Fingelia

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

Composition:

Active substance: fingolimod;

1 hard capsule contains 0.56 mg of fingolimod hydrochloride, equivalent to 0.5 mg of fingolimod;

Excipients: tricalcium phosphate 250, tricalcium phosphate 500, stearic acid 50;

capsule shell composition: gelatin, titanium dioxide (E 171), iron oxide yellow (E 172);

Composition of ink: black ink (shellac, iron oxide black (E 172)).

Pharmaceutical form. Hard capsules.

Main physico-chemical properties: hard gelatin capsule with a yellow opaque cap and a white opaque body; printed with the marking "0.5 mg" on the cap in black ink.

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 located on lymphocytes. It readily crosses the blood-brain barrier to bind to S1P type 1 receptors located on neural cells in the central nervous system (CNS). Acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the ability of lymphocytes to exit lymph nodes, resulting in redistribution rather than depletion of lymphocytes. Animal studies have shown that this redistribution reduces the infiltration of pathogenic lymphocyte cells, 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 act via interaction with S1P receptors on neural cells.

Pharmacodynamic Effects

Within 4–6 hours after the first dose of 0.5 mg fingolimod, 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 minimum of approximately 500 cells/μL or about 30% of baseline. In 18% of patients, the minimum lymphocyte count fell below 200 cells/μL at least once. The low lymphocyte count is maintained during continuous daily treatment. Most T- and B-lymphocytes regularly circulate through lymphoid organs, and these cells are primarily affected by fingolimod. Approximately 15–20% of T-lymphocytes have an effector memory phenotype, which is important for maintaining peripheral immune surveillance. Since this lymphocyte subset typically does not regularly pass through lymphoid organs, it is not significantly affected by fingolimod. An increase in peripheral lymphocyte count is observed within several days after discontinuation of fingolimod treatment, with return to normal levels occurring within 1–2 months. Continuous fingolimod use leads to 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 Warnings and Precautions for Use" and "Adverse Reactions"). The maximum reduction in heart rate occurs within the first 6 hours after dose administration, with about 70% of the negative chronotropic effect achieved on the first day. With continued treatment, heart rate returns to baseline within 1 month. The heart rate reduction induced by fingolimod 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 no increase in the frequency of atrial fibrillation/flutter, ventricular arrhythmias, or ectopy. Fingolimod treatment is not associated with a reduction in 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 depletion. 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 inward rectifying potassium channel or G-protein-activated inwardly rectifying K+ channel (IKACh/GIRK), while vasoconstriction is likely mediated by a mechanism dependent on Rho-kinase and calcium.

Treatment with single or multiple doses of 0.5 mg and 1.25 mg fingolimod over two weeks is not associated with a significant increase 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 a dose-dependent increase in airway resistance. Repeated administration of fingolimod at doses of 0.5 mg, 1.25 mg, or 5 mg is not associated with impaired oxygenation or exercise-induced hypoxia, nor with increased airway sensitivity to methacholine. Individuals taking fingolimod exhibit a normal bronchodilator response to inhaled beta-agonists.

Pharmacokinetics

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

The pharmacologically active metabolite is fingolimod phosphate.

Absorption

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

Food intake does not affect the maximum concentration (Cmax) or exposure (AUC) of fingolimod. The Cmax of fingolimod phosphate was slightly increased (by 34%), while AUC remained unchanged; therefore, fingolimod 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 involving four healthy volunteers who received a single intravenous dose of a radiolabeled iodine analog of fingolimod demonstrated that fingolimod reaches the brain. In 13 male patients with multiple sclerosis receiving fingolimod 0.5 mg daily, 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, biotransformation of fingolimod occurs via reversible 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 in blood, based on their contribution to the AUC of total radiolabeled components over 34 days post-dose, 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 (T½) is 6–9 days. Fingolimod and fingolimod phosphate decline similarly during the terminal phase, resulting in comparable elimination 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

The concentrations of fingolimod and fingolimod phosphate increase almost proportionally to dose after multiple administrations of 0.5 mg and 1.25 mg once daily.

