Drug Detail:Mayzent (Siponimod [ sye-poe-ni-mod ])
Drug Class: Selective immunosuppressants
Highlights of Prescribing Information
MAYZENT® (siponimod) tablets, for oral use
Initial U.S. Approval: 2019
Recent Major Changes
Warnings and Precautions (5.1, 5.2, 5.12) | 8/2023 |
Indications and Usage for Mayzent
MAYZENT is a sphingosine 1-phosphate (S1P) receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. (1)
Mayzent Dosage and Administration
- Assessments are required prior to initiating MAYZENT. (2.1)
- Titration is required for treatment initiation. (2.2, 2.3)
- The recommended maintenance dosage is 2 mg. (2.2)
- The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. (2.3)
- Administer tablets whole; do not split, crush, or chew. (2.2, 2.3)
- First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree [Mobitz type I] atrioventricular (AV) block, or a history of myocardial infarction or heart failure. (2.4)
Dosage Forms and Strengths
Tablets: 0.25 mg, 1 mg, and 2 mg (3)
Contraindications
- Patients with a CYP2C9*3/*3 genotype. (4)
- In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure. (4)
- Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker. (4)
Warnings and Precautions
- 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)
- Progressive Multifocal Leukoencephalopathy (PML): Withhold MAYZENT at the first sign or symptom of PML. (5.2)
- Macular Edema: An ophthalmic evaluation is recommended before starting treatment and if there is any change in vision while taking MAYZENT. Diabetes mellitus and uveitis increase the risk. (5.3)
- 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, 7.2, 7.3)
- Respiratory Effects: May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. (5.5)
- Liver Injury: Obtain liver enzyme results before initiation. Closely monitor patients with severe hepatic impairment. Discontinue if significant liver injury occurs. (5.6)
- Cutaneous Malignancies: Skin examination at the start of treatment and periodically is recommended. (5.7)
- Increased Blood Pressure: Monitor blood pressure (BP) during treatment. (5.8)
- Fetal Risk: Women of childbearing potential should use effective contraception during and for 10 days after stopping MAYZENT. (5.9)
Adverse Reactions/Side Effects
Most common adverse reactions (incidence greater than 10%) are headache, hypertension, and transaminase increases. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
- Vaccination: Avoid live-attenuated vaccines during and for up to 4 weeks after treatment with MAYZENT. (7.4)
- CYP2C9 and CYP3A4 Inhibitors: Increase in siponimod exposure; concomitant use of MAYZENT with moderate CYP2C9 and moderate or strong CYP3A4 inhibitors is not recommended. (7.5)
- 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.
Revised: 8/2023
Full Prescribing Information
1. Indications and Usage for 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.
2. Mayzent Dosage and Administration
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 (5.3)].
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)].
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 (5.6)].
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)].
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)].
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)].
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.
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)]
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)].
3. Dosage Forms and Strengths
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.
4. Contraindications
MAYZENT is contraindicated in patients who have:
- A CYP2C9*3/*3 genotype [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.5)]
- In the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
- Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker [see Warnings and Precautions (5.4)]
5. Warnings and Precautions
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)].
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. The majority of cases of PML associated with S1P receptor modulators, including MAYZENT, have occurred in patients treated for at least 2 years. The relationship between the risk of PML and the duration of treatment is unknown.
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.
5.3 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% 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.
5.4 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 3-4 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 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)].
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 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 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 FEV1 were similar in this subgroup compared with the overall population. Spirometric evaluation of respiratory function should be performed during therapy with MAYZENT if clinically indicated.
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.
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 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. Cases of other cutaneous malignancies, including melanoma, have also been reported in patients treated with MAYZENT and in patients treated with another S1P modulator [see Adverse Reactions (6.1)].
Skin examinations are recommended at 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.
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.
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.
5.10 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.
5.11 Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies
When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation, when initiating MAYZENT.
