Ponvory

Ponesimod · Tablet, Film Coated · Oral

Prescription (Rx) Sphingosine 1-phosphate Receptor Modulator

Uses

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 )

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 treatment initiation and in stable condition [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.2 )] . 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.

Dosage forms and strengths

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 )

Contraindications

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 )

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. ( 5.1 ) 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. ( 5.2 , 7.2 , 7.3 ) Respiratory Effects : May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. ( 5.3 ) Liver Injury : Discontinue if significant liver injury is confirmed. Obtain liver function tests before initiating PONVORY. ( 5.4 ) Increased Blood Pressure (BP) : Monitor BP during treatment. ( 5.5 ) Cutaneous Malignancies : Skin examination prior to or shortly after the start of treatment and periodically is recommended. Suspicious skin lesions should be evaluated. ( 5.6 ) Fetal Risk : Women of childbearing potential should use effective contraception during and for 1 week after stopping PONVORY. ( 5.7 ) 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. ( 5.8 ) 5.1 Infections 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 [see Clinical Pharmacology ( 12.2 )] . 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. In Study 1 [see Clinical Studies ( 14 )] , the overall rate of infections was comparable between the PONVORY-treated patients and those receiving teriflunomide 14 mg (54.2% vs 52.1%, respectively). PONVORY increased the risk of upper respiratory tract infections. Serious or severe infections occurred in 1.6% of PONVORY-treated patients compared to 0.9% of patients receiving teriflunomide 14 mg. Before initiating treatment with PONVORY, results from a recent (i.e., 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. Lymphocyte counts returned to the normal range in 90% of patients within 1 week of stopping therapy in modeling studies [see Clinical Pharmacology ( 12.2 )] . In Study 1, peripheral lymphocyte counts returned to normal range within 2 weeks after discontinuation of PONVORY, which was the first timepoint evaluated. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for 1 to 2 weeks after discontinuation of PONVORY, vigilance for infection should be continued for 1 to 2 weeks after PONVORY is discontinued [see Warnings and Precautions ( 5.12 )] . In Study 1, the proportion of patients who experienced lymphocyte counts less than 0.2x10 9 /L was 3.2%. 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. In Study 1, the rate of herpetic infections was 4.8% 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. PML has been reported in patients treated with S1P receptor modulators and other multiple sclerosis (MS) therapies and has been associated with some risk factors (e.g., 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.

Side effects

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 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. Seizures In Study 1, cases of seizures were reported in 1.4% of PONVORY-treated patients, compared to 0.2% 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. Respiratory Effects In Study 1, dose-dependent reductions in FEV 1 were observed in patients treated with PONVORY [see Warnings and Precautions ( 5.3 )] . Malignancies In Study 1, two cases of basal cell carcinoma (0.4%) were reported in PONVORY-treated patients, compared to one case of basal cell carcinoma (0.2%) in patients receiving teriflunomide 14 mg, and a case of malignant melanoma was reported in a PONVORY-treated patient. An increased risk of cutaneous malignancies has been reported in association with other S1P receptor modulators, including PONVORY [see Warnings and Precautions ( 5.6 )] .

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 )] .

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 with PONVORY [see Use in Specific Populations ( 8.1 )] . Since it takes approximately one week to eliminate ponesimod from the body after stopping treatment, the potential risk to the fetus may persist, and women should use effective contraception during this period [see Warnings and Precautions ( 5.7 )] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of ponesimod (0, 1, 10, 30, or 100 mg/kg/day) to young rats from postnatal day 28 to 91 resulted in lung histopathology (alveolar histiocytosis/edema) and decreased immune function (T-cell dependent antibody response) at the two highest doses tested. Decreased growth (body weight gain and/or long bone length) was observed at all but the low dose, and neurobehavioral impairment (increased locomotor activity) was observed at the highest dose tested. Decreased lymphocyte count and neurobehavioral impairment persisted at the end of a 4- week recovery period. 8.5 Geriatric Use Clinical studies of PONVORY did not include patients 65 years of age and over to determine whether they respond differently from younger subjects. Use of PONVORY in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] . 8.6 Hepatic Impairment No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A) [see Clinical Pharmacology ( 12.3 )] . PONVORY is not recommended 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 Clinical Pharmacology ( 12.3 )] .

Pregnancy

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.

Pediatric use

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Juvenile Animal Toxicity Data Oral administration of ponesimod (0, 1, 10, 30, or 100 mg/kg/day) to young rats from postnatal day 28 to 91 resulted in lung histopathology (alveolar histiocytosis/edema) and decreased immune function (T-cell dependent antibody response) at the two highest doses tested. Decreased growth (body weight gain and/or long bone length) was observed at all but the low dose, and neurobehavioral impairment (increased locomotor activity) was observed at the highest dose tested. Decreased lymphocyte count and neurobehavioral impairment persisted at the end of a 4- week recovery period.

