PONVORY

Dosage and Administration ( 2.1 ) 06/2024 Warnings and Precautions ( 5.1 , 5.11 ) 08/2023 Warnings and Precautions ( 5.1 , 5.6 , 5.8 ) 06/2024

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 )

2 DOSAGE AND ADMINISTRATION Assessments are required prior to initiating PONVORY ( 2.1 ) Titration is required for treatment initiation ( 2.2 ) The recommended maintenance dosage is 20 mg taken orally once daily ( 2.2 ) First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of myocardial infarction or heart failure ( 2.3 ) 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. In patients with certain preexisting conditions, advice from a cardiologist should be sought and first-dose monitoring is recommended [see Dosage and Administration ( 2.3 ) and Warnings and Precautions ( 5.2 )] . Complete Blood Count Obtain a recent (i.e., within the last 6 months or after discontinuation of prior MS therapy) complete blood count (CBC), including lymphocyte count [see Warnings and Precautions ( 5.1 )] . Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 , 7.3 )] . Liver Function Tests Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels [see Warnings and Precautions ( 5.4 )] . Ophthalmic Evaluation Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with PONVORY [see Warnings and Precautions ( 5.8 )] . Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of PONVORY. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions ( 5.6 )] . Current or Prior Medications with Immune System Effects If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with PONVORY [see Warnings and Precautions ( 5.1 , 5.10 ) and Drug Interactions ( 7.1 )] . Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating PONVORY; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with PONVORY [see Warnings and Precautions ( 5.1 )] . If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of PONVORY. 2.2 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. Treatment Initiation A starter pack must be used for patients initiating treatment with PONVORY [see How Supplied/Storage and Handling ( 16.1 )] . Initiate PONVORY treatment with a 14-day titration; start with one 2 mg tablet orally once daily and progress with the titration schedule as shown in Table 1 [see Warnings and Precautions ( 5.2 )] . Table 1: Dose Titration Regimen Titration Day Daily Dose Days 1 and 2 2 mg Days 3 and 4 3 mg Days 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 Days 12, 13, and 14 10 mg Maintenance Daily Dose Day 15 and thereafter 20 mg If dose titration is interrupted, missed dose instructions must be followed [see Dosage and Administration ( 2.4 )] . 2.3 First Dose Monitoring in Patients with Certain Preexisting Cardiac Conditions Because initiation of PONVORY treatment results in a decrease in heart rate, first-dose 4-hour monitoring is recommended for patients with sinus bradycardia [heart rate 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 trea …

3 DOSAGE FORMS AND STRENGTHS PONVORY is available as round, biconvex, film-coated tablets for oral use. PONVORY contains ponesimod in the following dosage strengths (see Table 2 ): Table 2: Dosage Form and Strengths for PONVORY Tablet Strength Tablet Color Tablet Size Tablet Debossing 2 mg White 5.0 mm "2" on one side and an arch on the other side. 3 mg Red 5.0 mm "3" on one side and an arch on the other side. 4 mg Purple 5.0 mm "4" on one side and an arch on the other side. 5 mg Green 8.6 mm "5" on one side and an arch and an "A" on the other side. 6 mg White 8.6 mm "6" on one side and an arch and an "A" on the other side. 7 mg Red 8.6 mm "7" on one side and an arch and an "A" on the other side. 8 mg Purple 8.6 mm "8" on one side and an arch and an "A" on the other side. 9 mg Brown 8.6 mm "9" on one side and an arch and an "A" on the other side. 10 mg Orange 8.6 mm "10" on one side and an arch and an "A" on the other side. 20 mg Yellow 8.6 mm "20" on one side and an arch and an "A" on the other side. Tablets: 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg ( 3 )

