Mayzent

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.

• Assessments are required prior to initiating MAYZENT. (
  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)]

  .
  )
• Titration is required for treatment initiation. (
  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 (5.4)]

  . A 12-tablet 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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg
  Day 5	1.25 mg	5 x 0.25 mg

  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 (5.4)

  and

  Use in Specific Populations (8.6)]

  . A 7-tablet starter pack should be used for patients who will be titrated to the 1-mg maintenance dosage

  [see How Supplied/Storage and Handling (16.1, 16.2)]

  .

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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg

  If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
  )
• The recommended maintenance dosage is 2 mg. (
  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 (5.4)]

  . A 12-tablet 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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg
  Day 5	1.25 mg	5 x 0.25 mg

  If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
  )
• The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. (
  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 (5.4)

  and

  Use in Specific Populations (8.6)]

  . A 7-tablet starter pack should be used for patients who will be titrated to the 1-mg maintenance dosage

  [see How Supplied/Storage and Handling (16.1, 16.2)]

  .

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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg

  If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
  )
• Administer tablets whole; do not split, crush, or chew. (
  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 (5.4)]

  . A 12-tablet 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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg
  Day 5	1.25 mg	5 x 0.25 mg

  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 (5.4)

  and

  Use in Specific Populations (8.6)]

  . A 7-tablet starter pack should be used for patients who will be titrated to the 1-mg maintenance dosage

  [see How Supplied/Storage and Handling (16.1, 16.2)]

  .

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

  Titration	Titration dose	Titration regimen
  Day 1	0.25 mg	1 x 0.25 mg
  Day 2	0.25 mg	1 x 0.25 mg
  Day 3	0.50 mg	2 x 0.25 mg
  Day 4	0.75 mg	3 x 0.25 mg

  If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
  )
• 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     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 Contraindications (4), Warnings and Precautions (5.4),

  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 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 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 (5.4)]
  • 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 (5.4)
    and
    Drug Interactions (7.2)]
  • Receiving concurrent therapy with drugs that slow heart rate or AV conduction
    [see Drug Interactions (7.2, 7.3)]
  )

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.

1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side.

2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side.

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 MotherToBaby@health.ucsd.edu, or visiting www.mothertobaby.org/join-study.

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 (

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.

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 the recommended human dose (RHD) of 2 mg/day.

When siponimod (0, 0.1, 1, or 5 mg/kg) was orally administered to pregnant rabbits during the period of organogenesis, embryolethality and increased incidences of fetal skeletal variations were observed at all but the lowest dose tested. Plasma exposure (AUC) at the no-effect dose (0.1 mg/kg) for adverse effects on embryo-fetal development in rabbits is less than that in humans at the RHD.

When siponimod (0, 0.05, 0.15, or 0.5 mg/kg) was orally administered to female rats throughout pregnancy and lactation, increased mortality, decreased body weight, and delayed sexual maturation were observed in the offspring at all but the lowest dose tested. An increase in malformations was observed at all doses. A no-effect dose for adverse effects on pre- and postnatal development in rats was not identified. The lowest dose tested (0.05 mg/kg) is less than the RHD, on a mg/m² basis.

• Infections:
  MAYZENT may increase the risk. Obtain a complete blood count (CBC) before initiating treatment. Monitor for infection during treatment. Do not start in patients with active infection. (
  5.1     Infections

  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

  [see Clinical Pharmacology (12.2)]

  . Life-threatening and rare fatal infections have occurred in association with MAYZENT.

  In Study 1

  [see Clinical Studies (14)]

  , the overall rate of infections was comparable between the MAYZENT-treated patients and those on placebo (49.0% vs. 49.1%, respectively). However, herpes zoster, herpes infection, bronchitis, sinusitis, upper respiratory infection, and fungal skin infection were more common in MAYZENT-treated patients. In Study 1, serious infections occurred at a rate of 2.9% in MAYZENT-treated patients compared to 2.5% of patients receiving placebo.

  Before initiating treatment with MAYZENT, results from a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be reviewed.

  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

  [see Warnings and Precautions (5.13)]

  .

  Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with MAYZENT should be considered if a patient develops a serious infection.

