INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KIENDRA (KIENDRA)

Composition:

Active substance: siponimod;

One film-coated tablet contains 0.25 mg of siponimod (as siponimod fumarate);

One film-coated tablet contains 2 mg of siponimod (as siponimod fumarate);

Excipients: lactose monohydrate; microcrystalline cellulose, crospovidone, glycerol dibehenate, colloidal anhydrous silicon dioxide, polyvinyl alcohol, titanium dioxide (E 171), iron oxide yellow (E 172) – for 2 mg strength only, iron oxide red (E 172), iron oxide black (E 172) – for 0.25 mg strength only, talc, lecithin (E 322), xanthan gum.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

film-coated tablets, 0.25 mg: pale red, without a breakline, round, biconvex film-coated tablets with beveled edges, embossed with the logo « » on one side and «T» on the other;

film-coated tablets, 2 mg: pale yellow, without a breakline, round, biconvex film-coated tablets with beveled edges, embossed with the logo « » on one side and «II» on the other.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Selective immunosuppressants. ATC code L04A A42.

Pharmacological Properties

Pharmacodynamics

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod selectively binds to two of the five G-protein-coupled S1P receptors, specifically S1P\1 and S1P\5. As a functional antagonist of S1P\1 receptors on the surface of lymphocytes, siponimod inhibits their egress from lymph nodes. This leads to a reduction in the recirculation of T-lymphocytes into the central nervous system (CNS), thereby limiting CNS inflammation. Siponimod crosses the blood-brain barrier. Siponimod does not exert a prolonged effect on effector memory T-cells in peripheral tissues and blood and does not impair lymphocyte activation.

In animal studies, a direct effect of siponimod on neural cells has been demonstrated: via S1P\1 on astrocytes and via S1P\5 on oligodendrocytes. In a mouse model of experimental autoimmune encephalomyelitis, a direct neuroprotective effect of centrally administered siponimod (via intracerebroventricular infusion) was demonstrated, independent of its effects on lymphocytes.

Immune System

The medicinal product Mayzent causes a dose-dependent reduction in lymphocyte count in peripheral blood within 6 hours after the first dose, due to reversible sequestration of lymphocytes in lymphoid tissue.

With continued daily administration, lymphocyte counts continue to decline, reaching a median nadir (90% CI) of approximately 0.560 (0.271–1.08) cells/nL, which corresponds to 20–30% of baseline levels in typical non-Japanese patients with secondary progressive multiple sclerosis (SPMS) carrying the CYP2C9 *1*1 or *1*2 genotype. Low lymphocyte counts are maintained during prolonged daily treatment.

In the vast majority (90%) of SPMS patients, lymphocyte counts return to normal levels within 10 days after treatment discontinuation. The full effect of reduced peripheral lymphocyte count may persist for 3–4 weeks after the last dose of Mayzent.

Cardioelectrophysiology

Heart Rate and Rhythm

Initiation of Mayzent treatment causes a transient decrease in heart rate and atrioventricular conduction (see section "Adverse Reactions"), which is mechanistically related to activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels via S1P\1 receptor stimulation, resulting in cellular hyperpolarization and reduced excitability. Due to the functional antagonism of siponimod at S1P\1 receptors during initial dose titration, a sequential desensitization of GIRK channels occurs, which is observed before reaching the maintenance dose.

Potential for QT Interval Prolongation

The effect of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarization was evaluated in a dedicated QT study. Results did not confirm an arrhythmogenic potential related to QT interval prolongation, as mean placebo-corrected QTcF (ΔΔQTcF) adjusted for baseline increased by more than 5 ms at 3 hours post-dose, with a mean peak effect of 7.8 ms at the 2 mg dose and 7.2 ms at the 10 mg dose. The upper bound of the one-sided 95% confidence interval for ΔΔQTcF at all time points remained below 10 ms. Categorical analysis revealed no instances of QTc > 480 ms during treatment, no cases of QTc increase > 60 ms from baseline, and no occurrences of corrected or uncorrected QT/QTc > 500 ms.

Lung Function

Administration of single or multiple doses of Mayzent over 28 days was not associated with clinically significant increases in airway resistance, as assessed by FEV\1 and forced expiratory flow at 25–75% of forced vital capacity (MEF 25–75%). A single administration of a non-therapeutic dose (>10 mg) was associated with a minor tendency toward reduced FEV\1. Repeated dosing led to mild or moderate changes in FEV\1 and MEF 25–75%, regardless of dose level and time of day, without clinical signs of increased airway resistance.

Clinical Efficacy

The efficacy of Mayzent was evaluated in a Phase III dose assessment study with a 2 mg once-daily dose of Mayzent in patients with SPMS. A Phase II dose-ranging study in patients with relapsing-remitting multiple sclerosis (RRMS) demonstrated a dose-dependent reduction in inflammatory lesions on MRI, indicating that the 2 mg dose of Mayzent provides nearly maximal effect.

Study A2304 (EXPAND) in Patients with SPMS

Study A2304 was a randomized, double-blind, placebo-controlled, event- and duration-driven Phase III trial involving patients with SPMS who had documented evidence of disease progression within the prior 2 years, irrespective of relapses, with no evidence of relapse within the 3 months prior to enrollment, and with a median Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry.

The median baseline EDSS score was 6.0. Patients over the age of 61 years were not included in the study. Regarding disease activity, signs indicative of inflammatory activity in SPMS may include relapses or imaging findings (i.e., gadolinium [Gd]-enhancing lesions on T1-weighted images or active [new or enlarging] lesions on T2-weighted images).

Patients were randomized in a 2:1 ratio to receive either Mayzent 2 mg once daily or placebo. Clinical assessments were performed at screening, every 3 months, and during relapses. MRI assessments were conducted at screening and every 12 months.

The primary endpoint was time to 3-month confirmed disability progression (CDP), defined as an increase of at least 1 point from baseline EDSS score (0.5 points for patients with baseline EDSS of 5.5 or higher), sustained for 3 months. Key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the Timed 25-Foot Walk (T25W) and change in T2 lesion volume compared to baseline. Additional secondary endpoints included time to 6-month CDP, percent change in brain volume, and measures of inflammatory disease activity (annualized relapse rate; MRI-identified lesions). An exploratory endpoint was change in cognitive processing speed, assessed by the Symbol Digit Modalities Test (SDMT).

Study duration varied among individual patients (median study duration was 21 months, range from 1 day to 37 months).

A total of 1651 patients were randomized in the study: 1105 to Mayzent 2 mg and 546 to placebo. Eighty-two percent of patients receiving Mayzent and 78% of those receiving placebo completed the study. At study entry, the median age was 49 years, mean disease duration was 16 years, and mean EDSS score was 6.0. Sixty-four percent of patients had no relapses in the 2 years prior to study start, and 76% had no gadolinium (Gd)-enhancing lesions on baseline MRI. Seventy-eight percent of patients had prior disease-modifying therapy for MS.

Time to onset of 3-month and 6-month confirmed disability progression was significantly delayed with siponimod, with a 21% reduction in risk of 3-month CDP compared to placebo (hazard ratio [HR] 0.79, p = 0.0134) and a 26% reduction in risk of 6-month CDP compared to placebo (HR 0.74, p = 0.0058).

Results of this study are presented in Table 1 and Figures 1 and 2.