Characteristics in Specific Patient Populations

Sex, Ethnic Origin, and Renal Impairment

The pharmacokinetics of fingolimod and fingolimod phosphate do not differ between men and women, among patients of different ethnic origins, 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 Cmax of fingolimod were observed, but AUC increased by 12%, 44%, and 103%, respectively. In patients with severe hepatic impairment (Child–Pugh class C), Cmax of fingolimod phosphate was reduced by 22%, and 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). This medicinal product 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; therefore, fingolimod should be used with caution in this age group.

Pediatric Population

In pediatric patients (aged 10 years and older), the concentration of fingolimod phosphate appears to increase dose-proportionally within the 0.25–0.5 mg range.

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 this medicinal product in children under 10 years of age.

Clinical characteristics.

Indications.

The medicinal product Fingelia is indicated as 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 full and adequate (at least one year) course of treatment with at least one disease-modifying agent (exceptions and information on washout periods are provided in sections “Pharmacological properties” and “Special precautions”) has not demonstrated therapeutic efficacy.

• 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 at increased risk of opportunistic infections, including patients with impaired immunity (including those undergoing immunosuppressive therapy or patients with pre-existing immunodeficiency prior to treatment).

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

Contraindicated in patients with malignancies.

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

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

Myocardial infarction that occurred within the past 6 months.

Unstable angina.

Stroke. Transient ischemic attack.

Decompensated heart failure requiring hospitalization.

Heart failure class III/IV according to the New York Heart Association classification.

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

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

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 required when switching from prolonged-action immunomodulatory therapies 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 incidence of infections.

Vaccination

Vaccination may be less effective during treatment with Fingelia and for 2 months after discontinuation of therapy. Administration 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 concomitantly with medicinal products that reduce heart rate, such as atenolol and diltiazem, has been studied. In interaction studies in healthy volunteers, co-administration of fingolimod with atenolol resulted in an additional 15% reduction in heart rate at the beginning of fingolimod treatment; this effect was not observed with diltiazem. Concomitant use of the medicinal product is contraindicated in patients receiving beta-blockers or other medicinal products that may reduce heart rate, such as class Ia and III antiarrhythmics, calcium channel blockers (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 Fingelia is planned, consultation with a cardiologist is recommended regarding switching the patient to agents that do not reduce heart rate or appropriate monitoring at treatment initiation. Monitoring for at least one night is recommended if the concomitant agent reducing heart rate cannot be discontinued.

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

Pharmacokinetic effect of other medicinal products on fingolimod

Fingolimod is primarily metabolized by CYP4F2. Other enzymes, such as CYP3A4, may also be involved in its metabolism, particularly in cases of strong CYP3A4 induction. Significant effects of potent transporter protein inhibitors on fingolimod distribution are not expected. Concomitant administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in AUC of fingolimod and fingolimod phosphate due to inhibition of CYP4F2. Caution should be exercised when prescribing fingolimod concomitantly with medicinal products 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 medicinal products 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 CYP2D6 inhibitors), or carbamazepine (potent enzyme inhibitor) on fingolimod and fingolimod phosphate. Furthermore, 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 them to secondary lymphoid organs, peripheral blood lymphocyte count cannot be used to assess lymphocyte status.

Laboratory testing of circulating mononuclear cells may require larger blood volumes due to reduced circulating lymphocyte count.

Pharmacokinetic interactions of fingolimod with other substances

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

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

Special precautions for use.

Bradycardia

Initiation of fingolimod treatment is associated with a transient decrease in heart rate and may also be associated with atrioventricular conduction delay. There have been isolated reports of transient complete atrioventricular block (AV block) that resolves spontaneously (see sections "Pharmacodynamics" and "Adverse reactions").

Following the first dose, reduction in heart rate begins within 1 hour and reaches its maximum around 6 hours. This effect persists for several subsequent days, although symptoms are usually milder and resolve within a few weeks. With continued treatment, heart rate typically returns to baseline levels within 1 month, although in some patients it may not return to baseline by the end of the first month. Pathological conduction abnormalities have generally been transient and asymptomatic, did not require treatment, and resolved within the first 24 hours with continued therapy. If needed, fingolimod-induced bradycardia can be reversed by parenteral administration of atropine or isoprenaline.

