Gilenya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GILENYA (GILENYA™)

Composition:

Active substance: fingolimod;

1 capsule contains 0.5 mg of fingolimod (as hydrochloride);

Excipients: mannitol (E 421), magnesium stearate, yellow iron oxide (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

capsules with a white opaque body and a bright yellow opaque cap; black ink radial imprint “FTY 0.5 mg” on the cap and two radial yellow bands on the body; capsule size: 3;

contents of the capsule: powder from white to almost white.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Selective immunosuppressants. ATC code L04A A27.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator. Fingolimod is metabolized by sphingosine kinase to its active metabolite, fingolimod phosphate. Fingolimod phosphate binds with high affinity at low nanomolar concentrations to S1P type 1 receptors (S1P₁) located on lymphocytes. It readily crosses the blood-brain barrier to bind to S1P₁ receptors located on neural cells in the central nervous system (CNS). Acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate inhibits the ability of lymphocytes to exit from lymph nodes, resulting in redistribution rather than depletion of lymphoid tissue. Animal studies have shown that this redistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they may contribute to nerve inflammation and neural tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also exert effects through interaction with S1P receptors on neural cells.

Pharmacodynamic effects

Within 4–6 hours after the first dose of fingolimod 0.5 mg, the number of lymphocytes in peripheral blood decreases to approximately 75% of baseline. With continuous daily administration, lymphocyte counts continue to decline over a 2-week period, reaching a nadir of approximately 500 cells/µL, or about 30% of baseline levels. 18% of patients reached a minimum lymphocyte count below 200 cells/µL at least once. Low lymphocyte levels are maintained during continuous daily treatment. Most T- and B-lymphocytes regularly recirculate through lymphoid organs, and these cells are primarily affected by fingolimod. Approximately 15–20% of T-lymphocytes have an effector memory cell phenotype, which is important for peripheral immune surveillance. Since this lymphocyte subset generally does not recirculate through lymphoid organs, it is not affected by fingolimod. Lymphocyte counts begin to increase within days after discontinuation of fingolimod, with return to normal levels typically occurring within 1–2 months. Continuous fingolimod treatment results in a modest reduction in neutrophil counts, to approximately 80% of baseline. Monocytes are not affected by fingolimod.

Fingolimod causes a transient decrease in heart rate and atrioventricular conduction delay at the initiation of treatment (see sections "Special precautions" and "Adverse reactions"). The maximum reduction in heart rate occurs within the first 6 hours after dose administration, with approximately 70% of the negative chronotropic effect achieved on the first day. With continued treatment, heart rate returns to baseline levels within 1 month. The fingolimod-induced reduction in heart rate can be reversed by administration of atropine or isoprenaline. A moderate positive chronotropic effect of inhaled salmeterol has also been demonstrated. At treatment initiation, an increased frequency of atrial extrasystoles is observed, but there is no increase in the frequency of atrial fibrillation/flutter, ventricular arrhythmias, or ectopy. Fingolimod treatment is not associated with reduced cardiac output. Autonomic cardiac responses, including diurnal heart rate variability and response to exercise, are not impaired during fingolimod treatment.

S1P₄ may partially contribute to the effect but is not the primary receptor responsible for lymphoid tissue redistribution. The mechanism of bradycardia and vasoconstriction has also been studied in vitro in guinea pigs and in isolated rabbit aorta and coronary artery. It has been concluded that bradycardia may be mediated via activation of the inwardly rectifying potassium channel or G-protein-activated inwardly rectifying K⁺ channel (I_KACh/GIRK), while vasoconstriction is likely mediated by a Rho-kinase- and calcium-dependent mechanism.

Treatment with fingolimod at single or multiple doses of 0.5 mg and 1.25 mg over two weeks is not associated with significant increases in airway resistance, measured by forced expiratory volume (FEV₁) and forced expiratory flow (FEF) at 27–75%. However, single administration of fingolimod at doses ≥ 5 mg (10 times the recommended dose) is associated with dose-dependent increases in airway resistance. Repeated administration of fingolimod at doses of 0.5, 1.25, or 5 mg is not associated with impaired oxygenation or hypoxia during exercise, or with increased airway sensitivity to methacholine. Individuals receiving fingolimod treatment exhibit a normal bronchodilator response to inhaled beta-agonists.

Pharmacokinetics.

Pharmacokinetic data were obtained in healthy volunteers, renal transplant patients, and patients with multiple sclerosis.

The pharmacologically active metabolite is fingolimod phosphate.

Absorption

Fingolimod is slowly (T_max 12–16 hours) and extensively (≥ 85%) absorbed. The predicted absolute bioavailability after oral administration is 93% (95% confidence interval: 79–111%). Steady-state concentrations in blood are reached within 1–2 months after once-daily administration and are approximately 10-fold higher than after the first dose.

Food intake does not affect C_max or exposure (AUC) of fingolimod: C_max of fingolimod phosphate was slightly increased (by 34%), while AUC remained unchanged. Therefore, Gilenya can be administered independently of food intake (see section "Dosage and administration").

Distribution

Fingolimod is extensively distributed into erythrocytes, with a blood cell fraction of 86%. Fingolimod phosphate has a lower blood cell uptake ratio – < 17%. Both fingolimod and fingolimod phosphate are highly bound to plasma proteins (> 99%).

Fingolimod is extensively distributed into body tissues, with a volume of distribution of approximately 1200 ± 260 liters. A study in four healthy volunteers who received a single intravenous dose of radiolabeled fingolimod analog demonstrated that fingolimod reaches the brain. In 13 male patients with multiple sclerosis receiving fingolimod 0.5 mg/day in a study, the average amount of fingolimod (and fingolimod phosphate) in semen at steady state was approximately 10,000 times lower than the administered dose (0.5 mg).

Biotransformation

In humans, fingolimod undergoes biotransformation via stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated via oxidative biotransformation, primarily catalyzed by CYP4F2 and possibly other isoenzymes, followed by degradation similar to fatty acids into inactive metabolites. Formation of pharmacologically inactive, nonpolar ceramide analogs of fingolimod has also been observed. The main enzyme involved in fingolimod metabolism is partially defined: it may be either CYP4F2 or CYP3A4.

After a single oral dose of [14C]fingolimod, the major circulating components related to fingolimod, based on their contribution to the AUC of total radioactivity over 34 days after dosing, were fingolimod (23%), fingolimod phosphate (10%), and inactive metabolites (carboxylic acid metabolite M3 (8%), ceramide metabolite M29 (9%), and ceramide metabolite M30 (7%)).

Elimination

The blood clearance of fingolimod is 6.3 ± 2.3 L/h, and the mean apparent terminal half-life (T_1/2) is 6–9 days. Fingolimod and fingolimod phosphate decline similarly during the terminal phase, resulting in comparable half-lives.

