Ponvory 20 Mg Tablets

PONVORY is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) defined by clinical or imaging features.

Posology
Assessments prior to first dose of PONVORY
Before initiation of treatment with PONVORY, assess the following:

• Complete blood count
  Review results of a complete blood count (CBC) with differential White Blood Cell (WBC) count obtained within the last 6 months (see section 4.4 - Infections).
• Liver function tests
  Review results of serum transaminase enzymes and bilirubin levels obtained within the last 6 months (see section 4.4 - Liver Injury).
• Pregnancy test
  Before initiation of treatment in women of childbearing potential, a recent negative pregnancy test result must be available (see section 4.6 - Contraception).
• Ophthalmic evaluation
  Obtain an expert evaluation of the fundus, including the macula (see section 4.4 - Macular Oedema).
• Cardiac evaluation
  Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first dose monitoring is essential (see section 4.2 - First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions and section 4.4 u2013 Brady-dysrhythmia and Atrioventricular Conduction Delays).

Determine whether patients are taking other medicines that could slow heart rate or atrioventricular (AV) conduction (see section 4.5 u2013 Anti-Dysrhythmic Medicines, QT Prolonging Medicines, Medicines That May Decrease Heart Rate and Beta-Blockers).

Current or prior medications
If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these medicines, consider possible unintended additive immunosuppressive effects before initiating treatment with PONVORY (see section 4.4 - Infections and Interactions - Anti Neoplastic, Immunosuppressive, or Immune-Modulating Therapies).

Vaccinations
Test patients for antibodies to varicella zoster virus (VZV) before initiating PONVORY; VZV vaccination of antibody-negative patients is essential prior to commencing treatment with PONVORY (see section 4.4 - Infections).

Recommended dosage
Treatment initiation
The starter pack must be used for patients initiating treatment with PONVORY (see section 6.5). Initiate PONVORY treatment with a 14-day up-titration; start with one 2 mg tablet orally once daily and progress with the titration schedule outlined in Table 1 (see section 4.4 -Bradydysrhythmia and Atrioventricular Conduction Delays).

Table 1: Dose Titration Regimen
Titration day Daily dose
Day 1 and 2 2 mg
Day 3 and 4 3 mg
Day 5 and 6 4 mg
Day 7 5 mg
Day 8 6 mg
Day 9 7 mg
Day 10 8 mg
Day 11 9 mg
Day 12, 13 and 14 10 mg

If dose titration is interrupted, missed dose instructions must be followed (see section 4.2 u2013 Missed Doses).

Maintenance dosage
After dose titration is complete (see section 4.2 - Treatment Initiation), the recommended maintenance dosage of PONVORY is one 20 mg tablet taken orally once daily.

First dose monitoring in patients with certain preexisting cardiac conditions
Because initiation of PONVORY treatment results in a decrease in heart rate (HR), first dose 4 hour monitoring is recommended for patients with sinus bradycardia (HR less than 55 beats per minute [bpm]), first- or second degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure occurring more than 6 months prior to treatment initiation and in stable condition (see section 4.4 u2013 Bradydysrhythmia and Atrioventricular Conduction Delays and section 5.1).

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 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:
u2022 The heart rate 4 hours post dose is less than 45 bpm.
u2022 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 yet occurred.
u2022 The ECG 4 hours post dose shows new onset second-degree or higher AV block.

If post-dose symptomatic bradycardia, brady-dysrhythmia, 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.

Note: If at any time during initiation of PONVORY treatment, the findings or symptoms are considered clinically significant, PONVORY treatment should be stopped. Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with PONVORY is considered in patients:

• With some preexisting heart and cerebrovascular conditions (see section 4.4 u2013 Bradydysrhythmia and Atrioventricular Conduction Delays).
• With a prolonged QTc interval before dosing or during the 4-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging medicines with a known risk of torsades de pointes (see section 4.4 - Bradydysrhythmia and Atrioventricular Conduction Delays and Interactions - Anti-Dysrhythmic Medicines, QT Prolonging Medicines, Medicines That May Decrease Heart Rate).
• Receiving concurrent therapy with medicines that slow heart rate or AV conduction (see section 4.5 - Anti-Dysrhythmic Medicines, QT Prolonging Medicines, Medicines That May Decrease Heart Rate and Beta-Blockers).

