Ponesimod is an active pharmaceutical ingredient in the Sphingosine-1-Phosphate (S1p) Receptor Modulators group (L04AE). The information below is compiled per regulator from the product labels on record, with direct links to the original documents.
GBOfficial regulatory label· revised March 6, 2026[1]
Ponvory is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features.
How to take
GB
USUnited States· FDA
1 product
Uses
USOfficial regulatory label· revised December 4, 2025[2]
1 INDICATIONS AND USAGE PONVORY is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
PONVORY is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
( 1 )
How to take
EUEuropean Union· EMA
1 product
Uses
EUOfficial regulatory label· revised March 10, 2026[3]
Ponvory is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features.
How to take
EU
CACanada· Health Canada
1 product
1 product on record with this regulator. Detailed label text (uses, dosage, side effects) is being ingested — the original document is linked under Sources [4].
[1]MHRA (UK) · PLGB433110002 · revised March 6, 2026
[2]FDA DailyMed · 0c025ba8-ba51-27… · revised December 4, 2025 [PDF]
[3]European Medicines Agency · EMEA/H/C/005163 · revised March 10, 2026
[4]Health Canada (DPD) · 02515482 · revised August 28, 2025
[5]OpenFDA adverse-event reports (US), 12 months ending June 4, 2026.
Information on this page is compiled from public regulatory records. Drugvu is not affiliated with any regulator or pharmaceutical manufacturer. This is not medical advice. Always consult a qualified healthcare professional.
Treatment should be initiated under the supervision of a physician experienced in the management of multiple sclerosis. 5). Treatment starts with one 2 mg tablet orally once daily on day 1 and dose-escalation progresses with the titration schedule outlined in Table 1.
2, “Re-initiation of therapy following treatment interruption during dose titration or maintenance period”). 2, Treatment initiation), the recommended maintenance dose is one 20 mg tablet taken orally once daily. Re-initiation of therapy following treatment interruption during dose titration or maintenance period - if less than 4 consecutive doses are missed, resume treatment with the first missed dose.
- if 4 or more consecutive doses are missed, reinitiate treatment with day 1 (2 mg) of the titration regimen (new treatment initiation pack). The same first dose monitoring as for treatment initiation is recommended when 4 or more consecutive doses of ponesimod are missed during the titration or maintenance periods.
Special populations Elderly population Clinical studies of ponesimod did not include patients aged 65 years and older. Ponesimod should be prescribed with caution in patients aged 65 years and over due to the lack of data on safety and efficacy.
2). 2). 2). Paediatric population The safety and efficacy of Ponvory in children and adolescents aged less than 18 years have not been established. No data are available. Method of administration Ponesimod should be administered orally once daily.
2).
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
GBOfficial regulatory label· Adverse reactions· revised March 6, 2026[1]
9%) and upper respiratory tract infection (11%). Tabulated list of adverse reactions Adverse reactions reported with ponesimod in controlled clinical trials and uncontrolled extension trials are ranked by frequency, with the most frequent reactions first.
Frequencies were defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
6% of patients receiving teriflunomide 14 mg. Patients who experienced bradycardia were generally asymptomatic. Bradycardia resolved in all patients without intervention and did not require discontinuation of ponesimod treatment. On day 1, 3 patients treated with ponesimod had asymptomatic post-dose HR below or equal to 40 bpm; all 3 patients had baseline HRs below 55 bpm.
Initiation of ponesimod treatment has been associated with transient AV conduction delays that follow a similar temporal pattern as the observed decrease in HR during dose titration. 2% of patients receiving teriflunomide 14 mg in the OPTIMUM study.
No second-degree AV blocks, Mobitz type I (Wenckebach), were observed in OPTIMUM. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of ponesimod treatment.
1% respectively). Nasopharyngitis and viral infections were more common in ponesimod-treated patients. 9% of patients receiving teriflunomide 14 mg. 8%). 2 x 109/L while remaining on treatment with ponesimod. 1% of ponesimod-treated patients compared to none of the patients receiving teriflunomide 14 mg.
5% of patients receiving, teriflunomide 14 mg, respectively. 1% in patients receiving teriflunomide 14 mg. The majority of elevations occurred within 6 or 12 months of starting treatment. ALT levels returned to normal after discontinuation of ponesimod.
Most cases of ALT increases ≥3×ULN resolved on continued ponesimod treatment, and the remaining cases resolved upon treatment discontinuation. In clinical trials, ponesimod was discontinued if the elevation exceeded a 3 -fold increase and the patient showed symptoms related to hepatic dysfunction.