After oral administration, approximately 81% of the dose is slowly excreted in urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted unchanged in urine but are the main components in feces, each accounting for less than 2.5% of the dose. By day 34, 89% of the administered dose is excreted.

Linearity

Concentrations of fingolimod and fingolimod phosphate increase almost proportionally with dose after multiple administrations of 0.5 mg and 1.25 mg once daily.

Characteristics in specific patient populations

Sex, ethnicity, and renal impairment

The pharmacokinetics of fingolimod and fingolimod phosphate are not different between men and women, among patients of different ethnic backgrounds, or in patients with mild to severe renal impairment.

Hepatic impairment

In patients with mild, moderate, or severe hepatic impairment (Child-Pugh classes A, B, and C), no changes in C_max of fingolimod were observed, but AUC increased by 12%, 44%, and 103%, respectively. In patients with severe hepatic impairment (Child-Pugh class C), C_max of fingolimod phosphate was reduced by 22%, while AUC was not significantly altered. The pharmacokinetics of fingolimod phosphate were not evaluated in patients with mild or moderate hepatic impairment.

The apparent half-life of fingolimod remained unchanged in patients with mild hepatic impairment but was prolonged by approximately 50% in patients with moderate or severe hepatic impairment.

Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C). Fingolimod should be used with caution in patients with mild or moderate hepatic impairment (see section "Dosage and administration").

Elderly patients

Clinical experience and pharmacokinetic data in patients aged 65 years and older are limited. Gilenya should be used with caution in patients aged 65 years and older.

Pediatric population

In pediatric patients (aged 10 years and older), fingolimod phosphate concentrations appear to increase in proportion to dose within the range of 0.25–0.5 mg.

Steady-state concentrations of fingolimod phosphate are approximately 25% lower in children (aged 10 years and older) receiving daily doses of 0.25 mg or 0.5 mg compared to adult patients receiving 0.5 mg once daily.

There are no data on the use of the medicinal product in children under 10 years of age.

Clinical characteristics.

Indications.

Gilenya is indicated as a monotherapy for modifying highly active relapsing-remitting multiple sclerosis in the following groups of adult patients and children aged 10 years and older:

• Patients with high disease activity.

This group includes patients in whom a complete and adequate (at least one year) course of treatment with at least one disease-modifying therapy (exceptions and information on washout periods are provided in the sections "Special precautions" and "Pharmacological properties") has not demonstrated a therapeutic effect.

• Patients with rapidly progressing severe relapsing-remitting multiple sclerosis.

Presence of two or more disabling relapses within one year or detection on brain MRI of one or more gadolinium-enhancing lesions or an increase in the number of T2-hyperintense lesions compared to the previous MRI.

Contraindications.

Immunodeficiency syndrome.

Contraindicated in patients with an increased risk of opportunistic infections, including those with compromised immune systems (including patients undergoing immunosuppressive therapy, or patients with pre-existing immunodeficiency).

Severe acute infections, active chronic infections (hepatitis, tuberculosis).

Contraindicated in patients with malignancies.

Contraindicated in patients with severe hepatic impairment (Child-Pugh class C).

Myocardial infarction occurred within the past 6 months.

Unstable angina.

Stroke. Transient ischemic attack.

Decompensated heart failure requiring hospitalization.

Heart failure classified as NYHA class III/IV.

Marked cardiac arrhythmia requiring concomitant use of antiarrhythmic agents of class Ia or class III.

Existing or history of second-degree Mobitz type II atrioventricular block or third-degree atrioventricular block.

Sick sinus syndrome (if the patient does not have a functioning pacemaker).

Baseline QTc interval ≥ 500 ms.

Contraindicated in pregnant women and women of childbearing potential who are not using highly effective contraceptive methods.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

Antineoplastic, immunosuppressive or immunomodulatory therapy

Concomitant use of antineoplastic, immunosuppressive or immunomodulatory agents should be administered with caution due to the risk of additive effects on the immune system (see sections "Contraindications" and "Special precautions").

Caution is also advised when transitioning from therapies with prolonged immune system effects, such as natalizumab or mitoxantrone (see section "Special precautions"). In clinical trials of multiple sclerosis, short-term treatment of relapses with corticosteroids did not result in increased frequency of infections.

Vaccination

Vaccination may be less effective during treatment with Gilenya and for 2 months after discontinuation of treatment. The use of live attenuated vaccines may pose a risk of infection and is therefore not recommended (see sections "Special precautions" and "Adverse reactions").

Medicinal products inducing bradycardia

Treatment with fingolimod has been studied concomitantly with medicinal products that reduce heart rate, such as atenolol and diltiazem. When fingolimod was co-administered with atenolol in interaction studies in healthy volunteers, an additional 15% reduction in heart rate was observed at the beginning of fingolimod treatment; this effect was not observed with diltiazem. Concomitant use is contraindicated in patients receiving beta-blockers or other agents that may reduce heart rate, such as class Ia and III antiarrhythmic agents, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, anticholinesterase agents, or pilocarpine, due to additive effects on heart rate (see sections "Special precautions" and "Adverse reactions").

If combination therapy with Gilenya is planned, consultation with a cardiologist is recommended regarding switching the patient to medications that do not reduce heart rate or regarding appropriate monitoring at the initiation of treatment. Monitoring is recommended for at least the first night if concomitant use of a heart rate-lowering agent cannot be discontinued.

Administration of a single dose of fingolimod together with isoprenaline or atropine did not alter the effect of the drug. Furthermore, co-administration of atenolol, diltiazem, and fingolimod did not alter the pharmacokinetics of fingolimod.

Pharmacokinetic effect of other medicinal products on fingolimod

Fingolimod is metabolized primarily by CYP4F2. Other enzymes, such as CYP3A4, may also be involved in its metabolism, especially in cases of pronounced CYP3A4 induction. Strong inhibitors of transport proteins are not expected to affect the distribution of fingolimod. Concomitant administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in exposure to fingolimod and fingolimod phosphate (AUC) due to inhibition of CYP4F2. Caution should be exercised when prescribing fingolimod concomitantly with agents that may inhibit CYP3A4 activity (protease inhibitors, azole antifungals, certain macrolides such as clarithromycin or telithromycin).

Concomitant administration of carbamazepine at a dose of 600 mg twice daily at steady state and a single 2 mg dose of fingolimod reduced the AUC of fingolimod and its metabolite by approximately 40%. Other strong inducers of CYP3A4 enzyme, such as rifampicin, phenobarbital, phenytoin, efavirenz, and St. John's wort, may reduce the AUC of fingolimod and its metabolite to at least the same extent. Since this may potentially affect efficacy, concomitant use of these agents should be prescribed with caution.

Concomitant use of St. John's wort is not recommended (see section "Special precautions").

Pharmacokinetic data on potential interactions do not indicate a significant effect of fluoxetine, paroxetine (potent inhibitors of CYP2D6), or carbamazepine (potent enzyme inhibitor) on fingolimod and fingolimod phosphate. In addition, the following substances also had no clinically significant effect on fingolimod and fingolimod phosphate: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteroids, and oral contraceptives.

