Ponesimod

Ponesimod is a prescription medicine used to treat relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

• Ponesimod is available under the following different brand names: Ponvory

Common side effects of Ponesimod include:

• upper respiratory tract infection
• liver transaminase elevation
• high blood pressure (hypertension)
• urinary tract infection (UTI)
• shortness of breath
• dizziness
• cough
• pain in extremity
• drowsiness
• fever
• increased C-reactive protein
• high cholesterol
• spinning sensation (vertigo)

Serious side effects of Ponesimod include:

• slow heartbeat
• sore throat, shortness of breath, body aches, fever, burning with urination, chills, cough, and other signs of infection during treatment and for up to 1 to 2 weeks after your treatment
• weakness on one side of the body or clumsiness of the arms or legs that worsens over time; changes in the  thinking, memory, or balance; confusion or personality changes; or loss of strength
• blurriness, shadows, or a blind spot in the center of the vision; sensitivity to light; unusual color to the vision or other vision problems
• nausea
• vomiting
• loss of appetite
• abdominal pain
• yellowing of skin or eyes, or dark urine
• new or worsening shortness of breath

Rare side effects of Ponesimod include:

• none 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet

• 2 mg
• 3 mg
• 4 mg
• 5 mg
• 6 mg
• 7 mg
• 8 mg
• 9 mg
• 10 mg
• 20 mg

Multiple sclerosis

Adult dosage

• Initiation
  • Starter pack must be used for initiating treatment
  • 2 mg orally once a day initially; increase dose as per dose titration regimen (14-day titration)
• Dose titration regimen
  • Days 1 to 2: 2 mg once a day
  • Days 3 to 4: 3 mg once a day
  • Days 5 to 6: 4 mg once a day
  • Day 7: 5 mg once a day
  • Day 8: 6 mg once a day
  • Day 9: 7 mg once a day
  • Day 10: 8 mg once a day
  • Day 11: 9 mg once a day
  • Days 12 to 14: 10 mg once a day
• Maintenance
  • Day 15 and thereafter: 20 mg once a day

Dosage Considerations – Should be Given as Follows:

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Ponesimod has severe interactions with no other drugs
• Ponesimod has serious interactions with at least 124 other drugs
• Ponesimod has moderate interactions with at least 155 other drugs
• Ponesimod has minor interactions with no other drugs

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• In the past 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization, or Class III/IV HF
• Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless the patient has a functioning pacemaker

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Ponesimod?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Ponesimod?”