4 CONTRAINDICATIONS PONVORY is contraindicated in patients who: In the last 6 months, have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III or IV heart failure [see Warnings and Precautions ( 5.2 )] Have presence of Mobitz type II second-degree, third-degree AV block, sick sinus syndrome, or sino-atrial block, unless patient has a functioning pacemaker [see Warnings and Precautions ( 5.2 )] 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 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in labeling: Infections [see Warnings and Precautions ( 5.1 )] Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions ( 5.2 )] Respiratory Effects [see Warnings and Precautions ( 5.3 )] Liver Injury [see Warnings and Precautions ( 5.4 )] Increased Blood Pressure [see Warnings and Precautions ( 5.5 )] Cutaneous Malignancies [see Warnings and Precautions ( 5.6 )] Fetal Risk [see Warnings and Precautions ( 5.7 )] Macular Edema [see Warnings and Precautions ( 5.8 )] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions ( 5.9 )] Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions ( 5.10 )] Severe Increase in Disability After Stopping PONVORY [see Warnings and Precautions ( 5.11 )] Immune System Effects After Stopping PONVORY [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (incidence at least 10%) are upper respiratory tract infection, hepatic transaminase elevation, and hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals, Inc. at 833-933-9331, FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. In Study 1, 82% of PONVORY-treated patients completed 2 years of study treatment, compared to 82.2% of patients receiving teriflunomide 14 mg. Adverse events led to discontinuation of treatment in 8.7% 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. Adverse Reaction PONVORY N=565 (%) Teriflunomide 14 mg N=566 (%) Upper respiratory infection a 37 34 Hepatic transaminase elevation b 23 12 Hypertension c 10 9 Urinary tract infection 6 5 Dyspnea 5 1 Dizziness 5 3 Cough 4 2 Pain in extremity 4 3 Somnolence 3 2 Pyrexia 2 1 C-reactive protein increased 2 1 Hypercholesterolemia 2 1 Vertigo 2 1 In Study 1, the following adverse reactions occurred in less than 2% of PONVORY-treated patients, but at a rate at least 1% higher than in patients receiving teriflunomide 14 mg: viral infection, herpes zoster, hyperkalemia, lymphopenia [see Warnings and Precautions ( 5.1 ) , and macular edema [see Warnings and Precautions ( 5.8 )] . Adverse reactions in patients treated …

7 DRUG INTERACTIONS Vaccines: Avoid live attenuated vaccines during and for up to 1-2 weeks after treatment with PONVORY. ( 7.4 ) 7.1 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 Warnings and Precautions ( 5.1 )] . 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 [see Warnings and Precautions ( 5.10 )] . Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with PONVORY after alemtuzumab is not recommended. PONVORY can generally be started immediately after discontinuation of beta interferon or glatiramer acetate. 7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs that may Decrease Heart Rate PONVORY has not been studied in patients taking QT prolonging drugs. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs 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 generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., digoxin) [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.3 )] . If treatment with PONVORY is considered, advice from a cardiologist should be sought. 7.3 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 Warnings and Precautions ( 5.2 )] . Beta-blocker treatment can be initiated in patients receiving stable doses of PONVORY. 7.4 Vaccination During, and for up to 1 to 2 weeks after discontinuation of, treatment with PONVORY, vaccinations may be less effective. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during PONVORY treatment and for 1 to 2 weeks after discontinuation of treatment with PONVORY [see Warnings and Precautions ( 5.1 )] .

8 USE IN SPECIFIC POPULATIONS Hepatic Impairment: PONVORY is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C). ( 8.6 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of PONVORY in pregnant women. In animal studies, administration of ponesimod during pregnancy produced adverse effects on development, including embryo lethality and fetal malformations, in the absence of maternal toxicity. In rats and rabbits, visceral and skeletal malformations occurred at clinically relevant maternal ponesimod exposures (see Data) . The receptor affected by ponesimod (sphingosine-1-phosphate receptor 1) has been demonstrated to have an important role in embryogenesis, including vascular and neural development. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When ponesimod (0, 1, 10, or 40 mg/kg/day) was orally administered to pregnant rats during the period of organogenesis, increased incidences of fetal malformations primarily involving the limbs (syndactyly and ectrodactyly) and cardiovascular system (including ventricular septal defects) were observed at all but the lowest dose tested. A high incidence of embryofetal death was observed at the highest dose tested. Maternal toxicity was not observed, indicating a selective effect on the fetus. Plasma exposure (AUC) at the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development in rats was lower than that in humans at the recommended human dose (RHD) of 20 mg/day. When ponesimod (0, 0.25, 1, or 4 mg/kg/day) was orally administered to pregnant rabbits during the period of organogenesis, an increase in post-implantation loss and fetal variations (visceral and skeletal) were noted at the highest dose tested. No maternal toxicity was observed. Plasma exposure at the no-effect dose (1 mg/kg/day) for adverse effects on embryofetal development in rabbits was lower than that in humans at the RHD. In a dose-range finding study in pregnant rabbits, oral administration of ponesimod (0, 6, 20, or 60 mg/kg/day) during organogenesis, an increase in embryofetal death and fetal limb malformation (brachydactyly) were observed at the lowest dose tested; at the higher doses, there were no live fetuses. When ponesimod (5, 10, or 20 mg/kg) was orally administered to female rats throughout pregnancy and lactation, the offspring exhibited decreased survival, reduced body weight gain, and reduced fertility and reproductive performance (increases in pre- and post-implantation loss) at the highest dose tested, neurobehavioral impairment (increased locomotor activity) at the mid and high doses, and delayed sexual maturation at all doses tested. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. Plasma exposure (AUC) in dams at the lowest dose tested was less than that in humans at the RHD. 8.2 Lactation Risk Summary There are no data on the presence of PONVORY in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. When ponesimod was orally administered to female rats during pregnancy and lactation, ponesimod was detected in the plasma of the offspring, suggesting excretion of ponesimod in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PONVORY and any potential adverse effects on the breastfed infant from PONVORY or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Females Before initiation of PONVORY treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment wit …