Missed doses
Interruption during treatment, especially during titration, should be avoided, however:
u2022 if less than 4 consecutive doses are missed, resume treatment with the first missed dose.
u2022 if 4 or more consecutive doses are missed, reinitiate treatment with Day 1 of the titration regimen (new starter pack).

During treatment initiation or maintenance, if treatment needs to be reinitiated with Day 1 of the titration regimen, complete first dose monitoring in patients for whom it is recommended (see section 4.2 - First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions).

Special populations
Paediatric patients (younger than 18 years of age)
The safety and efficacy of PONVORY have not been established in paediatric patients younger than 18 years of age.

Elderly (65 years of age and older)
Clinical studies of PONVORY did not include patients aged 65 years and over to determine whether they respond differently from younger subjects, therefore PONVORY should be used with caution in this population (see section 5.2 - Special populations, Age).

Renal impairment
Based on clinical pharmacology studies, no dose adjustment is needed in patients with mild to severe renal impairment (see section 5.2 - Special populations, Renal impairment).

Hepatic impairment
No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A) (see section 5.2 - Special populations, Hepatic impairment). Based on clinical pharmacology studies in adult subjects with moderate or severe hepatic impairment, ponesimod AUC (0-inf) was increased 2,0- and 3,1-fold respectively, compared to healthy subjects. PONVORY is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B and C, respectively), as the risk of adverse reactions may be greater (see section 5.2 - Special populations, Hepatic impairment).

Method Administration
PONVORY should be administered orally once daily. The tablet should be swallowed whole. PONVORY can be taken with or without food.

PONVORY is contraindicated:

• Hypersensitivity to the active substance or to any of the excipients (see section 6.1).
• Immunodeficient states (see section 4.4).
• 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.
• Patients who have presence of Mobitz type II second-degree, third-degree atrioventricular (AV) block, or sick sinus syndrome, unless patient has a functioning pacemaker (see section 4.4).
• Severe active infections, active chronic infections.
• Active malignancies.
• Moderate or severe hepatic impairment. (Child-Pugh class B and C, respectively).
• During pregnancy and in women of childbearing potential not using highly effective contraception (see section 4.6).

Infections
Risk of infections
PONVORY causes a dose-dependent reduction in peripheral lymphocyte count to 30-40 % of baseline values due to reversible sequestration of lymphocytes in lymphoid tissues. PONVORY may therefore increase the risk of infections. No cases of fatal infections have been reported in PONVORY treated patients in the development program, however, life-threatening and rare fatal infections have been reported in association with other S1P receptor modulators. In the Phase 3 OPTIMUM study the overall rate of infections was 54,2 %. Nasopharyngitis and viral infections have been reported in PONVORY-treated patients. Serious or severe infections occurred in 1,6 % in PONVORY-treated patients.

Before initiating treatment with PONVORY, results from a recent complete blood count with differential (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed. Absolute lymphocyte counts of < 0,2 x 10 9 /L if confirmed, should lead to interruption of PONVORY therapy until the levels reach u2265 0,8 x 10 9 /L when re-initiation of PONVORY can be considered. Initiation of treatment with PONVORY should be delayed in patients with severe active infection until resolution. In the development program, pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, were restored to normal within 1 week after discontinuation of PONVORY. In the OPTIMUM study, peripheral lymphocyte counts were restored to normal within 2 weeks after discontinuation of PONVORY, which was the first timepoint evaluated. Vigilance for signs and symptoms of infection should be continued for 1-2 weeks after PONVORY is discontinued (see section 4.4 - Reversibility of Immune System Effects After Stopping PONVORY).

Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with PONVORY should be considered if a patient develops a serious infection.

Herpes viral infections
Cases of herpes viral infection have been reported in the development program of PONVORY. In the OPTIMUM study, the rate of herpetic infections was 4,8 % in PONVORY treated patients. In 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 below).

Cryptococcal infections
Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. No cases of CM have been reported in PONVORY treated patients in the development program. Medical practitioners 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.