Effect on laboratory tests

Since fingolimod reduces blood lymphocyte count by redistributing lymphocytes to secondary lymphoid organs, peripheral blood lymphocyte counts cannot be used to assess overall lymphocyte status.

Laboratory testing of circulating mononuclear cells may require larger blood volumes due to reduced numbers of circulating lymphocytes.

Pharmacokinetic interactions of fingolimod with other substances

It is unlikely that fingolimod interacts with agents metabolized primarily by CYP450 enzymes or substrates of major transporter proteins.

No changes in exposure to cyclosporine or fingolimod were observed when fingolimod was co-administered with cyclosporine. Therefore, it is not expected that fingolimod will affect the pharmacokinetics of medicinal products that are substrates of the CYP3A4 isoenzyme.

No changes in exposure to oral contraceptives (ethinylestradiol and levonorgestrel) were observed with concomitant administration of fingolimod. Drug interaction studies with oral contraceptives containing other progestogens have not been conducted, but it is not expected that fingolimod will affect their exposure.

Special precautions for use.

Bradycardia

Initiation of fingolimod treatment is associated with a temporary decrease in heart rate and may also be associated with atrioventricular conduction delay. Isolated cases of transient complete AV block, which spontaneously resolves, have been reported (see sections "Adverse reactions" and "Pharmacodynamics").

After administration of the first dose, reduction in heart rate begins within 1 hour and reaches its maximum at approximately 6 hours. This effect persists for several subsequent days after administration, although symptoms are usually milder and resolve within several weeks. With continued treatment, heart rate on average returns to baseline within 1 month, although in some patients it may not return to baseline levels by the end of the first month. Pathological conduction changes were generally transient and asymptomatic. These changes usually did not require treatment and resolved within the first 24 hours with continued therapy. In case of fingolimod-induced bradycardia requiring intervention, parenteral administration of atropine or isoprenaline may be used.

An electrocardiogram (ECG) and blood pressure measurement should be performed before initiating treatment and at the end of the 6-hour observation period after the first dose in all patients. Monitoring of all patients with hourly measurement of pulse rate and blood pressure for 6 hours is recommended to detect symptoms of bradycardia. Continuous (real-time) ECG monitoring during this 6-hour period is recommended.

The same precautions as for the first dose are recommended when patients switch from a dose of 0.25 mg to a daily dose of 0.5 mg.

If symptoms of post-dose bradyarrhythmia develop, appropriate treatment should be administered as needed, and monitoring should continue until symptoms resolve. If pharmacological intervention is required during the observation period after the first dose, overnight monitoring in a medical facility is recommended, as well as monitoring after the second dose of Gilenia.

If the heart rate at the 6th hour is the lowest since the first dose (maximum pharmacodynamic effect on the heart may not have been reached yet), monitoring should be continued for at least 2 additional hours and until the heart rate increases again. Additionally, if at 6 hours the heart rate is < 45 beats per minute in adults, < 55 beats per minute in children aged 12 years, or < 60 beats per minute in children aged 10 to 12 years, or if ECG shows development of second-degree or higher AV block, or QTc interval ≥ 500 ms, extended monitoring (at least overnight) should be performed until symptoms resolve. The occurrence of third-degree AV block at any time also requires extended monitoring (at least overnight).

The effect of the drug on heart rate and atrioventricular conduction may reoccur upon resumption of fingolimod treatment and depends on the duration of the treatment interruption and the time since initiation of therapy. Monitoring after the first dose, as at the beginning of treatment, is recommended in case of treatment interruption (see section "Dosage and administration").

Very rare cases of T-wave inversion have been reported in adult patients receiving fingolimod. In case of T-wave inversion, the physician should ensure the absence of associated signs or symptoms of myocardial ischemia. If myocardial ischemia is suspected, cardiology consultation is recommended.

Due to the risk of serious cardiac arrhythmias or severe bradycardia, Gilenia is contraindicated in patients with sinoatrial block, symptomatic bradycardia, history of recurrent syncope, history of cardiac arrest, or significant QT interval prolongation (QTc > 470 ms (adult females), QTc > 460 ms (female children) or > 450 ms (adults and male children)), uncontrolled hypertension, or severe sleep apnea (see also section "Contraindications").

Treatment with Gilenia in such patients should be considered only if the expected benefit outweighs the potential risk.

Cardiology consultation regarding appropriate monitoring is recommended before initiating treatment, and extended monitoring (at least overnight) should be performed (see also section "Interaction with other medicinal products and other forms of interaction").

The use of fingolimod in patients with arrhythmias requiring treatment with class Ia antiarrhythmic agents (such as quinidine, disopyramide) or class III antiarrhythmics (such as amiodarone, sotalol) has not been studied. Class Ia and class III antiarrhythmics have been associated with cases of torsades de pointes in patients with bradycardia (see section "Contraindications").

Experience with the use of Gilenia in patients receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce heart rate (such as verapamil or diltiazem), or other agents that reduce heart rate (such as ivabradine, digoxin, anticholinesterase agents, or pilocarpine) is limited. Since a reduction in heart rate has also been observed at the beginning of fingolimod treatment (see also section "Adverse reactions", Bradycardia), concomitant use of these agents at the start of treatment may be associated with the development of severe bradycardia and heart block. Due to the potential additive effect on heart rate, treatment with Gilenia should generally not be prescribed to patients receiving concomitant therapy with these agents (see also section "Interaction with other medicinal products and other forms of interaction"). Prescribing Gilenia to these patients may be considered only if the expected benefit outweighs the risk. In case of prescribing Gilenia, cardiology consultation regarding switching the patient to agents that do not reduce heart rate is recommended. If treatment with agents that reduce heart rate cannot be discontinued, cardiology consultation regarding appropriate monitoring of the first dose and extended monitoring (at least overnight) is recommended (see also section "Interaction with other medicinal products and other forms of interaction").

QT interval prolongation

In a thorough QT study at steady-state fingolimod doses of 1.25 or 2.5 mg, when the negative chronotropic effect of fingolimod was still present, treatment with this agent resulted in QTc prolongation with an upper bound of the 90% CI ≤ 13.0 ms. There was no dose- or exposure-response relationship for QTc prolongation. There was no signal indicating an increased frequency of QTc interval deviations, whether absolute change or change compared to baseline, associated with fingolimod use.

The clinical significance of these findings is unknown. In clinical trials involving patients with multiple sclerosis, clinically significant effects of the drug on QTc interval prolongation were not observed, but patients with an increased risk of QT interval prolongation were not included in clinical trials.

It is advisable to avoid prescribing medicinal products that may cause QTc interval prolongation to patients with relevant risk factors, such as hypokalemia or congenital QT interval prolongation.

