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

Composition:

Active substance: fingolimod;

1 capsule contains fingolimod hydrochloride equivalent to 0.5 mg of fingolimod;

Excipients: microcrystalline cellulose, titanium dioxide (E 171), magnesium stearate; hard gelatin capsule (composition: titanium dioxide (E 171), yellow iron oxide (E 172), gelatin, sodium lauryl sulfate).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

Hard gelatin capsule of size "4" with a bright yellow cap and an opaque white body, marked with the letter “H” printed in black ink on the cap and “F7” printed in blue ink on the body; filled with powder of white to almost white color.

Pharmacotherapeutic group. 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 at low nanomolar concentrations to S1P type 1 receptors located on lymphocytes and 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 inhibits 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 lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they could contribute to nerve inflammation and neural tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also act through interaction with S1P receptors on neural cells.

Pharmacodynamic effects

Within 4–6 hours after the first dose of 0.5 mg fingolimod, lymphocyte counts in peripheral blood decrease to approximately 75% of baseline. With continuous daily dosing, lymphocyte counts continue to decline over a 2-week period, reaching a minimum of approximately 500 cells/µL or about 30% of baseline. 18% of patients reached a minimum count below 200 cells/µL at least once. Low lymphocyte counts are maintained with continued daily dosing. Most T- and B-lymphocytes regularly circulate through lymphoid organs and are primarily affected by fingolimod. Approximately 15–20% of T-lymphocytes have an effector memory phenotype, cells important for peripheral immune surveillance. Since this lymphocyte subset typically does not regularly pass through lymphoid organs, they are not significantly affected by fingolimod. Peripheral lymphocyte counts begin to increase within a few days after discontinuation of fingolimod treatment, with return to normal levels typically occurring within 1–2 months. Continuous fingolimod use results in a slight 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. The maximum reduction in heart rate occurs within the first 6 hours after dose administration, with 70% of the negative chronotropic effect achieved on the first day. With continued treatment, heart rate returns to baseline 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 salmeterol has also been demonstrated with inhaled administration. At the start of fingolimod treatment, an increased frequency of atrial extrasystoles is observed, but there is no increase in the frequency of atrial fibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a reduction in cardiac output. Autonomic cardiac responses, including diurnal heart rate variability and exercise-induced heart rate response, are not affected by 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 an inward rectifier potassium channel or a G-protein-activated inward rectifier K+ channel (IKACh/GIRK), while vasoconstriction is likely mediated by a Rho kinase-dependent and calcium-dependent mechanism.

Treatment with one or multiple doses of fingolimod 0.5 mg and 1.25 mg 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 or increased airway sensitivity to methacholine. Patients receiving fingolimod treatment 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 bioavailability after oral administration is 93% (95% confidence interval (CI): 79–111%). Steady-state concentrations in blood are reached within 1–2 months after once-daily dosing, with steady-state levels approximately 10-fold higher than after the first dose.

Food intake does not affect the maximum concentration (Cmax) or area under the concentration-time curve (AUC) of fingolimod. Cmax of fingolimod phosphate was increased by 34%, while AUC remained unchanged. Therefore, Finmod can be administered regardless 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 analog of fingolimod demonstrated that fingolimod reaches the brain. In 13 male patients with multiple sclerosis who received oral 0.5 mg daily 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, 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 main components related to fingolimod in blood, based on their contribution to the AUC of total radioactivity 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 (T1/2) 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 has been eliminated.

Linearity

Concentrations of fingolimod and fingolimod phosphate increase almost proportionally with dose after multiple doses 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 do not differ 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 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 have not been 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.

Elderly patients

Clinical experience and pharmacokinetic data in patients aged 65 years and older are limited; therefore, caution should be exercised when administering the drug to patients in this age group.

Children

In pediatric patients (aged 10 years and older), the concentration of fingolimod phosphate appears to increase proportionally between 0.25 mg and 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 fingolimod compared to adult patients receiving 0.5 mg fingolimod once daily.