Initiating treatment with MAYZENT after treatment with alemtuzumab is not recommended [see Drug Interactions (7.1)].
5.12 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.
After stopping MAYZENT in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS) [see Warnings and Precautions (5.2)].
5.13 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.
Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy [see Clinical Pharmacology (12.2)]. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore caution should be applied 3 to 4 weeks after the last dose of MAYZENT [see Drug Interactions (7.1)].
6. Adverse Reactions/Side Effects
The following serious adverse reactions are described elsewhere in the labeling:
- Infections [see Warnings and Precautions (5.1)]
- Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.2)]
- Macular Edema [see Warnings and Precautions (5.3)]
- Bradyarrhythmia and Atrioventricular Conduction Delays [see Warnings and Precautions (5.4)]
- Respiratory Effects [see Warnings and Precautions (5.5)]
- Liver Injury [see Warnings and Precautions (5.6)]
- Cutaneous Malignancies [see Warnings and Precautions (5.7)]
- Increased Blood Pressure [see Warnings and Precautions (5.8)]
- Fetal Risk [see Warnings and Precautions (5.9)]
- Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.10)]
- Unintended Additive Immunosuppressive Effects From Prior Treatment With Immunosuppressive or Immune-Modulating Therapies [see Warnings and Precautions (5.11)]
- Severe Increase in Disability After Stopping MAYZENT [see Warnings and Precautions (5.12)]
- Immune System Effects After Stopping MAYZENT [see Warnings and Precautions (5.13)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 1737 MS patients have received MAYZENT at doses of at least 2 mg daily. These patients were included in Study 1 [see Clinical Studies (14)] and in a Phase 2 placebo-controlled study in patients with MS. In Study 1, 67% of MAYZENT-treated patients completed the double-blind part of the study, compared to 59.0% of patients receiving placebo. Adverse events led to discontinuation of treatment in 8.5% of MAYZENT-treated patients, compared to 5.1% of patients receiving placebo. The most common adverse reactions (incidence at least 10%) in MAYZENT-treated patients in Study 1 were headache, hypertension, and transaminase increases.
Table 3 lists adverse reactions that occurred in at least 5% of MAYZENT-treated patients and at a rate at least 1% higher than in patients receiving placebo.
Terms were combined as follows: aheadache, tension headache, sinus headache, cervicogenic headache, drug withdrawal headache, and procedural headache. bhypertension, blood pressure increased, blood pressure systolic increased, essential hypertension, blood pressure diastolic increased. calanine aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, liver function test increased, hepatic function abnormal, liver function test abnormal, transaminases increased. dedema peripheral, joint swelling, fluid retention, swelling face. ebradycardia, sinus bradycardia, heart rate decreased. fpain in extremity and limb discomfort. |
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Adverse reaction | MAYZENT 2 mg (N = 1099) % | Placebo (N = 546) % |
Headachea | 15 | 14 |
Hypertensionb | 13 | 9 |
Transaminase increasedc | 11 | 3 |
Falls | 11 | 10 |
Edema peripherald | 8 | 4 |
Nausea | 7 | 4 |
Dizziness | 7 | 5 |
Diarrhea | 6 | 4 |
Bradycardiae | 6 | 3 |
Pain in extremityf | 6 | 4 |
The following adverse reactions have occurred in less than 5% of MAYZENT-treated patients but at a rate at least 1% higher than in patients receiving placebo: herpes zoster, lymphopenia, seizure, tremor, macular edema, AV block (1st and 2nd degree), asthenia, and pulmonary function test decreased [see Warnings and Precautions (5.1, 5.3, 5.4, 5.5)].
Seizures
In Study 1, cases of seizures were reported in 1.7% of MAYZENT-treated patients, compared to 0.4% in patients receiving placebo. It is not known whether these events were related to the effects of MS, to MAYZENT, or to a combination of both.
Respiratory Effects
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with MAYZENT [see Warnings and Precautions (5.5)].