Cautions

• Elevated transaminases may occur; if symptoms (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, a rash with eosinophilia, jaundice, dark urine) occur during therapy, check hepatic enzymes; if significant liver injury is confirmed, discontinue therapy
• Hypertensive events reported; first detected approximately 1 month after treatment initiation and persisted with continued treatment; monitor BP and manage appropriately
• Based on animal studies, fetal harm may occur
• Consider the possibility of severe exacerbation of disease after discontinuing therapy; monitor for a severe increase in disability upon discontinuation and appropriately treat
• Risk of infections
  • May cause a dose-dependent reduction in peripheral lymphocyte count to 30 to 40% of baseline; potentially increasing susceptibility to infections
  • Life-threatening and rare fatal infections (herpes simplex encephalitis, varicella zoster meningitis, cryptococcal meningitis [CM], disseminated cryptococcal infections) reported with other sphingosine 1-phosphate (S1P) receptor modulators
  • Cases of herpes viral infection reported; confirm the history of varicella (chicken pox) or full course of vaccination against VZV; if no proper documentation, tests for antibodies against VZV
  • Monitor for clinical signs and symptoms of CM; if CM is suspected, suspend therapy until CM is ruled out and undergo prompt diagnostic evaluation and treatment; if CM is diagnosed, initiate appropriate treatment
  • Progressive multifocal leukoencephalopathy (PML) reported in patients treated with S1P receptor modulators and other MS therapies and is associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants); monitor for clinical symptoms or MRI findings; if PML is suspected, suspend treatment; if PML is confirmed, discontinue treatment
  • Delay initiating treatment in patients with an active infection until resolution
  • After discontinuation, the lowering effect on peripheral lymphocyte count may persist for 1 to 2 weeks; continue vigilance for infection during these 1 to 2 weeks
• Bradyarrhythmias and AV conduction delays
  • Initiating treatment may result in transient decreases in HR and AV conduction delays
  • After the first dose of titration, a decrease in HR typically begins within an hour and reaches its nadir within 2 to 4 hours; less pronounced with up-titration after Day 1
  • Conduction abnormalities typically were transient, asymptomatic, resolved without intervention within 24 hours, and did not require discontinuing treatment
  • Not recommended for patients with the following
• History of cardiac arrest
  • Cerebrovascular disease (e.g., TIA, stroke occurring above 6 months before initiating therapy)
  • Uncontrolled hypertension
  • Severe untreated sleep apnea
  • Consult a cardiologist if considering treatment for patients with the following:
  • Significant QT prolongation (QTc above 500 msec)
  • Atrial flutter/fibrillation or arrhythmia treated with Class Ia or Class III anti-arrhythmic drugs
  • Unstable ischemic heart disease, cardiac decompensated failure occurring above 6 months before initiation, history of cardiac arrest, cerebrovascular disease (TIA, stroke occurring above 6 months before initiation), or uncontrolled hypertension
  • History of Mobitz type II second-degree AV block or higher-grade AV block, sick sinus syndrome, or sinoatrial heart block
• Respiratory effects
  • Dose-dependent reductions in FEV1 and reductions in diffusion lung capacity for carbon monoxide were observed mostly occurring in the first month after initiating therapy
  • Data are insufficient on the reversibility of the decrease in FEV1 or forced vital capacity after discontinuation
  • Use with caution in patients with severe respiratory disease (e.g., pulmonary fibrosis, asthma, chronic obstructive pulmonary disease)
  • Perform spirometry evaluation of respiratory function during therapy if clinically indicated
• Cutaneous malignancies
  • Basal cell carcinoma and other skin malignancies reported with S1P receptor modulators, including ponesimod
  • Perform skin examination for all patients, particularly those with risk factors for skin cancer
  • Advise to monitor suspicious skin lesions; if suspicious skin is observed, promptly evaluate
  • Limit exposure to sunlight and UV light and use sunscreen with high protection factors in patients with an increased risk of skin cancer
  • Concomitant phototherapy with UV-B radiation or psoralen plus UV A-photochemotherapy is not recommended
• Macular edema
  • S1P receptor modulators, including ponesimod, have been associated with an increased risk of macular edema
  • Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema; these patients should have regular follow-up examinations of the fundus, including the macula, during treatment
  • Continuation of therapy in patients with macular edema not evaluated; consider risks and benefits on whether to discontinue treatment
• Posterior reversible encephalopathy syndrome
  • Rare cases of posterior reversible encephalopathy syndrome (PRES) were reported with S1P receptor modulators
  • If unexpected neurological or psychiatric signs/symptoms develop, promptly schedule a complete physical and neurological examination, and consider an MRI
  • Symptoms are usually reversible but may evolve into an ischemic stroke or cerebral hemorrhage.
  • Delayed diagnosis and treatment may lead to permanent neurological sequelae
  • If PRES is suspected, discontinued treatment
• Drug interaction overview
  • Antineoplastic, immune-modulating, or immunosuppressive therapies
  • Use with caution
  • May increase the risk of additive immune effects during therapy and in weeks following administration
  • When switching from drugs with prolonged immune effects, consider the half-life and mode of action of such drugs to avoid unintended additive effects
  • Initiating Ponesimod after alemtuzumab is not recommended
  • May be started immediately after discontinuing beta interferon or glatiramer acetate
• Vaccinations
  • Avoid the use of live attenuated vaccines at least 1 month before initiating, during, and for 1 to 2 weeks after treatment
  • If tested negative for VZV antibodies, a full course of the varicella vaccine is recommended before initiating ponesimod
  • Vaccinations may be less effective if administered during treatment
  • Antiarrhythmic drugs, QT prolonging drugs, drugs that may decrease HR
  • Consult a cardiologist if considering treatment
  • Class Ia (eg, Quinidine, Procainamide) and Class III (eg, Amiodarone, Sotalol) anti-arrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia
  • Generally, should not be initiated in patients who are concurrently taking QT-prolonging drugs with known arrhythmogenic properties, HR-lowering calcium channel blockers (eg, Verapamil, Diltiazem), or other drugs that may decrease HR (eg, Digoxin)
• Beta-blockers
  • Use with caution
  • Beta-blockers may have additive effects on lowering HR
  • Patients on a stable dose of beta-blocker; consider resting HR before initiating Ponesimod
  • If resting HR is above 55 bpm under long-term beta-blocker treatment, therapy may be introduced
  • If resting HR is lower than 55 bpm, interrupt beta-blocker until baseline HR is above 55 bpm; Ponesimod can then be initiated; restart beta-blocker once Ponesimod is up-titrated to a maintenance dose
• Strong CYP3A4 and UGT1A1 inducers
  • Not recommended
  • In vitro assessments and limited clinical data indicated that concomitant use of strong CYP3A4 and UGT1A1 inducers (eg, Rifampin, Phenytoin, Carbamazepine) may decrease the systemic exposure of ponesimod; clinical relevance is unclear

Pregnancy and Lactation

• There are no adequate and well-controlled studies in pregnant women
• Contraception
  • Women’s a childbearing potential
  • Before initiating: Counsel on the potential risks to the fetus
  • During treatment: Use effective contraception
  • Discontinuation: Elimination of ponesimod from the body may take approximately 1 week, and potential risk to the fetus may persist; use effective contraception during this period
• Lactation
  • No data are available on the presence of human milk, its effects on breastfed infants, or its effects on milk production
  • When orally administered to women rats during pregnancy and lactation, the drug was detected in the plasma of offspring, suggesting excretion in milk