Table 1

Clinical and MRI Outcomes from Study A2304

Fig. 1. Patients with 3- and 6-month confirmed disability progression based on the Expanded Disability Status Scale – Kaplan-Meier curves (full analysis set, study A2304)

The study results demonstrated consistent risk reduction in 3- and 6-month CDP with KESIMENDA compared to placebo across subgroups defined by sex, age, prior multiple sclerosis therapy, relapse activity before study initiation, baseline MRI disease activity, disease duration, and baseline disability scores.

KESIMENDA showed a positive effect on the Symbol Digit Modalities Test (SDMT). Change from baseline was stable or improved with KESIMENDA and worsened with placebo, with significant differences between groups: 1.1 points at 12 months (p = 0.0132) and 2.3 points at 24 months (p = 0.0002).
In a pre-specified analysis, KESIMENDA reduced the risk of confirmed
4-point worsening in the SDMT at 6 months by 25% (p = 0.0163) compared to placebo.
A 4-point decline was considered clinically meaningful.

In the subgroup of patients (47.1%, n=779) with active disease (defined as patients with a relapse within 2 years prior to the study and/or presence of Gd-enhancing lesions on T1-weighted images at baseline), baseline characteristics were similar to those in the overall population. Median age at study initiation was 47 years, mean disease duration was 15 years, and mean EDSS score was 6.0 (see section "Pharmacokinetics"). Time to onset of 3-month and 6-month CDP was significantly delayed in patients with active disease receiving siponimod: by 31% compared to placebo (hazard ratio [HR] 0.69; 95% CI: 0.53, 0.91) and by 37% compared to placebo (HR 0.63; 95% CI: 0.47, 0.86), respectively. The rate of ARR (confirmed relapses) was reduced by 46% (ARR ratio 0.54; 95% CI: 0.39, 0.77) compared to placebo. The relative reduction in the total number of Gd-enhancing lesions on T1-weighted images over 24 months was 85% (risk ratio 0.155; 95% CI: 0.104, 0.231) compared to placebo. Differences in change of T2 lesion volume and percent change in brain volume (mean at 12 and 24 months) compared to placebo were -1163 mm³ (95% CI: -1484, -843 mm³) and 0.141% (95% CI: 0.020, 0.261%), respectively.

In the subgroup of patients (n=827) without evidence or symptoms of disease activity (defined as patients without relapse within 2 years prior to the study and without moderate enhancing lesions on contrast-enhanced T1-weighted images at baseline), the effect on 3-month and 6-month confirmed disability progression was minimal (risk reductions of 7% and 13%, respectively).

Fig. 2. Patients with confirmed 3- and 6-month disability progression based on the Expanded Disability Status Scale – Kaplan-Meier curves – subgroup with active inflammatory disease (full analysis set, study A2304)

Pharmacokinetics

Absorption

The time (Tmax) to reach maximum plasma concentration (Cmax) of siponimod after multiple oral doses is approximately 4 hours (range from 2 to 12 hours). Absolute bioavailability of siponimod following oral administration is about 84%. After administration of 2 mg siponimod once daily for 10 days, the mean Cmax on day 10 was 30.4 ng/mL, and the mean AUCtau was 558 h*ng/mL on day 10. Steady state was reached approximately 6 days after repeated once-daily dosing.

Food intake did not affect systemic exposure to siponimod (Cmax and AUC). Therefore, Kisimpta can be administered independently of food intake.

Distribution

Siponimod distributes into tissues, with a mean volume of distribution of 124 L. The fraction of siponimod in human plasma is 68%. Animal studies show that siponimod readily crosses the blood-brain barrier. The extent of binding of siponimod to plasma proteins in healthy volunteers and in patients with hepatic or renal impairment is >99.9%.

Metabolism

Siponimod is extensively metabolized, primarily by cytochrome CYP2C9 (79.3%) and to a lesser extent by CYP3A4 (18.5%).

The pharmacological activity of the major metabolites M3 and M17 is not expected to contribute to the clinical efficacy and safety of siponimod in humans.

Elimination

In patients with MS, estimated systemic clearance (CL/F) was 3.11 L/h. The pharmacokinetically relevant elimination half-life is approximately 30 hours.

Siponimod is eliminated from systemic circulation primarily via metabolism followed by biliary/fecal excretion. Approximately 86.7% of the siponimod dose is excreted in feces, of which 9.2% is unchanged. Only a small amount of the dose is excreted in urine (3.6%). Unchanged siponimod was not detected in urine.

Mean elimination half-lives of siponimod metabolites M17 and M3 after oral administration are approximately 155 hours and 30 hours, respectively.

Linearity/Non-linearity

Siponimod concentration increases proportionally with dose, as observed after multiple doses of siponimod ranging from 0.3 to 20 mg once daily.

Steady-state concentrations of siponimod are 2–3 times higher than after the first dose and are reached approximately 6 days after once-daily administration. A six-day titration phase is required to achieve the clinically therapeutic dose of 2 mg, followed by an additional 4 days of dosing to reach steady-state plasma concentrations.

Pharmacokinetics in Special Patient Populations

Genotype CYP2C9

CYP2C9 genotype has a significant impact on siponimod metabolism.

Treatment with Kisimpta is contraindicated in patients who are homozygous for the CYP2C9*3 allele (CYP2C9*3*3 genotype) (see sections "Contraindications", "Special warnings and precautions for use", and "Interaction with other medicinal products and other forms of interaction"). In these patients, use of Kisimpta results in a marked increase in plasma levels of siponimod. The recommended maintenance dose of Kisimpta is 1 mg daily for patients with CYP2C9*2*3 or *1*3 genotypes to avoid increased exposure to siponimod (see section "Dosage and administration").

Other, less common CYP2C9 polymorphisms exist. The pharmacokinetics of siponimod has not been evaluated in carriers of these genotypes. Some of these polymorphisms, including alleles *5, *6, *8, and *11, are also associated with reduced or loss of enzyme function (see also sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

After administration of a single 0.25 mg dose of siponimod, AUCinf and AUClast were approximately 2–4 times higher in patients with CYP2C9 *2*3 and *3*3 genotypes, respectively, although only a slight increase of 21% and 16%, respectively, was observed compared to extensive metabolizers (CYP2C9 *1*1). Mean elimination half-life was prolonged in carriers of the CYP2C9 *2*3 and *3*3 genotypes (51 hours and 126 hours, respectively).

Apparent systemic clearance (CL/F) of 3.11 L/h was estimated in extensive CYP2C9 metabolizers (CYP2C9 *1*1 and *1*2 genotypes) in patients with SPMS after multiple oral doses of siponimod. CL/F values were 2.5, 1.9, 1.6, and 0.9 L/h in patients with CYP2C9 *2*2, *1*3, *2*3, and *3*3 genotypes, respectively. The resulting increases in siponimod AUC were 25%, 61%, 91%, and 285% in patients with CYP2C9 *2*2, *1*3, *2*3, and *3*3 genotypes, respectively, compared to patients with the *1*1 genotype. Since apparent clearance estimated for patients with the *1*2 genotype was comparable to that in patients with the *1*1 genotype, a similar effect of siponimod is expected for both genotypes.

Patients with Renal Impairment

Dose adjustment of siponimod is not required in patients with mild, moderate, or severe renal impairment. Mean elimination half-life and Cmax values of siponimod (total and unbound) were comparable between patients with severe renal impairment and healthy subjects. Total and unbound AUC values were slightly increased (by 23–33%) compared to values in healthy subjects. The effect of end-stage renal disease or hemodialysis on siponimod pharmacokinetics has not been studied. Due to the high plasma protein binding of siponimod (>99.9%), hemodialysis is unlikely to alter concentrations of total and unbound siponimod; therefore, dose adjustment is not expected to be necessary.