  Cryptococcal Infections

  Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with another sphingosine 1-phosphate (S1P) receptor modulator. Rare cases of CM have also occurred with MAYZENT. 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. MAYZENT treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

  Herpes Viral Infections

  Cases of herpes viral infection, including cases of meningitis or meningoencephalitis caused by VZV reactivation, have been reported with MAYZENT. In Study 1, the rate of herpetic infections was 4.6% in MAYZENT-treated patients compared to 3.0% of patients receiving placebo. In Study 1, an increase in the rate of herpes zoster infections was reported in 2.5% of MAYZENT-treated patients compared to 0.7% of patients receiving placebo. 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 MAYZENT (

  see Vaccinations below

  ).

  Prior and Concomitant Treatment with Anti-neoplastic, Immune-Modulating, or Immunosuppressive Therapies

  Anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) should be coadministered with caution because of the risk of additive immune system effects during such therapy

  [see Drug Interactions (7.1)]

  .

  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.

  Vaccinations may be less effective if administered during MAYZENT treatment.

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

  [see Drug Interactions (7.4)]

  .
  )
  
• Progressive Multifocal Leukoencephalopathy (PML):
  Withhold MAYZENT at the first sign or symptom of PML. (
  5.2     Progressive Multifocal Leukoencephalopathy

  Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS treated with S1P receptor modulators, including MAYZENT. 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. PML has occurred in MAYZENT-treated patients who had not been treated previously with natalizumab (which has a known association with PML), were not taking any other immunosuppressive or immunomodulatory medications concomitantly, and did not have any ongoing systemic medical conditions resulting in compromised immune system function. Longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators: the majority of cases of PML associated with S1P receptor modulators, including MAYZENT, have occurred in patients treated for at least 18 months.

  At the first sign or symptom suggestive of PML, withhold MAYZENT and perform an appropriate diagnostic evaluation. 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. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including S1P receptor modulators. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

  If PML is confirmed, treatment with MAYZENT should be discontinued.

  Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including MAYZENT, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.
  )
  
• Macular Edema:
  Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with MAYZENT. Conduct an evaluation of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Consider discontinuing MAYZENT if macular edema develops. Diabetes mellitus and uveitis increase the risk. (
  5.3     Macular Edema

  S1P receptor modulators, including MAYZENT, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with MAYZENT. Perform an examination of the fundus, including the macula, periodically while on therapy, and any time there is a change in vision.

  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.

  Continuation of MAYZENT therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing MAYZENT if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.

  Macular Edema in Patients with a History of Uveitis or Diabetes Mellitus

  Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during MAYZENT therapy. In the clinical trial experience in adult patients with all doses of MAYZENT, the rate of macular edema was higher in MS patients with a history of uveitis or diabetes mellitus compared to those without a history of these diseases (approximately 10% vs. 2%, respectively).
  )
  
• Bradyarrhythmia and Atrioventricular Conduction Delays:
  MAYZENT may result in a transient decrease in heart rate; titration is required for treatment initiation. Consider resting heart rate with concomitant beta-blocker use; obtain cardiologist consultation before concomitant use with other drugs that decrease heart rate. (
  5.4     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

  [see Dosage and Administration (2.2, 2.3)

  and

  Clinical Pharmacology (12.2)]

  .

  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
    [see Drug Interactions (7.2)]

  Reduction in Heart Rate

  After the first titration dose of MAYZENT, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5 to Day 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5 to 6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation.

  In Study 1, bradycardia occurred in 4.4% of MAYZENT-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention

  [see Adverse Reactions (6.1)]

  . Heart rates below 40 bpm were rarely observed.

  Atrioventricular Conduction Delays

  Initiation of MAYZENT treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The AV conduction delays manifested in most of the cases as first-degree AV block (prolonged PR interval on ECG), which occurred in 5.1% of MAYZENT-treated patients and in 1.9% of patients receiving placebo in Study 1. Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed at the time of treatment initiation with MAYZENT in less than 1.7% of patients in clinical trials. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours, rarely required treatment with atropine, and did not require discontinuation of MAYZENT treatment.

  If treatment with MAYZENT is considered, advice from a cardiologist should be sought in patients with:

  • Significant QT prolongation (QTc greater than 500 msec)
  • Arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs
    [see Drug Interactions (7.2)]
  • Ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
  • A history of second-degree Mobitz type II or higher AV block, sick-sinus syndrome, or sino-atrial heart block
    [see Contraindications (4)]