No data are available for 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 full 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 "Pharmacological properties" and "Special instructions") 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 with increased risk of opportunistic infections, including those with compromised immune systems (including patients receiving 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).

Myocardial infarction occurred within the last 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 Mobitz type II atrioventricular block (AV block) or third-degree AV 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 do not use highly effective contraceptive methods.

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

Interaction with other medicinal products and other types of interactions.

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 instructions").

Caution is also required when transitioning from treatment with long-acting immunomodulatory agents such as natalizumab or mitoxantrone (see section "Special instructions"). Data indicate that short-term corticosteroid treatment for multiple sclerosis relapse is not associated with increased frequency of infections.

Vaccination

Vaccination may be less effective during treatment with Gilenya and for 2 months after discontinuation of treatment. Administration of live attenuated vaccines may pose a risk of infection and is therefore not recommended (see sections "Special instructions" 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, additional reduction in heart rate by 15% was observed when fingolimod was used with atenolol at the beginning of treatment; this effect was not observed with diltiazem. Treatment 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 such as verapamil or diltiazem, digoxin, anticholinesterase agents, or pilocarpine, due to additive effects on heart rate (see sections "Special instructions" and "Adverse reactions").

If such combination therapy with Gilenya 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 is recommended for at least overnight if the 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 the latter.

Pharmacokinetic effect of other medicinal products on fingolimod

Fingolimod is primarily metabolized by CYP4F2. Other enzymes, such as CYP3A4, may also participate in its metabolism, especially in cases of pronounced 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 instructions").

Pharmacokinetic data on potential interactions show no significant effect of fluoxetine, paroxetine (potent inhibitors of CYP2D6), or carbamazepine (potent enzyme inhibitor) on fingolimod and fingolimod phosphate. Additionally, the following medicinal products also had no clinically significant effect on fingolimod and fingolimod phosphate: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteroids, and oral contraceptives.

Pharmacokinetic interactions of fingolimod with other medicinal products

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

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

Oral contraceptives. 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; however, it is not expected that fingolimod will affect their exposure.

Effect on laboratory tests

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

Laboratory testing of circulating mononuclear cells requires a larger blood volume due to reduced numbers of circulating lymphocytes.

Special precautions for use.

Bradycardia

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

After administration of the first dose, reduction in heart rate begins within 1 hour and reaches its maximum approximately at 6 hours. This effect persists for several subsequent days after administration, although symptoms are usually less pronounced and resolve within several weeks. With continued treatment, average heart rate 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 usually transient and asymptomatic. These changes typically 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 measurement should be performed before administration of the first dose and at the end of the 6-hour observation period for all patients. Continuous monitoring of pulse rate and blood pressure on an hourly basis for 6 hours is recommended to detect symptoms of bradycardia. Prolonged (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 daily dose of 0.25 mg to a daily dose of 0.5 mg.

If symptoms of post-dose bradyarrhythmia occur, appropriate treatment should be administered as needed, and patients should be monitored 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 observation after the second dose of fingolimod.

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 after 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, expanded monitoring (at least overnight) should be conducted 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 reappear upon resumption of treatment and depends on the duration of the treatment interruption and time since initiation of therapy. After administration of the first dose, overnight hospitalization and monitoring are required, and the first-dose monitoring should be repeated after the second dose of fingolimod. 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, consultation with a cardiologist is recommended.

Due to the risk of serious cardiac arrhythmias or severe bradycardia, Fynmod is contraindicated in patients with sinoatrial block, symptomatic bradycardia, history of recurrent syncope, cardiac arrest, or significant QT prolongation (QTc > 470 ms (adult women), QTc > 460 ms (girls) or > 450 ms (men and boys)), uncontrolled hypertension, or severe sleep apnea (see also section "Contraindications"). Treatment with Fynmod in such patients should be considered only if the expected benefit outweighs the potential risk.