4). 6% of patients receiving teriflunomide 14 mg. 4% in patients receiving teriflunomide 14 mg. The changes in FEV1 and DLCO appear to be partially reversible after treatment discontinuation. In the OPTIMUM study, 7 patients discontinued ponesimod because of pulmonary adverse events (dyspnoea).
Ponesimod has been tested in MS patients with mild to moderate asthma or chronic obstructive pulmonary disease. The changes in FEV1 were […]
GBOfficial regulatory label· Warnings and precautions· revised March 6, 2026[1]
Bradyarrhythmia Initiation of treatment with ponesimod Prior to treatment initiation with ponesimod, an electrocardiogram (ECG) in all patients should be obtained to determine whether pre-existing conduction abnormalities are present.
In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below). 2). After the first dose of ponesimod, the decrease in HR typically begins within an hour and reaches its nadir within 2-4 hours. The HR typically recovers to baseline levels 4-5 hours after administration.
The mean decrease in HR on day 1 of dosing (2 mg) was 6 bpm. With up-titration after day 1, the decrease in HR is less pronounced with no further post-dose decrease in HR observed after day 3. 5). For patients receiving a stable dose of a beta-blocker, the resting HR should be considered before introducing ponesimod treatment.
If the resting HR is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting HR is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline HR is greater than 55 bpm.
5). Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. 1). Administer the first dose of ponesimod 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 an ECG in these patients at the end of the 4- hour observation period. Additional monitoring after 4-hours is recommended if any of the following abnormalities are present (even in the absence of symptoms), continue monitoring until the abnormality resolves: - HR 4 hours postdose is less than 45 bpm - HR 4 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred - The ECG 4 hours postdose shows new onset second-degree or higher AV block If postdose 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 greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
GBOfficial regulatory label· Contraindications· revised March 6, 2026[1]
1. 4). - Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation, or New York Heart Association (NYHA) Class III or IV heart failure.
4). - Severe active infections, active chronic infections. - Active malignancies. - Moderate or severe hepatic impairment (Child-Pugh class B and C, respectively). 6).
This is not medical advice. Consult a qualified healthcare professional.
USOfficial regulatory label· revised December 4, 2025[2]
1 Assessments Prior to First Dose of PONVORY Before initiation of treatment with PONVORY, assess the following: Cardiac Evaluation Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present.
2 )] . 1 )] . 3 )] . 4 )] . 8 )] . Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of PONVORY. 6 )] . 1 )] . 1 )] . If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of PONVORY.
2 Recommended Dosage Maintenance Dosage After dose titration is complete (see Treatment Initiation) , the recommended maintenance dosage of PONVORY is 20 mg taken orally once daily starting on Day 15. Administer PONVORY orally once daily.
Swallow the tablet whole. PONVORY can be taken with or without food. 1 )] . 2 )] . 4 )] . 2 )] . First Dose 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 an ECG in these patients prior to dosing and at the end of the 4-hour observation period.
Additional Monitoring After 4-Hour Monitoring If any of the following abnormalities are present after 4 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves: The heart rate 4 hours post-dose is less than 45 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 greater than or equal to 500 msec, 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. 4 Reinitiation of PONVORY After Treatment Interruption Interruption during treatment, especially during titration, is not recommended; however: If fewer 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 during titration or maintenance: treatment should be reinitiated with Day 1 of the titration regimen (new starter pack). 3 )] .
This is not medical advice. Consult a qualified healthcare professional.
Most-reported reactions to the US regulator (12 mo to June 4, 2026): 5 reports total. [5]
Covid-19 1
Dyspnoea 1
Feeling Abnormal 1
Infection 1
Loss Of Consciousness 1
Multiple Sclerosis 1
Uveal Melanoma 1
Side effects & warnings
USOfficial regulatory label· Adverse reactions· revised December 4, 2025[2]
12 )] Most common adverse reactions (incidence at least 10%) are upper respiratory tract infection, hepatic transaminase elevation, and hypertension. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals, Inc. gov/medwatch .
1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 1438 MS patients have received PONVORY at doses of at least 2 mg daily. These patients were included in Study 1 (2-year active-controlled versus teriflunomide 14 mg) [see Clinical Studies ( 14 )] and in a Phase 2 (6-month placebo-controlled) study in patients with MS and the uncontrolled extension studies.