Immunosuppression

Fingolimod exerts an immunosuppressive effect, increasing the risk of infections, including opportunistic infections, which may be fatal, and increasing the risk of lymphomas and other malignancies, including skin cancer. Physicians should carefully monitor patients, especially those with comorbidities or known risk factors, such as previous immunosuppressive therapy. If such a risk is suspected, the physician should consider the possibility of discontinuing treatment in each individual case (see also sections "Special precautions for use", Infections and Skin tumors; and section "Adverse reactions", Lymphoma).

Infections

The main pharmacodynamic effect of fingolimod is dose-dependent reduction in the number of lymphocytes in peripheral blood to 20–30% of baseline values. This occurs due to the reversible sequestration of lymphocytes in lymphoid tissue (see section "Pharmacodynamics").

Before initiating treatment with Gilenia, the most recent complete blood count results (i.e., performed within the last 6 months or after discontinuation of the previous treatment course) should be available. Complete blood count is also recommended periodically during treatment, at 3 months of therapy and at least annually thereafter, as well as in case of signs of infectious disease. If confirmed absolute lymphocyte count is < 0.2 × 10⁹/L, treatment should be temporarily discontinued until normalization of the parameter, as treatment with fingolimod was temporarily discontinued in clinical trials in patients with absolute lymphocyte count < 0.2 × 10⁹/L.

Initiation of treatment with Gilenia should be delayed in patients with active acute infectious disease until its resolution.

The effect of Gilenia on the immune system may increase the risk of infections, including opportunistic infections (see section "Adverse reactions"). Therefore, effective diagnostic and treatment methods should be used for patients with symptoms of infectious disease occurring during treatment. When evaluating a patient suspected of infection that may be serious, consideration should be given to consulting a physician experienced in treating such infections. Patients should be informed about the need to immediately report symptoms of infectious diseases during treatment with Gilenia.

Temporary discontinuation of Gilenia should be considered in case of development of serious infectious disease, and benefit-risk assessment should be performed before resuming therapy.

After discontinuation of treatment, elimination of fingolimod from the body may take up to two months; therefore, monitoring for infection should continue during this period. Patients should be informed about the need to report symptoms of infectious disease during the period up to 2 months after discontinuation of fingolimod treatment.

Herpes viral infection

Serious, life-threatening, and sometimes fatal cases of encephalitis, meningitis, or meningoencephalitis caused by herpes simplex virus and varicella-zoster virus have been observed at any time during treatment with Gilenia. In case of development of herpes encephalitis, meningitis, or meningoencephalitis, administration of Gilenia should be discontinued and appropriate treatment of the respective infection should be initiated.

Before initiating therapy with Gilenia, the immunity status of patients to varicella (chickenpox) should be assessed. It is recommended that patients without a history of medically confirmed chickenpox or without documented complete vaccination against varicella-zoster virus (VZV) undergo testing for VZV antibodies before initiating therapy with fingolimod. It is recommended that patients with negative results for VZV antibodies receive a complete course of vaccination against chickenpox before initiating therapy with Gilenia (see section "Adverse reactions"). Initiation of fingolimod treatment should be delayed for 1 month to allow full vaccine effect.

Cryptococcal meningitis

Cases of cryptococcal meningitis (fungal infection), sometimes fatal, have been reported during the post-marketing period after approximately 2–3 years of treatment, although the exact relationship with treatment duration is unknown (see section "Adverse reactions"). Patients with symptoms and signs consistent with cryptococcal meningitis (e.g., headache accompanied by changes in mental status, such as confusion, hallucinations, and/or personality changes) should undergo immediate thorough diagnostic evaluation. In case of diagnosis of cryptococcal meningitis, fingolimod treatment should be discontinued and appropriate therapy should be initiated. Consultations with other physicians (e.g., an infectious disease specialist) should be conducted if resumption of fingolimod treatment is necessary.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML) have been reported during the post-approval period during fingolimod treatment (see section "Adverse reactions").
PML is an opportunistic infection caused by the John Cunningham virus (JC virus) that can lead to death or severe disability. Cases of PML have been reported after 2–3 years of monotherapy without prior use of natalizumab, although the exact relationship with treatment duration is unknown. Additional cases of PML occurred in patients who previously received natalizumab, the use of which is known to be associated with PML. PML may develop exclusively in the presence of JC viral infection. When testing for JC virus, it should be remembered that the impact of lymphopenia on the reliability of JC virus antibody testing in patients receiving fingolimod has not been studied. It should also be considered that a negative result for JC virus antibodies does not exclude the possibility of subsequent JC viral infection. Before initiating fingolimod treatment, baseline MRI results should be available (usually MRI is performed no earlier than 3 months before treatment initiation). MRI results may indicate disease before clinical signs or symptoms. During standard MRI (according to national and local recommendations), physicians should pay special attention to lesions that may indicate the presence of PML. MRI can be considered one of the elements of comprehensive measures for monitoring patients at risk of developing PML. Cases of asymptomatic PML based on MRI results and positive DNA analysis for JC virus in cerebrospinal fluid have been reported in patients using fingolimod.
In case of suspicion of PML, diagnostic MRI should be performed immediately and fingolimod therapy should be suspended until suspected PML is ruled out.

Human papillomavirus (HPV)

Infections caused by human papillomavirus (HPV), including papilloma, dysplasia, warts, and HPV-related cancer, have been reported during post-marketing use of fingolimod (see section "Adive reactions"). Due to the immunosuppressive properties of fingolimod, HPV vaccination should be considered before initiating fingolimod treatment, taking into account vaccination recommendations. Screening for cancer, including Pap test, is recommended according to standard care.

Macular edema

Macular edema with or without ocular symptoms was reported in 0.5% of patients receiving fingolimod at a dose of 0.5 mg (see section "Adverse reactions").

Therefore, ophthalmological examination is recommended 3–4 months after initiation of treatment. If patients report visual disturbances at any time during treatment, fundus examination including macula should be performed.

The risk of developing macular edema is increased in patients with a history of uveitis and in patients with diabetes mellitus (see section "Adverse reactions"). The use of fingolimod in patients with multiple sclerosis and concomitant diabetes mellitus has not been studied. Ophthalmological examination before initiation of treatment and periodically during treatment is recommended for patients with multiple sclerosis and diabetes mellitus or a history of uveitis.

Continuation of fingolimod use in patients with macular edema has not been evaluated.
In case of development of macular edema in a patient, discontinuation of treatment is recommended. When deciding on resumption of therapy after resolution of macular edema, potential benefits and risks should be considered for each individual patient.