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

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

Experience with the use of the drug in patients receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce heart rate (such as verapamil or diltiazem), or other drugs that reduce heart rate (e.g., ivabradine, digoxin, anticholinesterase agents, or pilocarpine) is limited. Since a decrease in heart rate is also observed at the beginning of drug administration, concomitant use of these drugs at the start of Fynmod treatment may be associated with the development of severe bradycardia and heart block. Due to the possible additive effect on heart rate, Fynmod treatment should generally not be prescribed to patients receiving concomitant therapy with these drugs. Prescribing the drug to such patients is possible only if the expected benefit outweighs the risk. If Fynmod treatment is prescribed, cardiologist consultation regarding switching the patient to drugs that do not reduce heart rate is recommended. If discontinuation of drugs that reduce heart rate is not possible, cardiologist consultation regarding appropriate first-dose monitoring and expanded monitoring (at least overnight) is recommended (see also section "Interaction with other medicinal products and other forms of interaction").

QT interval prolongation

Fingolimod at doses of 1.25 mg or 2.5 mg at steady state, when the negative chronotropic effect of fingolimod was still observed, has been reported to affect the QT interval, leading to QTc prolongation with an upper limit of the 90% CI ≤ 13.0 ms. There is no dose- or exposure-response relationship between fingolimod and QTc prolongation. There is 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 QTc prolongation was not observed; however, patients with an increased risk of QT prolongation were not included in clinical trials.

The use of drugs that may cause QTc prolongation should be avoided in patients with relevant risk factors, such as hypokalemia or congenital QT 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, especially 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.

Infections

The primary pharmacodynamic effect of fingolimod is a dose-dependent reduction in peripheral blood lymphocyte count to 20–30% of baseline values. This occurs due to the reversible sequestration of lymphocytes in lymphoid tissue.

Prior to initiating treatment, the most recent complete blood count results (i.e., performed within 6 months or after discontinuation of the previous therapy course) should be available. Complete blood count is also recommended periodically during treatment, at month 3 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, as fingolimod treatment was temporarily discontinued in clinical trials in patients with absolute lymphocyte count < 0.2×10⁹/L.

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

The drug's effect 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 a potentially serious infection, consultation with a physician experienced in treating such infections should be considered. During treatment with Fynmod, patients should be informed about the need to report symptoms of infectious diseases to their physician.

Consideration should be given to temporarily discontinuing the drug in case of a 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 for up to 2 months after discontinuation of fingolimod.

Herpesvirus infections

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. In case of herpes encephalitis, meningitis, or meningoencephalitis, the drug should be discontinued and appropriate treatment for the infection should be initiated.

Prior to initiating Fynmod therapy, the patient's immunity status to Varicella zoster virus (VZV) should be assessed. It is recommended that patients without documented history of physician-confirmed chickenpox or documented complete VZV vaccination series undergo testing for VZV antibodies before starting therapy. It is recommended that patients with negative VZV antibody test results receive a complete course of varicella vaccination prior to starting therapy, and initiation of Fynmod treatment should be delayed for 1 month to allow full vaccine effect.

Cryptococcal infections

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. 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. Consultation with other physicians (e.g., infectious disease specialist) should be considered if resumption of fingolimod treatment is necessary.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported during fingolimod treatment. PML is an opportunistic infection caused by the John Cunningham virus (JC virus) that may lead to fatal outcome or severe disability. 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 have been observed in patients previously treated with natalizumab, which is known to be associated with PML. PML can 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 noted that a negative JC virus antibody test result does not exclude the possibility of future JC viral infection. Prior to initiating fingolimod treatment, baseline MRI results should be available (usually 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 PML. MRI can be considered as one of the elements of comprehensive monitoring in patients at risk of PML. Cases of asymptomatic PML based on MRI results and positive JC virus DNA test in cerebrospinal fluid have been reported in patients treated with fingolimod. In case of suspected PML, diagnostic MRI should be performed immediately and fingolimod therapy should be suspended until PML is ruled out.

Human papillomavirus

Infections caused by human papillomavirus (HPV), including papilloma, dysplasia, warts, and HPV-related cancers, have been reported during post-marketing use of fingolimod. Due to the immunosuppressive properties of fingolimod, HPV vaccination should be considered before initiating fingolimod treatment, in accordance with vaccination recommendations. Cancer screening, including Pap test, is recommended according to standard care.