Patients with Hepatic Impairment

Dose adjustment of siponimod is not required in patients with hepatic impairment. Unbound siponimod AUC values were 15–50% higher in patients with moderate and severe hepatic impairment compared to patients with normal liver function, following administration of the investigational dose of 0.25 mg. Mean elimination half-life of siponimod remained unchanged in patients with hepatic impairment.

Elderly Patients

Clinical studies included patients up to 61 years of age (see section "Dosage and administration").

Gender

Gender does not influence the pharmacokinetics of siponimod.

Race/Ethnic Group

Pharmacokinetic parameters of a single dose in Japanese patients and Caucasian patients did not differ, indicating no ethnic influence on siponimod pharmacokinetics.

Preclinical Safety Data

The preclinical safety profile of siponimod was evaluated in single- and repeat-dose toxicity studies in mice (up to 13 weeks), rats (up to 26 weeks), and monkeys (up to 52 weeks). Dose-limiting toxic effects included nephrotoxicity in mice, increased body weight in rats, and adverse effects on the CNS and gastrointestinal tract in monkeys. Major target organs of toxicity identified in histopathological evaluations in rodents were lungs, liver, thyroid gland, kidneys, and uterus/vagina. Effects on muscle and skin were observed in individual monkeys.

The NOAEL in rats was established at 50 mg/kg/day and 15 mg/kg/day for males and females, respectively, and at 10 mg/kg/day for both sexes in monkeys. Safety margins based on AUC for systemic effects (factor 171) were calculated using the 2 mg/day maintenance dose.

Genotoxicity and Carcinogenicity

In vitro tests to assess genotoxic potential (reverse mutation test, micronucleus test, and chromosomal aberration analysis in human lymphocyte cultures), as well as the in vivo micronucleus test in rats, revealed no genotoxic potential of siponimod.

In carcinogenicity studies, siponimod induced lymphomas, hemangiomas, and hemangiosarcomas in mice, while follicular adenoma and carcinoma of the thyroid gland were observed in male rats. These tumor findings were considered either mouse-specific or related to hepatic metabolic adaptations in rats. The clinical relevance to humans is unknown.

Plasma concentrations of siponimod (AUC) at the lowest dose tested in mice were approximately 29 times higher than at the recommended human dose of 2 mg.

Fertility and Reproductive Toxicity

Siponimod did not affect fertility in male and female rats up to the highest dose tested, establishing a safety margin 16 times higher than the systemic exposure (AUC) in humans at the 2 mg daily dose. No effects on reproductive organs were observed in rats and monkeys after long-term administration.

Reproductive and developmental studies in pregnant rats and rabbits demonstrated siponimod-induced embryotoxicity and fetotoxicity in both species, and teratogenicity in rats. Increased rates of post-implantation loss and fetal abnormalities (external, urogenital, and skeletal) in rats, as well as embryofetal deaths, abortions, and fetal changes (skeletal and visceral) in rabbits, were observed after prenatal exposure to siponimod at doses equivalent to the recommended human daily dose of 2 mg.

Exposure levels in rats and rabbits, at which no developmental abnormalities or embryofetal death were reported, were subclinical. This indicates that at the 2 mg daily maintenance dose, there is no safety margin regarding effects on embryofetal and pre-/postnatal development. In lactating rats administered a single oral dose of 10 mg/kg, siponimod and its metabolites were detected in milk.

Clinical characteristics.

Indications.

Kesimpta (siponimod) is indicated for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, evidenced by relapses or signs of inflammatory activity.

Contraindications.

• Hypersensitivity to the active substance siponimod, to peanut, soya, or to any of the excipients (see section "Composition").
• Immunodeficiency syndrome.
• History of progressive multifocal leukoencephalopathy (PML) or cryptococcal meningitis.
• Active malignant neoplasms.
• Severe hepatic impairment (Child-Pugh class C).
• Diagnosis within the previous 6 months of myocardial infarction (MI), unstable angina, stroke/transient ischaemic attack (TIA), decompensated heart failure requiring hospitalization, or NYHA class III/IV heart failure.
• History of second-degree Mobitz type II atrioventricular (AV) block, third-degree AV block, sinoatrial block, or sick sinus syndrome, if a pacemaker is not in use (see section "Special precautions").
• Homozygosity for the CYP2C9*3 genotype (CYP2C9*3*3).
• Pregnancy. The drug is also contraindicated in women of childbearing potential who are not using effective contraception.

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions

Potential for other medicinal products to affect siponimod pharmacokinetics

Siponimod is primarily metabolized by cytochrome P450 2C9 (CYP2C9) (79.3%) and to a lesser extent by cytochrome P450 3A4 (CYP3A4) (18.5%). CYP2C9 is a polymorphic enzyme, and genotype influences the contribution of each of the two oxidative metabolic pathways to overall elimination. PBPK modeling indicates differential inhibition of CYP2C9 genotype and induction of CYP3A4 pathways. Therefore, the predicted drug-drug interaction effect in the presence of substances affecting CYP3A or CYP2C9 depends on the CYP2C9 genotype (see sections "Special precautions" and "Pharmacokinetics").

The CYP2C9*5, *6, *8, and *11 genotypes are also associated with partial or complete loss of CYP2C9 enzyme activity. Pharmacokinetic studies of these polymorphisms have not been conducted. However, increased levels of other CYP2C9 substrates such as phenytoin or warfarin have been observed in carriers of these genotypes, requiring dose adjustments of these substrates (see also sections "Special precautions" and "Pharmacokinetics").

Inhibitors of CYP2C9 and CYP3A4

Concomitant use of siponimod with medicinal products that moderately inhibit CYP2C9 and moderately or strongly inhibit CYP3A4 is not recommended due to a significant increase in siponimod exposure. Such a combination may consist of a moderate dual inhibitor of CYP2C9/CYP3A4 (e.g., fluconazole) or a moderate CYP2C9 inhibitor combined with a moderate or strong CYP3A4 inhibitor.

Concomitant administration of fluconazole (a moderate inhibitor of CYP2C9/strong inhibitor of CYP3A4) at a dose of 200 mg once daily at steady state and a single 4 mg dose of siponimod in healthy volunteers with the CYP2C9 *1*1 genotype resulted in a doubling of siponimod AUC. According to physiologically-based pharmacokinetic (PBPK) modeling, a maximum two-fold increase in siponimod AUC is predicted for CYP2C9 genotypes *1*1, *1*2, *1*3, and *2*3 in the presence of any type of CYP3A4 and CYP2C9 inhibitors. In patients with the CYP2C9 *2*2 genotype, a 2.7-fold increase in siponimod AUC is expected in the presence of moderate CYP2C9/CYP3A4 inhibitors.

Data on interactions with inhibitors of CYP2C9 and CYP3A4 are not available for other CYP2C9 genotypes with reduced or absent CYP2C9 activity.

Inducers of CYP2C9 and CYP3A4

Due to clinically significant reduction in siponimod exposure, caution is required when co-administering Kesimpta with medicinal products that moderately induce CYP2C9 and strongly induce CYP3A4. Such concomitant therapy may include a moderate dual inducer of CYP2C9/potent CYP3A4 (e.g., rifampicin or carbamazepine) or a moderate CYP2C9 inducer combined with a separate potent CYP3A4 inducer.

