have suboptimal response. Antagonized by strong CYP3A4 and UGT1A1 inducers (eg, rifampin, phenytoin, carbamazepine): concomitant use not recommended. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy: not recommended.

    Ponvory Adverse Reactions

    Adverse Reactions

    Upper respiratory tract infection, hepatic transaminase elevation, hypertension, UTI, dyspnea, dizziness; macular edema, basal cell carcinoma/melanoma, decreased pulmonary function; rare: posterior reversible encephalopathy syndrome (discontinue if suspected).

    Ponvory Clinical Trials

    Clinical Trials

    The approval was based on results from a phase 3 head-to-head, randomized trial of Ponvory vs teriflunomide. A total of 1133 patients with relapsing MS, were randomly assigned to either Ponvory 20mg once daily or teriflunomide 14mg once daily.

    Results showed that the annualized relapse rate from baseline to Week 108 was reduced by 30.5% for the Ponvory group vs the teriflunomoide group, meeting the trial’s primary endpoint (P =.0003). Moreover, 70.7% of patients treated with Ponvory had no confirmed relapses compared with 60.6% of patients treated with teriflunomide.

    Moreover, Ponvory showed superiority in reducing the number of new gadolinium-enhancing (GdE) T1 and T2 lesions compared with  teriflunomide by 58.5% and 55.7%, respectively (for both P <.0001).

    Ponvory Note

    Not Applicable

    Ponvory Patient Counseling

    Patient Counseling

    Administration

    • Tell patients not to discontinue Ponvory without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidentally take more Ponvory than prescribed.

    Risk of Infections 

    • Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking Ponvory and for 1 to 2 weeks after discontinuing, and that they should contact their physician if they develop symptoms of infection. 

    • Advise patients that the use of some vaccines (live attenuated vaccines) should be avoided during treatment with Ponvory and should be paused 1 week prior and until 4 weeks after a planned vaccination. 

    • Recommend patients to delay treatment with Ponvory for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.

    Cardiac Effects

    • Advise patients that initiation of Ponvory treatment results in a transient decrease in heart rate. 

    • Advise patients that dose titration is required if 4 or more consecutive daily doses are missed during initiation or maintenance.

    • Inform patients with certain preexisting cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 4 hours after the first dose, after reinitiation if treatment is interrupted or discontinued for certain periods.

    Respiratory Effects

    • Contact health care provider if new onset or worsening of dyspnea occurs.

    Liver Injury

    • Ponvory may increase liver enzymes. Advise patient to contact their health care provider if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.

    Cutaneous Malignancies

    • Advise patients that basal cell carcinoma, melanoma, and squamous cell carcinoma are associated with use of Ponvory. Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor. 

    Pregnancy and Fetal Risk

    • Inform patients that Ponvory may cause fetal harm.

    • Advise women of childbearing potential of the need for effective contraception during treatment with Ponvory and for one week after stopping Ponvory. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant.

    Macular Edema

    • Advise patients that Ponvory may cause macular edema, and that they should contact their physician if they experience any changes in their vision. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.

    Posterior Reversible Encephalopathy Syndrome

    • Advise patients to immediately report to their healthcare provider any symptoms involving 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 After Stopping Ponvory 

    • Inform patients that severe increase in disability has been reported after discontinuation of Ponvory. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of Ponvory.

    Immune System Effects After Stopping Ponvory 

    • Advise patients that Ponvory continues to have effects, such as lowering effects on peripheral lymphocyte count, for 1 to 2 weeks after the last dose.

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