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MAYZENT®
(siponimod) Tablets
MAYZENT tablets contains siponimod, a sphingosine 1-phosphate 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]-3azetidinecarboxylic 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:
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It is a white to almost white powder.
MAYZENT is provided as 0.25 mg and 2 mg film-coated tablets for oral use. Each tablet contains 0.25 mg or 2 mg siponimod, equivalent to 0.28 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 behenate, lactose monohydrate, microcrystalline cellulose, with a film coating containing iron oxides (black and red iron oxides for the 0.25 mg strength and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
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.
Before initiation of treatment with MAYZENT, assess the following:
Test patients for CYP2C9 variants to determine CYP2C9 genotype [see Recommended Dosage in Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2 and Recommended Dosage in Patients With CYP2C9 Genotypes *1/*3 or *2/*3, CONTRAINDICATIONS, and Use In Specific Populations]. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.
Review results of a recent complete blood count (CBC) [see WARNINGS AND PRECAUTIONS].
Obtain an evaluation of the fundus, including the macula [see WARNINGS AND PRECAUTIONS].
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 First Dose Monitoring in Patients With Certain Preexisting Cardiac Conditions and WARNINGS AND PRECAUTIONS].
Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see DRUG INTERACTIONS].
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 and DRUG INTERACTIONS].
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].
Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels [see WARNINGS AND PRECAUTIONS].
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 Recommended Dosage in Patients With CYP2C9 Genotypes *1/*3 or *2/*3].
Initiate MAYZENT with a 5-day titration, as shown in Table 1 [see WARNINGS AND PRECAUTIONS]. A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage [see HOW SUPPLIED/Storage And Handling].
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.
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.
Initiate MAYZENT with a 4-day titration, as shown in Table 2 [see WARNINGS AND PRECAUTIONS and Use In Specific  Populations]. Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.
Table 2 : Dose Titration Regimen to Reach MAYZENT 1 mg
Maintenance Dosage
| 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.
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 and CLINICAL PHARMACOLOGY].
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.
If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves:
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:
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]; also complete first-dose monitoring in patients for whom it is recommended [see DOSAGE AND ADMINISTRATION].
0.25 mg tablet: Pale red, unscored, round biconvex film-coated tablet with beveled edges, debossed with logo on one side & Â 'T' on other side.
2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with logo on one side & 'II' on other side.
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 logo on one side and 'T' on other side.
Starter Pack* – blister card of twelve 0.25 mg tablets in a calendarized blister wallet ......... NDC 0078-0979-12
*This starter pack is only intended for patients who will receive the 2 mg maintenance dosage.
Bottle of 28 tablets ......... NDC 0078-0979-50
2 mg tablet: Pale yellow, unscored, round biconvex film-coated tablet with beveled edges, debossed with logo on one side and 'II' on other side.
Bottle of 30 tablets ......... NDC 0078-0986-15
Store unopened containers of MAYZENT 0.25 mg and 2 mg film-coated tablets in a refrigerator between 2°C to 8°C (36°F to 46°F).
Store opened containers of MAYZENT as follows:
Starter Pack/Blister Card
MAYZENT 0.25 mg film-coated tablets in the Starter Pack may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 1 week after opening the blister. Store in original container.
Bottles
MAYZENT 0.25 mg and 2 mg film-coated tablets in bottles may be stored at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature] for up to 1 month after opening the bottles.
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: Mar 2019
The following serious adverse reactions are described elsewhere in labeling:
Because clinical trials are conducted under widely varying conditions, adverse reactions 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] 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.
Table 3 : Adverse Reactions Reported in Study 1
(Occurring in at Least 5% of MAYZENT-Treated Patients and at a Rate at Least 1%
Higher Than in Patients Receiving Placebo)
| 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 |
| P ain in extremityf | 6 | 4 |
| Terms were combined as follows: a headache,tensionheadache,sinusheadache,cervicogenicheadache,drugwithdrawal headache,andproceduralheadache b hypertension,bloodpressureincreased,blood pressuresystolicincreased, essentialhypertension,bloodpressurediastolic increased c alanine aminotransferase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, aspartateaminotransferase increased, bloodalkaline phosphataseincreased,liverfunctiontest increased,hepaticfunctionabnormal, liverfunctiontestabnormal, transaminases increased d edema peripheral, joint swelling, fluid retention, swelling face e bradycardia, sinus bradycardia, heart rate decreased f pain in extremity and limb discomfort |
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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].
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.
Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) were observed in patients treated with MAYZENT [see WARNINGS AND PRECAUTIONS].
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 such as malignant melanoma in situ and seminoma were reported in MAYZENT-treated patients in Study 1. An increased risk of cutaneous malignancies has been reported in association with another S1P modulator.
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].
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].
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.
MAYZENT has not been studied in patients taking QT prolonging drugs.
Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic 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 and DRUG INTERACTIONS]. 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.
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]. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT [see CLINICAL PHARMACOLOGY].