Caution is also required when co-administering Kesimpta with moderate CYP3A4 inducers (e.g., modafinil) or potent CYP3A4 inducers in patients with the CYP2C9 *1*3 or *2*3 genotype, for whom dose adjustment is recommended (see section "Special dosage recommendations"). Data on interactions with inducers of CYP2C9 and CYP3A4 are not available for other CYP2C9 genotypes with reduced or absent CYP2C9 activity.

Under these conditions, a significant reduction in siponimod exposure (up to 76% and 51%, respectively) is expected, based on clinical drug interaction studies and in silico (physiologically-based pharmacokinetic) testing with potent CYP3A4 inducers/moderate CYP2C9 inducers (e.g., carbamazepine) and moderate CYP3A4 inducers (e.g., modafinil).

Concomitant administration of 2 mg siponimod once daily and 600 mg rifampicin once daily (a potent CYP3A4 inducer and moderate CYP2C9 inducer) reduced siponimod AUCtau,ss and Cmax,ss by 57% and 45%, respectively, in patients with the CYP2C9 *1*1 genotype.

Siponimod is not a substrate of efflux transporters P-gp, BCRP, or MRP. Therefore, medicinal products affecting the activity of these transporters are not expected to influence siponimod pharmacokinetics.

Hepatocellular uptake of siponimod occurs exclusively via passive diffusion. Therefore, siponimod is not expected to interact with hepatic uptake transporters (OATP, OCT, OAT).

Potential for siponimod to affect the pharmacokinetics of other medicinal products

In vitro studies indicate that siponimod and its metabolites (M17 and M3) do not inhibit or only minimally inhibit the activity of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5) at therapeutically relevant concentrations, and do not induce or only minimally induce (CYP1A2, CYP2B6, CYP2C9, and CYP3A4/5).

Based on in vitro data, siponimod and its metabolites (M17 and M3) are not expected to inhibit the hepatic uptake of co-administered medicinal products or biologically active substances transported by OATP1B1, OATP1B3, OAT1, OAT3, OCT1, or OCT2. They are also not expected to inhibit the efflux of co-administered medicinal products or biologically active substances transported by BCRP, BSEP, MATE1, MATE2K, or P-gp at therapeutic concentrations.

Pharmacodynamic interactions

Antineoplastic, immunomodulatory, or immunosuppressive therapy

The use of Kesimpta in combination with antineoplastic, immunomodulatory, or immunosuppressive agents has not been studied. Caution should be exercised when co-administering these agents with siponimod due to the risk of cumulative effects on the immune system during therapy and for several weeks after discontinuation of any of these agents (see section "Special precautions").

When switching patients from another disease-modifying therapy, the half-life and mechanism of action of the previous therapy should be considered to avoid additive immune effects while minimizing the risk of disease reactivation.

Due to the characteristics and duration of immunosuppressive effects of alemtuzumab, as described in the product information, initiation of Kesimpta after alemtuzumab is not recommended unless the benefit clearly outweighs the risk for an individual patient.

Treatment with Kesimpta should be initiated immediately after discontinuation of interferon beta or glatiramer acetate.

Antiarrhythmic agents, QT-prolonging drugs, and drugs that may reduce heart rate

At the initiation of Kesimpta treatment, concomitant use with class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents, QT-prolonging drugs with known arrhythmogenic properties, heart rate-lowering calcium channel blockers (e.g., verapamil or diltiazem), or other agents capable of reducing heart rate (e.g., ivabradine or digoxin) should be avoided due to potential additive effects. Cardiology consultation should be obtained before initiating therapy with Kesimpta (see section "Special precautions").

Beta-blockers

Caution should be exercised when initiating siponimod in patients receiving beta-blockers due to the potential for additive effects on heart rate reduction (see section "Special precautions"). Beta-blocker therapy may be initiated in patients receiving stable doses of Kesimpta.

The negative chronotropic effect of concomitant siponimod and propranolol was evaluated in a dedicated pharmacodynamics/safety study. Adding propranolol to siponimod therapy at steady state was associated with a less pronounced negative chronotropic effect (compared to additive effect) than adding siponimod to propranolol therapy at steady state (additive effect on heart rate).

Vaccination

Live attenuated vaccines

Since administration of live attenuated vaccines (e.g., varicella and yellow fever vaccines) may increase the risk of infections, immunization with live attenuated vaccines should be avoided during treatment with Kesimpta and for up to 4 weeks after treatment (see section "Special precautions").

Other types of vaccines

Vaccination may be less effective during treatment with Kesimpta and for up to 4 weeks after treatment. Efficacy is expected to be preserved if therapy with siponimod is interrupted one week before planned vaccination and resumed no earlier than 4 weeks after vaccination (see subsection "Resumption of maintenance therapy after treatment interruption"). In a dedicated phase I study in healthy volunteers, the immune response to a quadrivalent influenza vaccine administered after up to 10 days of uninterrupted siponimod treatment or during a 10- to 14-day treatment interruption was approximately 15–30% lower compared to placebo. In contrast, the immune response to PPV23 vaccination was not significantly altered during concomitant siponimod treatment compared to placebo (see section "Special precautions").

Oral contraceptives

The efficacy of tested oral contraceptives (a combination of ethinylestradiol and levonorgestrel) was maintained during siponimod treatment. Siponimod had no effect on the pharmacodynamics of contraceptives (estradiol, progesterone; FSH, LH, follicle size, Hogland scoring, HSG). Compared to single administration of oral contraceptives, concomitant use of siponimod increased the area under the curve of levonorgestrel (AUCtau) by 1.29-fold (geometric mean ratio (GMR): 1.29, 90% CI: 1.24, 1.34) and steady-state peak plasma concentrations (Cmax,ss) by 1.18-fold (GMR: 1.18, 90% CI: 1.11, 1.26). Siponimod did not affect the pharmacokinetics of ethinylestradiol (GMR AUCtau: 1.00, 90% CI: 0.96, 1.05; Cmax,ss GMR: 1.02, 90% CI: 0.96, 1.08).

No interaction studies with oral contraceptives containing other progestogens have been conducted.

Special precautions for use.

Infections

The primary pharmacodynamic effect of Kaindra is a dose-dependent reduction in the number of lymphocytes in peripheral blood to 20–30 % of baseline values. This is due to a reversible redistribution of lymphocytes into lymphoid tissues (see section "Pharmacological properties").

The effect of Kaindra on the immune system may increase the risk of infections.

Prior to initiating treatment with Kaindra, the most recent complete blood count results should be obtained (i.e., within the last 6 months or after discontinuation of prior therapy). Complete blood count should also be evaluated approximately 3–4 months after initiation of treatment, then at least annually, and at the first signs of infection. If confirmed absolute lymphocyte count is < 0.2 × 10⁹/L, the dose should be reduced to 1 mg, as in clinical trials, siponimod dose was reduced in patients with absolute lymphocyte count < 0.2 × 10⁹/L. Confirmed absolute lymphocyte count < 0.2 × 10⁹/L in patients already receiving siponimod at a dose of 1 mg should lead to temporary discontinuation of siponimod therapy until levels reach 0.6 × 10⁹/L, at which time reinitiation of siponimod therapy may be considered.

Initiation of treatment with Kaindra should be delayed in patients with severe active infections until recovery. Since residual pharmacodynamic effects, such as reduced impact on lymphocyte count in peripheral blood, may persist for 3–4 weeks after discontinuation of the drug, monitoring of infection progression should continue throughout this period (see section "Discontinuation of therapy").