Liver injury

Elevations in liver enzymes, particularly alanine aminotransferase (ALT), as well as gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST), have been reported in patients with multiple sclerosis receiving fingolimod. Cases of acute liver failure requiring liver transplantation and clinically significant liver injury have also been reported. Signs of liver injury, including markedly elevated liver enzymes in serum and elevated total bilirubin, were observed as early as ten days after the first dose and after prolonged use. In clinical trials, elevations in ALT more than 3 times the upper limit of normal (ULN) were observed in 8% of patients receiving fingolimod at a dose of 0.5 mg compared to 1.9% of patients receiving placebo. Five-fold elevation of ULN was observed in 1.8% of patients receiving fingolimod and in 0.9% of patients receiving placebo.
In clinical trials, treatment with fingolimod was discontinued if liver transaminase levels exceeded ULN by 5 times. Recurrent increases in liver transaminase levels were observed upon resumption of fingolimod treatment in some patients, confirming the association of this adverse event with fingolimod use. In clinical trials, increases in transaminase levels occurred at any time during treatment, although most cases occurred within the first 12 months. Elevated transaminase levels in serum returned to normal within approximately 2 months after discontinuation of fingolimod treatment.

Fingolimod has not been studied in patients with severe pre-existing liver function impairment (Child-Pugh class C). Gilenia should not be prescribed to these patients (see section "Contraindications").

Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in patients with active viral hepatitis until its resolution.

Recent (i.e., obtained within the last 6 months) results of tests determining transaminase and bilirubin levels should be available before initiation of treatment. In the absence of clinical symptoms, monitoring of liver transaminase activity and bilirubin levels in serum should be performed at 1, 3, 6, 9, and 12 months of treatment and then periodically up to 2 months after discontinuation of Gilenia. In the absence of clinical symptoms, if liver transaminase levels exceed ULN by >3 but <5 times without increase in serum bilirubin, more frequent monitoring, including measurement of bilirubin and alkaline phosphatase (ALP) in serum, is required to determine whether further increase occurs and to identify alternative etiologies of liver dysfunction. If liver transaminase levels exceed ULN by at least 5 times or at least 3 times with any increase in serum bilirubin, administration of Gilenia should be discontinued. Monitoring of liver function should be continued. After normalization of serum transaminase levels (including if an alternative cause of liver dysfunction is identified), administration of Gilenia may be resumed based on careful benefit-risk assessment for the patient.

In patients with symptoms indicating liver function impairment, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine of unknown etiology, liver enzyme activity and bilirubin should be immediately checked, and therapy should be discontinued if significant liver injury is confirmed.

Treatment should not be resumed if a probable alternative etiology of liver injury signs and symptoms cannot be established.

Although there are no data indicating an increased risk of elevated liver test results with the use of Gilenia in patients with pre-existing liver disease, caution should be exercised when prescribing Gilenia to patients with significant liver disease in history.

Effect on blood pressure

Special precautions should be taken when prescribing Gilenia to patients with uncontrolled hypertension not included in pre-marketing clinical trials.

In clinical trials of multiple sclerosis, in patients receiving fingolimod at a dose of 0.5 mg, an increase in mean systolic blood pressure of approximately 3 mm Hg and diastolic blood pressure of approximately 1 mm Hg was observed, first noted about 1 month after initiation of treatment. This increase persisted with continued treatment. In a two-year placebo-controlled study, hypertension was reported as an adverse event in 6.5% of patients receiving fingolimod at a dose of 0.5 mg and in 3.3% of patients receiving placebo. Therefore, regular monitoring of blood pressure should be performed during treatment.

Respiratory effects

Minor dose-dependent decreases in forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) were observed with fingolimod use from the first month of treatment and remained stable thereafter. Gilenia should be prescribed with caution to patients with severe respiratory disease, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Reversible posterior encephalopathy syndrome

Rare cases of reversible posterior encephalopathy syndrome (PRES) have been reported in clinical trials and during the post-marketing period with the use of the drug at a dose of 0.5 mg (see section "Adverse reactions"). Symptoms included sudden onset of severe headache, nausea, vomiting, changes in mental status, visual disturbances, and seizures. PRES symptoms are usually reversible but may progress to ischemic stroke or intracranial hemorrhage. Delay in diagnosis and treatment may lead to irreversible neurological consequences. If PRES is suspected, the drug should be discontinued.

Prior immunosuppressive or immunomodulatory treatment

Studies evaluating the efficacy and safety of fingolimod in switching patients from teriflunomide, dimethyl fumarate, or alemtuzumab to Gilenia have not been conducted. When switching patients from another disease-modifying therapy to Gilenia, its half-life and mechanism of action should be considered to avoid additive immune effects while minimizing the risk of disease reactivation. Complete blood count is recommended before initiating Gilenia to ensure that the effect of prior therapy on the immune system (i.e., cytopenia) has already been eliminated.

Interferon beta, glatiramer acetate, or dimethyl fumarate

Initiation of Gilenia can usually be started immediately after discontinuation of interferon beta, glatiramer acetate, or dimethyl fumarate. For dimethyl fumarate, the washout period should be sufficient for blood parameters to return to normal before initiation of Gilenia treatment.

Natalizumab or teriflunomide

Due to the long half-life of natalizumab, its elimination period usually lasts up to 2–3 months after discontinuation.

Teriflunomide is also slowly eliminated from plasma. Without accelerated elimination procedure, clearance of teriflunomide from plasma may take from several months to 2 years. As indicated in the summary of product characteristics for teriflunomide, an accelerated elimination procedure is recommended or alternatively a washout period of at least 3.5 months.

Caution should be exercised regarding potential concomitant effects on the immune system when switching patients from natalizumab or teriflunomide to Gilenia. Careful assessment of treatment initiation timing is recommended in each individual case.

Alemtuzumab

Alemtuzumab has a profound and prolonged immunosuppressive effect. Since the actual duration of this effect is unknown, initiation of Gilenia therapy after alemtuzumab use is not recommended except when the benefit of such treatment clearly outweighs the risks for a specific patient.

The decision regarding concomitant use of prolonged corticosteroid therapy should be carefully considered.

Concomitant use of potent CYP450 inducers

Fingolimod should be used with caution concomitantly with potent CYP450 inducers. Concomitant use with St. John's wort is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Malignant neoplasms

Skin tumors

Cases of basal cell carcinoma (BCC) and other skin tumors, including malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, and Merkel cell carcinoma, have been reported in patients receiving Gilenia (see section "Adverse reactions"). Enhanced monitoring for skin lesions is recommended, as well as medical skin evaluation at initiation of treatment and every 6–12 months, considering clinical assessment. In case of suspicious lesions, the patient should be referred to a dermatologist.

Since there is a potential risk of growth of malignant tumors, patients taking fingolimod should be warned about risks associated with unprotected sun exposure. Concomitant UV-B phototherapy or PUVA therapy (photochemotherapy) is contraindicated in these patients.

Lymphomas

Cases of lymphomas of various types have been reported in clinical trials and during post-marketing use (see section "Adverse reactions"). Reported cases were heterogeneous in nature, mainly non-Hodgkin's lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have been observed. A fatal case of Epstein-Barr virus (EBV)-positive B-cell lymphoma has also been reported. Therapy should be discontinued if lymphoma is suspected.