2% of patients receiving teriflunomide 14 mg. 7% of PONVORY-treated patients, compared to 6% of patients receiving teriflunomide 14 mg. The most common adverse reactions (incidence at least 10%) in PONVORY-treated patients in Study 1 were upper respiratory tract infection, hepatic transaminase elevation, and hypertension.
Table 3 lists adverse reactions that occurred in at least 2% of PONVORY-treated patients and at a higher rate than in patients receiving teriflunomide 14 mg.
Table 3:
Adverse Reactions Reported in Study 1 Occurring in at Least 2% of PONVORY-Treated Patients and at a Higher Rate Than in Patients Receiving Teriflunomide 14 mg a Includes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, respiratory tract infection viral, viral upper respiratory tract infection, tracheitis, and laryngitis.
b Includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased. c Includes the following terms: hypertension, hypertensive crisis, blood pressure increased, blood pressure systolic increased, and blood pressure diastolic increased.
8 )] . Adverse reactions in patients treated with PONVORY in an additional 6-month placebo-controlled study were generally similar to those in Study 1. The following additional adverse reactions occurred in at least 2% of PONVORY 20 mg-treated patients and at a higher rate than in patients receiving placebo (but did not meet the reporting rate criteria for inclusion in Study 1): rhinitis, fatigue, chest discomfort, peripheral edema, joint swelling, blood cholesterol increased, migraine, insomnia, depression, dyspepsia, dry mouth, bradycardia, back pain, and sinusitis.
Additionally, in uncontrolled extension trials, the adverse reaction of pneumonia was reported. 2% in patients receiving teriflunomide 14 mg. It is not known whether these events were related to the effects of MS, to PONVORY, or to a combination of both.
3 )] . 2%) in patients receiving teriflunomide 14 mg, and a case of malignant melanoma was reported in a PONVORY-treated patient. 6 )] .
USOfficial regulatory label· Warnings and precautions· revised December 4, 2025[2]
5 WARNINGS AND PRECAUTIONS Infections : PONVORY may increase the risk of infections. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment and for 1-2 weeks after discontinuation. Do not start PONVORY in patients with active infection.
1 ) Bradyarrhythmia and Atrioventricular Conduction Delays : PONVORY may result in a transient decrease in heart rate; titration is required for treatment initiation. Check an electrocardiogram (ECG) to assess for preexisting cardiac conduction abnormalities before starting PONVORY.
Consider cardiology consultation for conduction abnormalities or concomitant use with other drugs that decrease heart rate. 3 ) Respiratory Effects : May cause a decline in pulmonary function. , spirometry) if clinically indicated. 3 ) Liver Injury : Discontinue if significant liver injury is confirmed.
Obtain liver function tests before initiating PONVORY. 4 ) Increased Blood Pressure (BP) : Monitor BP during treatment. 5 ) Cutaneous Malignancies : Skin examination prior to or shortly after the start of treatment and periodically is recommended.
Suspicious skin lesions should be evaluated. 6 ) Fetal Risk : Women of childbearing potential should use effective contraception during and for 1 week after stopping PONVORY. 7 ) Macular Edema : Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with PONVORY.
Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing PONVORY if macular edema develops. Diabetes mellitus and uveitis increase the risk.
2 )] . PONVORY may therefore increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators. 1%, respectively). PONVORY increased the risk of upper respiratory tract infections.
9% of patients receiving teriflunomide 14 mg. , within 6 months or after discontinuation of prior therapy) complete blood count including lymphocyte count should be reviewed. Initiation of treatment with PONVORY should be delayed in patients with active infection until resolution.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
USOfficial regulatory label· Contraindications· revised December 4, 2025[2]
2 )] In the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure ( 4 ) Presence of Mobitz type II second-degree, third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker ( 4 )
This is not medical advice. Consult a qualified healthcare professional.
Treatment should be initiated under the supervision of a physician experienced in the management of multiple sclerosis. 5). Treatment starts with one 2 mg tablet orally once daily on day 1 and dose-escalation progresses with the titration schedule outlined in Table 1.
2, “Re-initiation of therapy following treatment interruption during dose titration or maintenance period”). 2, Treatment initiation), the recommended maintenance dose is one 20 mg tablet taken orally once daily. Re-initiation of therapy following treatment interruption during dose titration or maintenance period - if less than 4 consecutive doses are missed, resume treatment with the first missed dose.
