Arelopatan

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

Composition:

Active substance: fingolimod;

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

Excipients: light calcium phosphate, heavy calcium phosphate, stearic acid, capsule (gelatin, titanium dioxide (E 171), yellow iron oxide (E 172), black ink (E 172)).

Pharmaceutical form. Hard capsules.

Main physical and chemical properties: capsule with a yellow opaque cap and a white opaque body, printed with black ink "0.5 mg" on the cap.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Sphingosine-1-phosphate (S1P) receptor modulators. ATC code L04A E01.

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 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 from lymph nodes, resulting in redistribution rather than depletion of lymphoid tissue. Animal studies have shown that this redistribution reduces the migration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they may contribute to nerve inflammation and neural tissue damage. Animal studies and in vitro experiments indicate that fingolimod may also interact 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 two-week period, reaching a nadir of approximately 500 cells/µL or about 30% of baseline. 18% of patients reached a minimum count below 200 cells/µL at least once. This low lymphocyte level 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 peripheral immune surveillance. Since this lymphocyte subset typically does not recirculate through lymphoid organs, it remains unaffected by fingolimod. Lymphocyte counts begin to increase within days after discontinuation of fingolimod, with return to normal levels within 1–2 months. Continuous fingolimod use leads to a modest reduction in neutrophil counts, to approximately 80% of baseline. Fingolimod does not affect monocytes.

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

S1P4 may partially contribute to the effect but is not the primary receptor responsible for lymphoid tissue reduction. 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 rectifying potassium channel or a G-protein-activated inward rectifying K+ channel (IKACh/GIRK), while vasoconstriction is likely mediated by a Rho-kinase- and calcium-dependent mechanism.

Treatment with fingolimod at single or multiple doses of 0.5 mg and 1.25 mg over two weeks is not associated with 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 dose-dependent increases 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 hypoxia during physical exercise, nor with increased airway sensitivity to methacholine. Patients taking fingolimod show normal bronchodilator response to inhaled beta-agonists.

Pharmacokinetics.

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

The pharmacologically active metabolite is fingolimod phosphate.

Absorption

Fingolimod is absorbed slowly (Tmax 12–16 hours) and extensively (≥ 85%). 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 dosing and are approximately 10 times higher than after the first dose.

Food intake does not affect the maximum concentration (Cmax) or exposure (AUC) of fingolimod: Cmax of fingolimod phosphate was slightly increased (by 34%), while AUC remained unchanged. Therefore, Aralaptan 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 (< 17%). Both fingolimod and fingolimod phosphate are highly bound to plasma proteins (> 99%).

Fingolimod is extensively distributed into body tissues, with a volume of distribution of approximately 1200 ± 260 liters. A study in four healthy volunteers who received a single intravenous dose of radiolabeled iodinated fingolimod analog demonstrated that fingolimod reaches the brain. In 13 male patients with multiple sclerosis receiving fingolimod 0.5 mg daily, the mean 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 circulating components related to fingolimod, based on their contribution to the AUC of total radioactivity over 34 days after dosing, were fingolimod (23%), fingolimod phosphate (10%), and inactive metabolites (carboxylic acid metabolite M3 (8%), ceramide metabolite M29 (9%), and ceramide metabolite M30 (7%)).

Elimination

The blood clearance of fingolimod is 6.3 ± 2.3 L/h, and the mean apparent terminal half-life (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 is excreted.

Linearity

The concentrations of fingolimod and fingolimod phosphate increase almost proportionally with dose after repeated administration 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%, while 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 (see section "Dosage and administration").

Elderly patients

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

Children

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

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

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

Clinical characteristics.

Indications.

Arilaptan as monotherapy, a disease-modifying treatment for 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 course (at least one year) of treatment with at least one disease-modifying agent (exceptions and washout period information are provided in sections "Pharmacological properties" and "Special precautions") has failed to demonstrate therapeutic effect.