Tumefactive lesions

Rare cases of tumefactive lesions associated with relapse of multiple sclerosis have been reported in post-marketing settings. In case of severe relapses, MRI should be performed to rule out tumefactive lesions. Discontinuation of therapy should be considered by the physician in each individual case considering individual benefit and risks.

Disease reactivation (rebound) after discontinuation of fingolimod therapy

In the post-marketing period, severe exacerbation of the disease has been rarely observed in some patients who discontinued fingolimod. This usually occurred within 12 weeks after discontinuation of fingolimod, but also occurred within the period up to 24 weeks after discontinuation of fingolimod. Caution is also advised when discontinuing fingolimod therapy. If discontinuation of fingolimod is considered necessary, the possibility of rebound of extremely high disease activity should be considered. Therefore, patients should be monitored for appropriate signs and symptoms and appropriate treatment should be initiated if necessary.

Discontinuation of therapy

If a decision is made to discontinue treatment with Gilenia, a 6-week interval without medication is required due to the drug's half-life to eliminate fingolimod from the bloodstream (see section "Pharmacokinetics"). In most patients, lymphocyte count usually returns to the normal range within 1–2 months after discontinuation of treatment (see section "Pharmacodynamics"), although complete return to normal range in some patients may take significantly longer. Resumption of treatment during this period will result in concomitant exposure to fingolimod. Use of immunosuppressants shortly after discontinuation of Gilenia may lead to additive effects on the immune system, so caution is required.

Interference with serological tests

Since fingolimod reduces the number of lymphocytes in blood by redistributing them to secondary lymphoid organs, the peripheral blood lymphocyte count cannot be used to assess the status of lymphocyte subsets in patients who have received Gilenia treatment. For laboratory tests using circulating mononuclear cells, a larger blood volume is required due to the reduced number of circulating lymphocytes.

Children

The safety profile in pediatric patients is similar to that in adults; therefore, special precautions for adults also apply to children.

Specifically, the following should be noted when prescribing Gilenia to children:

• Observe precautions during the first dose administration (see "Bradycardia"). The same precautions as for the first dose are recommended when patients switch from a daily dose of 0.25 mg to 0.5 mg.
• In the controlled pediatric study D2311, seizures, anxiety, depressed mood, and depression were reported with higher frequency in patients receiving fingolimod compared to those receiving interferon beta-1a. Caution is required when using this subgroup (see section "Adverse reactions", Children).
• Mild isolated elevation of bilirubin has been observed in children receiving Gilenia.
• Pediatric patients are recommended to receive all vaccinations according to current vaccination recommendations before initiation of Gilenia therapy (see "Infections").
• There is very limited data on use in children aged 10 to 12 years with body weight less than 40 kg or Tanner stage < 2 (see sections "Adverse reactions" and "Pharmacodynamics"). Use in these subgroups requires caution due to very limited data available from clinical trials.
• Data on safety with long-term use in children are lacking.

Use during pregnancy or breastfeeding.

Women of childbearing potential/contraception in women

Due to the risk to the fetus, fingolimod is contraindicated in pregnant women and women of childbearing potential who do not use effective contraception (see section "Contraindications").

Before initiating treatment with Gilenia, women of childbearing potential should be informed about the serious risk to the fetus and the need for effective contraception during treatment and should have a negative pregnancy test result.

Women of childbearing potential should use effective contraceptive methods during treatment and for 2 months after discontinuation of Gilenia. Since elimination of fingolimod from the body takes about two months after discontinuation of treatment, the potential risk to the fetus may persist, so contraception should be continued during this period.

When discontinuing fingolimod therapy for planned pregnancy, possible reactivation of the disease should be considered.

Pregnancy

Post-marketing data suggest that in humans, use of fingolimod during pregnancy is associated with a twofold increased risk of major congenital malformations compared to the general population (2–3%; EUROCAT).

The most frequently reported major defects were:

• congenital heart defects, such as atrial and ventricular septal defects, tetralogy of Fallot;
• kidney function disorders;
• musculoskeletal disorders.

There are no data on the effect of fingolimod on labor and delivery.

In animal studies, reproductive toxicity, including fetal death and organ malformations, such as common arterial trunk and ventricular septal defect, has been demonstrated. Additionally, the receptor affected by fingolimod (sphingosine-1-phosphate receptor) is involved in vascular formation during embryogenesis.

As a result, fingolimod is contraindicated during pregnancy (see section "Contraindications"). Fingolimod should be discontinued 2 months before planned pregnancy.

If a woman becomes pregnant while taking Gilenia, administration of the drug should be discontinued. Medical consultation regarding the risk of harmful effects on the fetus associated with treatment and ultrasound examination should be provided.

Lactation period

Fingolimod penetrated into the milk of animals administered the drug during lactation at concentrations 2–3 times higher than plasma concentrations in maternal animals. Due to the possibility of serious adverse reactions to fingolimod in infants, women should discontinue breastfeeding during use of the drug.

Fertility

Preclinical study data do not indicate that fingolimod may be associated with an increased risk of reduced fertility.

Ability to affect reaction speed when driving or operating machinery.

Fingolimod has no effect or a negligible effect on the ability to drive vehicles and operate machinery.

However, dizziness or somnolence may occasionally occur at the beginning of therapy. At the beginning of treatment, it is recommended that patients be under supervision for 6 hours after dose administration (see section "Special precautions for use").

Method of Administration and Dosage

Treatment should be initiated and supervised by a physician experienced in the management of multiple sclerosis.

Dosage

The recommended dose of fingolimod for adults is 1 capsule of 0.5 mg taken orally once daily.

For children (aged 10 years and older), the recommended dose depends on body weight:

• For children with body weight ≤ 40 kg: 1 capsule of 0.25 mg (if such dosage strength is available) taken orally once daily;
• For children with body weight ≥ 40 kg: 1 capsule of 0.5 mg taken orally once daily.

Children who start treatment with 0.25 mg capsules (if such dosage strength is available) and subsequently reach a stable body weight above 40 kg should switch to 0.5 mg capsules.

When switching from a daily dose of 0.25 mg (if such dosage strength is available) to 0.5 mg, monitoring after the first dose is recommended, similar to the initiation of treatment.

The medicinal product is intended for oral administration.

Gilenya can be administered independently of food intake (see section "Pharmacokinetics"). Capsules should always be swallowed whole, without opening.

Monitoring after the first dose, similar to treatment initiation, is recommended in case of treatment interruption:

• For 1 day or more during the first 2 weeks of treatment;
• For more than 7 days during weeks 3 and 4 of treatment;
• For more than 2 weeks after one month of treatment.

If the treatment interruption is shorter than specified above, treatment should be continued with the next dose (see section "Special Instructions").

Dosage for Specific Patient Groups

Elderly Patients

Gilenya should be used with caution in patients aged 65 years and older due to insufficient data on safety and efficacy (see section "Pharmacokinetics").