Macular edema

Macular edema, with or without ocular symptoms, occurred in 0.5% of patients treated with fingolimod 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 macular edema is increased in patients with a history of uveitis and in patients with diabetes mellitus (see section "Adverse reactions"). Fingolimod has not been studied in patients with multiple sclerosis and concomitant diabetes mellitus. Ophthalmological examination before initiation of treatment and periodically during treatment is recommended for patients with multiple sclerosis and diabetes mellitus or history of uveitis.

Continuation of the drug 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, potential benefits 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. Cases of acute liver failure requiring liver transplantation and clinically significant liver injury have also been reported. Signs of liver injury, including markedly elevated serum liver enzymes and elevated total bilirubin, were observed as early as 10 days after the first dose and after prolonged use.

During clinical trials, ALT levels more than 3 times the upper limit of normal (ULN) were observed in 8% of patients treated with fingolimod 0.5 mg compared to 1.9% of patients receiving placebo. Fivefold ULN elevation was observed in 1.8% of patients receiving fingolimod and in 0.9% of patients receiving placebo. In clinical trials, fingolimod treatment was discontinued if liver transaminase levels exceeded 5 times ULN. Recurrent elevation of liver transaminases was 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 occurred within the first 12 months. Elevated serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod treatment.

The effect of fingolimod has not been studied in patients with severe pre-existing liver dysfunction (Child-Pugh class C); therefore, it 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 (obtained within the last 6 months) test results for transaminase and bilirubin levels should be available before initiating treatment. In the absence of clinical symptoms, monitoring of liver transaminase activity and serum bilirubin levels should be performed at months 1, 3, 6, 9, and 12 of treatment and then periodically up to 2 months after discontinuation of the drug. 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 above ULN associated with any increase in serum bilirubin, Fynmod should be discontinued. Monitoring of liver function should be continued. If serum transaminase levels normalize (including if an alternative cause of liver dysfunction is identified), the drug may be resumed based on careful benefit-risk assessment for the patient.

In patients with symptoms indicating liver dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine of unknown etiology, liver enzyme activity and bilirubin levels should be checked, and therapy should be discontinued if significant liver injury is confirmed. Therapy should not be resumed if a probable alternative etiology of liver injury signs and symptoms cannot be established.

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

Effect on blood pressure

Patients with uncontrolled hypertension were not included in pre-marketing clinical trials, and special precautions should be taken when using Fynmod in patients with uncontrolled hypertension.

In patients with multiple sclerosis treated with fingolimod 0.5 mg, an average increase in systolic pressure of approximately 3 mm Hg and diastolic 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 0.5 mg and in 3.3% of patients receiving placebo. Therefore, regular monitoring of blood pressure is necessary during Fynmod 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 drug use from the first month of treatment and remained stable thereafter. Fynmod should be prescribed with caution to patients with severe respiratory diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Reversible posterior encephalopathy syndrome

Rare cases of reversible posterior encephalopathy syndrome (PRES) have been reported with use of the drug at a dose of 0.5 mg (see section "Adverse reactions"). Symptoms included sudden onset of severe headache, nausea, vomiting, mental status changes, 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 immunosuppressant or immunomodulator therapy

No studies have been conducted to evaluate the efficacy and safety of switching patients from teriflunomide, dimethyl fumarate, or alemtuzumab to fingolimod. When switching patients from another disease-modifying therapy to fingolimod, the half-life and mechanism of action of the previous drug should be considered to avoid additive immune effects while minimizing the risk of disease reactivation. Complete blood count is recommended before initiating treatment to ensure that the effect of prior therapy on the immune system (i.e., cytopenia) has resolved.

Interferon beta, glatiramer acetate, or dimethyl fumarate

Fynmod treatment 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 starting Fynmod treatment.

Natalizumab or teriflunomide

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

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, teriflunomide clearance from plasma may take several months to 2 years. As stated in the teriflunomide product characteristics, an accelerated elimination procedure is recommended or, alternatively, a washout period of at least 3.5 months.