• Patients with rapidly progressing severe relapsing-remitting multiple sclerosis

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

Contraindications.

Immunodeficiency syndrome.

Contraindicated in patients with increased risk of opportunistic infections, including patients with compromised immune system (including patients undergoing immunosuppressive therapy, or patients with pre-existing immunosuppression prior to treatment).

Suspected or confirmed progressive multifocal leukoencephalopathy (PML).

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

Contraindicated in patients with neoplasms.

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

Myocardial infarction occurring within the previous 6 months.

Unstable angina.

Stroke. Transient ischemic attack.

Decompensated heart failure requiring hospitalization.

Class III/IV heart failure according to New York Heart Association classification.

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

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

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

Patients with QTc interval ≥ 500 ms prior to initiation of treatment (see section "Special precautions").

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

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

Interaction with other medicinal products and other types of interactions.

Antineoplastic, immunosuppressive or immunomodulating therapy

Concomitant use of antineoplastic, immunosuppressive or immunomodulating 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 transitioning from treatment with long-acting immunomodulatory agents such as natalizumab or mitoxantrone (see section "Special precautions"). In clinical trials of multiple sclerosis, short-term corticosteroid treatment for relapse did not result in increased incidence of infections.

Vaccination

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

If combination therapy with Arilaptan is planned, consultation with a cardiologist is recommended regarding switching the patient to agents that do not reduce heart rate or regarding appropriate monitoring at treatment initiation. Monitoring for at least one night is recommended 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 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 via CYP4F2. Other enzymes, such as CYP3A4, may also be involved in its metabolism, particularly 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 precautions").

Pharmacokinetic data on potential interactions indicate no significant effect of fluoxetine, paroxetine (potent inhibitors of CYP2D6) and 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 lymphocytes to secondary lymphoid organs, peripheral blood lymphocyte count cannot be used to assess lymphocyte status.

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

Pharmacokinetic interaction 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 administered concomitantly 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, but 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 (AV) block that spontaneously resolves (see sections "Pharmacodynamics" and "Undesirable effects").

Following administration of the first dose, reduction in heart rate begins within 1 hour and reaches its maximum at approximately 6 hours. This effect persists for several subsequent days, although symptoms are usually milder and resolve within several weeks. With continued treatment, heart rate generally returns to baseline within one month, although in some patients it may not return to baseline levels until after the first month. Pathological conduction abnormalities were generally transient and asymptomatic. These changes usually did not require treatment and resolved within the first 24 hours of 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 hourly monitoring of pulse rate and blood pressure for 6 hours is recommended in all patients to detect symptoms of bradycardia. Continuous (real-time) ECG monitoring is recommended during this 6-hour period.

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

In case of symptomatic post-dose bradycardia, appropriate treatment should be administered if needed, and the patient should be monitored until symptoms resolve. If pharmacological intervention is required during the observation period after the first dose, monitoring should continue overnight in a medical facility, and observation should also be conducted after the second dose of Aralaptan.

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 or until the heart rate increases again. Additionally, if 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, extended monitoring (at least overnight) should be performed until symptoms resolve. The occurrence of third-degree AV block at any time also requires extended monitoring (at least overnight).

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

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

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

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

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

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

Experience with Aralaptan in patients receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce heart rate (e.g., 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 has also been observed at the beginning of fingolimod treatment (see also section "Undesirable effects", "Bradycardia"), concomitant use of these drugs at the beginning of treatment may be associated with the development of severe bradycardia and heart block. Due to the possible additive effect on heart rate, Aralaptan treatment should generally not be prescribed to patients receiving concomitant therapy with these drugs (see also section "Interaction with other medicinal products and other forms of interaction"). Prescribing Aralaptan to these patients may be considered only if the expected benefit outweighs the potential risk. If Aralaptan treatment is prescribed, cardiology consultation regarding switching the patient to drugs that do not reduce heart rate is recommended. If treatment with heart rate-lowering drugs cannot be discontinued, cardiology consultation regarding appropriate monitoring of the first dose and extended monitoring (at least overnight) is recommended (see also section "Interaction with other medicinal products and other forms of interaction").