  Treatment-Initiation Recommendations

  • Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present.
  • In all patients, a dose titration is recommended for initiation of MAYZENT treatment to help reduce cardiac effects
    [see Dosage and Administration (2.2, 2.3)]
    .
  • In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure, if not contraindicated, ECG testing and first-dose monitoring is recommended
    [see Dosage and Administration (2.1, 2.4)
    and
    Contraindications (4)]
    .
  • Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, MAYZENT is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
  • Use of MAYZENT in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
  • Experience with MAYZENT is limited in patients receiving concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, calcium channel blockers - diltiazem and verapamil, and other drugs that may decrease heart rate, such as ivabradine and digoxin). Concomitant use of these drugs during MAYZENT initiation may be associated with severe bradycardia and heart block.
    • For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing MAYZENT treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, MAYZENT can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart rate is greater than 50 bpm. Treatment with MAYZENT can then be initiated and treatment with a beta-blocker can be reinitiated after MAYZENT has been up-titrated to the target maintenance dosage
      [see Drug Interactions (7.3)]
      .
    • For patients taking other drugs that decrease heart rate, treatment with MAYZENT should generally not be initiated without consultation from a cardiologist because of the potential additive effect on heart rate
      [see Dosage and Administration (2.4)
      and
      Drug Interactions (7.2)]
      .

  Missed Dose During Treatment Initiation and Reinitiation of Therapy Following Interruption

  If a titration dose is missed, or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations

  [see Dosage and Administration (2.2, 2.3)]

  .
  ,
  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 treatment can be initiated in patients receiving stable doses of MAYZENT

  [see Clinical Pharmacology (12.2)]

  .
  )
  
• Respiratory Effects:
  May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. (
  5.5     Respiratory Effects

  Dose-dependent reductions in absolute forced expiratory volume over 1 second (FEV₁) were observed in MAYZENT-treated patients as early as 3 months after treatment initiation. In a placebo-controlled trial in adult patients, the decline in absolute FEV₁from baseline compared to placebo was 88 mL [95% confidence interval (CI): 139, 37] at 2 years. The mean difference between MAYZENT-treated patients and patients receiving placebo in percent predicted FEV₁at 2 years was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV₁after drug discontinuation. In Study 1, five patients discontinued MAYZENT because of decreases in pulmonary function testing. MAYZENT has been tested in MS patients with mild to moderate asthma and chronic obstructive pulmonary disease. The changes in FEV₁were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with MAYZENT if clinically indicated.
  )
  
• Liver Injury:
  Obtain liver enzyme results before initiation. Closely monitor patients with severe hepatic impairment. Discontinue if significant liver injury occurs. (
  5.6     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.

  In Study 1, elevations in transaminases and bilirubin were observed in 10.1% of MAYZENT-treated patients compared to 3.7% of patients receiving placebo, mainly because of transaminase [alanine aminotransferase/aspartate aminotransferase/gamma-glutamyltransferase (ALT/AST/GGT)] elevations.

  In Study 1, ALT or AST increased to three and five times the upper limit of normal (ULN) in 5.6% and 1.4% of MAYZENT-treated patients, respectively, compared to 1.5% and 0.5% of patients receiving placebo, respectively. ALT or AST increased eight and ten times ULN in MAYZENT-treated patients (0.5% and 0.2%, respectively) compared to no patients receiving placebo. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of MAYZENT. In clinical trials, MAYZENT was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic dysfunction.

  Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should have liver enzymes checked. MAYZENT should be discontinued if significant liver injury is confirmed.

  Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test values when taking MAYZENT, caution should be exercised when using MAYZENT in patients with a history of significant liver disease.
  )
  
• Cutaneous Malignancies:
  Skin examination prior to or shortly after the start of treatment and periodically thereafter is recommended. Suspicious skin lesions should be evaluated. (
  5.7     Cutaneous Malignancies

  The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Use of MAYZENT has been associated with an increased risk of BCC and SCC. In Study 1, the incidence of BCC and SCC was 1.1% and 0.2%, respectively, in MAYZENT-treated patients

  [see Adverse Reactions (6.1)]

  . Cases of other cutaneous malignancies, including melanoma, have also been reported in patients treated with MAYZENT and in patients treated with other S1P receptor modulators. Kaposi’s sarcoma and Merkel cell carcinoma have also been reported in patients treated with S1P receptor modulators in the postmarketing setting.

  Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking MAYZENT.
  )
  
• Increased Blood Pressure:
  Monitor blood pressure during treatment. (
  5.8     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.
  )
  
• Fetal Risk:
  Women of childbearing potential should use effective contraception during and for 10 days after stopping MAYZENT. (
  5.9     Fetal Risk

  Based on animal studies, MAYZENT may cause fetal harm

  [see Use in Specific Populations (8.1)]

  . 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.
  )