MAYZENT® (siponimod) tablets

MAYZENT® (siponimod) tablets

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MAYZENT® (siponimod) tablets

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-[(1E)-1-[[[4-Cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino]ethyl]-2-ethylphenyl]methyl]-3­ azetidinecarboxylic acid (2E)-2-butenedioate (2:1). Its molecular formula is C4H4O4 ● 2C29H35F3N2O3, and its molecular weight is 1149.29 g/mol.

MAYZENT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, glyceryl behenate, lactose monohydrate, microcrystalline cellulose, with a film coating containing iron oxides (black and red iron oxides for the 0.25 mg strength and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.

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.

Mechanism of Action

Siponimod is an S1P receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Dosage and administration

Before initiation of treatment with MAYZENT, assess the following:

CYP2C9 Genotype Determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.

Complete Blood Count: Review results of a recent complete blood count (CBC)

Ophthalmic Evaluation: Obtain an evaluation of the fundus, including the macula

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. Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction

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

Vaccinations: Test patients for antibodies to varicella zoster virus (VZV) before initiating MAYZENT; VZV vaccination of antibodynegative patients is recommended prior to commencing treatment with MAYZENT

Liver Function Tests: Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels

Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2

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 patients with a CYP2C9*1/*3 or *2/*3 genotype. Administer tablets whole; do not split, crush, or chew MAYZENT tablets.

Recommended Dosage in Patients With CYP2C9 Genotypes *1/*3 or *2/*3

In patients with a CYP2C9*1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5. Administer tablets whole; do not split, crush, or chew MAYZENT tablets.

Contraindications

MAYZENT is contraindicated in patients who have:

  • A CYP2C9*3/*3 genotype
  • 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 AVblock, or sick sinus syndrome, unless patient has a functioning pacemaker

Warnings and precautions

Risk of Infections: MAYZENT causes a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. MAYZENT may therefore increase the risk of infections, some serious in nature. Life-threatening and rare fatal infections have occurred in association with MAYZENT.

Initiation of treatment with MAYZENT should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after discontinuation of MAYZENT, vigilance for infection should be continued throughout this period.

Vaccinations: Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating MAYZENT treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with MAYZENT, following which initiation of treatment with MAYZENT should be postponed for 4 weeks to allow the full effect of vaccination to occur.

The use of live attenuated vaccines should be avoided while patients are taking MAYZENT and for 4 weeks after stopping treatment

Vaccinations may be less effective if administered during MAYZENT treatment. MAYZENT treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.

Macular Edema: Macular edema was reported in 1.8% of MAYZENT-treated patients compared to 0.2% of patients receiving placebo. The majority of cases occurred within the first four months of therapy.

An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision while taking MAYZENT.

Continuation of MAYZENT therapy in patients with macular edema has not been evaluated. A decision on whether or not MAYZENT should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Bradyarrhythmia and Atrioventricular Conduction: Delays Since initiation of MAYZENT treatment results in a transient decrease in heart rate and atrioventricular conduction delays, an up-titration scheme should be used to reach the maintenance dosage of MAYZENT

MAYZENT was not studied in patients who had:

  • In the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), or decompensated heart failure requiring hospitalization
  • New York Heart Association Class II-IV heart failure
  • Cardiac conduction or rhythm disorders, including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome, Mobitz type II second degree AV-block or higher grade AV-block (either history or observed at screening), unless patient has a functioning pacemaker
  • Significant QT prolongation (QTc greater than 500 msec)
  • Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs

Respiratory Effects: Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV1) were observed in MAYZENTtreated patients as early as 3 months after treatment initiation.

Liver Injury: Elevations of transaminases may occur in MAYZENT-treated patients. Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of MAYZENT therapy.

Cutaneous Malignancies: Long-term use of S1P modulators, including MAYZENT, have been associated with an increased risk of basal cell carcinoma (BCC).

Increased Blood Pressure: In Study 1, MAYZENT-treated patients had an average increase over placebo of approximately 3 mmHg in systolic pressure and 1.2 mmHg in diastolic pressure, which was first detected after approximately 1 month of treatment initiation and persisted with continued treatment. Hypertension was reported as an adverse reaction in 12.5% of MAYZENT-treated patients and in 9.2% of patients receiving placebo. Blood pressure should be monitored during treatment with MAYZENT and managed appropriately.

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Fetal Risk: Based on animal studies, MAYZENT may cause fetal harm. Because it takes approximately 10 days to eliminate MAYZENT from the body, women of childbearing potential should use effective contraception to avoid pregnancy during and for 10 days after stopping MAYZENT treatment.

Posterior Reversible Encephalopathy Syndrome: Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving an S1P receptor modulator. Such events have not been reported for MAYZENT-treated patients in the development program. However, should a MAYZENT-treated patient develop any unexpected neurological or psychiatric symptoms/signs (e.g., cognitive deficits, behavioral changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, MAYZENT should be discontinued.

Severe Increase in Disability After Stopping MAYZENT: Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of an S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping MAYZENT treatment. Patients should be observed for a severe increase in disability upon MAYZENT discontinuation and appropriate treatment should be instituted, as required.

Immune System Effects After Stopping MAYZENT: After stopping MAYZENT therapy, siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.

Drug interactions

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

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.

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.

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.

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. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT

Vaccination: During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective; therefore MAYZENT treatment should be paused 1 week prior and for 4 weeks after vaccination. The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during MAYZENT treatment and for up to 4 weeks after discontinuation of treatment with MAYZENT

CYP2C9 and CYP3A4 Inhibitors: Because of a significant increase in exposure to siponimod, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition is not recommended. This concomitant drug regimen can consist of a moderate CYP2C9/CYP3A4 dual inhibitor (e.g., fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate – moderate or strong CYP3A4 inhibitor.

CYP2C9 and CYP3A4 Inducers: Because of a significant decrease in siponimod exposure, concomitant use of MAYZENT and drugs that cause moderate CYP2C9 and strong CYP3A4 induction is not recommended for all patients. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducer (e.g., rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.

Use in specific populations

Pregnancy: 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

Lactation: There are no data on the presence of siponimod in human milk, the effects of MAYZENT on the breastfed infant, or the effects of the drug on milk production. A study in lactating rats has shown excretion of siponimod and/or its metabolites in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MAYZENT and any potential adverse effects on the breastfed infant from MAYZENT or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of MAYZENT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

CYP2C9 Genotype: Before initiation of treatment with MAYZENT, test patients to determine CYP2C9 genotype. MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately 0.4% to 0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod.

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.

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.

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