Vascular Events
Vascular events, including ischemic strokes, pulmonary embolisms, and myocardial infarctions, were reported in 3.0% of MAYZENT-treated patients compared to 2.6% of patients receiving placebo. Some of these events were fatal. Physicians and patients should remain alert for the development of vascular events throughout treatment, even in the absence of previous vascular symptoms. Patients should be informed about the symptoms of cardiac or cerebral ischemia caused by vascular events and the steps to take if they occur.
Malignancies
Malignancies, such as basal cell carcinoma, squamous cell carcinoma, malignant melanoma, and seminoma were reported in MAYZENT-treated patients in Study 1 (in the core or extension parts). An increased risk of cutaneous malignancies has been reported in association with S1P modulators. The risk of basal cell carcinoma and squamous cell carcinoma is increased in MAYZENT-treated patients [see Warnings and Precautions (5.7)].
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of MAYZENT. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections and Infestations: Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)].
7. Drug Interactions
7.1 Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies
MAYZENT has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during such therapy and in the weeks following administration [see Warnings and Precautions (5.1)].
When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects [see Warnings and Precautions (5.11)].
Because of the characteristics and duration of alemtuzumab immune suppressive effects, initiating treatment with MAYZENT after alemtuzumab is not recommended.
MAYZENT can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
7.2 Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs That May Decrease Heart Rate
MAYZENT has not been studied in patients taking QT prolonging drugs.
Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with MAYZENT is considered, advice from a cardiologist should be sought.
Because of the potential additive effects on heart rate, treatment with MAYZENT should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin) [see Warnings and Precautions (5.4) and Drug Interactions (7.3)]. If treatment with MAYZENT is considered, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.
7.3 Beta-Blockers
Caution should be applied when MAYZENT is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of MAYZENT [see Warnings and Precautions (5.4)]. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT [see Clinical Pharmacology (12.2)].
7.4 Vaccination
During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective [see Warnings and Precautions (5.1)].
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 [see Warnings and Precautions (5.1)].
7.5 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.
Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inhibitors.
7.6 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.
Caution should be exercised for concomitant use of MAYZENT with moderate CYP2C9 inducers.
Concomitant use of MAYZENT and moderate (e.g., modafinil, efavirenz) or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 or *2/*3 genotype [see Clinical Pharmacology (12.3)].
8. Use In Specific Populations
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to MAYZENT during pregnancy. Healthcare providers are encouraged to enroll pregnant patients, or pregnant women may register themselves in the MotherToBaby Pregnancy Study in Multiple Sclerosis by calling 1-877-311-8972, sending an email to [email protected], or visiting www.mothertobaby.org/join-study.
Risk Summary
There are no adequate data on the developmental risk associated with the use of MAYZENT in pregnant women. Based on animal data and its mechanism of action, MAYZENT can cause fetal harm when administered to a pregnant woman (see Data). Reproductive and developmental studies in pregnant rats and rabbits have demonstrated MAYZENT-induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital, and skeletal) in rat and of embryo-fetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod starting at a dose 2 times the exposure in humans at the highest recommended dose of 2 mg/day.
In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data
Animal Data
When siponimod (0, 1, 5, or 40 mg/kg) was orally administered to pregnant rats during the period of organogenesis, post-implantation loss and fetal malformations (visceral and skeletal) were increased at the lowest dose tested, the only dose with fetuses available for evaluation. A no-effect dose for adverse effects on embryo-fetal development in rats was not identified. Plasma exposure AUC at the lowest dose tested was approximately 18 times that in humans at 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.
8.2 Lactation
Risk Summary
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.
8.3 Females and Males of Reproductive Potential
Contraception
Females
Before initiation of MAYZENT treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with MAYZENT [see Use in Specific Populations (8.1)]. Since it takes approximately 10 days to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period [see Warnings and Precautions (5.9)].