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

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

If symptoms of post-dose bradycardia occur, appropriate treatment should be administered and the patient monitored until symptoms resolve. If pharmacological intervention is required during the observation period after the first dose, monitoring should continue overnight in a medical setting, and observation should also be conducted after the second dose of Fingelia.

If the heart rate at the 6th hour is the lowest since the first dose (maximum pharmacodynamic effect on the heart may not yet have occurred), monitoring should be extended for at least 2 additional hours and until the heart rate increases again. Furthermore, 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 the ECG shows development of second-degree or higher AV block, or QTc interval ≥ 500 ms, expanded monitoring (at least overnight) should be performed until symptoms resolve. The occurrence of third-degree AV block at any time also requires expanded 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 time since the start of drug administration. 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 reports 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, consultation with a cardiologist is recommended.

Due to the risk of serious cardiac arrhythmias or marked bradycardia, the medicinal product Fingelia 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").

Administration of Fingelia to such patients should only be considered if the expected benefit outweighs the potential risk.

Prior to initiating treatment, consultation with a cardiologist regarding appropriate monitoring is recommended, as well as expanded monitoring, at least overnight (see also section "Interaction with other medicinal products and other forms of interaction").

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

Experience with the use of Fingelia in patients receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce heart rate (such as verapamil or diltiazem), or other medicinal products 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 section "Adverse reactions" ("Bradycardia")), concomitant use of these medicinal products at the beginning of Fingelia treatment may be associated with the development of severe bradycardia and heart block. Due to the potential additive effect on heart rate, Fingelia should generally not be prescribed to patients receiving concomitant therapy with these medicinal products (see also section "Interaction with other medicinal products and other forms of interaction"). Prescribing Fingelia to these patients is possible only if the expected benefit outweighs the potential risk. If Fingelia is prescribed, consultation with a cardiologist regarding switching the patient to treatment with agents that do not reduce heart rate is recommended. If treatment with heart rate-lowering agents cannot be discontinued, consultation with a cardiologist regarding appropriate monitoring of the first dose and expanded 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 of fingolimod at doses of 1.25 mg or 2.5 mg at steady state, when the negative chronotropic effect of fingolimod was still present, administration of this medicinal product resulted in QTc prolongation with an upper bound of the 90% CI ≤ 13.0 ms.

There is no dose- or exposure-response relationship for QTc prolongation with fingolimod. There is no signal indicating an increased frequency of QTc interval deviations, whether absolute change or change from 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 prolongation were not included in clinical trials.

Patients with relevant risk factors, such as hypokalemia or congenital QT prolongation, are advised to avoid using medicinal products that may lead to QTc 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 cancers. Physicians should carefully monitor patients, particularly those with comorbidities or known risk factors such as prior 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 neoplasms") and "Adverse reactions" ("Lymphoma")).

Infections

The primary pharmacodynamic effect of fingolimod is a 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").

Prior to initiating Fingelia, the results of the most recent complete blood count (i.e., performed within the last 6 months or after discontinuation of the previous treatment course) must 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 the absolute lymphocyte count is confirmed to be < 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 an absolute lymphocyte count < 0.2 × 10⁹/L.

Fingolimod should not be initiated in patients with an active acute infectious disease until its resolution.

The effect of Fingelia 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 having an infection that may be serious, consideration should be given to consulting a physician experienced in treating such infections. During the period of Fingelia use, patients should be informed about the need to immediately report symptoms of infectious diseases to their physician.

Fingelia should be temporarily discontinued in case of development of a serious infectious disease, and the benefit-risk ratio should be evaluated before resuming therapy.

After discontinuation of treatment, elimination of fingolimod from the body may take up to 2 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 fingolimod treatment. In case of herpes encephalitis, meningitis, or meningoencephalitis, fingolimod should be discontinued and appropriate treatment for the respective infection should be initiated.