No cases of PML have been reported in PONVORY treated patients in the development program; however, PML has been reported in patients treated with an S1P-receptor modulator and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Medical practitioners should be vigilant for clinical symptoms or 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/or concomitant treatment with anti-neoplastic, immune modulating, or immunosuppressive therapies
In patients that are taking anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) or if there is a history of prior use of these medicines, possible unintended additive immune system effects should be considered before initiating treatment with PONVORY (see section 4.5)

When switching from medicines with prolonged immune effects, the half-life and mode of action of these medicines must be considered in order to avoid unintended additive effects on the immune system while at the same time minimising risk of disease reactivation, when initiating PONVORY. Pharmacokinetic/pharmacodynamic modeling indicates lymphocyte counts returned to the normal range in >90% of healthy subjects within 1 week of stopping PONVORY therapy (see section 5.1). In the development program, pharmacodynamic effects, such as lowering of peripheral lymphocyte counts, were restored to normal within 1 week after the last dose.

Use of immunosuppressants may lead to an additive effect on the immune system, and therefore caution should be applied up to 1 week after the last dose of PONVORY (see section 4.5).

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. Delay treatment with PONVORY for 4 weeks after vaccination 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.

Avoid the use of live attenuated vaccines while patients are taking PONVORY. If the use of live attenuated vaccine immunization is required, PONVORY treatment should be paused from 1 week prior to and 4 weeks after a planned vaccination (see section 4.5 - Vaccines).

Macular oedema
PONVORY increases the risk of macular oedema. 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. In the clinical trial experience in patients with all doses of PONVORY, the rate of macular oedema was 0,7 %. Most cases occurred within the first 6 months of therapy. In the OPTIMUM study, macular oedema was reported in 1,1 % of PONVORY treated patients. Continuation of PONVORY therapy in patients with macular oedema has not been evaluated. A decision on whether PONVORY should be discontinued should take into account the potential benefits and risks for the individual patient.

Macular oedema 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 oedema during therapy with S1P receptor modulators. Therefore, these patients should have regular follow up examinations of the fundus, including the macula, during treatment with PONVORY and have follow-up evaluations while receiving therapy.

Bradydysrhythmia 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) see section 4.2 - Recommended Dosage, section 5.1 - Heart Rate and Rhythm).

PONVORY was not studied in patients who had:

• Myocardial infarction or unstable ischaemic 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 dysrhythmia, 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.

Reduction in heart rate
After the first 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 decrease in heart rate is less pronounced.

In the OPTIMUM study, bradycardia at treatment initiation (sinus bradycardia on ECG (HR less than 50 bpm) occurred in 5,8 % of PONVORY treated patients. Patients who experienced bradycardia were generally asymptomatic. Bradycardia resolved in all patients without intervention and did not require discontinuation of PONVORY treatment. On Day 1, 3 patients treated with PONVORY had asymptomatic post dose HR below or equal to 40 bpm; all 3 patients had baseline HRs 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. In the OPTIMUM study, the AV conduction delays manifested as first-degree AV block (prolonged PR interval on ECG), which occurred in 3,4 % of PONVORY treated patients. No second-degree AV blocks, Mobitz type I (Wenckebach), were observed in OPTIMUM study. The conduction abnormalities were transient, asymptomatic, resolved within 24 hours, resolved without intervention, and did not require discontinuation of PONVORY treatment.

If treatment with PONVORY is considered, advice from a cardiologist should be sought:

• In patients with significant QT prolongation (QTc greater than 500 msec).
• In patients with atrial flutter/fibrillation or dysrhythmias treated with Class Ia or Class III anti-arrhythmic medicines (see section 4.5 - Anti- Dysrhythmic Medicines, QT Prolonging medicines, Medicines That May Decrease Heart Rate).
• In patients with unstable ischaemic 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), and uncontrolled hypertension.
• In patients 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 section 4.3).

Treatment initiation recommendations
u2022 Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
u2022 In all patients, a dose titration is recommended for initiation of PONVORY treatment to mitigate cardiac effects (see section 4.2 - Recommended Dosage).
u2022 In 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, ECG testing and first dose monitoring is recommended (see section 4.2 - Assessments Prior to First Dose of PONVORY, First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions).
u2022 PONVORY is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring more than 6 months prior to treatment initiation), or uncontrolled hypertension, 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 to determine if treatment can be initiated and the most appropriate monitoring strategy.
u2022 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.

u2022 Experience with PONVORY is limited in patients receiving concurrent therapy with medicines that decrease heart rate (e.g., beta blockers, non-dihydropyridine calcium channel blockers - diltiazem and verapamil, and other medicines that may decrease heart rate such as digoxin). Concomitant use of these medicines 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 strategy or if treatment can be initiated.

u2022 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. Treatment with PONVORY can then be initiated and treatment with a beta-blocker can be reinitiated after PONVORY has been up titrated to the target maintenance dosage (see section 4.5 - Beta-Blockers).

u2022 For patients taking other medicines that decrease heart rate, treatment with PONVORY should not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate (see section 4.2 - First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions and Interactions, Anti-Dysrhythmic medicines, QT Prolonging Medicines, Medicines That May Decrease Heart Rate).

