www.ponvoryhcp.com Open in urlscan Pro
2606:4700::6812:1ee3  Public Scan

Form analysis
0 forms found in the DOM

Text Content

Skip to main content
Google Tag Manager

Learn more about Janssen’s COVID-19 response and our continued support to help
patients afford and access our medicines.

[x]

For US Healthcare Professionals

 * Important Safety Information
 * Prescribing Information
 * Full Prescribing Information
 * Medication Guide
 * For US Patients

Register for
Updates

Access and
Affordability



Toggle navigation
 * About PONVORY™
   * OPTIMUM Study
   * Efficacy
   * Safety
   * MOA
 * Prescribing PONVORY™
   * Initiation
   * Dosing
   * Reversibility
   * Elimination
 * Support and Resources
 * Relapsing MS


PONVORY™ (PONESIMOD) HCP


PONVORY™ WAS PROVEN SUPERIOR AT REDUCING RELAPSES AND LESIONS VS AUBAGIO® IN A
STUDY LASTING ~2 YEARS1

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

HELPING CONTROL MS TODAY

MAKING PLANS FOR TOMORROW

‹›


HELPING CONTROL
MS TODAY

MAKING PLANS
FOR TOMORROW

HELPING CONTROL
MS TODAY

MAKING PLANS
FOR TOMORROW

HELPING CONTROL
MS TODAY

MAKING PLANS
FOR TOMORROW

HELPING CONTROL
MS TODAY

MAKING PLANS
FOR TOMORROW

‹›



PONVORY™: A NEW ORAL, ONCE-DAILY, SELECTIVE S1P1 THERAPY FOR RELAPSING MS IN
ADULTS1-3*


Access and review the full OPTIMUM study publication.

Superior efficacy
vs Aubagio® (teriflunomide)
in relapses and lesions1†

In a phase 3 study, PONVORY™ proved superior in reducing the ARR and the number
of new GdE T1 lesions and new or enlarging T2 lesions1

Onboarding steps made convenient and flexible patient management1

No genetic testing; no first-dose monitoring for most patients‡; no known food
restrictions; ~7-day reversibility of lymphocyte count reduction, as seen in
PK-PD assessments; 1-week elimination allows for pregnancy 7 days after stopping
PONVORY™; no rapid elimination procedure required1

Comparable
overall rates of TEAEs and SAEs
vs Aubagio®4

Overall, the proportion of patients experiencing at least 1 treatment-emergent
adverse event (TEAE) or serious adverse event (SAE) was similar across treatment
groups4

50% of patients remained on PONVORY™ 20 mg for >8 years in a phase 2, long-term,
safety extension study5

SEE how to start your patients on once-daily PONVORY™
DOWNLOAD the Prescription Enrollment Form to help get your patients started on
PONVORY™ today

ARR = annualized relapse rate; GdE = gadolinium-enhancing; PD = pharmacodynamic;
PK = pharmacokinetic; S1P1 = sphingosine-1-phosphate 1.

*The exact mechanism by which PONVORY™ exerts therapeutic effects in MS is
unknown but may involve reduction of lymphocyte migration into the central
nervous system.1

†As studied in OPTIMUM, a 108-week, randomized, double-blind, phase 3 study.1

‡First-dose, 4-hour monitoring is recommended for patients with sinus
bradycardia (heart rate <55 beats per minute), first- or second-degree
atrioventricular block (Mobitz type I), or a history of myocardial infarction or
heart failure occurring >6 months prior to treatment initiation and in stable
condition.1

X

The OPTIMUM Study Is Now Available

Discover the full results from this phase 3, active-comparator study comparing
the efficacy, safety, and tolerability of PONVORY™ and Aubagio® (teriflunomide)1

Access the Publication for Free

This independent, peer reviewed research article may contain data, conclusions,
and recommendations that are not present in the PONVORY™ product label. PONVORY™
should be used only as specified in the full Prescribing Information.

Access to this article is currently free for a limited time. Future interactions
may require a subscription to the publishing journal.

Janssen is not responsible for the privacy policy, the content, or the accuracy
of any websites accessed through a link on the ponvoryhcp.com site. A link to
other websites does not constitute an endorsement of Janssen or the linked site,
its products, or services. We encourage you to read the privacy policy of every
online service you visit.

The browser window or tab for ponvoryhcp.com will remain open. To return to
ponvoryhcp.com at any time, close this tab or window.

Reference: 1. Kappos L, Fox RJ, Burcklen M, et al. Ponesimod compared with
teriflunomide in patients with relapsing multiple sclerosis in the
active-comparator phase 3 OPTIMUM study: a randomized clinical trial. JAMA
Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405

INDICATION

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.


IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

PONVORY™ is contraindicated in patients who:

 * In the last 6 months experienced myocardial infarction, unstable angina,
   stroke, transient ischemic attack (TIA), decompensated heart failure
   requiring hospitalization, or Class III or IV heart failure.
 * Have presence of Mobitz Type II second-degree, third-degree atrioventricular
   (AV) block, or sick sinus syndrome, or sino-atrial block, unless patient has
   a functioning pacemaker.

WARNINGS AND PRECAUTIONS

Risk of Infections

PONVORY™ causes a dose-dependent reduction in peripheral lymphocyte count to
30-40% of baseline values because of reversible sequestration of lymphocytes in
lymphoid tissues. PONVORY™ may increase the susceptibility to infections.
Life-threatening and rare fatal infections have been reported in association
with other sphingosine 1-phosphate (S1P) receptor modulators.  Before initiating
treatment with PONVORY™, results from a recent complete blood count including
lymphocyte count should be reviewed.  

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.  Patients without a healthcare
professional confirmed history of varicella (chickenpox) or without
documentation of a full course of vaccination should be tested for antibodies to
VZV prior to initiating PONVORY™.

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 (PML)

PML has been reported in patients treated with a S1P receptor modulator and
other multiple sclerosis (MS) therapies and has been associated with some risk
factors (e.g., immunocompromised patients, polytherapy with immunosuppressants).
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.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or
Immunosuppressive Therapies

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including
corticosteroids) should be co-administered with caution because of the risk of
additive immune system effects.

Vaccinations

Patients without a 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
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 vaccines 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 of PONVORY™.

Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of PONVORY™ treatment results in a transient decrease in heart
rate and atrioventricular (AV) conduction delays, an up-titration scheme must be
used to reach the maintenance dosage of PONVORY™ (20 mg).

Reduction in Heart Rate

Initiation of PONVORY™ may result in a transient decrease in heart rate.  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.

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. If treatment with
PONVORY™ is considered, advice from a cardiologist should be sought for
individuals:

 * With significant QT prolongation (QTc greater than 500 msec).
 * With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class
   III anti-arrhythmic drugs.
 * 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.

Obtain an ECG in all patients to determine whether preexisting conduction
abnormalities are present.  For patients taking other drugs that decrease heart
rate, treatment with PONVORY™ should generally not be initiated without
consultation from a cardiologist because of the potential effect on heart rate. 
In all patients, a dose titration is recommended for initiation of PONVORY™
treatment to help reduce cardiac effects.

Respiratory Effects

Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and
reductions in diffusion lung capacity for carbon monoxide (DLCO) were observed
in PONVORY™-treated patients mostly occurring in the first month after treatment
initiation. Spirometric evaluation of respiratory function should be performed
during therapy with PONVORY™ if clinically indicated.

Liver Injury

Elevations of transaminases may occur in PONVORY™-treated patients. Obtain
transaminase and bilirubin levels, if not recently available (i.e., within last
6 months) before initiation of PONVORY™ therapy.

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). PONVORY™ is not recommended in patients with moderate or
severe hepatic impairment (Child-Pugh class B and C, respectively).

Increased Blood Pressure

PONVORY™-treated patients had an average increase of 2.9 mmHg in systolic blood
pressure and 2.8 mmHg in diastolic blood pressure. Blood pressure should be
monitored during treatment with PONVORY™ and managed appropriately.

Cutaneous Malignancies

Cases of basal cell carcinoma and other skin malignancies have been reported in
patients treated with S1P receptor modulators, including PONVORY™. Periodic skin
examination is recommended 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™.

Fetal Risk

Based on animal studies, PONVORY™ may cause fetal harm. 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.

Macular Edema

S1P receptor modulators, including PONVORY™, have been associated with an
increased risk of macular edema. An ophthalmic evaluation of the fundus,
including the macula, is recommended in all patients before starting treatment
and again at any time if a patient reports any change in vision while on
PONVORY™ therapy.  Continuation of therapy in patients with macular edema 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™. Therefore, these patients should have regular follow-up
examinations of the fundus, including the macula, during treatment with
PONVORY™.

Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been
reported in patients receiving a sphingosine 1-phosphate (S1P) receptor
modulator. Such events have not been reported for PONVORY™-treated patients in
the development program. However, should a PONVORY™-treated patient develop any
unexpected neurological or psychiatric symptoms/signs (e.g., 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.

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.

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.

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. Lymphocyte counts returned to the normal range in 90% of
patients within 1 week of stopping therapy, however, residual pharmacodynamics
effects, such as lowering effects on peripheral lymphocyte count, may persist
for 1 to 2 weeks after the last dose. Use of immunosuppressants within this
period may lead to an additive effect on the immune system, and therefore
caution should be applied 1 to 2 weeks after the last dose of PONVORY™.