Prior to initiating Fingelia, the immune 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 prior to starting fingolimod therapy. It is recommended that patients with negative antibody test results receive a complete course of chickenpox vaccination prior to initiating Fingelia (see section "Adverse reactions"), and initiation of fingolimod treatment should be delayed by 1 month to allow for full vaccine effect.

Cryptococcal meningitis

Cases of cryptococcal meningitis (fungal infection), sometimes fatal, have been reported during the post-marketing period approximately 2–3 years after treatment initiation, 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 diagnosed cryptococcal meningitis, fingolimod treatment should be discontinued and appropriate therapy 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 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 severe disability or death. Cases of PML have been reported after 2–3 years of monotherapy without prior natalizumab use, although the exact relationship with treatment duration is unknown. Additional cases of PML occurred in patients who had previously received natalizumab, which is known to be associated with PML. PML can develop only 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 noted that a negative JC virus antibody test result does not exclude the possibility of subsequent JC viral infection. Prior to initiating fingolimod treatment, baseline MRI results should be available (typically MRI 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 monitoring measures for patients at risk of developing PML. Cases of asymptomatic PML based on MRI results and positive JC virus DNA testing in cerebrospinal fluid have been reported in patients receiving fingolimod. In case of suspicion of PML, a diagnostic MRI should be performed immediately and fingolimod therapy should be suspended until PML is ruled out.

Human papillomavirus (HPV)

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

Macular edema

Macular edema, with or without ocular symptoms, was reported in 0.5% of patients treated with fingolimod 0.5 mg (see section "Adverse reactions"). Macular edema was most commonly observed within the first 3–4 months of treatment.

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

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

Continuation of fingolimod in patients with macular edema has not been evaluated. In case of macular edema development, discontinuation of treatment is recommended. When considering resumption of therapy after resolution of macular edema, the potential benefit and risks should be weighed 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. Isolated cases of acute liver failure requiring liver transplantation and clinically significant liver injury have also been reported. Signs of liver injury, including significant elevations in serum liver enzymes and increased total bilirubin levels, were observed as early as 10 days after the first dose and also after prolonged use of the medicinal product. In clinical trials, 8% of patients receiving fingolimod 0.5 mg experienced ALT elevations > 3 times the upper limit of normal (ULN) compared to 1.9% of patients receiving placebo. Fivefold ULN elevations were 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 5 times the ULN. Recurrent elevations in liver transaminases were observed upon resumption of fingolimod treatment in some patients, confirming the association of this adverse event with fingolimod use. In clinical trials, transaminase elevations occurred at any time during treatment, although most cases were observed within the first 12 months. Elevated serum transaminase levels returned to normal approximately within 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). Fingelia 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 resolution.

Recent (i.e., obtained within the last 6 months) test results for transaminase and bilirubin levels should be available prior to initiating Fingelia. In the absence of clinical symptoms, monitoring of liver transaminase activity and serum bilirubin levels should be performed at 1, 3, 6, 9, and 12 months of treatment and then periodically up to 2 months after discontinuation of fingolimod. 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 increases occur and to identify alternative etiologies of liver dysfunction. If liver transaminase levels exceed ULN by at least 5 times or at least 3 times the ULN associated with any increase in serum bilirubin, fingolimod administration should be discontinued. Monitoring of liver function should continue. Upon normalization of serum transaminase levels (including if an alternative cause of liver dysfunction is identified), fingolimod administration 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 checked immediately, 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 parameters with Fingelia use in patients with pre-existing liver disease, caution should be exercised when prescribing Fingelia to patients with significant liver disease in their history.

Effect on blood pressure

Special precautions should be observed when administering fingolimod to patients with arterial hypertension not controlled by medication, who were not included in pre-marketing clinical trials.

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

Respiratory effects

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

Posterior reversible encephalopathy syndrome (PRES)

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported during clinical trials and in 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, altered mental status, visual disturbances, and seizures. PRES symptoms are usually reversible but may progress to ischemic stroke or intracerebral hemorrhage. Delay in diagnosis and treatment may lead to irreversible neurological consequences. If PRES is suspected, the drug should be discontinued.