12.1 Mechanism of Action Ponesimod is a S1P receptor 1 modulator that binds with high affinity to S1P receptor 1. Ponesimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ponesimod exerts therapeutic effects in MS is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

11 DESCRIPTION PONVORY (ponesimod) is a sphingosine 1-phosphate receptor modulator. The chemical name for ponesimod is (2Z,5Z)-5-[3-chloro-4-[(2 R )-2,3- dihydroxypropoxy]benzylidene]-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one. It has one chiral center with absolute configuration of (R) . Its molecular formula is C 23 H 25 ClN 2 O 4 S and its molecular weight is 460.97 g/mol. Ponesimod has the following structural formula: Ponesimod is a white to light yellowish powder that is practically insoluble or insoluble in water. PONVORY ® (ponesimod) tablets are provided as 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg film-coated tablets for oral administration. Each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30, silica colloidal anhydrous, and sodium lauryl sulfate. Each tablet coating contains ferrosoferric oxide (included in 4 mg, 5 mg, 8 mg, and 9 mg film-coated tablets), hydroxypropyl methylcellulose 2910, iron oxide red (included in 3 mg, 4 mg, 7 mg, 8 mg, 9 mg, and 10 mg film-coated tablets), iron oxide yellow (included in 3 mg, 5 mg, 7 mg, 9 mg, 10 mg, and 20 mg film-coated tablets), lactose monohydrate, polyethylene glycol 3350, titanium dioxide, and triacetin. Chemical Structure

10 OVERDOSAGE Symptoms and Signs In patients with overdosage of PONVORY, especially upon initiation/reinitiation 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 [see Warnings and Precautions ( 5.2 , 5.5 ) and Clinical Pharmacology ( 12.2 )] . Treatment 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied PONVORY ® (ponesimod) tablet is available as round, biconvex, film-coated tablets supplied in the following dosage strengths and package configurations. Starter Pack Tablet Strength Tablet Color Tablet Size Tablet Debossing Pack Size NDC Code 2 mg White 5.0 mm "2" on one side and an arch on the other side. Child Resistant Starter Pack (14 tablets) NDC 43068-610-09 3 mg Red 5.0 mm "3" on one side and an arch on the other side. 4 mg Purple 5.0 mm "4" on one side and an arch on the other side. 5 mg Green 8.6 mm "5" on one side and an arch and an "A" on the other side. 6 mg White 8.6 mm "6" on one side and an arch and an "A" on the other side. 7 mg Red 8.6 mm "7" on one side and an arch and an "A" on the other side. 8 mg Purple 8.6 mm "8" on one side and an arch and an "A" on the other side. 9 mg Brown 8.6 mm "9" on one side and an arch and an "A" on the other side. 10 mg Orange 8.6 mm "10" on one side and an arch and an "A" on the other side. Maintenance Dose Bottle Tablet Strength Tablet Color Tablet Size Tablet Debossing Pack Size NDC Code 20 mg Yellow 8.6 mm "20" on one side and an arch and an "A" on the other side. Bottle of 30 tablets with child-resistant closure. Each bottle contains a desiccant sachet. NDC 43068-620-01 16.2 Storage and Handling Starter Pack Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Store in the original package. Maintenance Dose Bottle Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Store in the original package. Do not discard desiccant. Protect from moisture. Keep out of reach of children.