Patients taking Kaindra should be instructed to immediately report symptoms of infection to their physician. Effective diagnostic and therapeutic strategies should be applied for patients presenting symptoms of infection during therapy. If a patient develops a serious infection, treatment with Kaindra should be suspended.

Cases of cryptococcal meningitis (CM) associated with the use of Kaindra have been reported. Cases of CM have also been reported with another sphingosine-1-phosphate receptor (S1P) modulator. Physicians should remain vigilant for clinical symptoms or signs of CM. Prompt diagnostic evaluation should be performed in patients with symptoms and signs suggestive of CM. Treatment with Kaindra should be suspended until CM is ruled out. If CM is diagnosed, appropriate treatment should be initiated immediately. Reinitiation of Kaindra therapy in such cases is contraindicated (see section "Contraindications").

Cases of progressive multifocal leukoencephalopathy (PML) have been reported with S1P receptor modulators, including Kaindra, and other MS treatments (see "Adverse reactions"). Physicians should carefully monitor for clinical symptoms or MRI findings suggestive of PML. If PML is suspected, treatment with Kaindra should be suspended until PML is ruled out. If PML is confirmed, appropriate treatment should be initiated immediately. Reinitiation of Kaindra therapy after confirmed PML is contraindicated (see section "Contraindications").

Cases of herpes virus infections (including meningitis or meningoencephalitis caused by varicella-zoster virus (VZV)) have been reported during treatment with Kaindra. Patients without documented history of varicella or complete VZV vaccination should be tested for VZV antibodies prior to initiating Kaindra therapy (see subsection "Vaccination").

Vaccination

Patients lacking VZV antibodies should complete the full vaccination course prior to starting Kaindra, and initiation of Kaindra should be delayed for 1 month to allow full immune response to vaccination (see section "Adverse reactions").

Live attenuated vaccines

Since the use of live attenuated vaccines (e.g., varicella vaccine, yellow fever vaccine) may pose an infection risk, they should be avoided during treatment with Kaindra and for 4 weeks after discontinuation of therapy (see section "Interaction with other medicinal products and other forms of interaction").

Other types of vaccines

The effectiveness of vaccination with other types of vaccines may be reduced if administered during treatment with Kaindra. It is recommended to interrupt treatment 1 week before planned vaccination and for 4 weeks thereafter. The decision on continuing or discontinuing Kaindra therapy should be based on individual benefit-risk assessment (see subsection "Discontinuation of siponimod therapy" and section "Interaction with other medicinal products and other forms of interaction").

When discontinuing siponimod therapy for vaccination, potential reactivation of disease activity should be considered (see subsection "Discontinuation of siponimod therapy").

Concomitant treatment with antineoplastic, immunomodulatory, or immunosuppressive agents

Antineoplastic, immunomodulatory, or immunosuppressive therapy (including corticosteroids) should be prescribed with caution due to the risk of additive effects on the immune system (see section "Interaction with other medicinal products and other forms of interaction").

Macular edema

Macular edema (see section "Adverse reactions"), with or without visual symptoms, occurred more frequently with siponimod (1.8 %) than with placebo (0.2 %) in the phase III clinical trial A2304. Most cases occurred within the first 3–4 months of therapy. Therefore, an ophthalmological evaluation is recommended approximately 3–4 months after initiation of treatment. Since cases of macular edema have also been observed during long-term treatment, patients should be advised to report visual disturbances at any time during Kaindra therapy, and a fundus examination, including the macular area, is recommended.

Kaindra should be used with caution in patients with diabetes mellitus, uveitis, or pre-existing or concomitant retinal disease due to the potential increased risk of macular edema. These patients are recommended to undergo ophthalmological examination prior to starting therapy and regularly during treatment with Kaindra to detect macular edema.

Continuation of Kaindra therapy in patients with macular edema has not been evaluated. If macular edema develops, discontinuation of siponimod is recommended. The decision on whether to reinitiate Kaindra therapy after resolution of macular edema should be based on individual benefit-risk assessment.

Bradycardia and bradyarrhythmia

Heart rate

Due to the risk of serious cardiac rhythm disturbances or significant bradycardia, Kaindra should not be used in patients with the following conditions:

• history of cardiac arrest more than 6 months prior to initiation of Kaindra therapy;
• cerebrovascular disease;
• symptomatic bradycardia or recurrent syncope in medical history;
• uncontrolled hypertension; or
• severe untreated sleep apnea.

If treatment is considered, cardiology consultation should be obtained prior to initiation to determine the most appropriate monitoring strategy.

Siponimod therapy should be considered for such patients only if the expected benefit outweighs the potential risks.

Detailed QT studies did not demonstrate a significant direct QT-prolonging effect, and Kaindra was not associated with arrhythmogenic potential related to QT interval prolongation. Initiation of treatment may lead to a decrease in heart rate and indirect prolongation of the QT interval during the titration phase. The use of Kaindra has not been studied in patients with significant QT prolongation (QTc > 500 msec) or in patients receiving medicinal products that prolong the QT interval. If Kaindra therapy is considered for patients with pre-existing clinically significant QT prolongation or for patients already receiving QT-prolonging drugs with known arrhythmogenic properties, cardiology consultation should be obtained prior to initiation to determine the most appropriate monitoring strategy at the start of treatment.

The use of Kaindra has not been studied in patients with arrhythmias requiring antiarrhythmic drugs of class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol). The use of class IA and III antiarrhythmic drugs has been associated with cases of torsades de pointes ventricular tachycardia in patients with bradycardia. Since heart rate decreases at the start of treatment, Kaindra should not be used concomitantly with these medicinal products at initiation of therapy.

Limited experience exists with the use of Kaindra in patients receiving concomitant therapy with calcium channel blockers that reduce heart rate (such as verapamil or diltiazem) or other agents that may reduce heart rate (e.g., ivabradine or digoxin). The use of these medicinal products in patients receiving Kaindra has not been studied in clinical trials. Concomitant use of these agents at initiation of therapy may be associated with severe bradycardia and heart block. Generally, patients receiving these agents should not initiate Kaindra therapy due to the potential additive effect on heart rate (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant therapy with one of the above-mentioned agents is considered at initiation of Kaindra therapy, consultation with a cardiologist should be sought regarding switching to a non-heart rate-lowering agent or appropriate monitoring for initiation of Kaindra therapy.

Initiation of Kaindra therapy leads to a temporary decrease in heart rate (see section "Adverse reactions"), and therefore a dose titration schedule is applied to reach the maintenance dose of Kaindra on day 6 (see section "Dosage and administration").

After the first dose titration, heart rate reduction begins within one hour, and the maximum reduction on the first day occurs approximately 3–4 hours after dosing. With continued gradual dose escalation, further heart rate reduction occurs over the following days, with maximum reduction compared to day 1 (baseline) reached on days 5–6. The greatest daily decrease in absolute mean hourly heart rate after dosing occurs on the first day, with heart rate decreasing on average by 5–6 beats per minute (bpm). Subsequent daily post-dose reductions are less pronounced. With continued dosing, heart rate begins to increase after 6 days and reaches levels observed with placebo within 10 days after initiation of treatment.

Heart rates below 40 bpm were rarely observed. Bradycardia was generally asymptomatic. A few patients experienced mild to moderate symptoms, including dizziness and fatigue, which resolved within 24 hours without intervention (see section "Adverse reactions"). If heart rate reduction caused by siponimod requires treatment, it can be reversed by parenteral administration of atropine or isoprenaline.