QT interval prolongation

In a thorough QT study evaluating the effect of fingolimod at doses of 1.25 mg or 2.5 mg on QT interval at steady state, when the negative chronotropic effect of fingolimod was still present, administration of Aralaptan resulted in QTc prolongation with an upper bound of the 90% CI ≤ 13.0 ms. There was no dose- or exposure-response relationship for QTc prolongation with fingolimod. There was 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 QTc prolongation was not observed; however, patients with an increased risk of QT prolongation were not included in clinical trials.

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

Immunosuppression

Fingolimod has 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 risk is suspected, the physician should consider discontinuing treatment on a case-by-case basis (see also sections "Special precautions for use" ("Infections and skin malignancies") and "Undesirable effects" ("Lymphoma")).

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 reversible sequestration of lymphocytes in lymphoid tissue (see section "Pharmacodynamics").

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

Initiation of Aralaptan treatment should be delayed in patients with an acute infection in the active stage until resolution.

The effect of Aralaptan on the immune system may increase the risk of infections, including opportunistic infections (see section "Undesirable effects"). Therefore, effective diagnostic and treatment methods should be used for patients with symptoms of infection 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 Aralaptan, patients should be informed about the need to immediately report symptoms of infection to their physician.

Temporary discontinuation of Aralaptan should be considered in case of a serious infection, 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 infection for up to two months after discontinuation of fingolimod treatment.

Herpes viral infection

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

Prior to initiating Aralaptan therapy, the patient's immunity status to varicella (chickenpox) should be evaluated. It is recommended that patients without a history of physician-confirmed chickenpox or without documented complete vaccination against varicella-zoster virus (VZV) undergo testing for VZV antibodies before starting fingolimod therapy. It is recommended that patients with negative VZV antibody test results receive complete vaccination against chickenpox prior to starting Aralaptan (see section "Undesirable effects"). Initiation of fingolimod treatment should be delayed by one 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 after approximately 2–3 years of treatment, although the exact relationship with treatment duration is unknown (see section "Undesirable effects"). 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., an infectious disease specialist) should be performed if resumption of fingolimod treatment is necessary.

Progressive multifocal leukoencephalopathy (PML)

Cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-approval use of fingolimod (see section "Undesirable effects").
PML is an opportunistic infection caused by the John Cunningham virus (JC virus) that may lead to severe disability or death. Cases of PML have been reported after 2–3 years of monotherapy without prior use of natalizumab, although the exact relationship with treatment duration is unknown. Additional cases of PML occurred in patients who previously received natalizumab, 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 considered that a negative JC virus antibody test result does not exclude the possibility of subsequent JC virus 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 particular attention to lesions that may indicate PML. MRI may be considered as one element of comprehensive monitoring measures in patients at risk of PML. Cases of asymptomatic PML based on MRI findings and positive JC virus DNA testing in cerebrospinal fluid have been reported in patients receiving fingolimod.

In case of suspected PML, diagnostic MRI should be performed immediately and fingolimod therapy should be suspended until PML is ruled out. If PML is confirmed, fingolimod treatment should be permanently discontinued (see section "Contraindications").

In patients who received sphingosine-1-phosphate (S1P) receptor modulators, including fingolimod, and developed PML, cases of immune reconstitution inflammatory syndrome (IRIS) have been reported after discontinuation of treatment.

IRIS manifests as clinical worsening of the patient's condition, which may be rapid, lead to serious neurological complications or death, and is often associated with characteristic MRI changes. The time to onset of IRIS in PML patients was typically from several weeks to months after discontinuation of S1P receptor modulator. Monitoring for IRIS development and appropriate treatment of associated inflammation should be performed.

