Mayzent

Infections

• Obtain a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) before initiating treatment. 

• Delay initiatiing treatment in patients with severe active infection until resolution. Residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after discontinuation of Mayzent, so vigilance for infection should be continued throughout this period.

• Cryptococcal Infections:

• Be alert for clinical symptoms or signs of cryptococcal meningitis (CM), which may be fatal. Perform prompt diagnostic evaluation and treatment in patients with symptoms or signs consistent with a cryptococcal infection. 

• Suspend Mayzent treatment if CM is suspended until a cryptococcal infection has been excluded. Appropriate treatment should be initiated if CM is diagnosed.

• Herpes Viral Infections:

• Test for VZV antibodies before initiating treatment in patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV.

• Progressive Multifocal Leukoencephalopathy (PML):

• Be alert for clinical symptoms or magnetic resonance imaging (MRI) findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. 

• Suspend treatment if PML is suspected until PML has been excluded.

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

• Use caution with anti-neoplastic, immune-modulating, or immunosuppressive therapies (including corticosteroids) because of the risk of additive immune system effects during such therapy.

• Vaccinations:

• Test for VZV antibodies before initiating treatment in patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against VZV.

• A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to initiating 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.

• Avoid use of live-attenuated vaccines during and for 4 weeks after stopping treatment.

Macular Edema

• Perform ophthalmic evaluation of the fundus, including the macula, in all patients before starting treatment and at any time if there is any change in vision during treatment. 

• Continuation of Mayzent therapy in patients with macular edema has not been evaluated. Assess potential benefits and risks on whether or not to discontinue Gilenya therapy. 

• Increased risk of macular edema during Mayzent therapy in patients with a history of uveitis and patients with diabetes mellitus. MS patients with diabetes mellitus or a history of uveitis should have regular follow-up examinations prior to treatment, in addition to the examination of the fundus, including the macula.  

Bradyarrhythmia and Atrioventricular Conduction Delays

• 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

• 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. 

• Atrioventricular Conduction Delays 

• 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 antiarrhythmic drugs

• 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 

• 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.

• If not contraindicated, ECF testing and first-dose monitoring is recommended 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. 

• Not recommended for use in patients with a history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea. 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.

• Evaluate overall benefit-risk assessment in patients with a history of recurrent syncope or symptomatic bradycardia. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.

• Limited data available for the use of Mayzent 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 >50 bpm under chronic beta-blocker treatment, Mayzent can be introduced. If resting heart rate is ≤50 bpm, beta-blocker treatment should be interrupted until the baseline heart rate is >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.

    • 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.

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. There is insufficient information to determine the reversibility of the decrease in FEV1 after drug discontinuation. 

• 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. 

• Perform spirometric evaluation of respiratory function during therapy if clinically indicated.

Liver Injury

• Recent (i.e., within last 6 months) transaminase and bilirubin levels should be reviewed before initiation of Mayzent therapy.

• Check liver enzymes in 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. 

• Discontinue treatment if significant liver injury is confirmed.

• Use caution when using Mayzent in patients with a history of significant liver disease. There are no data to establish that patients with preexisting liver disease are at increased risk. 

Cutaneous Malignancies

• Increased risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma).

• Skin examinations are recommended at the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. 

• Monitor for suspicious skin lesions. Promptly evaluate if a suspicious skin lesion is observed.

• Limit exposure to sunlight and ultraviolet (UV) light by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy is not recommended in patients taking Mayzent.

Increased Blood Pressure

• Monitor blood pressure and manage appropriately during treatment. 

Fetal Risk

• Advise women of childbearing potential to use effective contraception to avoid pregnancy during and for 10 days after stopping Mayzent treatment.

Posterior Reversible Encephalopathy Syndrome (PRES)

• Promptly schedule a complete physical and neurological examination and should consider an MRI if a Mayzent-treated patient develops 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.

• 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. 

• Discontinue treatment if PRES is suspected.

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. 

• Not recommended to initiate treatment with Mayzent after treatment with alemtuzumab. 

Severe Increase in Disability After Stopping Mayzent

• The possibility of severe exacerbation of disease should be considered after stopping Mayzent treatment. Observe for a severe increase in disability upon Mayzent discontinuation and appropriate treatment should be instituted, as required.

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. Use of immunosuppressants within this period may lead to an additive effect on the immune system. 

• Use caution for 3 to 4 weeks after the last dose of Mayzent.