OVERDOSAGE

In patients with overdosage of PONVORY™, especially upon
initiation/re-initiation of treatment, it is important to observe for signs and
symptoms of bradycardia as well as AV conduction blocks, which may include
overnight monitoring. Regular measurements of pulse rate and blood pressure are
required, and ECGs should be performed.

There is no specific antidote to ponesimod. Neither dialysis nor plasma exchange
would result in meaningful removal of ponesimod from the body. The decrease in
heart rate induced by PONVORY™ can be reversed by atropine.

In the event of overdose, PONVORY™ should be discontinued, and general
supportive treatment given until clinical toxicity has been diminished or
resolved. It is advisable to contact a poison control center to obtain the
latest recommendations for the management of an overdose.

ADVERSE REACTIONS

Most common adverse reactions (incidence at least 10%) are upper respiratory
tract infection, hepatic transaminase elevation, and hypertension.

Please see full Prescribing Information and Medication Guide.

cp-214886v2

References: 1. PONVORY™. Prescribing information. Janssen Pharmaceuticals, Inc;
2021. 2. Bolli MH, Abele S, Binkert C, et al. 2-imino-thiazolidin-4-one
derivatives as potent, orally active S1P1 receptor agonists. J Med Chem.
2010;53(10):4198-4211. doi:10.1021/jm100181s 3. D'Ambrosio D, Freedman MS, Prinz
J. Ponesimod, a selective S1P1 receptor modulator: a potential treatment for
multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis.
2016;7(1):18-33. doi:10.1177/2040622315617354 4. Kappos L, Fox RJ, Burcklen M,
et al. Ponesimod compared with teriflunomide in patients with relapsing multiple
sclerosis in the active-comparator phase 3 OPTIMUM study: a randomized clinical
trial. JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405 5. Data
on file. Interim Clinical Study Report. Janssen Pharmaceuticals, Inc; 2020.



© Janssen Pharmaceuticals, Inc. 2021. All rights reserved.

This site is published by Janssen Pharmaceuticals, Inc., which is solely
responsible for its contents. This site is intended for use by healthcare
professionals of the United States and Puerto Rico. Janssen Pharmaceuticals,
Inc., recognizes that the Internet is a global communications medium; however,
laws, regulatory requirements, and medical practices for pharmaceutical products
vary from country to country. The Prescribing Information included here may not
be appropriate for use outside the United States and Puerto Rico.

Third party trademarks used herein are trademarks of their respective owners.

Legal Notice | Privacy Policy |  Medical Information Center Contact Us 

Do not sell my personal information

Last Updated 7/21 | cp-198295v3

Legal Notice Privacy Policy Medical Information Center Contact Us

Do not sell my personal information

Last updated: 7/21 | cp-198295v3

Additional Links

 * Legal Notice
 * Privacy Policy
 * Medical Information Center
 * Contact Us
 * Do not sell my personal information

Quick Links

 * Register for Updates
 * Support and Resources
 * Download Prescription Enrollment Form


YOU ARE NOW LEAVING PONVORYHCP.COM


Janssen is not responsible for the privacy policy, the content, or the accuracy
of any websites accessed through a link on the ponvoryhcp.com site. A link to
other websites does not constitute an endorsement of Janssen or the linked site,
its products, or services. We encourage you to read the Privacy Policy of every
online service you visit.

The browser window or tab for ponvoryhcp.com will remain open.
To return to ponvoryhcp.com at any time, close this tab or window.

Continue

Stay on ponvoryhcp.com


 
INDICATION

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.


IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

PONVORY™ is contraindicated in patients who:

 * In the last 6 months experienced myocardial infarction, unstable angina,
   stroke, transient ischemic attack (TIA), decompensated heart failure
   requiring hospitalization, or Class III or IV heart failure.
 * Have presence of Mobitz Type II second-degree, third-degree atrioventricular
   (AV) block, or sick sinus syndrome, or sino-atrial block, unless patient has
   a functioning pacemaker.

WARNINGS AND PRECAUTIONS

Risk of Infections

PONVORY™ causes a dose-dependent reduction in peripheral lymphocyte count to
30-40% of baseline values because of reversible sequestration of lymphocytes in
lymphoid tissues. PONVORY™ may increase the susceptibility to infections.
Life-threatening and rare fatal infections have been reported in association
with other sphingosine 1-phosphate (S1P) receptor modulators.  Before initiating
treatment with PONVORY™, results from a recent complete blood count including
lymphocyte count should be reviewed.  

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.  Patients without a healthcare
professional confirmed history of varicella (chickenpox) or without
documentation of a full course of vaccination should be tested for antibodies to
VZV prior to initiating PONVORY™.

