ience has not identified differences in responsesbetween the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflectingthe 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 iscontraindicated 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 tosiponimod [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 mayinclude overnight monitoring. Regular measurements of pulse rate and blood pressure are required, and ECGs should beperformed [see Warnings and Precautions (5.3, 5.6) and Clinical Pharmacology (12.2)].
There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningfulremoval of siponimod from the body. The decrease in heart rate induced by MAYZENT can be reversed by atropine orisoprenaline.
11 DESCRIPTION
MAYZENT tablets contains siponimod, a sphingosine 1-phosphate receptor modulator, as 2:1 co-crystal of siponimodand 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 and 2 mg film-coated tablets for oral use. Each tablet contains 0.25 mg or 2 mgsiponimod, 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 forthe 0.25 mg strength and red and yellow iron oxides for the 2 mg strength), lecithin (soy), polyvinyl alcohol, talc, titaniumdioxide, and xanthan gum.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes inperipheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but mayinvolve reduction of lymphocyte migration into the central nervous system.
12.2 Pharmacodynamics
Immune System
MAYZENT induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose,caused by the reversible sequestration of lymphocytes in lymphoid tissues.
With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocytecount of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9* |