- if 4 or more consecutive doses are missed, reinitiate treatment with day 1 (2 mg) of the titration regimen (new treatment initiation pack). The same first dose monitoring as for treatment initiation is recommended when 4 or more consecutive doses of ponesimod are missed during the titration or maintenance periods.
Special populations Elderly population Clinical studies of ponesimod did not include patients aged 65 years and older. Ponesimod should be prescribed with caution in patients aged 65 years and over due to the lack of data on safety and efficacy.
2). 2). 2). Paediatric population The safety and efficacy of Ponvory in children and adolescents aged less than 18 years have not been established. No data are available. Method of administration Ponesimod should be administered orally once daily.
2).
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
EUOfficial regulatory label· Adverse reactions· revised March 10, 2026[3]
9%) and upper respiratory tract infection (11%). Tabulated list of adverse reactions Adverse reactions reported with ponesimod in controlled clinical trials and uncontrolled extension trials are ranked by frequency, with the most frequent reactions first.
Frequencies were defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
6% of patients receiving teriflunomide 14 mg. Patients who experienced bradycardia were generally asymptomatic. Bradycardia resolved in all patients without intervention and did not require discontinuation of ponesimod treatment. On day 1, 3 patients treated with ponesimod had asymptomatic post-dose HR below or equal to 40 bpm; all 3 patients had baseline HRs below 55 bpm.
15 Initiation of ponesimod treatment has been associated with transient AV conduction delays that follow a similar temporal pattern as the observed decrease in HR during dose titration. 2% of patients receiving teriflunomide 14 mg in the OPTIMUM study.
No second-degree AV blocks, Mobitz type I (Wenckebach), were observed in OPTIMUM. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of ponesimod treatment.
1% respectively). Nasopharyngitis and viral infections were more common in ponesimod-treated patients. 9% of patients receiving teriflunomide 14 mg. 8%). 2 × 109/L while remaining on treatment with ponesimod. 1% of ponesimod-treated patients compared to none of the patients receiving teriflunomide 14 mg.
5% of patients receiving, teriflunomide 14 mg, respectively. 1% in patients receiving teriflunomide 14 mg. The majority of elevations occurred within 6 or 12 months of starting treatment. ALT levels returned to normal after discontinuation of ponesimod.
Most cases of ALT increases ≥3×ULN resolved on continued ponesimod treatment, and the remaining cases resolved upon treatment discontinuation. In clinical trials, ponesimod was discontinued if the elevation exceeded a 3 -fold increase and the patient showed symptoms related to hepatic dysfunction.
4). 6% of patients receiving teriflunomide 14 mg. 4% in patients receiving teriflunomide 14 mg. The changes in FEV1 and DLCO appear to be partially reversible after treatment discontinuation. In the OPTIMUM study, 7 patients discontinued ponesimod because of pulmonary adverse events (dyspnoea).
Ponesimod has been tested in MS patients with mild to moderate asthma or chronic obstructive pulmonary disease. The changes in FEV1 […]
EUOfficial regulatory label· Warnings and precautions· revised March 10, 2026[3]
Bradyarrhythmia Initiation of treatment with ponesimod Prior to treatment initiation with ponesimod, an electrocardiogram (ECG) in all patients should be obtained to determine whether pre-existing conduction abnormalities are present.
In patients with certain pre-existing conditions, first-dose monitoring is recommended (see below). 2). After the first dose of ponesimod, the decrease in HR typically begins within an hour and reaches its nadir within 2-4 hours. The HR typically recovers to baseline levels 4-5 hours after administration.
The mean decrease in HR on day 1 of dosing (2 mg) was 6 bpm. With up-titration after day 1, the decrease in HR is less pronounced with no further post-dose decrease in HR observed after day 3. 5). For patients receiving a stable dose of a beta-blocker, the resting HR should be considered before introducing ponesimod treatment.
If the resting HR is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting HR is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline HR is greater than 55 bpm.
5). Beta-blocker treatment can be initiated in patients receiving stable doses of ponesimod. 1). Administer the first dose of ponesimod 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 an ECG in these patients at the end of the 4-hour observation period. Additional monitoring after 4-hours is recommended if any of the following abnormalities are present (even in the absence of symptoms), continue monitoring until the abnormality resolves: - HR 4 hours postdose is less than 45 bpm - HR 4 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred - The ECG 4 hours postdose shows new onset second-degree or higher AV block 7 If postdose 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 greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
EUOfficial regulatory label· Contraindications· revised March 10, 2026[3]
1. 4). - Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation, or New York Heart Association (NYHA) Class III or IV heart failure.