Renal Impairment

The use of fingolimod in patients with multiple sclerosis and renal impairment has not been studied in clinical trials. Clinical pharmacology studies indicate that dose adjustment is not required in patients with mild to severe renal impairment.

Hepatic Impairment

Gilenya is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section "Contraindications"). Although dose adjustment is not required in patients with mild to moderate hepatic impairment, therapy should be initiated with caution in these patients (see sections "Special Instructions" and "Pharmacokinetics").

Children

The safety and efficacy of fingolimod in children under 10 years of age have not been established. No data are available.

Limited data exist on the use of the drug in children aged 10 to 12 years (see sections "Special Instructions", "Adverse Reactions", and "Pharmacokinetics").

Overdose

Single doses up to 80 times higher than the recommended dose (0.5 mg) were well tolerated by healthy volunteers. Following a 40 mg dose, 5 out of 6 subjects reported mild sensations of chest tightness or discomfort, clinically consistent with mild respiratory reactivity.

Fingolimod may induce bradycardia at the start of treatment. Heart rate typically begins to decrease within one hour after the first dose, with maximum reduction observed within 6 hours. The negative chronotropic effect of Gilenya persists beyond 6 hours and gradually diminishes over subsequent days of treatment. Reports of slowed atrioventricular conduction have been received, along with isolated cases of transient complete atrioventricular block that resolved spontaneously (see sections "Special Instructions" and "Adverse Reactions").

If overdose occurs upon first administration of Gilenya, it is essential to monitor the patient with prolonged ECG monitoring, hourly measurement of pulse rate and blood pressure for at least the first 6 hours (see section "Special Instructions").

Additionally, if the heart rate is < 45 beats per minute in adults, < 55 beats per minute in children aged 12 years and older, or < 60 beats per minute in children aged 10 to 12 years, or if second-degree or higher atrioventricular block or QTc interval ≥ 500 ms is observed on ECG 6 hours after the first dose, monitoring should be extended and continued at least overnight and until the observed abnormalities resolve. The occurrence of third-degree atrioventricular block at any time also requires extended monitoring, including overnight monitoring.

Dialysis or plasma exchange does not result in significant elimination of fingolimod from the body.

Adverse Reactions

Summary of Safety Profile

The most common adverse reactions (frequency ≥ 10%) observed with use at the dose of 0.5 mg were headache (24.5%), increased liver enzyme activity (15.2%), diarrhea (12.6%), cough (12.3%), influenza (11.4%), sinusitis (10.9%), and back pain (10.0%).

List of adverse reactions in tabular form

Adverse reactions reported in clinical trials, as well as those known from post-marketing experience through spontaneous case reports or published literature, are listed below. Adverse reactions are listed by frequency: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are presented in order of decreasing severity.

Infections and infestations
Very common	influenza virus infections, sinusitis
Common	herpes virus infections, bronchitis, pityriasis versicolor
Uncommon	pneumonia
Unknown	progressive multifocal leukoencephalopathy (PML)**, cryptococcal infections**
Benign, malignant and unspecified neoplasms (including additional cysts and polyps)
Common	basal cell carcinoma
Uncommon	malignant melanoma****
Rare	lymphoma***, squamous cell carcinoma****
Very rare	Kaposi's sarcoma****
Unknown	Merkel cell carcinoma***
Blood and lymphatic system disorders
Common	lymphopenia, leukopenia
Uncommon	thrombocytopenia
Unknown	autoimmune hemolytic anemia***, peripheral edema***
Immune system disorders
Unknown	hypersensitivity reactions, including rash, urticaria, and angioedema after initiation of treatment***
Psychiatric disorders
Common	depression
Uncommon	depressed mood
Nervous system disorders
Very common	headache
Common	dizziness, migraine
Uncommon	seizures
Rare	reversible posterior encephalopathy syndrome (PRES)*
Unknown	severe exacerbation of disease after fingolimod discontinuation***
Eye disorders
Common	blurred vision
Uncommon	macular edema
Cardiac disorders
Common	bradycardia, atrioventricular block
Very rare	T-wave inversion***
Vascular disorders
Common	arterial hypertension
Respiratory, thoracic and mediastinal disorders
Very common	cough
Common	dyspnea

Disorders of the digestive system
Very common	diarrhea
Uncommon	nausea***
Disorders of the liver and biliary system
Unknown	acute liver failure***
Disorders of the skin and subcutaneous tissue
Common	eczema, alopecia, pruritus
Disorders of the musculoskeletal and connective tissue
Very common	back pain
Common	myalgia, arthralgia
General disorders and administration site conditions
Common	asthenia
Abnormal laboratory findings
Very common	increased liver enzyme activity (increased levels of alanine aminotransferase, gamma-glutamyl transferase, aspartate aminotransferase)
Common	weight decrease***, increased blood triglyceride levels
Uncommon	decreased neutrophil count
*Frequency category is based on estimated exposure in approximately 10,000 patients who received fingolimod in all clinical trials. **PML and cryptococcal infections, including cases of cryptococcal meningitis, were observed in the post-marketing experience. ***Adverse reactions from spontaneous reports and publications. ****Frequency category and risk assessment were based on estimated exposure to 0.5 mg fingolimod in over 24,000 patients during clinical trials.

Description of individual adverse reactions

Infections

In clinical trials of multiple sclerosis, the overall incidence of infections (65.1%) with the 0.5 mg dose was similar to that with placebo. However, lower respiratory tract infections, primarily bronchitis, and to a lesser extent herpes virus infections, and pneumonia occurred more frequently in patients receiving fingolimod.

Several cases of disseminated herpes infection, including fatal cases, were observed even with the 0.5 mg dose.

During the post-marketing period, cases of infections caused by opportunistic microorganisms have been reported, including viral (including varicella zoster virus [VZV], John Cunningham virus [JC virus], which causes progressive multifocal leukoencephalopathy, herpes simplex virus [HSV]), fungal (including yeast-like fungi, such as cryptococcal meningitis), or bacterial (including atypical mycobacteria), some of which were fatal (see section "Special precautions for use").

Cases of human papillomavirus (HPV) infection, including papilloma, dysplasia, warts, and HPV-related cancers, have been reported during post-marketing use of fingolimod (see section "Special precautions for use"). Due to the immunosuppressive properties of fingolimod, HPV vaccination should be considered prior to initiating treatment with fingolimod, in accordance with vaccination guidelines. Screening for cancer, including Pap testing, is recommended according to standard of care.

Macular edema

In clinical trials of multiple sclerosis, macular edema occurred in 0.5% of patients receiving the recommended dose of 0.5 mg and in 1.1% of patients receiving the maximum dose of 1.25 mg. Most cases occurred within the first 3–4 months of treatment. Some patients developed blurred vision or decreased visual acuity, while in others the condition was asymptomatic and diagnosed during routine ophthalmological examination. Macular edema generally decreased or resolved spontaneously after discontinuation of therapy. The risk of recurrence upon re-initiation of the drug has not been evaluated.