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Juvenile Animal Toxicity Data
Oral administration of siponimod (0, 5, 15, or 50 mg/kg/day) to young rats from postnatal day 25 to day 70 resulted in mortality, lung histopathology (alveolar/interstitial edema, fibrin, interstitial mixed cell infiltration) and decrease in body weight gain at the mid and high doses. Neurobehavioral impairment (decreased acoustic startle response) was observed at the high dose but was reversible by the end of the recovery period. Decrease in immune function (T-cell dependent antibody response) was observed at all doses and had not fully recovered by 4 weeks after the end of dosing. A no-effect dose for adverse effects in juvenile animals was not identified.
8.5 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.
8.6 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) because of substantially elevated siponimod plasma levels. The *3/*3 genotype is present in approximately 0.5% of white patients and 1% of Asian patients, and is less prevalent in other racial/ethnic groups.
MAYZENT dosage adjustment is recommended in patients with CYP2C9*1/*3 or *2/*3 genotype because of an increase in exposure to siponimod [see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)]. The *1/*3 or *2/*3 genotypes are present in 2% to 20% of the population depending on ancestry.
There are other less frequently occurring polymorphisms in CYP2C9. Some polymorphisms, such as *5, *6, *8, and *11, are associated with decreased or loss of enzyme function. The impact of variants other than *2 and *3 on the pharmacokinetics of siponimod has not been evaluated. It is anticipated that variants that result in loss of CYP2C9 function (e.g., *6) will have similar effects on siponimod pharmacokinetics as the *3 variant [see Dosage and Administration (2.3) and Clinical Pharmacology (12.5)].
10. Overdosage
In patients with overdosage of MAYZENT, it is important to observe for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should be performed [see Warnings and Precautions (5.4, 5.8) and Clinical Pharmacology (12.2)].
There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body. The decrease in heart rate induced by MAYZENT can be reversed by atropine or isoprenaline.
11. Mayzent Description
MAYZENT tablets contains siponimod, an S1P receptor modulator, as 2:1 co-crystal of siponimod and fumaric acid and has the following chemical name:
1-[[4-[(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.
Its structure is shown below:
It is a white to almost white powder.
MAYZENT is provided as 0.25 mg, 1 mg, and 2 mg film-coated tablets for oral use. Each tablet contains 0.25 mg, 1 mg, or 2 mg siponimod, equivalent to 0.28 mg, 1.11 mg, or 2.22 mg as 2:1 co-crystal of siponimod and fumaric acid, respectively.
MAYZENT tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, glyceryl dibehenate, lactose monohydrate, microcrystalline cellulose, with a film coating containing iron oxides (black and red iron oxides for the 0.25 mg and 1 mg strengths and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
16. How is Mayzent supplied
16.1 How Supplied
MAYZENT film-coated tablets are supplied as follows:
0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘T’ on other side.
Starter Pack for 1-mg maintenance dosage – blister card of seven 0.25 mg tablets in a calendarized blister wallet.....NDC 0078-0979-89
Starter Pack for 2-mg maintenance dosage – blister card of twelve 0.25 mg tablets in a calendarized blister wallet.....NDC 0078-0979-12
Bottle of 28 tablets.....NDC 0078-0979-50
1 mg tablet: Violet white, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘L’ on other side.
Bottle of 30 tablets.....NDC 0078-1014-15
2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with on one side and ‘II’ on other side.
Bottle of 30 tablets.....NDC 0078-0986-15
Bottle of 15 tablets.....NDC 0078-0986-45
16.2 Storage and Handling
Unopened Containers
Store MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F). After pharmacy dispensing to patient, MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months.
Opened Containers
Bottles
MAYZENT 0.25 mg, 1 mg, and 2 mg film-coated tablets may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 3 months. Do not 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.
MAYZENT
siponimod tablet, film coated |
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MAYZENT
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MAYZENT
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Labeler - Novartis Pharmaceuticals Corporation (002147023) |