MAYZENT Film-coated tablet Ref.[9922] Active ingredients: Siponimod

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.

Complete Blood Count:

Review results of a recent complete blood count (CBC) [see Warnings and Precautions (5.1)].

Ophthalmic Evaluation:

Obtain an evaluation of the fundus, including the macula [see Warnings and Precautions (5.2)].

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 (5.3)].

Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Drug Interactions (7.2, 7.3)].

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)].

Liver Function Tests:

Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels [see Warnings and Precautions (5.5)].

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 patients with a CYP2C9*1/*3 or *2/*3 genotype [see Dosage and Administration (2.3)].

Administer tablets whole; do not split, crush, or chew MAYZENT tablets.

Treatment Initiation

Initiate MAYZENT with a 5-day titration, as shown in Table 1 [see Warnings and Precautions (5.3)]. A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage [see How Supplied/Storage and Handling (16.1, 16.2)].

Table 1. Dose Titration Regimen to Reach MAYZENT 2 mg Maintenance Dosage:

If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.

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

Maintenance Dosage

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.

Treatment Initiation

Initiate MAYZENT with a 4-day titration, as shown in Table 2 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)]. Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.

Table 2. Dose Titration Regimen to Reach MAYZENT 1 mg Maintenance Dosage:

If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.

2.4 First Dose Monitoring in Patients With Certain Preexisting Cardiac Conditions

Because initiation of MAYZENT treatment results in a decrease in heart rate (HR), first-dose 6-hour monitoring is recommended for patients with sinus bradycardia [HR 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].

First Dose 6-Hour Monitoring

Administer the first dose of MAYZENT in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG in these patients at the end of the Day 1 observation period.

Additional Monitoring After 6-Hour Monitoring

If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:

• The heart rate 6 hours postdose is less than 45 bpm
• The heart rate 6 hours postdose is at the lowest value postdose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred
• The ECG 6 hours postdose shows new onset second-degree or higher AV block

If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours postdose 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 6-hour monitoring after the second dose.

Advice from a cardiologist should be sought to determine the most appropriate monitoring strategy (which may include overnight monitoring) during treatment initiation, if treatment with MAYZENT is considered in patients:

• With some preexisting heart and cerebrovascular conditions [see Warnings and Precautions (5.3)]
• With a prolonged QTc interval before dosing or during the 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes [see Warnings and Precautions (5.3) and Drug Interactions (7.2)]
• Receiving concurrent therapy with drugs that slow heart rate or AV conduction [see Drug Interactions (7.2, 7.3)]

2.5 Reinitiation of MAYZENT After Treatment Interruption

After the initial titration is complete, if MAYZENT treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen [see Dosage and Administration (2.2, 2.3)]; also complete first-dose monitoring in patients for whom it is recommended [see Dosage and Administration (2.4)].

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 (5.3, 5.6) 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.

Unopened Containers

Store MAYZENT 0.25 mg and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F). After pharmacy dispensing to patient, MAYZENT 0.25 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 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 refrigerate after opening.

Starter Pack/Blister Card

MAYZENT 0.25 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 refrigerate after opening. Store in original calendarized blister wallet container.