The incidence of macular edema is increased in patients with a history of multiple sclerosis and uveitis (17% in those with a history of uveitis compared to 0.6% in those without). The use of Gilenya in patients with multiple sclerosis and diabetes, a condition associated with an increased risk of macular edema, has not been studied. In kidney transplant studies involving patients with diabetes, treatment with Gilenya at doses of 2.5 mg and 5 mg was associated with a two-fold increase in the incidence of macular edema.

Bradycardia

Initiation of fingolimod treatment is associated with a transient decrease in heart rate and may also be associated with atrioventricular conduction delay. In clinical trials of multiple sclerosis, the maximum decrease in heart rate occurred 6 hours after initiation of treatment, with a mean reduction in heart rate of 12–13 beats per minute during treatment with fingolimod 0.5 mg. Heart rates below 40 beats per minute in adults and below 50 beats per minute in children were infrequently observed in patients receiving Gilenya 0.5 mg. On average, heart rate returned to baseline within 1 month of continuous treatment. Bradycardia was generally asymptomatic, but some patients experienced mild or moderate symptoms, including hypotension, dizziness, weakness, and/or palpitations, which resolved within the first 24 hours after treatment initiation (see sections "Special precautions for use" and "Pharmacodynamics").

In clinical trials of multiple sclerosis, first-degree atrioventricular block (prolonged PR interval on ECG) occurred after treatment initiation in 4.7% of patients treated with Gilenya 0.5 mg, in 2.8% of patients treated with intramuscular interferon beta-1a, and in 1.6% of placebo-treated patients. Second-degree atrioventricular block was observed in less than 0.2% of patients treated with fingolimod 0.5 mg. According to post-marketing surveillance data, isolated cases of transient complete atrioventricular block, which resolved spontaneously, occurred 6 hours after the first dose of Gilenya. Patients recovered without symptomatic treatment. Conduction disturbances observed in clinical trials and during post-marketing surveillance were mostly transient, asymptomatic, and resolved within the first 24 hours after treatment initiation. Although most patients did not require medical intervention, one patient receiving fingolimod 0.5 mg was treated with isoprenaline for asymptomatic second-degree atrioventricular block, Mobitz type I.

During post-marketing surveillance, rare delayed events occurred within 24 hours after the first dose, including transient asystole and a fatal case of unknown cause. In these cases, concomitant medications were used and/or patients had other underlying conditions. A causal relationship to Gilenya administration has not been established.

Blood pressure

In clinical trials of multiple sclerosis, treatment with fingolimod 0.5 mg was associated with a slight increase of approximately 3 mm Hg in mean systolic blood pressure and approximately 1 mm Hg in diastolic blood pressure, observed about 1 month after treatment initiation. This elevation persisted during continued treatment. Hypertension was observed in 6.5% of patients receiving fingolimod 0.5 mg and in 3.3% of patients receiving placebo. During post-marketing surveillance, cases of hypertension were reported within the first month after treatment initiation and on the first day of treatment, which may have required antihypertensive treatment or discontinuation of Gilenya (see also section "Special precautions for use").

Liver function

Elevations in liver enzymes have been reported in patients with multiple sclerosis receiving Gilenya. In clinical trials of multiple sclerosis, asymptomatic elevations in serum ALT levels greater than 3 times the upper limit of normal (ULN) and greater than 5 times ULN occurred in 8.0% and 1.8% of patients receiving fingolimod 0.5 mg, respectively. Recurrent elevations in liver transaminases were observed in some cases upon re-initiation of treatment, confirming an association with the drug. In clinical trials, transaminase elevations occurred at any time during treatment, although most cases occurred within the first 12 months. ALT levels returned to normal within approximately 2 months after discontinuation of therapy. In a small number of patients (N = 10 for 1.25 mg, N = 2 for 0.5 mg) with ALT elevations greater than 5 times ULN who continued fingolimod treatment, ALT levels normalized within approximately 5 months (see also section "Special precautions for use", Hepatic effects).

Nervous system disorders

Rare cases of nervous system disorders were observed in patients treated with Gilenya at high doses (1.25 or 5.0 mg) in clinical trials, including ischemic and hemorrhagic stroke and atypical neurological disorders such as acute disseminated encephalomyelitis (ADEM)-like symptoms.

Cases of seizures, including status epilepticus, have been reported during clinical trials and in post-marketing use of fingolimod.

Vascular reactions

Peripheral arterial occlusive disease was rarely observed in patients receiving Gilenya at higher doses (1.25 mg).

Respiratory system

Minor dose-dependent reductions in forced expiratory volume (FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) were observed during the first month of treatment with Gilenya and remained stable thereafter. At 24 months of treatment, the percentage reduction from predicted baseline FEV1 was 2.7% in patients receiving fingolimod 0.5 mg and 1.2% in placebo-treated patients, with the difference being that this effect resolved after discontinuation of treatment. For DLCO, the reduction at 24 months was 3.3% in patients receiving fingolimod 0.5 mg and 2.7% in placebo-treated patients.

Lymphomas

Cases of various types of lymphoma have been reported in clinical trials and post-marketing use, including a fatal case of Epstein-Barr virus (EBV)-positive B-cell lymphoma. In clinical trials, the incidence of lymphoma (B-cell and T-cell) was higher than expected in the general population.

Post-marketing studies have also reported cases of T-cell lymphoma (mycosis fungoides) (see also section "Special precautions for use", Lymphomas).

Hemophagocytic syndrome

Very rare cases of hemophagocytic syndrome (HPS) with fatal outcome have been reported in patients receiving fingolimod who developed infections. HPS is a rare condition described in association with infections, immunosuppression, and various autoimmune diseases.

Children

In the controlled pediatric study D2311, the safety profile in children aged 10 to 18 years receiving 0.25 mg or 0.5 mg of fingolimod daily was generally similar to that in adult patients. However, a higher incidence of neurological and psychiatric disorders was observed. Caution is advised in this subgroup due to the very limited data available from clinical trials.

Seizures occurred in 5.6% of patients receiving fingolimod and in 0.9% of patients receiving interferon beta-1a in the pediatric study.

Depression and anxiety are known to occur with increased frequency in patients with multiple sclerosis. Depression and anxiety have also been reported in children receiving fingolimod.

Mild isolated elevations in bilirubin have been observed in children taking fingolimod.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions via the national adverse reaction reporting systems.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging to protect from moisture. Keep out of the reach and sight of children.

Packaging.

7 capsules in a blister; 1 blister in a cardboard box.

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

Prescription status.

Prescription only.

Manufacturer.

Novartis Pharma Stein AG / Novartis Pharma Stein AG.

Manufacturer's address and location of operations.

Schaffhauserstrasse, 4332 Stein, Switzerland / Schaffhauserstrasse, 4332 Stein, Switzerland.