During and for up to one month after discontinuation of treatment with MAYZENT, vaccinations may be less effective; therefore MAYZENT treatment should be paused 1 week prior and for 4 weeks after vaccination [see WARNINGS AND PRECAUTIONS].
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].
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.
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 and*2/*3 genotype [see CLINICAL PHARMACOLOGY].
Included as part of the PRECAUTIONS section.
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]. Life-threatening and rare fatal infections have occurred in association with MAYZENT.
In Study 1 [see Clinical Studies], 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 Immune System Effects After Stopping MAYZENT].
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 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.
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].
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].
Vaccinations may be less effective if administered during MAYZENT treatment. MAYZENT treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended.
Macular edema 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.
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.
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 and CLINICAL PHARMACOLOGY].
MAYZENT was not studied in patients who had:
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]. Heart rates below 40 bpm were rarely observed.
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:
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].
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.
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.
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.
Based on animal studies, MAYZENT may cause fetal harm [see Use In Specific Populations]. 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.
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate (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 a 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.
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].
Severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a 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 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 ]. However, residual pharmacodynamics effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3-4 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 3-4 weeks after the last dose of MAYZENT [see DRUG INTERACTIONS].
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Tell patients not to discontinue MAYZENT without first discussing this with the prescribing physician. Advise patients to contact their physician if they accidently take more MAYZENT than prescribed.
Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking MAYZENT, and that they should contact their physician if they develop symptoms of infection [see WARNINGS AND PRECAUTIONS]. Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment with MAYZENT and MAYZENT should be paused 1 week prior and until 4 weeks after a planned vaccination. Recommend that patients postpone treatment with MAYZENT for at least 1 month after VZV vaccination. Inform patients that prior or concomitant use of drugs that suppress the immune system may increase the risk of infection.
Advise patients that MAYZENT may cause macular edema, and that they should contact their physician if they experience any changes in their vision while taking MAYZENT [see WARNINGS AND PRECAUTIONS]. Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.
Advise patients that initiation of MAYZENT treatment results in transient decrease in heart rate [see WARNINGS AND PRECAUTIONS]. Inform patients that to reduce this effect, dosage titration is required. Advise patients that dosage titration is also required if a dose is missed for more than 24 hours during the titration or if 4 or more consecutive daily maintenance doses are missed [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Inform certain patients with certain pre-existing cardiac conditions that they will need to be observed in the doctor's office or other facility for at least 6 hours after the first dose and after reinitiation if treatment is interrupted or discontinued for certain periods [see DOSAGE AND ADMINISTRATION].
Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea [see WARNINGS AND PRECAUTIONS].
Inform patients that MAYZENT may increase liver enzymes. Advise patient that they should contact their physician if they experience any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment [see WARNINGS AND PRECAUTIONS].
Inform patients that, based on animal studies MAYZENT may cause fetal harm [see WARNINGS AND PRECAUTIONS]. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Advise women of childbearing potential of the need for effective contraception during treatment with MAYZENT and for 10 days after stopping MAYZENT. Advise a female patient to immediately inform that prescriber if she is pregnant or planning to become pregnant [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Advise patients to immediately report to their healthcare provider any symptoms involving sudden onset of severe headache, altered mental status, visual disturbances, or seizure. Inform patients that delayed treatment could lead to permanent neurological sequelae [see WARNINGS AND PRECAUTIONS].
Inform patients that severe increase in disability has been reported after discontinuation of another sphingosine 1phosphate (S1P) receptor modulator like MAYZENT. Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of MAYZENT [see WARNINGS AND PRECAUTIONS].
Advise patients that MAYZENT continues to have effects, such as lowering effects on peripheral lymphocyte count, for up to 3-4 weeks after the last dose [see WARNINGS AND PRECAUTIONS].
Instruct patients to store any unopened containers of MAYZENT in a refrigerator. Inform patients that opened starter packs may be stored at room temperature for 1 week and opened bottles may be stored at room temperature for 1 month [see HOW SUPPLIED/Storage And Handling].
Oral carcinogenicity studies of spinomod were conducted in mice and rats. In mice administered siponimod (0, 2, 8, or 25 mg/kg/day) for up to 104 weeks, there was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day, on a body surface area (mg/m²) basis.
In rats, administration of siponimod (0, 10, 30, or 90 mg/kg/day in males; 0, 3, 10, or 30 mg/kg/day in females) for up to 104 weeks, there was an increase in thyroid follicular cell adenoma and combined thyroid follicular cell adenoma and carcinoma in males at the highest dose tested. These findings are considered secondary to liver enzyme induction in rats and are not considered relevant to humans. Plasma siponimod exposure (AUC) at the highest dose tested is approximately 200 times that in humans at the RHD.
Siponimod was negative in a battery of in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays.
When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) prior to and throughout the mating period, there was a dose-related increase in precoital interval at all doses. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were observed at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the RHD on a mg/m² basis.