Atrioventricular conduction

Initiation of Kaindra therapy was associated with transient slowing of atrioventricular conduction, with a time course similar to that observed with heart rate reduction during the titration phase. Slowed atrioventricular conduction most commonly manifests as first-degree atrioventricular (AV) block (prolonged PR interval on electrocardiogram). In clinical trials, second-degree AV block, usually Mobitz type I (Wenckebach block), was observed in less than 1.7 % of patients at initiation of Kaindra therapy. Conduction disturbances were usually transient, asymptomatic, resolved within 24 hours, and did not require discontinuation of Kaindra therapy.

Recommendations for treatment initiation

As a precaution, patients with the following cardiac conditions should be monitored for signs and symptoms of bradycardia for 6 hours after the first dose of Kaindra:

• sinus bradycardia (heart rate < 55 bpm);
• first- or second-degree AV block (Mobitz type I) in medical history;
• history of myocardial infarction or heart failure, provided there are no contraindications.

For these patients, electrocardiogram (ECG) is recommended before dosing and at the end of the monitoring period. If bradyarrhythmia or conduction-related symptoms occur after dosing, or if a new onset of second-degree or higher AV block or corrected QTc interval ≥ 500 msec is observed on ECG 6 hours after dosing, appropriate treatment should be initiated and monitoring continued until symptoms resolve/recovery of parameters. If pharmacological treatment is required, monitoring should continue overnight with repetition of the 6-hour monitoring after the second dose.

The bradycardic effect is more pronounced when Kaindra is used concomitantly with beta-blockers. In patients receiving beta-blockers at stable doses, resting heart rate should be assessed prior to initiation. Use of Kaindra with chronic beta-blocker therapy is possible if resting heart rate is > 50 bpm. If resting heart rate is ≤ 50 bpm, beta-blocker therapy should be discontinued until heart rate recovers to > 50 bpm. Resumption of beta-blocker therapy may be considered after completion of the titration phase and achievement of the maintenance dose of Kaindra (see section "Interaction with other medicinal products and other forms of interaction").

Missed dose at treatment initiation and resumption of therapy after discontinuation

If a titration dose is missed on any day during the first six days of treatment or if four or more consecutive daily doses are missed during maintenance therapy, the same initial titration and monitoring recommendations should be applied (see section "Dosage and administration").

Hepatic function

Prior to initiating Kaindra therapy, results of transaminase and bilirubin measurements should be obtained (i.e., within six months prior to initiation of therapy). In study A2304, 5.6 % of patients receiving Kaindra 2 mg and 1.5 % of patients receiving placebo experienced alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels more than three times the upper limit of normal (ULN) (see section "Adverse reactions"). In clinical trials, Kaindra treatment was discontinued if transaminase levels exceeded ULN by more than three times and the patient had symptoms related to liver dysfunction, or if transaminase levels exceeded ULN by more than five times.

Patients developing symptoms suggestive of liver dysfunction, such as nausea of unknown etiology, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia, or jaundice and/or dark urine during treatment, should undergo monitoring of liver enzyme levels, and Kaindra should be discontinued if significant liver injury is confirmed. Reinitiation of therapy will depend on whether another cause of liver injury is identified and on the benefit-risk assessment for resuming therapy versus the risk of recurrence of liver dysfunction.

Although there are no data indicating that patients with pre-existing liver disease have an increased risk of elevated liver tests when taking Kaindra, caution should be exercised in patients with clinically significant liver disease in medical history.

Skin neoplasms

In study A2304, basal cell carcinoma (BCC) was the most common neoplasm reported with similar frequency in the siponimod 2 mg (1.1 %, 12 patients) and placebo (1.3 %, 7 patients) groups. The frequency of squamous cell carcinoma (SCC) in study A2304 was the same (0.2 %) in patients receiving Kaindra and those receiving placebo. In long-term studies, a slight increase in the incidence of BCC and SCC was observed during prolonged use.

However, in patients receiving siponimod and in patients receiving long-term therapy with another S1P modulator, other malignant skin neoplasms, including melanoma, have also been reported.

Skin examination is recommended for all patients at the start of treatment and then every 6–12 months, depending on clinical assessment.

Patients should be advised to immediately report any suspicious skin lesions to their physician.

Patients receiving siponimod therapy should be warned about the necessity of using sun protection measures. Additionally, regular dermatological examinations are recommended, especially for patients with known risk factors for skin tumors and patients with known suspicious skin lesions. Patients taking Kaindra should not receive concomitant phototherapy with ultraviolet B radiation or PUVA photochemotherapy.

Unanticipated neurological or psychiatric symptoms/signs

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported with another sphingosine-1-phosphate receptor (S1P) modulator. Such events were not observed with Kaindra in clinical trial programs. However, in case of any unanticipated neurological or psychiatric symptoms or signs (e.g., cognitive disturbance, behavioral changes, cortical visual disturbances, or any other cortical neurological symptoms/signs or any other symptoms/signs suggestive of increased intracranial pressure) or rapid worsening of neurological status during therapy, immediate comprehensive physical and neurological evaluation should be performed, and MRI should be considered.

Prior immunosuppressive or immunomodulatory therapy

When switching patients from another disease-modifying agent, the half-life and mechanism of action of the prior therapy should be considered to avoid additive immune effects while minimizing the risk of disease reactivation. Prior to initiating Kaindra therapy, peripheral blood lymphocyte count (CBC) should be determined to ensure that the prior therapy's impact on the immune system (i.e., cytopenia) has resolved.

Effect on blood pressure

Patients with uncontrolled hypertension not managed by medication were excluded from pre-registration clinical trials, and special caution is required when treating such patients with siponimod.

In study A2304 in patients with RMS, arterial hypertension was more frequently reported in patients receiving siponimod (12.6 %) than in those receiving placebo (9.0 %). Siponimod treatment led to an increase in systolic and diastolic blood pressure, beginning early after initiation, reaching maximum at approximately 6 months (systolic pressure – 3 mmHg, diastolic pressure – 1.2 mmHg), and remaining stable thereafter. This effect persists with continued treatment.

Regular blood pressure monitoring is required during siponimod use and antihypertensive treatment.

CYP2C9 genotype

Prior to initiating Kaindra therapy, patients should undergo CYP2C9 genotyping to determine their CYP2C9 metabolizer status (see sections "Contraindications", "Dosage and administration", and "Pharmacokinetics"). Kaindra therapy should not be prescribed to patients who are homozygous carriers of the CYP2C9*3 genotype (*3*3 CYP2C9 gene) (approximately 0.3–0.4 % of the Caucasian population; less frequent in other ethnicities), as use of Kaindra in these patients leads to significantly increased plasma levels of siponimod (see sections "Pharmacokinetics" and "Contraindications").

The recommended maintenance dose of Kaindra for carriers of the *2*3 CYP2C9 genotype (1.4–1.7 % of patients) and for patients with the *1*3 genotype (9–12 % of patients) is 1 mg daily to avoid increased siponimod exposure (see sections "Dosage and administration" and "Pharmacokinetics").