Alemtuzumab

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

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

Concomitant use of strong CYP450 inducers

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

Neoplasms

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 dermatological evaluation at the start 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 risk of developing skin malignancies, patients receiving fingolimod should be warned to avoid excessive sun exposure. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA photochemotherapy.

Lymphomas

Cases of various types of lymphoma have been reported in clinical trials and during post-marketing use (see section "Adverse reactions"). Reported cases were heterogeneous in nature, mostly 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. If lymphoma is suspected, fingolimod use should be discontinued.

Women of childbearing potential

Due to the risk to the fetus, fingolimod is contraindicated during pregnancy and in women of childbearing potential who do not use effective contraception. Before initiating treatment, women of childbearing potential should be informed of this risk to the fetus, should have a negative pregnancy test, and should use effective contraception during treatment and for 2 months after discontinuation of treatment.

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 exclude tumefactive lesions. Discontinuation of fingolimod should be considered by the physician in each individual case, taking into account individual benefit and risks.

Disease activity rebound after discontinuation of fingolimod treatment

In post-marketing observations, severe exacerbation of the disease has been rarely observed in some patients after discontinuation of fingolimod treatment. This usually occurred within 12 weeks after discontinuation of fingolimod treatment, but may also occur up to 24 weeks after discontinuation. Therefore, caution should be exercised when discontinuing fingolimod therapy. If discontinuation of fingolimod treatment is considered necessary, the possibility of rebound with extremely high disease activity should be considered, and patients should be monitored for appropriate signs and symptoms, and appropriate treatment initiated if necessary (see "Discontinuation of therapy" below).

Discontinuation of therapy

If a decision is made to discontinue Fynmod treatment, 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 normal range within 1–2 months after discontinuation of treatment, although some patients may require significantly more time for full recovery. Use of other treatment methods during this interval will result in concomitant effects with fingolimod. Resuming treatment during this period will result in concomitant fingolimod exposure. Use of immunosuppressants shortly after discontinuation of the drug may lead to additive effects on the immune system, so caution is necessary.

Caution is also advised when discontinuing fingolimod therapy due to rebound risk (see above). If discontinuation of fingolimod is considered necessary, patients should be monitored during the discontinuation period for signs of possible rebound.

Interference with serological tests

Since fingolimod reduces lymphocyte count in blood by redistributing them to secondary lymphoid organs, peripheral blood lymphocyte count cannot be used to assess lymphocyte subset status in patients treated with Fynmod. For laboratory tests using circulating mononuclear cells, a larger blood volume is required due to reduced circulating lymphocyte count.

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 Fynmod to children:

Caution is required during administration of the first dose (see "Bradycardia" above). The same precautions as for the first dose are recommended when patients switch from a daily dose of 0.25 mg to a daily dose of 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 for this subgroup (see section "Adverse reactions").
Mild isolated bilirubin elevation has been reported in children receiving this drug.
Pediatric patients are recommended to be vaccinated according to current vaccination recommendations before initiating Fynmod therapy (see "Infections" above).
There is very limited data on use of the drug in children aged 10 to 12 years, with body weight less than 40 kg or Tanner stage < 2. Caution is required in these subgroups due to very limited clinical trial experience.
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").

Before initiating fingolimod treatment, women of childbearing potential should be informed of 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 contraception during treatment and for 2 months after discontinuation of the drug, as elimination of fingolimod from the body takes approximately 2 months after discontinuation of treatment, and potential risk to the fetus may persist; therefore, contraception should be continued during this period.

When discontinuing fingolimod therapy for pregnancy planning, possible return of disease activity 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 include:

congenital heart diseases, 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, such as persistent truncus arteriosus and ventricular septal defect. In addition, the receptor affected by fingolimod (sphingosine-1-phosphate receptor) is involved in vascular formation during embryogenesis.