Human papillomavirus (HPV)

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

Macular edema

Macular edema, with or without ocular symptoms, was reported in 0.5% of patients receiving fingolimod 0.5 mg (see section "Undesirable effects"). Macular edema occurred mostly within the first 3–4 months of treatment.

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.

Patients with a history of uveitis and patients with diabetes have an increased risk of developing macular edema (see section "Undesirable effects"). The use of fingolimod in patients with multiple sclerosis and concomitant diabetes has not been studied. Ophthalmological examination before initiation of treatment and periodically during treatment is recommended for patients with multiple sclerosis and diabetes 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, 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 liver enzymes in serum and elevated total bilirubin, were observed as early as ten days after the first dose and after prolonged use. During clinical trials, elevated ALT levels more than 3 times the upper limit of normal (ULN) were observed in 8% of patients receiving fingolimod 0.5 mg compared to 1.9% of patients receiving placebo. ALT levels exceeding 5 times ULN were observed in 1.8% of patients receiving fingolimod and in 0.9% of placebo recipients.

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 elevation occurred at any time during treatment, although most cases occurred 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 dysfunction (Child-Pugh class C). Aralaptan 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) results of tests for transaminase and bilirubin levels should be available before initiation of 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 until 2 months after discontinuation of Aralaptan. 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 in serum, is needed to determine whether further elevation occurs and to identify alternative etiologies of liver dysfunction. If liver transaminase levels exceed ULN by at least 5 times or exceed ULN by at least 3 times with any increase in serum bilirubin, Aralaptan should be discontinued. Monitoring of liver function should continue. After normalization of serum transaminase levels (including if an alternative cause of liver dysfunction is identified), Aralaptan 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 and bilirubin levels 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 suggesting an increased risk of elevated liver test results with Aralaptan use in patients with pre-existing liver disease, caution should be exercised when prescribing Aralaptan to patients with significant liver disease in their history.

Effect on blood pressure

Particular caution is required when prescribing Aralaptan to patients with uncontrolled hypertension, 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 blood pressure of approximately 3 mm Hg and diastolic blood pressure of approximately 1 mm Hg, first observed about 1 month after initiation of treatment. 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 placebo recipients. Therefore, regular blood pressure monitoring 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. Aralaptan should be prescribed with caution to patients with severe respiratory disease, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Reversible posterior encephalopathy syndrome

Rare cases of reversible posterior encephalopathy syndrome (PRES) have been reported in clinical trials and during the post-marketing period with Aralaptan 0.5 mg (see section "Undesirable effects"). 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 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 fingolimod when switching patients from teriflunomide, dimethyl fumarate, or alemtuzumab to Aralaptan. When switching patients from another disease-modifying therapy to Aralaptan, the drug's elimination half-life and mechanism of action should be considered to avoid additive immune effects while minimizing the risk of disease reactivation. Complete blood count is recommended before initiating Aralaptan to ensure that the prior therapy's effect on the immune system (i.e., cytopenia) has resolved.

Interferon beta, glatiramer acetate, or dimethyl fumarate

Aralaptan 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 Aralaptan.

Natalizumab or teriflunomide

Due to the long elimination half-life of natalizumab, its washout 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 summary of product characteristics, 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 Aralaptan. Careful evaluation of treatment initiation timing is recommended in each individual case.

Alemtuzumab

Alemtuzumab has a profound and prolonged immunosuppressive effect. Since the actual duration of this effect is unknown, initiating Aralaptan therapy after alemtuzumab 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 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 malignancies

Cases of basal cell carcinoma and other skin malignancies, including malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma, and Merkel cell carcinoma, have been reported in patients receiving Aralaptan (see section "Undesirable effects"). Enhanced monitoring for skin lesions is recommended, as well as dermatological evaluation at the start of treatment and every 6–12 months, depending on clinical assessment. In case of suspicious lesions, 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 lymphoma have been reported in clinical trials and during post-marketing use (see section "Undesirable effects"). 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 risk.