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 (PML)

PML has been reported in patients treated with a S1P receptor modulator and
other multiple sclerosis (MS) therapies and has been associated with some risk
factors (e.g., immunocompromised patients, polytherapy with immunosuppressants).
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.

Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or
Immunosuppressive Therapies

Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including
corticosteroids) should be co-administered with caution because of the risk of
additive immune system effects.

Vaccinations

Patients without a 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
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 vaccines 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 of PONVORY™.

Bradyarrhythmia and Atrioventricular Conduction Delays

Since initiation of PONVORY™ treatment results in a transient decrease in heart
rate and atrioventricular (AV) conduction delays, an up-titration scheme must be
used to reach the maintenance dosage of PONVORY™ (20 mg).

Reduction in Heart Rate

Initiation of PONVORY™ may result in a transient decrease in heart rate.  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.

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. If treatment with
PONVORY™ is considered, advice from a cardiologist should be sought for
individuals:

 * With significant QT prolongation (QTc greater than 500 msec).
 * With atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class
   III anti-arrhythmic drugs.
 * 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.

Obtain an ECG in all patients to determine whether preexisting conduction
abnormalities are present.  For patients taking other drugs that decrease heart
rate, treatment with PONVORY™ should generally not be initiated without
consultation from a cardiologist because of the potential effect on heart rate. 
In all patients, a dose titration is recommended for initiation of PONVORY™
treatment to help reduce cardiac effects.

Respiratory Effects

Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and
reductions in diffusion lung capacity for carbon monoxide (DLCO) were observed
in PONVORY™-treated patients mostly occurring in the first month after treatment
initiation. Spirometric evaluation of respiratory function should be performed
during therapy with PONVORY™ if clinically indicated.

Liver Injury

Elevations of transaminases may occur in PONVORY™-treated patients. Obtain
transaminase and bilirubin levels, if not recently available (i.e., within last
6 months) before initiation of PONVORY™ therapy.

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). PONVORY™ is not recommended in patients with moderate or
severe hepatic impairment (Child-Pugh class B and C, respectively).

Increased Blood Pressure

PONVORY™-treated patients had an average increase of 2.9 mmHg in systolic blood
pressure and 2.8 mmHg in diastolic blood pressure. Blood pressure should be
monitored during treatment with PONVORY™ and managed appropriately.

Cutaneous Malignancies

Cases of basal cell carcinoma and other skin malignancies have been reported in
patients treated with S1P receptor modulators, including PONVORY™. Periodic skin
examination is recommended 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™.

Fetal Risk

Based on animal studies, PONVORY™ may cause fetal harm. 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.

Macular Edema

S1P receptor modulators, including PONVORY™, have been associated with an
increased risk of macular edema. An ophthalmic evaluation of the fundus,
including the macula, is recommended in all patients before starting treatment
and again at any time if a patient reports any change in vision while on
PONVORY™ therapy.  Continuation of therapy in patients with macular edema 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™. Therefore, these patients should have regular follow-up
examinations of the fundus, including the macula, during treatment with
PONVORY™.

Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been
reported in patients receiving a sphingosine 1-phosphate (S1P) receptor
modulator. Such events have not been reported for PONVORY™-treated patients in
the development program. However, should a PONVORY™-treated patient develop any
unexpected neurological or psychiatric symptoms/signs (e.g., 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.

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.

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.

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. Lymphocyte counts returned to the normal range in 90% of
patients within 1 week of stopping therapy, however, residual pharmacodynamics
effects, such as lowering effects on peripheral lymphocyte count, may persist
for 1 to 2 weeks after the last dose. Use of immunosuppressants within this
period may lead to an additive effect on the immune system, and therefore
caution should be applied 1 to 2 weeks after the last dose of PONVORY™.

OVERDOSAGE

In patients with overdosage of PONVORY™, especially upon
initiation/re-initiation of treatment, it is important to observe for signs and
symptoms of bradycardia as well as AV conduction blocks, which may include
overnight monitoring. Regular measurements of pulse rate and blood pressure are
required, and ECGs should be performed.

There is no specific antidote to ponesimod. Neither dialysis nor plasma exchange
would result in meaningful removal of ponesimod from the body. The decrease in
heart rate induced by PONVORY™ can be reversed by atropine.

In the event of overdose, PONVORY™ should be discontinued, and general
supportive treatment given until clinical toxicity has been diminished or
resolved. It is advisable to contact a poison control center to obtain the
latest recommendations for the management of an overdose.

ADVERSE REACTIONS

Most common adverse reactions (incidence at least 10%) are upper respiratory
tract infection, hepatic transaminase elevation, and hypertension.

Please see full Prescribing Information and Medication Guide.

cp-214886v2