The effect of genotypes other than *2 and *3 on siponimod pharmacokinetics has not been studied. Although the impact of rarer CYP2C9 alleles *5, *6, *8, and *11 on siponimod metabolism has not been investigated, increased siponimod levels cannot be excluded due to reduced or absent enzyme activity in carriers of these CYP2C9 polymorphisms (see also sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetics"). The overall frequency of the four alleles *5, *6, *8, and *11 is 10 % in Africans/African descent, 2 % in Latin Americans, and < 0.4 % in Caucasians and Asians. However, due to insufficient data for these genotypes, no dose adjustment recommendations can be provided.

In clinical trials, administration of the unadjusted daily dose of 2 mg siponimod in heterozygous carriers of CYP2C9 *2 and *3 alleles, characterized by reduced CYP2C9 metabolism, did not result in any specific clinically significant symptoms of acute toxicity. A slight increase in the frequency of macular edema after prolonged exposure was observed (see also sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetics"). However, it is unclear whether these differences are related to increased siponimod exposure.

Women of childbearing potential

Due to the risk to the fetus, siponimod is contraindicated in pregnant women and women of childbearing potential who are not using effective contraception. Prior to initiating therapy in women of childbearing potential, they should be informed of this fetal risk; they must have a negative pregnancy test result and use effective contraception during treatment and for at least 10 days after discontinuation of therapy (see sections "Contraindications", "Pregnancy and breastfeeding").

Discontinuation of siponimod therapy

In rare cases, severe disease exacerbation, including symptom recurrence, has been reported after discontinuation of another S1P receptor modulator. The possibility of severe disease exacerbation after discontinuation of siponimod therapy should be considered. Patients should be monitored for signs of possible severe exacerbation or return of high disease activity after discontinuation of siponimod, and appropriate treatment should be initiated as necessary.

After discontinuation of therapy, Kaindra remains in the blood for up to 10 days. Initiation of other therapies during this period will result in concomitant siponimod effects.

In the majority (90 %) of RMS patients, lymphocyte count returns to normal within 10 days after discontinuation of therapy. However, residual pharmacodynamic effects, such as reduced lymphocyte count in peripheral blood, may persist for 3–4 weeks after the last dose. Use of immunosuppressants during this period may lead to additive effects on the immune system, and therefore caution should be exercised for 3–4 weeks after the last dose.

Effect on hematological test results

Since siponimod reduces blood lymphocyte count by redistributing them into secondary lymphoid organs, lymphocyte count in peripheral blood of a patient receiving siponimod cannot be used to assess lymphocyte subpopulation status. Laboratory tests using circulating mononuclear cells require larger blood volumes due to reduced circulating lymphocyte count.

Other components

Tablets contain phospholipids from soybeans. Patients with hypersensitivity to peanuts or soy should not take this medicinal product (see section "Contraindications").

Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Pregnancy and breastfeeding

Women of childbearing potential/contraception in women

Kaindra is contraindicated in women of childbearing potential who are not using effective contraception methods (see section "Contraindications").

Women of childbearing potential should be informed that animal studies have shown harm to the developing fetus with siponimod (see section "Preclinical data"). Women of childbearing potential must have a negative pregnancy test result at the start of siponimod therapy. Women must use effective contraception methods (methods with a pregnancy rate of less than 1 %) during Kaindra therapy and for at least 10 days after discontinuation of therapy (see section "Special precautions for use").

When discontinuing siponimod therapy for pregnancy planning, potential reactivation of disease activity should be considered.

Pregnancy

There are no adequate data on the use of Kaindra in pregnant women to inform about the associated risk of adverse developmental outcomes. Animal studies demonstrated siponimod-induced embryotoxicity and fetotoxicity in rats and rabbits, and teratogenicity in rats, including embryo and fetal death and skeletal or internal organ malformations at exposure levels comparable to the human daily dose of 2 mg (see section "Preclinical data"). Additionally, clinical experience with another sphingosine-1-phosphate receptor modulator demonstrated a twofold increased risk of severe congenital malformations when taken during pregnancy compared to the frequency observed in the general population.

Therefore, siponimod is contraindicated in women during pregnancy (see section "Contraindications"). Siponimod intake should be discontinued at least 10 days before planned pregnancy (see section "Special precautions for use"). If a woman becomes pregnant during treatment, siponimod intake must be discontinued. Medical counseling regarding the risk of harmful effects on the fetus associated with treatment and ultrasound examination should be provided.

Breastfeeding

It is unknown whether siponimod or its metabolites are excreted in human breast milk. Siponimod and its metabolites are excreted in rat milk. Siponimod should not be used during breastfeeding.

Fertility

The effect of siponimod on human fertility has not been evaluated. Siponimod did not affect reproductive organs in male rats and monkeys or fertility parameters in rats.

Ability to affect reaction speed when driving or operating machinery

Siponimod has no or negligible effect on the ability to drive or operate machinery.

However, dizziness and bradyarrhythmia may occasionally occur at the start of siponimod therapy. Therefore, patients should not drive or operate machinery on the first day of starting siponimod therapy (see section "Special precautions for use").

Dosage and Administration

Treatment with Kynmobi should be initiated and managed by a neurologist experienced in the treatment of patients with MS.

Before starting treatment, patients must undergo genotyping for CYP2C9.

Kynmobi should not be used in patients with the CYP2C9 *3*3 genotype (see also sections "Contraindications", "Special Warnings and Precautions for Use", and "Pharmacokinetics").

For patients with the CYP2C9 *2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg once daily (four 0.25 mg tablets) (see also sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Due to lack of data, dosing recommendations cannot be provided for carriers of other rare CYP2C9 alleles associated with reduced or absent CYP2C9 activity, such as CYP2C9 *5, *6, *8, and *11 alleles (see also sections "Contraindications", "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Pharmacokinetics").

The recommended maintenance dose of Kynmobi for all other patients with CYP2C9 genotype is 2 mg.

Kynmobi film-coated tablets should be taken once daily, regardless of food intake. The tablets should be swallowed whole with water.

Initiation of Therapy

Treatment should be initiated with a dose escalation regimen over 5 days.

Patients with certain pre-existing cardiac conditions should be monitored for signs and symptoms of bradycardia during the first 6 hours after administration of the first dose of Kynmobi (see section "Special Warnings and Precautions for Use").

Treatment should be initiated with a dose of 0.25 mg once daily on Day 1 and Day 2, followed by 0.5 mg once daily on Day 3, 0.75 mg once daily on Day 4, and 1.25 mg once daily on Day 5, to reach the proposed maintenance dose of Kynmobi starting on Day 6 (see Table 2).

During the first 6 days of treatment initiation, the recommended daily dose should be taken once daily in the morning, regardless of food intake.

Table 2

Dose Titration Schedule to Achieve the Maintenance Dose of Kynmobi

The recommended maintenance dose is 1 mg (4 × 0.25 mg) once daily for patients with the CYP2C9 *2*3 or *1*3 genotype. An additional 0.25 mg dose on day 5 does not compromise patient safety.

Missed dose during initial treatment

If a titration dose is missed on any day during the first six days of treatment, treatment must be restarted using a new dose-titration pack.

Missed dose after day 6

If a dose is missed, the next dose should be taken at the usual time the following day; the next dose should not be doubled.

Restarting maintenance therapy after interruption of treatment

If maintenance therapy with Kainendra is interrupted for four or more consecutive daily doses, treatment must be restarted using a new dose-titration pack (see section "Initiation of treatment"). If therapy is interrupted for fewer than 4 consecutive daily doses, re-titration is not required and treatment should continue with the maintenance dose.

