Siponimod
FDA Drug Information • Also known as: Mayzent
- Brand Names
- Mayzent
- Drug Class
- Sphingosine 1-phosphate Receptor Modulator [EPC]
- Route
- ORAL
- Dosage Form
- TABLET, FILM COATED
- Product Type
- HUMAN PRESCRIPTION DRUG
Description
11 DESCRIPTION MAYZENT tablets contains siponimod, an S1P receptor modulator, as 2:1 co-crystal of siponimod and fumaric acid and has the following chemical name: 1-[[4-[(1 E )-1-[[[4-Cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-3-azetidinecarboxylic acid (2 E )-2-butenedioate (2:1). Its molecular formula is C 4 H 4 O 4
What Is Siponimod Used For?
1 INDICATIONS AND USAGE MAYZENT 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. MAYZENT is a sphingosine 1-phosphate (S1P) 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.
Dosage and Administration
2 DOSAGE AND ADMINISTRATION Assessments are required prior to initiating MAYZENT. ( 2.1 ) Titration is required for treatment initiation. ( 2.2 , 2.3 ) The recommended maintenance dosage is 2 mg. ( 2.2 ) The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. ( 2.3 ) Administer tablets whole; do not split, crush, or chew. ( 2.2 , 2.3 ) 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. ( 2.4 ) 2.1 Assessments Prior to First Dose of MAYZENT Before initiation of treatment with MAYZENT, assess the following: CYP2C9 Genotype Determination Test patients for CYP2C9 variants to determine CYP2C9 genotype [see Dosage and Administration (2.2, 2.3), Contraindications (4) and Use in Specific Populations (8.6)] . An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available. 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 recommended [see Dosage and Administration (2.4) and Warnings and Precautions (5.4)] . Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Drug Interactions (7.2, 7.3)] . Complete Blood Count Review results of a recent complete blood count (CBC) [see Warnings and Precautions (5.1)] . Liver Function Tests Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.6)] . Ophthalmic Evaluation Obtain a baseline evaluation of the fundus, including the macula, near the start of the treatment with MAYZENT [see Warnings and Precautions (5.3)] . Skin Examination Obtain a baseline skin examination prior to or shortly after initiation of MAYZENT. If a suspicious skin lesion is observed, it should be promptly evaluated [see Warnings and Precautions (5.7)] . 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 drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with MAYZENT [see Warnings and Precautions (5.1) and Drug Interactions (7.1)] . Vaccinations Test patients for antibodies to varicella zoster virus (VZV) before initiating MAYZENT; VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with MAYZENT [see Warnings and Precautions (5.1)] . 2.2 Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2 Maintenance Dosage After treatment titration ( see Treatment Initiation ), the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in...
Side Effects (Adverse Reactions)
6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions (5.1)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.2)] Macular Edema [see Warnings and Precautions (5.3)] Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.4)] Respiratory Effects [see Warnings and Precautions (5.5)] Liver Injury [see Warnings and Precautions (5.6)] Cutaneous Malignancies [see Warnings and Precautions (5.7)] Increased Blood Pressure [see Warnings and Precautions (5.8)] Fetal Risk [see Warnings and Precautions (5.9)] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)] Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions (5.11)] Severe Increase in Disability After Stopping MAYZENT [see Warnings and Precautions (5.12)] Immune System Effects After Stopping MAYZENT [see Warnings and Precautions (5.13)] Most common adverse reactions (incidence greater than 10%) are headache, hypertension, and transaminase increases. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or 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 1737 MS patients have received MAYZENT at doses of at least 2 mg daily. These patients were included in Study 1 [see Clinical Studies (14)] and in a Phase 2 placebo-controlled study in patients with MS. In Study 1, 67% of MAYZENT-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of MAYZENT-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence at least 10%) in MAYZENT-treated patients in Study 1 were headache, hypertension, and transaminase increases. Table 3 lists adverse reactions that occurred in at least 5% of MAYZENT-treated patients and at a rate at least 1% higher than in patients receiving placebo. Table 3 Adverse Reactions Reported in Study 1 (Occurring in at Least 5% of MAYZENT-Treated Patients and at a Rate at Least 1% Higher Than in Patients Receiving Placebo) Terms were combined as follows: a headache, tension headache, sinus headache, cervicogenic headache, drug withdrawal headache, and procedural headache. b hypertension, blood pressure increased, blood pressure systolic increased, essential hypertension, blood pressure diastolic increased. c alanine aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, liver function test increased, hepatic function abnormal, liver function test abnormal, transaminases increased. d edema peripheral, joint swelling, fluid retention, swelling face. e bradycardia, sinus bradycardia, heart rate decreased. f pain in extremity and limb discomfort. Adverse reaction MAYZENT 2 mg (N = 1099) % Placebo (N = 546) % Headache a 15 14 Hypertension b 13 9 Transaminase increased c 11 3 Falls 11 10 Edema peripheral d 8 4 Nausea 7 4 Dizziness 7 5 Diarrhea 6 4 Bradycardia e 6 3 Pain in extremity f 6 4 The following adverse reactions have occurred in less than 5% of MAYZENT-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1 st and 2 nd degree), asthenia, and pulmonary function test decreased [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)] . Seizures In Study 1, cases of seizures were...