When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were observed up to the highest dose tested (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose tested is approximately 16 times that in humans at the RHD.
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 embryofetal 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%-4% and 15%-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
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 embryofetal 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 embryofetal development in rabbits is less that than 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 preand 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.
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.
Females
Before initiation of MAYZENT treatment, women of childbearing potential should be counselled 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]. 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].
Safety and effectiveness in pediatric patients have not been established.
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.
Before initiation of treatment with MAYZENT, test patients to determine CYP2C9 genotype. MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype), which is approximately 0.4%0.5% of Caucasians and less in others, because of substantially elevated siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype because of an increase in exposure to siponimod [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
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 and CLINICAL PHARMACOLOGY].
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.
MAYZENT is contraindicated in patients who have:
MAYZENT
(Ma zent) (siponimod) tablets, for oral use
What is the most important information I should know about MAYZENT?
1. MAYZENT may cause serious side effects, including: Slow heart rate (bradycardia or bradyarrhythmia) when you start taking MAYZENT. MAYZENT can cause your heart rate to slow down, especially after you take your first dose. You should have a test to check the electrical activity of your heart called an electrocardiogram (ECG) before you take your first dose of MAYZENT.
During the initial updosing period (4 days for the 1 mg daily dose or 5 days for the 2 mg daily dose), if you miss 1 or more doses of MAYZENT, you need to restart the updosing. Call your healthcare provider if you miss a dose of MAYZENT. See “How should I take MAYZENT?”
2. Infections. MAYZENT can increase your risk of serious infections that can be life-threatening and cause death. MAYZENT lowers the number of white blood cells (lymphocytes) in your blood. This will usually go back to normal within 3 to 4 weeks of stopping treatment. Your healthcare provider should review a recent blood test of your white blood cells before you start taking MAYZENT.
Call your healthcare provider right away if you have any of these symptoms of an infection during treatment with MAYZENT and for 3 to 4 weeks after your last dose of MAYZENT:
3. A problem with your vision called macular edema. Macular edema can cause some of the same vision symptoms as a multiple sclerosis (MS) attack (optic neuritis). You may not notice any symptoms with macular edema. If macular edema happens, it usually starts in the first 1 to 4 months after your start taking MAYZENT. Your healthcare provider should test your vision before you start taking MAYZENT and any time you notice vision changes during treatment with MAYZENT. Your risk of macular edema is higher if you have diabetes or have had an inflammation of your eye called uveitis.
Call your healthcare provider right away if you have any of the following:
See “What are possible side effects of MAYZENT?” for more information about side effects.
What is MAYZENT?
MAYZENT is a prescription medicine that is used to treat relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is not known if MAYZENT is safe and effective in children.
Who should not take MAYZENT?
Do not take MAYZENT if you:
What should I tell my healthcare provider before taking MAYZENT?
Before taking MAYZENT, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Especially tell your healthcare provider if you:
Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist when you get a new medicine.
Using MAYZENT and other medicines together may affect each other causing serious side effects.
How should I take MAYZENT?
The daily maintenance dose of MAYZENT is either 1 mg or 2 mg, depending on your CYP2C9 genotype. Ask your healthcare provider if you are not sure about your daily maintenance dose.
Start your treatment with MAYZENT using the following titration schedule:
| For the 1 mg daily maintenance dose: | Tablets a day |
| Day 1 | 1 x 0.25 mg tablet |
| Day 2 | 1 x 0.25 mg tablet |
| Day 3 | 2 x 0.25 mg tablets |
| Day 4 | 3 x 0.25 mg tablets |
| Day 5 and every day after | 4 x 0.25 mg tablets |
| For the 2 mg daily maintenance dose, use the starter pack: | Tablets a day |
| Day 1 | 1 x 0.25 mg tablet |
| Day 2 | 1 x 0.25 mg tablet |
| Day 3 | 2 x 0.25 mg tablets |
| Day 4 | 3 x 0.25 mg tablets |
| Day 5 | 5 x 0.25 mg tablets |
| Day 6 and every day after | 1 x 2 mg tablet |
What are the possible side effects of MAYZENT?
MAYZENT may cause serious side effects, including:
The most common side effects of MAYZENT include:
Tell your healthcare provider if you have any side effects that bother you or that do not go away.
These are not all of the possible side effects of MAYZENT. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store MAYZENT?
Before opening:
After opening:
Keep MAYZENT and all medicines out of the reach of children.
General information about the safe and effective use of MAYZENT
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use MAYZENT for a condition for which it was not prescribed. Do not give MAYZENT to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for more information about MAYZENT that is written for health professionals.
What are the ingredients in MAYZENT?
Active ingredient: siponimod
Inactive ingredients: colloidal silicon dioxide, crospovidone, glyceryl behenate, lactose monohydrate, microcrystalline cellulose, with a film coating containing iron oxides (black and red iron oxides for the 0.25 mg strength and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titanium dioxide, and xanthan gum.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