Anti-neoplastic, immune modulating, or immunosuppressive therapies
PONVORY has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration (see section 4.4 - Infection).

When switching from medicines with prolonged immune effects, the half-life and mode of action of these medicines must be considered in order to avoid unintended additive effects on the immune system (see section 4.4 - Unintended Additive Immunosuppressive Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Therapies).

Anti-Dysrhythmic medicines, QT prolonging medicines, medicines that may decrease heart rate
PONVORY has not been studied in patients taking QT prolonging medicines. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol). Anti-Dysrhythmic medicines have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with PONVORY is considered, advice from a cardiologist should be sought. Because of the potential additive effects on heart rate, treatment with PONVORY should not be initiated in patients who are concurrently treated with QT prolonging medicines with known dysrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other medicines that may decrease heart rate (e.g., digoxin) (see section 4.4 - Bradydysrhythmia and Atrioventricular Conduction Delays and Interactions - Beta-Blockers). If treatment with PONVORY is considered, advice from a cardiologist should be sought regarding the potential need to switch medications that have heart rate lowering effects and how to best monitor patients during treatment initiation, if treatment is initiated.

Beta-blockers
Caution should be applied when PONVORY is initiated in patients receiving treatment with a beta blocker because of the additive effects on lowering heart rate; temporary interruption of the beta blocker treatment may be needed prior to initiation of PONVORY (see section 4.4 u2013 Bradydysrhythmia and Atrioventricular Conduction Delays). Beta blocker treatment can be initiated in patients receiving stable doses of PONVORY.

In a medicine-medicine interaction study, the up-titration regimen of PONVORY (see section 4.2 u2013 Recommended Dosage) was administered to subjects receiving propranolol (80 mg) once daily at steady state. No significant changes in pharmacokinetics of ponesimod or propranolol were observed. Compared to PONVORY alone, the combination with propranolol after the first dose of PONVORY (2 mg) had a 12,4 bpm (90 % CI: -15,6 to -9,1) decrease in mean hourly heart rate and at the first dose of PONVORY (20 mg) after up titration a 7,4 bpm (90 % CI: -10,9 to -3,9) decrease in mean hourly heart rate.

Vaccines
Vaccinations may be less effective if administered while being treated with PONVORY and up to 1 week after its discontinuation (see section 4.4 - Infection). The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during PONVORY treatment and up to 1 week after its discontinuation of treatment with PONVORY (see section 4.4 - Infection).

Effect of other drugs on PONVORY
In vitro studies with human liver preparations indicate that metabolism of PONVORY occurs through multiple, distinct enzyme systems, including multiple CYP450 (CYP2J2, CYP3A4, CYP3A5, CYP4F3A, and CYP4F12), UGT (mainly UGT1A1 and UGT2B7) and non-CYP450 oxidative enzymes, without major contribution by any single enzyme. Medicines that are inhibitors of major CYP or UGT enzymes are unlikely to impact the pharmacokinetics of PONVORY.

Co administration of PONVORY with strong CYP3A4 and UGT1A1 inducers may decrease the systemic exposure of PONVORY. It is unclear whether this decrease in PONVORY systemic exposure would be considered of clinical relevance.

PONVORY is not a substrate of P-gp, BCRP, OATP1B1 or OATP1B3 transporters. Medicines that are inhibitors of these transporters are unlikely to impact the PK of PONVORY.

Effect of PONVORY on other medicines
In vitro investigations indicate that at the therapeutic dose of 20 mg once daily, PONVORY and its metabolite M13 do not show any clinically relevant medicine-medicine interaction potential for CYP or UGT enzymes, or transporters.