Special dosage recommendations

Patients with hepatic impairment

Siponimod should not be administered to patients with severe hepatic impairment (Child-Pugh class C) (see section "Contraindications"). Although dosage adjustment is not required in patients with mild or moderate hepatic impairment, caution should be exercised when initiating treatment in these patients (see sections "Special warnings and precautions for use", "Pharmacokinetics").

Patients with renal impairment

Dosage adjustment of Kainendra is not required in patients with renal impairment.

Elderly patients

The use of Kainendra in patients over 65 years of age has not been studied. Clinical trials included patients up to 61 years of age. Kainendra should be used with caution in elderly patients due to insufficient clinical data on efficacy and safety.

Children.

Studies in children have not been conducted.

Overdose.

Patients have received siponimod as single doses (ranging from 0.1 to 75 mg) or as multiple doses (ranging from 0.25 to 20 mg). Based on the occurrence of symptomatic bradycardia after a single 75 mg dose, the maximum tolerated single dose in healthy subjects was determined to be 25 mg. The highest multiple dose studied, 20 mg for 28 days, was well tolerated (9 patients received 100 mg on the last dosing day, and 5 patients accidentally received up to 200 mg once daily for 3–4 days). Some of the 9 subjects reported asymptomatic mild to moderate elevations in liver function tests.

One patient (with a history of depression) took 84 mg of siponimod. This patient experienced a slight increase in liver transaminase levels. No other adverse reactions were observed in this patient following overdose.

In case of overdose during the first dose or during the titration phase, the patient should be monitored for possible signs and symptoms of bradycardia, with possible continuation of monitoring until the next morning. Blood pressure, pulse rate, and ECG should be monitored regularly (see sections "Posology and method of administration" and "Special warnings and precautions for use").

There is no specific antidote for siponimod. Siponimod is not significantly removed from the body by haemodialysis or plasmapheresis.

Adverse Reactions

In the phase III clinical trial A2304, 1651 patients with RMS were randomized in a 2:1 ratio to receive either 2 mg of Mayzent once daily or placebo. The median duration of treatment was 18 months (range: 0 to 37 months). At the time of product registration, long-term safety data are very limited. The most common adverse reactions with 2 mg siponimod were headache (15.2%) and hypertension (12.6%).

Adverse reactions observed in clinical trials were primarily determined based on experience from the main study A2304 (Table 3) and are listed below by system organ class according to the MedDRA classification.

Within each system organ class, adverse reactions are listed in descending order of frequency, with the most frequent ones listed first. Additionally, the corresponding frequency category for each adverse drug reaction is indicated using the following conventional terms (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data).

Table 3

List of adverse reactions in tabular form

See also section "Special precautions for use".

* Adverse drug reactions identified in the open-label extension of phase 3 study A2304.

Description of selected adverse reactions

Infections

During clinical trial A2304, the overall incidence of infections in patients with secondary progressive multiple sclerosis (SPMS) was comparable between patients receiving siponimod and those receiving placebo (49.0% and 49.1%, respectively). However, an increased incidence of herpes zoster was reported in patients receiving siponimod (2.5%) compared to those receiving placebo (0.7%). No further increase in varicella zoster virus-related infections was observed with long-term exposure to siponimod. Cases of meningitis or meningoencephalitis caused by varicella zoster virus have also been reported during treatment with Mayzent (see section "Special precautions for use").

Cases of progressive multifocal leukoencephalopathy and cryptococcal meningitis (CM) have been reported with Mayzent treatment (see sections "Special precautions for use" and "Contraindications").

Macular edema

Macular edema occurred more frequently in patients receiving siponimod (1.8%) than in patients receiving placebo (0.2%). Although most cases occurred within 3–4 months after initiating siponimod, macular edema was also reported in patients receiving siponimod for six to twelve months (see section "Special precautions for use"). Some patients experienced blurred vision or decreased visual acuity, while others were asymptomatic and the condition was diagnosed during routine ophthalmological examination. Overall, improvement or spontaneous resolution of macular edema was observed after discontinuation of the drug. The risk of recurrence after resuming treatment has not been evaluated.

Bradycardia

Transient reduction in heart rate and slowing of atrioventricular conduction may occur at the initiation of siponimod therapy (see section "Special precautions for use"). Bradycardia was reported in 6.2% of patients receiving siponimod compared to 3.1% of patients receiving placebo, and atrioventricular (AV) block was observed in 1.7% of patients receiving siponimod compared to 0.7% of patients receiving placebo.

The maximum reduction in heart rate occurs within the first 6 hours after dose administration.

Transient, dose-dependent reduction in heart rate was observed during the initial dosing phase and reached a plateau at doses of 5 mg and higher. Bradyarrhythmic events (AV block and sinus pauses) occurred more frequently with siponimod treatment compared to placebo.

Most cases of AV block and sinus pauses occurred at the therapeutic dose of 2 mg, with a significantly higher incidence observed without dose titration compared to with titration.

Siponimod-induced reduction in heart rate can be reversed with atropine or isoprenaline.

Liver function tests

Elevations in liver enzymes (primarily ALT elevations) have been reported in patients with MS receiving siponimod.

In the clinical trial A2304 involving patients with SPMS, elevations in liver function tests were more frequently observed in patients receiving siponimod (11.3%) than in those receiving placebo (3.1%), primarily due to increases in hepatic transaminases (ALT/AST/GGT). A substantial proportion of cases of elevated liver function tests occurred within 6 months after initiation of therapy. Normalization of ALT activity was observed approximately within 1 month after discontinuation of siponimod (see section "Special precautions for use").

Blood pressure

In a phase III clinical trial involving patients with SPMS, arterial hypertension was reported more frequently in patients receiving siponimod (12.6%) than in those receiving placebo (9.0%) (see section "Special precautions for use").

Seizures

In clinical trial A2304 involving patients with SPMS, seizures were reported in 1.7% of patients receiving siponimod compared to 0.4% of patients receiving placebo. It is unknown whether these events were related to the consequences of MS, siponimod treatment, or both.

Effects on the respiratory system

Treatment with siponimod was associated with a slight reduction in forced expiratory volume in 1 second (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO). At three and six months of treatment in clinical trial A2304, mean changes from baseline in FEV1 in patients with SPMS in the siponimod group were 0.1 L at each time point, with no changes observed in the placebo group. These results were somewhat higher (mean change of approximately 0.15 L from baseline FEV1) in patients with pre-existing respiratory disorders such as chronic obstructive pulmonary disease (COPD) or asthma who received siponimod. During long-term treatment, this reduction did not lead to clinically significant adverse events and was not associated with an increased number of reports of cough or dyspnea.

Reporting of adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

18 months.

Storage conditions.

Store in a refrigerator (2–8 °C). Keep in the original packaging.

Store out of reach of children.

Packaging.

For 0.25 mg dosage:

12 tablets in a blister; 1 blister in a carton; 1 carton in a cardboard box.

For 2 mg dosage:

14 tablets in a blister; 2 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

1. Novartis Pharma GmbH / Novartis Pharma GmbH.
2. Novartis Farmaceutica, S.A. / Novartis Farmaceutica, S.A.

Manufacturer's address and location of its business operations.

1. Roonstrasse 25, Gostenhof, Nuremberg, Bavaria, 90429, Germany / Roonstrasse 25, Gostenhof, Nuremberg, Bavaria, 90429, Germany.
2. Gran Via de les Corts Catalanes 764, Barcelona, 08013, Spain / Gran Via de les Corts Catalanes 764, Barcelona, 08013, Spain.