Drug Interactions
7 DRUG INTERACTIONS Vaccination: Avoid live-attenuated vaccines during and for up to 4 weeks after treatment with MAYZENT. ( 7.4 ) CYP2C9 and Dual CYP2C9/3A4 Inhibitors: Strong CYP2C9 inhibitors increase siponimod exposure; concomitant use with MAYZENT is not recommended. Monitor for adverse reactions during concomitant use of MAYZENT with moderate CYP2C9 inhibitors or moderate CYP2C9/CYP3A4 dual inhibitors. ( 7.5 ) CYP2C9 and CYP3A4 Inducers: Dual moderate CYP2C9/strong CYP3A4 inducers decrease siponimod exposure; concomitant use with MAYZENT is not recommended. Monitor for loss of efficacy with concomitant use of MAYZENT and moderate or strong CYP3A4 inducers in patients with CYP2C9*1/*3 or *2/*3 genotypes. ( 7.6 ) 7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies MAYZENT 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 immunosuppressive effects [see Warnings and Precautions (5.11)] . Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with MAYZENT after alemtuzumab is not recommended. MAYZENT 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 MAYZENT has not been studied in patients taking QT prolonging drugs. Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with MAYZENT is considered, advice from a cardiologist should be sought. Because of the potential additive effects on heart rate, treatment with MAYZENT 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., ivabradine, digoxin) [see Warnings and Precautions (5.4) and Drug Interactions (7.3)] . If treatment with MAYZENT is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation. 7.3 Beta-Blockers Caution should be applied when MAYZENT 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 MAYZENT [see Warnings and Precautions (5.4)] . Beta-blocker...
Contraindications
4 CONTRAINDICATIONS MAYZENT is contraindicated in patients who have: A CYP2C9*3/*3 genotype [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.5)] In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.4)] Patients with a CYP2C9*3/*3 genotype. ( 4 ) In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure. ( 4 ) Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker. ( 4 )
Pregnancy and Breastfeeding
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MAYZENT during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the MotherToBaby Pregnancy Study in Multiple Sclerosis by calling 1-877-311-8972, sending an email to [email protected], or visiting www.mothertobaby.org/join-study . Risk Summary There are no adequate data on the developmental risk associated with the use of MAYZENT in pregnant women. Based on animal data and its mechanism of action, MAYZENT can cause fetal harm when administered to a pregnant woman ( see Data ). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated MAYZENT-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital, and skeletal) in rat and of embryo-fetal deaths, abortions, and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post-implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dose with fetuses available for evaluation. A no-effect dose for adverse effects on embryo-fetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at...
Overdosage
10 OVERDOSAGE In patients with overdosage of MAYZENT, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed [see Warnings and Precautions (5.4, 5.8) and Clinical Pharmacology (12.2)] . There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by MAYZENT can be reversed by atropine or isoprenaline.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied MAYZENT film-coated tablets are supplied as follows: 0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘T’ on other side. Starter Pack for 1-mg maintenance dosage – blister card of seven 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-89 Starter Pack for 2-mg maintenance dosage – blister card of twelve 0.25 mg tablets in a calendarized blister wallet...............NDC 0078-0979-12 Bottle of 28 tablets........................................................................................................................NDC 0078-0979-50 1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-1014-15 2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side. Bottle of 30 tablets.........................................................................................................................NDC 0078-0986-15 Bottle of 15 tablets.........................................................................................................................NDC 0078-0986-45 16.2 Storage and Handling Unopened Containers Store MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F). After dispensed by pharmacy to patient, MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Opened Containers Bottles MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not...
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.