`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
`
` These highlights do not include all the information needed to use
`
`
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`
`
` MAYZENT safely and effectively. See full prescribing information for
`
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`
`
` MAYZENT.
`
`
`
`
`
`
` MAYZENT® (siponimod) tablets, for oral use
` Initial U S. Approval: 2019
`
`
`
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`
`
` ----------------------------INDICATIONS AND USAGE-------------------------­
`
`
`
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`
`
`
`
`
` MAYZENT is a sphingosine 1-phosphate 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. (1)
`
`
`
`
`
`
`
`
`
`
`
`
` ----------------------DOSAGE AND ADMINIS TRATION----------------------­
`
`•
`
`•
`
`•
`
`•
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`
`
`
`
`
`
` Assessments are required prior to initiating MAYZENT (2.1)
`
`
` Titration is required for treatment initiation (2 2, 2.3)
`
`
`
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`
` The recommended maintenance dosage is 2 mg (2.2)
`
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` The recommended maintenance dosage in patients with a CYP2C9
`
`
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`
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` *1/*3 or *2/*3 genotype is 1 mg (2.3)
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` First-dose monitoring is recommended for patients with sinus
`
`
`
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` bradycardia, first- or second-degree [Mobitz type I] atrioventricular
`
`
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` (AV) block, or a history of myocardial infarction or heart failure (2.4)
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`•
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`
`
` ---------------------DOSAGE FORMS AND STRENGTHS --------------------­
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`
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`
`
`-------------------------------CONTRAINDICATIONS----------------------------­
`
`•
`
`•
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`
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`
` Patients with a CYP2C9*3/*3 genotype (4)
`
`
`
` In the last 6 months , experienced myocardial infarction, unstable angina,
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` stroke, TIA, decompensated heart failure requiring hospitalization, or
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` Class III/IV heart failure (4)
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` Presence of Mobitz type II second-degree, third-degree AV block, or
`
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` sick sinus syndrome, unless patient has a functioning pacemaker (4)
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`•
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` • Macular Edema: An ophthalmic evaluation is recommended before starting
`
`
` treatment and if there is any change in vision while taking MAYZENT.
`
`
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`
`
` Diabetes mellitus and uveitis increase the risk. (5.2)
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`
`
` • Bradyarrhythmia and Atrioventricular Conduction Delays : MAYZENT
`
`
`
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` may result in a transient decrease in heart rate; titration is required for
`
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` treatment initiation. Consider resting heart rate with concomitant beta-
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` blocker use; obtain cardiologist consultation before concomitant use with
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` other drugs that decrease heart rate (5.3, 7.2, 7 3)
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`
`
` • Respiratory Effects: May cause a decline in pulmonary function. Assess
`
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` pulmonary function (e.g , spirometry) if clinically indicated. (5.4).
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` • Liver Injury: Obtain liver enzyme results before initiation. Closely monitor
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` patients with severe hepatic impairment. Discontinue if significant liver
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` injury occurs. (5 5)
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` • Increased Blood Pressure (BP): Monitor BP during treatment. (5.6)
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`
`
` • Fetal Risk: Women of childbearing potential should use effective
`
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` contraception during and for 10 days after stopping MAYZENT. (5.7)
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`
`
` ------------------------------ADVERS E REACTIONS------------------------------
`
`
`
` Most common adverse reactions (incidence greater than 10%) are headache,
`
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`
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` hypertension, and transaminase increases. (6 1)
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`
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`
`
`
`
` To report SUSPECTED ADVERS E REACTIONS, contact Novartis
`
` Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA­
`