Prior immunosuppressant or immunomodulator therapy

No studies have been conducted to evaluate the efficacy and safety of Fingelia use when switching patients from teriflunomide, dimethyl fumarate, or alemtuzumab to fingolimod. When switching patients from another disease-modifying therapy to Fingelia, 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. A complete blood count is recommended prior to initiating Fingelia to ensure that the effect of prior therapy on the immune system (i.e., cytopenia) has already resolved.

Interferon beta, glatiramer acetate, or dimethyl fumarate

Fingolimod administration can usually be initiated 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 initiating Fingelia.

Natalizumab or teriflunomide

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

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

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

Alemtuzumab

Alemtuzumab exerts a profound and prolonged immunosuppressive effect. Since the actual duration of this effect is unknown, initiating Fingelia therapy after alemtuzumab use is not recommended, except in cases where the benefit clearly outweighs the risks for a specific patient.

The decision regarding concomitant use of prolonged courses of corticosteroids 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").

Malignancies

Skin neoplasms

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

Since there is a potential risk of malignant tumor growth, 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 various types of lymphomas have been reported in clinical trials and during post-marketing use (see section "Adverse reactions"). The reported cases were heterogeneous in nature, primarily 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 multiple sclerosis relapse 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, taking into account individual benefit and risks.

Disease activity rebound after discontinuation of fingolimod therapy

In the post-marketing period, severe disease exacerbation 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. 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 initiated if necessary.

Discontinuation of therapy

If a decision is made to discontinue Fingelia, a 6-week drug-free interval is required due to the drug's elimination half-life to clear 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. Resuming treatment during this period will lead to concomitant exposure to fingolimod. Use of immunosuppressants shortly after discontinuation of Fingelia may lead to additive effects on the immune system, so caution is required.

Effect on serological testing

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 lymphocyte subset status in patients who have received fingolimod. 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, when prescribing Fingelia to children, the following should be considered:

• Adhere to precautions during 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 occurred more frequently in patients receiving fingolimod compared to those receiving interferon beta-1a. Caution is required when using the medicinal product in this subgroup (see section "Adverse reactions" ("Children")).
• Mild isolated bilirubin elevation has been observed in children receiving fingolimod.
• Pediatric patients are recommended to complete all vaccinations according to current recommendations before initiating Fingelia (see "Infections").
• There is very limited data on the use of the medicinal product in children aged 10 to 12 years with body weight less than 40 kg or Tanner stage < 2 (see sections "Pharmacodynamics" and "Adverse reactions"). Use of the medicinal product in these subgroups requires caution due to very limited data available from clinical trials.
• Safety data for 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").

Prior to initiating Fingelia, women of childbearing potential should be informed about the serious risk to the fetus and the need for effective contraception during use of the medicinal product and should have a negative pregnancy test result.

Women of childbearing potential should use effective contraception during treatment and for 2 months after discontinuation of the drug. Since elimination of fingolimod from the body takes approximately 2 months after discontinuation of treatment, the potential risk to the fetus may persist; therefore, contraception should be continued during this period.

When discontinuing fingolimod therapy for pregnancy planning, the possible return of disease activity should be considered.

Pregnancy

Post-marketing data suggest that in humans, fingolimod use 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.

Animal studies have demonstrated reproductive toxicity, including fetal death and organ malformations, particularly persistent truncus arteriosus and ventricular septal defect. 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 Fingelia, it is recommended to discontinue the drug.

Medical consultation regarding the risk of harmful effects on the fetus associated with treatment and ultrasound examination should be provided.

Period of breastfeeding

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

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 fingolimod therapy. At the beginning of treatment, patients are recommended to 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 conducted under the supervision of 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. The medicinal product Fingelia can be administered regardless of food intake (see section "Pharmacokinetics"). Capsules should always be swallowed whole and must not be opened.

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 should be repeated as at the initiation of treatment.

Monitoring after the first dose, as at treatment initiation, is recommended in the 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 Warnings and Precautions for Use").