Therefore, fingolimod is contraindicated during pregnancy. Fingolimod should be discontinued 2 months before planned pregnancy. If a woman becomes pregnant while taking the drug, fingolimod use should be discontinued. Medical consultation regarding the risk of harmful effects on the fetus associated with treatment and ultrasound examination are recommended.

Breastfeeding period

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 infants, women should discontinue breastfeeding during drug use.

Fertility

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

There are no data on the effect on delivery period or male fertility.

Ability to affect reaction speed when driving or operating machinery.

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

However, dizziness or somnolence may occasionally occur at the beginning of therapy. At the beginning of treatment, patients should be under supervision for the first 6 hours after drug 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 Finmod 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 be switched to 0.5 mg capsules.

When increasing the daily dose from 0.25 mg (if such dosage strength is available) to 0.5 mg, the same first-dose monitoring as at treatment initiation is recommended.

First-dose monitoring, as at the beginning of treatment, is also 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 scheduled dose.

The medicinal product is intended for oral administration.

Finmod may be taken regardless of food intake. Capsules should always be swallowed whole, without opening. If a dose is missed, treatment should continue as planned.

Dosage in Specific Patient Populations

Elderly Patients

The drug should be used with caution in patients aged 65 years and older, as there is insufficient data on safety and efficacy in this patient population.

Renal Impairment

The use of fingolimod in patients with multiple sclerosis and renal impairment has not been studied. According to available data, no dose adjustment is required for patients with mild to severe renal impairment.

Hepatic Impairment

Finmod should not be administered to patients with severe hepatic impairment (Child–Pugh class C) (see section «Contraindications»). Although no dose adjustment is necessary for patients with mild to moderate hepatic impairment, caution should be exercised when initiating treatment in such patients (see sections «Special Warnings and Precautions for Use» and «Pharmacokinetics»).

Patients with Diabetes

The use of fingolimod in patients with multiple sclerosis and concomitant diabetes mellitus has not been studied. Finmod should be used with caution in patients with diabetes mellitus, as there may be an increased risk of macular edema. Regular ophthalmological examinations are required in these patients to detect macular edema.

Children

The safety and efficacy of fingolimod in children under 10 years of age have not been established. There are no available data. Limited data exist on the use of the medicinal product in children aged 10 to 12 years (see sections «Special Warnings and Precautions for Use», «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. After a 40 mg dose, mild chest tightness or discomfort was observed in 5 out of 6 subjects, 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 the drug persists beyond 6 hours and gradually diminishes over the following days of treatment. Reports of slowed atrioventricular conduction have been received, along with isolated cases of transient complete atrioventricular (AV) block that resolved spontaneously (see sections «Special Warnings and Precautions for Use» and «Adverse Reactions»).

If overdose occurs at the first administration of Finmod, it is essential to monitor the patient with continuous 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 the heart rate is < 45 beats per minute in adults, < 55 beats per minute in children aged 12 years or older, or < 60 beats per minute in children aged 10 to 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 resolution of the observed abnormalities. 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

The data below refer to adverse reactions reported during treatment with fingolimod at a dose of 0.5 mg.

Adverse reactions are listed according to 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); 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, shingles;
uncommon – pneumonia;
not known – 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****;
not known – Merkel cell carcinoma***.

Blood and lymphatic system disorders:

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

Immune system disorders:

not known – hypersensitivity reactions, including rash, urticaria, and angioedema following initiation of treatment***.

Psychiatric disorders:

common – depression;
uncommon – mood depressed.

Nervous system disorders:

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

Eye disorders:

common – blurred vision;
uncommon – macular edema.

Cardiac disorders:

common – bradycardia, atrioventricular (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 – weight decreased***, increased blood triglycerides;
uncommon – decreased neutrophil count.

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

Description of selected adverse reactions

Infections

The overall incidence of infections with fingolimod 0.5 mg was similar to that with placebo. However, lower respiratory tract infections, primarily bronchitis, and to a lesser extent, herpes virus infections and pneumonia, were more frequently observed in patients treated with 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 (e.g., atypical mycobacteria), some of which were fatal.