`
`
`
`
`
` 1088 or www.fda gov/ me dwatch.
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` Tablets: 0.25 mg and 2 mg (3)
`
` ------------------------------DRUG INTERACTIONS-----------------------------­
`
`
`
`• Vaccines: Avoid live attenuated vaccines during and for up to 4 weeks after
`
`
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`
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` treatment with MAYZENT (7.4)
`
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`
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` • CYP2C9 and CYP3A4 Inhibitors: Increase in siponimod exposure;
`
`
`
` concomitant use of MAYZENT with moderate CYP2C9 and moderate or
`
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`
`
`
`
`
`
` strong CYP3A4 inhibitors is not recommended (7.5)
`
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`
`
` • CYP2C9 and CYP3A4 Inducers: Decrease in siponimod exposure;
`
`
`
`
`
`
` concomitant use of MAYZENT with moderate CYP2C9 and strong
`
`
`
`
`
`
`
`
` CYP3A4 inducers is not recommended (7.6)
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
` Guide.
`
`
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`
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`
`
`
`
` Revised: 3/2019
`
`
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`
`2.3
`
`
`2.4
`
`
`3
`
`4
`
`5
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`7.2
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`8
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`
`10
`
`11
`
`12
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`13
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`14
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`16
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`6
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`
`7
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`
`
`Reference ID: 4409346
`
`
`
`
`
`
`
`
`
`
`
`
`
` -----------------------WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`• Infections: MAYZENT may increase the risk. Obtain a complete blood
`
`
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`
`
`
`
`
` count (CBC) before initiating treatment. Monitor for infection during
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`
` treatment. Do not start in patients with active infection. (5.1)
`
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`
`
`_______________________________________________________________________________________________________________________________________
`
`7.1
` Anti-Neoplastic, Immune-Modulating, or Immunosuppressive
`
`
`
`
`
`
`Therapies
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That
`
` INDICATIONS AND USAGE
`1
`
`
`
`
` may Decrease Heart Rate
`
`
`
`2
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
`2.1
`7.3
`
`
` Assessments Prior to First Dose of MAYZENT
`
`
`
`
`Beta-Blockers
`
`
`
`2.2
`7.4
`
` Recommended Dosage in Patients With CYP2C9 Genotypes
`
`
`
`
`Vaccination
`
`
`
`7.5
`
`
` *1/*1, *1/*2, or *2/*2
`
`
`
` CYP2C9 and CYP3A4 Inhibitors
`
`
`
`7.6
`
`
` Recommended Dosage in Patients With CYP2C9 Genotypes
`
`
` CYP2C9 and CYP3A4 Inducers
`
`
` *1/*3 or *2/*3
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`8.1
` First Dose Monitoring in Patients With Certain Preexisting
`
`
`Pregnancy
`
`
`
`8.2
` Cardiac Conditions
`
`Lactation
`
`
`
`
`2.5
`8.3
`
`
`
` Reinitiation of MAYZENT After Treatment Interruption
`
`
` Females and Males of Reproductive Potential
`
`
`
`
`
`
`8.4
` Pediatric Use
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
`8.5
`
` Geriatric Use
`CONTRAINDICATIONS
`
`
`
`8.6
`
` CYP2C9 Genotype
` WARNINGS AND PRECAUTIONS
`
`
`
`
`
`5.1
`Infections
`OVERDOSAGE
`
`
`
`5.2
` Macular Edema
`
`DESCRIPTION
`
`
`
`5.3
`
` Bradyarrhythmia and Atrioventricular Conduction Delays
` CLINICAL PHARMACOLOGY
`
`
`
`
`
`5.4
`12.1 Mechanism of Action
` Respiratory Effects
`
`
`
`
`
`
`
`5.5
`12.2
` Liver Injury
`
`Pharmacodynamics
`
`
`
`
`5.6
`12.3
` Increased Blood Pressure
`
`
`Pharmacokinetics
`
`
`
`
`5.7
`12.5
` Fetal Risk
`
`Pharmacogenomics
`
`
`
`5.8
`
`
` Posterior Reversible Encephalopathy Syndrome
`
` NONCLINICAL TOXICOLOGY
`
`
`
`
`5.9
`
`
`
` Unintended Additive Immunosuppressive Effects From Prior
`
`
`
` Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`
`
` Treatment With Immunosuppressive or Immune-Modulating
`
`
`
`
` CLINICAL STUDIES
`
`
`Therapies
`
` HOW SUPPLIED/STORAGE AND HANDLING
`
`
`5.10
`16.1
`
`
`
`
`
` Severe Increase in Disability After Stopping MAYZENT
`
`
`
`
` How Supplied
`
`
`5.11
`16.2
`
`
` Immune System Effects After Stopping MAYZENT
`
`
`
`
`
` Storage and Handling
`
`
`
`
` ADVERS E REACTIONS
`
` PATIENT COUNSELING INFORMATION
`
`
`
`
`6.1
` Clinical Trials Experience
`
`
`
` DRUG INTERACTIONS
`
`
`
`17
`
` *Sections or subsections omitted from the full prescribing information are not
`
` listed.
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`
`Biogen Exhibit 2143
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 25
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 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.
`
`
`
`
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 2
`
`
`
` 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 antineoplastic, 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)].
`
`
`
`
` 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)].
`
`
`
`
`Reference ID: 4409346
`
`Page 2 of 25
`
`