4). - Severe active infections, active chronic infections. - Active malignancies. - Moderate or severe hepatic impairment (Child-Pugh class B and C, respectively). 6).
This is not medical advice. Consult a qualified healthcare professional.
If pharmacological treatment is required, continue monitoring overnight and repeat 4- hour monitoring after the second dose. 5), consider potential need to switch to non-HR lowering medicinal products. Concomitant use of these medicinal products during ponesimod initiation may be associated with severe bradycardia and heart block.
Infections Risk of infections Ponesimod causes a dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline values due to reversible sequestration of lymphocytes in lymphoid tissues. 8). Life-threatening and rare fatal infections have been reported in association with sphingosine 1-phosphate (S1P) receptor modulators.
Before initiating treatment with ponesimod, results from a recent complete blood count (CBC) with differential (including lymphocyte count) […]
2 )] . In Study 1, peripheral lymphocyte counts returned to normal range within 2 weeks after discontinuation of PONVORY, which was the first timepoint evaluated. 12 )] . 2%. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy.
Consider interruption of treatment with PONVORY if a patient develops a serious infection. Herpes Viral Infections Cases of herpes viral infection have been reported in the development program of PONVORY; herpes simplex encephalitis and varicella zoster meningitis have been reported with other S1P receptor modulators.
8% for both PONVORY-treated patients and those receiving teriflunomide 14 mg. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY (see Vaccinations ) .
Cryptococcal Infections Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment.
PONVORY treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability.
Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
, immunocompromised patients, polytherapy with immunosuppressants, duration of use). Longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months.
Physicians should be vigilant for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with PONVORY should be suspended until PML has been excluded.
If PML is confirmed, treatment with PONVORY should be discontinued. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment.
IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation.
Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. 1 )] . Vaccinations Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating PONVORY treatment.
A full course of vaccination for antibody-negative patients with varicella vaccine 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.
No clinical data are available on the efficacy and safety of vaccinations in patients taking PONVORY. Vaccinations may be less effective if administered during PONVORY treatment. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of PONVORY.
Avoid the use of live attenuated vaccines during and for 1 to 2 weeks after treatment with PONVORY. 2 )] .
Study 1 did not include patients who had:
A resting heart rate less than 50 beats per minute (bpm) on baseline electrocardiogram Myocardial infarction or unstable ischemic heart disease in the last 6 months Cardiac failure (New York Heart Association class III-IV) or presence of any severe cardiac disease Cardiac conduction or rhythm disorders (including sino-atrial heart block, symptomatic bradycardia, atrial flutter or atrial fibrillation, ventricular arrhythmia, cardiac arrest) either in history or observed at screening Mobitz Type II second degree AV block or higher-grade AV block observed at screening QTcF interval greater than 470 ms (females) and greater than 450 ms (males) observed at screening History of syncope associated with cardiac disorders Uncontrolled systemic arterial hypertension Reduction in Heart Rate Initiation of PONVORY may result in a transient decrease in heart rate.
6% of patients receiving teriflunomide 14 mg. After the first titration dose of PONVORY, the decrease in heart rate typically begins within an hour and reaches its nadir within 2-4 hours. The heart rate typically recovers to baseline levels 4-5 hours after administration.
The mean decrease in heart rate on Day 1 of dosing was 6 bpm. With up-titration after Day 1, the post-dose decrease in heart rate is less pronounced. Bradycardia resolved in all patients in Study 1 without intervention and did not require discontinuation of PONVORY treatment.
On Day 1, 3 patients treated with PONVORY had asymptomatic post-dose heart rate below or equal to 40 bpm; all 3 patients had baseline heart rates below 55 bpm. Atrioventricular Conduction Delays Initiation of PONVORY treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration.
2% of patients receiving teriflunomide 14 mg. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of PONVORY treatment. In Study 1, second- and third-degree AV blocks were not reported in patients treated with PONVORY.
2 )] With 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 With a history of Mobitz Type II second degree AV block or higher-grade AV block, sick- sinus syndrome, or sino-atrial heart block [see Contraindications ( 4 )] Treatment Initiation Recommendations Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
2 )] . 3 )] . , TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
Use of PONVORY in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
, beta-blockers, non-dihydropyridine calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate such as digoxin). Concomitant use of these drugs during PONVORY initiation may be associated with severe bradycardia and heart block.