Oral contraceptives
Co-administration of PONVORY, with an oral hormonal contraceptive (containing 1 mg norethisterone/norethindrone and 35 u03bcg ethinyl estradiol) showed no clinically relevant pharmacokinetic interaction with PONVORY. Therefore, concomitant use of PONVORY is not expected to decrease the efficacy of hormonal contraceptives. No interaction studies have been performed with oral contraceptives containing other progestogens; however, an effect of PONVORY on their exposure is not expected.

Pregnancy
PONVORY is contraindicated during pregnancy (see section 4.3). If a woman becomes pregnant during treatment, PONVORY must be immediately discontinued.

Based on human experience in patients receiving another sphingosine 1 phosphate (S1P) receptor modulator, post-marketing data suggest that its use is associated with an increased risk of major congenital malformations. There are no adequate and well controlled studies of PONVORY in pregnant women. Based on animal data and its mechanism of action, PONVORY can cause embryofoetal harm when administered to a pregnant woman (see section 5.3). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated ponesimod-induced developmental toxicity, including embryo lethality and an increase in foetal malformations (skeletal and visceral). The AUC 0-24 in rats and rabbits at the no observed adverse effect level (NOAEL) (1 mg/kg/day in both species) are lower than the human systemic exposures at the recommended human dose (RHD) of 20 mg/day.

Contraception
Females
PONVORY is contraindicated in women of childbearing potential not using highly effective contraception (see section 4.3). Before initiation of PONVORY treatment in women of childbearing potential, a recent negative pregnancy test result must be available, and women should be counseled on the potential for a serious risk to the foetus and the need for highly effective contraception during treatment with PONVORY (see section 4.6 - Pregnancy). Since it takes approximately 1 week to eliminate the compound from the body after stopping treatment, the potential risk to the foetus may persist and women must use highly effective contraception during this period (see section 4.4 - Foetal Risk).

Breastfeeding
PONVORY should not be used during breastfeeding. It is unknown whether ponesimod or its metabolites are excreted in human milk. A study in lactating rats has shown excretion of ponesimod in milk (see section 5.3). A risk to newborns/infants cannot be excluded.

PONVORY may cause dizziness and somnolence. Patients should establish how PONVORY affects them before they drive or use machines.

A total of 1 438 MS patients have received PONVORY at doses of at least 2 mg daily. These patients were included in the OPTIMUM study and in a Phase 2 (6-month placebo controlled) study in patients with MS and their uncontrolled extension studies. In the OPTIMUM study, 83.1 % of PONVORY treated patients completed 2 years of study treatment. Adverse events led to discontinuation of treatment in 8,7 % of PONVORY treated patients. The most common adverse reactions (incidence at least 10 %) in PONVORY treated patients in the OPTIMUM study were alanine aminotransferase increases (19,5 %), nasopharyngitis (19,3 %) and upper respiratory tract infection (10,6 %).

Summary of the safety profile
Table 2 represents the adverse reactions reported with PONVORY in controlled clinical trials and uncontrolled extension trials, ranked by frequency, with the most frequent reactions first within each MedDRA System Organ Class. Frequencies were defined using the following convention: very common (u2265 1/10); common (u2265 1/100 to < 1/10); and uncommon (u2265 1/1000 to < 1/100).

Table 2: Adverse Reactions Reported with PONVORY in Controlled Clinical Trials and Uncontrolled Extension Trials.

MedDRA System Organ Class (SOC) Very Common Common Uncommon Infections and infestations Nasopharyngitis, Upper respiratory tract infection Urinary tract infection, Bronchitis, Influenza, Rhinitis, Respiratory tract infection, Respiratory tract infection viral, Pharyngitis, Sinusitis, Viral Infection, Herpes zoster, Laryngitis, Pneumonia Blood and lymphatic system disorders Lymphopenia, Lymphocyte count decreased Psychiatric disorders Depression, Insomnia, Anxiety Nervous system disorders Dizziness, Hypoesthesia, Somnolence, Migraine Eye disorders Macular oedema Ear and labyrinth Vertigo

Signs and symptoms
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 must include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed (see section 4.4 - Bradydysrhythmia and Atrioventricular Conduction Delays, Increased Blood Pressure and section 5.1 - Heart Rate and Rhythm).

Treatment
There is no specific antidote to PONVORY. Neither dialysis nor plasma exchange would result in meaningful removal of PONVORY 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 centre to obtain the latest recommendations for the management of an overdose.