Dosage in Specific Patient Populations

Renal Impairment

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

Hepatic Impairment

Fingelia 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 "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Elderly Patients

Fingelia should be used with caution in patients aged 65 years and older due to limited data on safety and efficacy (see section "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 are available on the use of the medicinal product in children aged 10 to 12 years (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use", and "Undesirable Effects").

Overdose

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

Fingolimod may induce bradycardia upon initiation 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 fingolimod persists for more than 6 hours and gradually diminishes over subsequent days of treatment. Cases of slowed atrioventricular conduction have been reported, along with isolated reports of transient complete atrioventricular (AV) block that resolved spontaneously (see sections "Special Warnings and Precautions for Use" and "Undesirable Effects").

If overdose occurs upon first administration of Fingelia, 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 Warnings and Precautions for Use").

Additionally, if 6 hours after dosing 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 10–12 years, or if second-degree or higher AV block is observed on ECG 6 hours after the first dose, or if QTc interval ≥ 500 ms, monitoring should be extended and continued at least overnight and until the observed abnormalities resolve. The occurrence of third-degree AV 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

Brief Summary of Safety Profile

The most common adverse reactions (frequency ≥10%) observed during administration of the medicinal product at a 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

Adverse reactions reported in clinical trials, as well as those known from post-marketing experience via spontaneous reports of adverse events or published literature, are listed below.

Adverse reactions are categorized according to frequency of occurrence: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Infections and infestations:

very common – influenza virus infections, sinusitis;
common – herpes virus infections, bronchitis, shingles;
uncommon – pneumonia;
frequency not known – cryptococcal infections**, progressive multifocal leukoencephalopathy (PML)**.

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****;
frequency not known – Merkel cell carcinoma***.

Blood and lymphatic system disorders:

common – lymphopenia, leukopenia;
uncommon – thrombocytopenia;
frequency not known – autoimmune hemolytic anemia***, peripheral edema***.

Immune system disorders:

frequency not known – hypersensitivity reactions, including rash, urticaria, and Quincke's edema, occurring after initiation of treatment***.

Psychiatric disorders:

common – depression;
uncommon – mood depression.

Nervous system disorders:

very common – headache;
common – dizziness, migraine;
uncommon – seizures;
rare – reversible posterior leukoencephalopathy syndrome (PRES)*;
frequency not known – severe exacerbation of disease after discontinuation of fingolimod***.

Eye disorders:

common – blurred vision;
uncommon – macular edema.

Cardiac disorders:

common – bradycardia, AV block;
very rare – T-wave inversion***.

Vascular disorders:

common – arterial hypertension.

Respiratory, thoracic and mediastinal disorders:

very common – cough;
common – dyspnea.

Gastrointestinal disorders:

very common – diarrhea;
uncommon – nausea***.

Hepatobiliary disorders:

frequency not known – acute liver failure***.

Skin and subcutaneous tissue disorders:

common – eczema, alopecia, pruritus.

Musculoskeletal and connective tissue disorders:

very common – back pain;
common – myalgia, arthralgia.

General disorders and administration site conditions:

common – asthenia.

Investigations:

very common – increased liver enzyme activity (elevated levels of ALT, GGT, AST);
common – decreased body weight***, increased blood triglyceride levels;
uncommon – decreased neutrophil count.

* Frequency category based on estimated exposure of approximately 10,000 patients receiving fingolimod across all clinical trials.
** PML and cryptococcal infections, including cases of cryptococcal meningitis, observed in post-marketing experience.
*** Adverse reactions from spontaneous reports and published literature.
**** Frequency category and risk assessment based on estimated exposure to fingolimod 0.5 mg in over 24,000 patients during clinical trials.

Description of Selected Adverse Reactions

Infections

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

Several cases of disseminated herpes infection, including fatal cases, have been 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 (e.g., varicella zoster virus [VZV], John Cunningham virus [JC virus] causing 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 Warnings and Precautions for Use").

Cases of human papillomavirus (HPV) infection, including papillomas, dysplasia, warts, and HPV-related cancers, have been reported during post-marketing use of fingolimod (see section "Special Warnings and Precautions for Use").