Geriatric use

8.5 Geriatric Use Clinical studies of PONVORY did not include patients 65 years of age and over to determine whether they respond differently from younger subjects. Use of PONVORY in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] .

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.

Description

(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

Mechanism of action

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.

How supplied

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.

Patient information

Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Administration Tell patients not to discontinue PONVORY without first discussing this with the prescribing healthcare provider. Advise patients to contact their healthcare provider if they accidently take more PONVORY than prescribed. Instruct patients to administer tablets whole. Risk of Infections Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking PONVORY and for 1 to 2 weeks after stopping it, and that they should contact their healthcare provider if they develop symptoms of infection [see Warnings and Precautions ( 5.1 )] . Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with PONVORY, and PONVORY should be paused 1 to 2 weeks prior and until 4 weeks after a planned vaccination. Recommend that patients postpone treatment with PONVORY for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection. Inform patients that cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with S1P receptor modulators. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that 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 [see Warnings and Precautions ( 5.1 )] . Cardiac Effects Advise patients that initiation of PONVORY treatment results in transient decrease in heart rate [see Warnings and Precautions ( 5.2 )] . Inform patients that to reduce this effect, dose titration is required. Advise patients that dose titration is also required if 4 or more consecutive daily doses are missed during treatment initiation or maintenance treatment [see Dosage and Administration ( 2.2 , 2.4 ) and Warnings and Precautions ( 5.2 )] . Inform certain patients with certain preexisting cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 4 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods [see Dosage and Administration ( 2.3 )] . Respiratory Effects Advise patients that they should contact their healthcare provider if they experience new onset or worsening of dyspnea [see Warnings and Precautions ( 5.3 )] . Liver Injury Inform patients that PONVORY may increase liver enzymes. Advise patient that they should contact their healthcare provider if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment [see Warnings and Precautions ( 5.4 )] . Cutaneous Malignancies Inform patients that the risk of basal cell carcinoma is increased with the use of PONVORY and that cases of melanoma and squamous cell carcinoma have been reported. Advise patients that any suspicious skin lesions should be promptly evaluated. Advise patients to limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with high protection factor [see Warnings and Precautions ( 5.6 )] . Pregnancy and Fetal Risk Inform patients that, based on animal studies, PONVORY may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with PONVORY and for one week after stopping PONVORY. Advise a female patient to immediately inform her healthcare provider if she is pregnant or planning to become pregnant [see Warnings and Precautions ( 5.7 )] . Macular Edema Advise patients that PONVORY may cause macular edema, and that they should obtain an eye exam near the start of treatment with PONVORY, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking PONVORY [see Warnings and Precautions ( 5.8 )] . Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased. Posterior Reversible Encephalopathy Syndrome Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae [see Warnings and Precautions ( 5.9 )] . Severe Increase in Disability After Stopping PONVORY Inform patients that severe increase in disability has been reported after discontinuation of another S1P receptor modulator like PONVORY. Advise patients to contact their healthcare provider if they develop worsening symptoms of MS following discontinuation of PONVORY [see Warnings and Precautions ( 5.11 )] . Immune System Effects After Stopping PONVORY Advise patients that PONVORY continues to have effects, such as lowering effects on peripheral lymphocyte count, for 1 to 2 weeks after the last dose [see Warnings and Precautions ( 5.12 )] . Active ingredient made in Austria. Distributed by: Vanda Pharmaceuticals, Inc. Washington, D.C. 20037, USA © 2024 Vanda Pharmaceuticals, Inc.

Label text from the FDA structured product label by Vanda Pharmaceuticals Inc. (revised Dec 4, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Ponesimod in 2 products

Ponvory NDC products (4)

NDC	Strength & form	Labeler	Type
50458-707	Kit	Janssen Pharmaceuticals, Inc	NDA
50458-720	Ponesimod 20 mg/1 Tablet, Film Coated	Janssen Pharmaceuticals, Inc	NDA
43068-610	Kit	Vanda Pharmaceuticals Inc.	NDA
43068-620	Ponesimod 20 mg/1 Tablet, Film Coated	Vanda Pharmaceuticals Inc.	NDA

Frequently asked questions

What is Ponvory used for?

What are the side effects of Ponvory?

Who makes Ponvory?

Ponvory is listed by 2 labelers in the FDA NDC directory, including Janssen Pharmaceuticals, Inc, Vanda Pharmaceuticals Inc..