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

Macular edema

Macular edema has been observed in patients receiving fingolimod at the recommended dose of 0.5 mg and at 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 others were asymptomatic and diagnosed during routine ophthalmological examination. Macular edema typically resolved or improved spontaneously after discontinuation of fingolimod. The risk of recurrence upon re-initiation of the drug has not been evaluated.

The risk of macular edema is increased in patients with a history of multiple sclerosis and uveitis. The use of fingolimod in patients with multiple sclerosis and diabetes mellitus, a condition associated with an increased risk of macular edema, has not been studied. Treatment with fingolimod at doses of 2.5 mg and 5 mg in kidney transplant patients has been associated with a two-fold increase in the incidence of macular edema.

Bradycardia

Initiation of treatment with fingolimod is associated with a transient decrease in heart rate and may also be associated with delayed atrioventricular conduction. The maximum decrease in heart rate was observed 6 hours after the first dose, with a mean reduction of 12–13 beats per minute with fingolimod 0.5 mg. Heart rates below 40 beats per minute were rarely observed in patients receiving fingolimod 0.5 mg. On average, heart rate returned to baseline within 1 month of continuous treatment. Bradycardia was usually asymptomatic, but in some patients, mild to moderate symptoms occurred, including hypotension, dizziness, weakness, and/or palpitations, which resolved within the first 24 hours after treatment initiation.

In clinical trials of multiple sclerosis, first-degree atrioventricular block (prolonged PR interval on ECG) occurred after treatment initiation in both adults and children. In adult patients during clinical trials, atrioventricular conduction delay occurred in 4.7% of patients receiving 0.5 mg fingolimod, compared to 2.8% receiving intramuscular interferon beta-1a and 1.6% receiving placebo. Second-degree AV block was observed in less than 0.2% of patients treated with fingolimod 0.5 mg. According to post-marketing surveillance, isolated cases of transient complete AV block, resolving spontaneously, were observed 6 hours after the first dose of fingolimod. Patients recovered without symptomatic treatment. Conduction disturbances were mainly 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 AV block, Mobitz type I.

During post-marketing surveillance, delayed events have been reported 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 comorbidities. The relationship of these events to fingolimod administration has not been established.

Blood pressure

Treatment with fingolimod 0.5 mg has been 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 increase persisted during continued treatment. Arterial hypertension has been observed in patients receiving fingolimod 0.5 mg. During post-marketing surveillance, cases of arterial hypertension have been 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 enzymes have been reported in patients with multiple sclerosis receiving fingolimod. In patients receiving fingolimod 0.5 mg, asymptomatic increases in serum ALT levels exceeding 3 times the upper limit of normal (ULN) and 5 times ULN were observed, respectively. Recurrent elevations in liver transaminases have been observed in some cases upon re-initiation of treatment, confirming the association with the drug. 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 fingolimod. In a small number of patients with ALT elevations exceeding 5 times ULN who continued fingolimod treatment, ALT levels normalized within approximately 5 months.

Nervous system disorders

Rare neurological events have been observed in patients treated with higher doses of fingolimod (1.25 mg or 5.0 mg), 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

In patients receiving higher doses of fingolimod (1.25 mg), peripheral arterial occlusive disease has been reported rarely.

Respiratory system

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

Lymphomas

Cases of various types of lymphoma have been reported, including a fatal case in a patient with Epstein-Barr virus (EBV)-positive B-cell lymphoma. The incidence of lymphoma (B-cell and T-cell) was higher than expected in the general population. Several cases of T-cell lymphoma (mycosis fungoides) have been reported during post-marketing surveillance. The relationship between lymphoma development and fingolimod use remains unclear.

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 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 observed in adult patients. However, a higher incidence of neurological and psychiatric disorders was observed. Caution is advised in this subgroup due to limited clinical data.

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

Depression and anxiety are known to occur more frequently in the multiple sclerosis patient population. Cases of depression and anxiety have also been reported in children receiving fingolimod.

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

Reporting of suspected adverse reactions

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

Shelf life.

2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

10 capsules per blister; 1 or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.