If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing PONVORY treatment.
If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, PONVORY can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart rate is greater than 55 bpm.
3 )] . 2 )] . 4 )] . 3 Respiratory Effects Dose-dependent reductions in forced expiratory volume over 1 second (FEV 1 ) and reductions in diffusion lung capacity for carbon monoxide (DL CO ) were observed in PONVORY-treated patients mostly occurring in the first month after treatment initiation.
4% in patients receiving teriflunomide 14 mg. In Study 1, 7 patients discontinued PONVORY because of pulmonary adverse events. There is insufficient information to determine the reversibility of the decrease in FEV 1 or FVC after treatment discontinuation.
, pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease). Spirometric evaluation of respiratory function should be performed during therapy with PONVORY if clinically indicated. 4 Liver Injury Elevations of transaminases may occur in PONVORY-treated patients.
, within last 6 months) before initiation of PONVORY. 5% of patients who received teriflunomide 14 mg. 3% of patients treated with teriflunomide 14 mg. The median time to an elevation of 3-fold the ULN was 3 months. The majority (89%) of patients with ALT increases 3-fold or greater the ULN continued treatment with PONVORY with values returning to less than three times the ULN within approximately 2-4 weeks.
9% of patients who received teriflunomide 14 mg. Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have hepatic enzymes checked.
PONVORY should be discontinued if significant liver injury is confirmed. No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). 3 )] . 1 mm Hg in patients receiving teriflunomide 14 mg, respectively.
An increase in blood pressure with PONVORY was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. 0% of patients receiving teriflunomide 14 mg. One patient treated with PONVORY experienced a hypertensive crisis but had evidence of longstanding hypertensive heart disease.
Blood pressure should be monitored during treatment with PONVORY and managed appropriately. 6 Cutaneous Malignancies The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators.
Use of PONVORY has been associated with an increased risk of BCC. 1 )] . Cases of other cutaneous malignancies, including melanoma and squamous cell carcinoma, have also been reported in patients treated with PONVORY and in patients treated with other S1P receptor modulators.
Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer.
Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking PONVORY. 3 )] . Because it takes approximately 1 week to eliminate PONVORY from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 1 week after stopping PONVORY treatment.
8 Macular Edema S1P receptor modulators, including PONVORY, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with PONVORY. Perform an examination of the fundus, including the macula, periodically while on therapy and any time there is a change in vision.
1% of PONVORY-treated patients compared to none of the patients receiving teriflunomide 14 mg. Continuation of PONVORY therapy in patients with macular edema has not been evaluated. , 6 months) can lead to permanent visual loss. Consider discontinuing PONVORY if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient.
The risk of recurrence after rechallenge has not been evaluated. Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during therapy with S1P receptor modulators, including PONVORY.
9 Posterior Reversible Encephalopathy Syndrome Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a S1P receptor modulator. Such events have not been reported for PONVORY-treated patients in the development program.
, cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI.
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. If PRES is suspected, PONVORY should be discontinued. 10 Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive effects on the immune system while at the same time minimizing risk of disease reactivation, when initiating PONVORY.
Initiating treatment with PONVORY after treatment with alemtuzumab is not recommended. 11 Severe Increase in Disability After Stopping PONVORY Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator.
The possibility of severe exacerbation of disease should be considered after stopping PONVORY treatment. Patients should be observed for a severe increase in disability upon PONVORY discontinuation and appropriate treatment should be instituted, as required.
1 )] . 12 Immune System Effects After Stopping PONVORY After stopping PONVORY therapy, ponesimod remains in the blood for up to 1 week. Starting other therapies during this interval will result in concomitant exposure to ponesimod. 2 )] .
However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for 1 to 2 weeks after the last dose. 1 )] .
If pharmacological treatment is required, continue monitoring overnight and repeat 4-hour monitoring after the second dose. 5), consider potential need to switch to non-HR lowering medicinal products. Concomitant use of these medicinal products during ponesimod initiation may be associated with severe bradycardia and heart block.
Infections Risk of infections Ponesimod causes a dose-dependent reduction in peripheral lymphocyte count to 30-40% of baseline values due to reversible sequestration of lymphocytes in lymphoid tissues. 8). Life-threatening and rare fatal infections have been reported in association with sphingosine 1-phosphate (S1P) receptor modulators.
Before initiating treatment with ponesimod, results from a recent complete blood count (CBC) with differential (including lymphocyte count) […]