`

`
`
` Table 1
`
`
` Titration
`
`
` Day 1
`
` Day 2
`
`
` Day 3
`
`
` Day 4
`
`
` Day 5
`
`
`
` Dose Titration Regimen to Reach MAYZENT 2 mg Maintenance Dosage
`
`
`
`
`
` Titration Regimen
` Titration Dose
` 1 x 0.25 mg
`
`
`
`
`
` 0.25 mg
`
` 1 x 0.25 mg
`
`
`
` 0.25 mg
`
`
` 2 x 0.25 mg
`
`
`
` 0.50 mg
`
`
` 3 x 0.25 mg
`
`
`
` 0.75 mg
`
`
` 5 x 0.25 mg
`
`
`
` 1.25 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.
`
`
`
`
`
` 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
`
`
` Titration
`
`
` Day 1
`
` Day 2
`
`
` Day 3
`
`
` Day 4
`
`
`
` Dose Titration Regimen to Reach MAYZENT 1 mg Maintenance Dosage
`
`
`
`
`
` Titration Regimen
` Titration Dose
`
`
`
` 1 x 0.25 mg
`
`
` 0.25 mg
`
` 1 x 0.25 mg
`
`
`
` 0.25 mg
`
`
` 2 x 0.25 mg
`
`
`
` 0.50 mg
`
`
` 3 x 0.25 mg
`
`
`
` 0.75 mg
`
`
`
`
`
`
` If one titration dose is missed for more than 24 hours, treatment needs to be reinitiated with Day 1 of the titration regimen.
`
`
`
`
`
` 2.4
`
`
`
` 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 postdose 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 (5.3)]
`
`
`
`
`
`Reference ID: 4409346
`
`Page 3 of 25
`
`

`

`
`
`
`
` 2.5
`
`
`•
`
`
`• 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)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
`
`
` 3
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
` 0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with
`‘T’ on other side.
`
`
`
`
` 2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with
`& ‘II’ on other side.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`on one side &
`
`on one side
`
`
`
` 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 (5.3)]
`
`
`
`
`
`
` 5
`
`
`
` WARNINGS AND PRECAUTIONS
`
`
`
` 5.1
`
`
`
` Infections
`
`
`
` Risk of Infections
`
`
`
` MAYZENT causes a dose-dependent reduction in peripheral lymphocyte count to 20%-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 complete blood count (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 3-4 weeks after discontinuation of MAYZENT, vigilance for infection should be continued throughout this period [see
`
`
` Warnings and Precautions (5.11)].
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 4409346
`
`Page 4 of 25
`
`

`

`
`
`
`
` 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 one case of reactivation of VZV infection leading to varicella zoster meningitis,
`
`
`
`
`
`
` have been reported in the development program of 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).
`
`
`
`
`
`Progressive Multifocal Leukoencephalopathy
`
`
`
` Progressive multifocal leukoencephalopathy (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. 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.
`
`
`
`
`
`
`
` No cases of PML have been reported in MAYZENT-treated patients in the development program; however, PML has
`
`
` been reported in patients treated with a S1P receptor modulator and other multiple sclerosis (MS) therapies and has been
`
`
`
` associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). Physicians
`
`
` should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent
`
`
` before clinical signs or symptoms. If PML is suspected, treatment with MAYZENT should be suspended until PML has
`
`
`
`
`
` been excluded.
`
`
`
`
` Prior and Concomitant Treatment with Antineoplastic, 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.
`
`
`
`
` The use of live attenuated vaccines should be avoided while patients are taking MAYZENT and for 4 weeks after
`
`
` stopping treatment [see Drug Interactions (7.1)].
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
` 5.2 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.
`
`
`
` 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. The incidence of macular edema is also increased in MS patients with a history of uveitis. In the
`
`
`
`
`
` clinical trial experience in adult patients with all doses of MAYZENT, the rate of macular edema was approximately 10%
`
`
`
`
`
`
`
`Reference ID: 4409346
`
`Page 5 of 25
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`

`

`
`
` in MS patients with a history of uveitis or diabetes mellitus versus 2% in those without a history of these diseases. In
`
`
`
`
`
` addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus or a
` history of uveitis should have regular follow-up examinations.
`
`
`
`
` 5.3
`
`
`
` 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, 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 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with
`
`
` maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean
`
`
` heart rate is observed on Day 1, with the pulse declining on average 5-6 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),
`
`
`
`
`
` In patients with arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs [see Drug
`
` Interactions (7.2)].
`
` In patients with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction,
`
`
`
`
`
` cerebrovascular disease, and uncontrolled hypertension
`
`
`
`
`
`
`•
`
`
`•
`
`
` In patients with a history of with 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.
`
`
`
`
`
`
`Reference ID: 4409346
`
`Page 6 of 25
`
`

`

`
`
`
`•
`
`
`•
`
` 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 with onset > 6 months prior to initiation, ECG testing and first-
`
`
`
`
` dose monitoring is recommended [see Dosage and Administration (2.1, 2.4)].
`
`
`
`
`
`• 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.
`
`
`o 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)].
`
`
`
`
`
`
`
`o 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)].
`
`
`
`
`
`
`
` 5.4
`
`
`
` 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 FEV1 from 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 FEV1 at 2 years
`
`
`
` was 2.8% (95% CI: -4.5, -1.0). There is insufficient information to determine the reversibility of the decrease in FEV1
`
`
`
`
`
`
` after drug discontinuation. In Study 1, five patients d