DRUG INTERACTIONS

­ • Vaccines: Avoid live attenuated vaccines during and for up to 4 weeks after treatment with MAYZENT 

• CYP2C9 and CYP3A4 Inhibitors: Increase in siponimod exposure; concomitant use of MAYZENT with moderate CYP2C9 and moderate or strong CYP3A4 inhibitors is not recommended 

• CYP2C9 and CYP3A4 Inducers: Decrease in siponimod exposure; concomitant use of MAYZENT with moderate CYP2C9 and strong CYP3A4 inducers is not recommended 

BRIEF SUMMARY

SIPONIMOD-(Mar 2019)

Indn-  To  treat adults with replasing froms of multiple sclerosis 

Comp-  Tablets: 0.25 mg and 2 mg   • 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 

CI- • Patients with a CYP2C9*3/*3 genotype 

WARNINGS-­ • Infections:  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.

Pat Inform-                                                                                                                   Risk of Infections-                                                                                                      Inform patients that they may have an increased risk of infections, some of which could be life-threatening, when taking the drug and that they should contact their physician if they develop symptoms of infection 

Advise patients that the use of some vaccines containing live virus (live attenuated vaccines) should be avoided during treatment should be paused 1 week prior and until 4 weeks after a planned vaccination.

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U.S. FDA APPROVED  DRUGS DURING 2019

Sr.No- 6

ADVERSE REACTIONS

 Most common adverse reactions (incidence greater than 10%) are headache, hypertension, and transaminase increases. 

CONTRAINDICATIONS

­ • Patients with a CYP2C9*3/*3 genotype 

• In the last 6 months, experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III/IV heart failure 

• Presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker 

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.

• 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.

• Bradarrhythmia 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 betablocker use; obtain cardiologist consultation before concomitant use with other drugs that decrease heart rate 

• Respiratory Effects: May cause a decline in pulmonary function. Assess pulmonary function (e.g., spirometry) if clinically indicated. 

• Liver Injury: Obtain liver enzyme results before initiation. Closely monitor patients with severe hepatic impairment. Discontinue if significant liver injury occurs.

• Increased Blood Pressure (BP): Monitor BP during treatment. 

• Fetal Risk: Women of childbearing potential should use effective contraception during and for 10 days after stopping MAYZENT. 

PATIENT COUNSELING INFORMATION

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.

Risk of Infections-                                                                                                      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 

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.

Macular Edema-                                                                                                         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 

Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased.

Cardiac Effects                                                                                                         Advise patients that initiation of MAYZENT treatment results in transient decrease in heart rate

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

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 

Respiratory Effects                                                                                                  Advise patients that they should contact their physician if they experience new onset or worsening of dyspnea 

Liver Injury                                                                                                                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 

Pregnancy and Fetal Risk                                                                                       Inform patients that, based on animal studies MAYZENT may cause fetal harm

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 

Posterior Reversible Encephalopathy Syndrome                                                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 

Severe Increase in Disability After Stopping MAYZENT                                            Inform patients that severe increase in disability has been reported after discontinuation of another sphingosine 1­ phosphate (S1P) receptor modulator like MAYZENT.

Advise patients to contact their physician if they develop worsening symptoms of MS following discontinuation of MAYZENT 

After Stopping MAYZENT                                                                                        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 

Storage and Handling                                                                                            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 

 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 MAYZENT is a trademark of Novartis AG

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.

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                   Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in Reference ID: 4409346 12 peripheral blood.

The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

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) lymphocyte count of approximately 0.560 (0.271-1.08) cells/nL in a typical CYP2C9*1/*1 or *1/*2, non-Japanese patient, corresponding to 20% to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing

Lymphocyte counts returned to the normal range in 90% of patients within 10 days of stopping therapy. After stopping MAYZENT treatment, residual lowering effects on peripheral lymphocyte count may persist for up to 3-4 weeks after the last dose

Heart Rate and Rhythm- MAYZENT causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation.

The maximum decline in heart rate is seen in the first 6 hours post dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by siponimod treatment. 

Pulmonary Function- Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in MAYZENT-treated patients and were greater than in patients taking placebo

3. Pharmacokinetics Siponimod concentration increases in an apparent dose-proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg. Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing, and steady-state levels are approximately 2-3-fold greater than the initial dose.

Siponimod absorption is extensive (greater than or equal to 70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated to infinity).

The absolute oral bioavailability of siponimod is approximately 84%. After administration of siponimod 2 mg once-daily over 10 days, a mean Cmax of 30.4 ng/mL and mean area under plasma concentration-time curve over dosing interval (AUCtau) of 558 h*ng/mL were observed on day 10.

Steady-state was reached after approximately 6 days of once daily administration of siponimod.

Food Effect Food intake resulted in delayed absorption (the median Tmax increased by approximately 2-3 hours). Food intake had no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, MAYZENT may be taken without regard to meals.

Distribution                                                                                                             Siponimod distributes to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found in plasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding of siponimod is greater than 99.9% in healthy subjects and in hepatic and renal impaired patients.

Elimination Metabolism                                                                                              Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.

Excretion An apparent systemic clearance (CL/F) of 3.11 L/h was estimated in MS patients. The apparent elimination half-life is approximately 30 hours. Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine.

Specific Populations Male and Female Patients                                                     Gender has no influence on siponimod pharmacokinetics (PK). Racial or Ethnic Groups The single-dose PK parameters were not different between Japanese and Caucasians healthy subjects, indicating absence of ethnic sensitivity on the PK of siponimod.

Patients with Renal Impairment                                                                                   No dose adjustments are needed in patients with renal impairment. Mean siponimod half-life and Cmax (total and unbound) were comparable between subjects with severe renal impairment and healthy subjects.

Patients with Hepatic Impairment                                                                                   No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod AUC parameters are 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied.

Drug Interaction Studies                                                                                     Siponimod (and Metabolites M3, M17) as a Causative Agent of Interaction In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once-daily for all investigated CYP enzymes and transporters.

Physiologically based PK modeling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.

Coadministration of Siponimod with CYP2C9 and CYP3A4 Inhibitors The coadministration of fluconazole (moderate CYP2C9 and CYP3A4 dual inhibitor) 200 mg daily at steady-state and a single dose of siponimod 4 mg in CYP2C9*1/*1 healthy volunteers led to a 2-fold increase in the AUC of siponimod.

Coadministration of Siponimod with CYP2C9 and CYP3A4 Inducers The coadministration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 dual inducer) decreased siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively in CY2C9*1/*1 subjects.

Oral Contraceptives The effects of coadministration of siponimod 2 mg and 4 mg (twice the recommended dosage) once daily with a monophasic oral contraceptive (OC) containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were assessed in 24 healthy female subjects (18 to 40 years of age; CYP2C9*1/*1 genotype).

 USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary                                                                                     There are no adequate data on the developmental risk associated with the use of MAYZENT in pregnant women.

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.

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.

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.

3 Females and Males of Reproductive Potential                                                  Contraception 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

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 

4.Pediatric Use                                                                                                                  Safety and effectiveness in pediatric patients have not been established.

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.

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.

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.