Due to the immunosuppressive properties of fingolimod, HPV vaccination should be considered prior to initiating treatment, in accordance with vaccination guidelines. Screening for cancer, including Pap testing, is recommended according to standard care practices.

Macular Edema

In clinical trials of multiple sclerosis, macular edema occurred in 0.45% 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 typically decreased or resolved spontaneously after discontinuation of therapy. The risk of recurrence upon re-initiation of treatment has not been evaluated.

The risk of macular edema is increased in patients with a history of multiple sclerosis and uveitis (17% in those with prior uveitis compared to 0.6% in those without). The use of fingolimod in patients with multiple sclerosis and diabetes, a condition associated with increased risk of macular edema, has not been studied. In kidney transplant studies involving patients with diabetes, treatment with fingolimod at doses of 2.5 mg and 5 mg was associated with a twofold 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 delayed atrioventricular conduction. In clinical trials of multiple sclerosis, the maximum reduction in heart rate occurred 6 hours after initiation of treatment, with a mean decrease of 12–13 beats per minute when using fingolimod 0.5 mg. Heart rates below 40 beats per minute in adults and below 50 beats per minute in children were rarely observed in patients receiving fingolimod 0.5 mg. Heart rate typically returned to baseline within 1 month of continuous treatment. Bradycardia was generally asymptomatic, but some patients experienced mild to moderate symptoms, including hypotension, dizziness, weakness, and/or palpitations, which resolved within the first 24 hours after treatment initiation (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

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

During post-marketing surveillance, delayed events within 24 hours after the first dose, including transient asystole and one fatal case of unknown cause, have been reported. Concomitant medications and/or underlying medical conditions were present in these cases. A causal relationship with fingolimod administration has not been established.

Blood Pressure

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

Liver Function

Elevations in liver enzyme levels have been reported in patients with multiple sclerosis receiving fingolimod. In clinical trials of multiple sclerosis, asymptomatic increases in serum ALT levels exceeding 3 times the upper limit of normal (ULN) occurred in 8.0% of patients and exceeding 5 times ULN in 1.8% of patients receiving fingolimod 0.5 mg. Recurrent elevations in liver transaminases were observed in some cases upon re-initiation of treatment, confirming the association with the medicinal product. 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 exceeding 5 times ULN who continued fingolimod treatment, ALT levels normalized within approximately 5 months (see also section "Special Warnings and Precautions for Use" ("Hepatic Injury")).

Nervous System Disorders

Rare cases of nervous system disorders were observed in patients receiving high-dose fingolimod (1.25 mg 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 post-marketing use of fingolimod.

Vascular Reactions

Peripheral arterial occlusive disease has been rarely observed in patients receiving higher doses (1.25 mg) of fingolimod.

Respiratory System

Minor, dose-dependent reductions in forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) were observed during the first month of fingolimod treatment 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 recipients; this effect resolved after discontinuation of treatment. The reduction in DLCO at 24 months was 3.3% in patients receiving fingolimod 0.5 mg and 2.7% in placebo recipients.

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 Warnings and Precautions for Use" ("Lymphomas")).

Hemophagocytic Syndrome

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

Pediatric Population

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 adults. However, a higher incidence of neurological and psychiatric disorders was observed. Caution is advised when using this medicinal product in this subgroup due to limited clinical trial data.

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

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

Mild isolated elevations in bilirubin were observed in children taking fingolimod.

Reporting of Suspected Adverse Reactions

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

Shelf Life. 2 years from the date of manufacture in bulk.

Storage Conditions.
No special storage conditions required. Keep out of the reach of children.

Packaging. 14 capsules in a blister, 2 blisters per carton.

Prescription Status. Prescription only.

Manufacturer. JSC "Farmak"
(secondary packaging, quality control, batch release from bulk product manufactured by: Farmathen International S.A., Greece or Farmathen S.A., Greece).

Manufacturer's Address and Location of Operations.
74 Kyrylivska Street, Kyiv, 04080, Ukraine.