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 should be initiated if necessary.

Discontinuation of therapy

If a decision is made to discontinue Aralaptan therapy, 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 may take significantly longer in some patients. After discontinuation of fingolimod in PML, patients should be monitored for IRIS development (see above subsection "Progressive multifocal leukoencephalopathy (PML)").

Resuming treatment during this period will result in concomitant exposure to fingolimod. Use of immunosuppressants shortly after discontinuation of Aralaptan may lead to additive effects on the immune system, so caution is required.

Interference with serological tests

Since fingolimod reduces lymphocyte count 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 Aralaptan. 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 recommendations should be followed when prescribing Aralaptan to children:

• Observe 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 in this subgroup (see section "Undesirable effects", "Children").
• Mild isolated bilirubin elevation has been observed in children receiving Aralaptan.
• Pediatric patients are recommended to receive all vaccinations according to current vaccination recommendations before starting Aralaptan therapy (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 "Undesirable effects"). Use in these subgroups requires caution due to very limited data from clinical trials.
• Safety data on long-term use in children are lacking.

Use during pregnancy or breastfeeding.

Women of reproductive potential/contraception in women

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

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

Women of reproductive potential should use effective contraception during treatment and for two months after discontinuation of the drug. Since elimination of fingolimod from the body takes about two 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, 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 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 common arterial trunk and ventricular septal defect. Additionally, the receptor affected by fingolimod (sphingosine-1-phosphate receptor) is involved in vascular formation during embryogenesis.

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

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

Lactation 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 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 vehicles or operating machinery.

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

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

Method of Administration and Dosage

Treatment should be initiated and managed by a physician experienced in the treatment of multiple sclerosis.

Dosage

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

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

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

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

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

The medicinal product is intended for oral administration.

Arrelaptan may be administered with or without food (see section “Pharmacokinetics”). Capsules should always be swallowed whole and must not be opened.

Monitoring after the first dose, as at the initiation of treatment, is recommended in case of treatment interruption:

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

If the treatment interruption is shorter than specified above, treatment should be continued with the next scheduled dose (see section “Special Warnings and Precautions for Use”).

Dosage for Specific Patient Groups

Elderly Patients

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

Renal Impairment

The use of fingolimod in patients with multiple sclerosis and renal impairment has not been studied in clinical trials. Pharmacokinetic studies indicate that no dose adjustment is necessary for patients with mild to severe renal impairment.

Hepatic Impairment

Arrelaptan is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see section “Contraindications”). Although no dose adjustment is required for 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”).

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 drug in children aged 10 to 12 years (see sections “Pharmacokinetics”, “Special Warnings and Precautions for Use”, and “Adverse Reactions”).

Overdose

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

Fingolimod may induce bradycardia at the start of treatment. Heart rate (HR) typically begins to decrease within one hour after the first dose, with maximum reduction observed within 6 hours. The negative chronotropic effect of Arrelaptan persists beyond 6 hours and gradually diminishes over the following days of treatment. Cases of slowed atrioventricular conduction have been reported, along with isolated reports of transient complete AV block that resolved spontaneously (see sections “Special Warnings and Precautions for Use” and “Adverse Reactions”).

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

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

Adverse Reactions

Summary of safety profile

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

List of adverse reactions in tabular form

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

Description of individual adverse reactions

Infections

In clinical trials of multiple sclerosis, the overall incidence of infections (65.1%) with the 0.5 mg dose was similar to that with placebo. However, lower respiratory tract infections, primarily bronchitis, and to a lesser extent, herpes virus infections, and pneumonia occurred more frequently in patients 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 (including varicella zoster virus [VZV], John Cunningham virus [JC virus], which causes progressive multifocal leukoencephalopathy, herpes simplex virus [HSV]), fungal (including yeast-like fungi, including cryptococcal meningitis), or bacterial (including atypical mycobacteria), some of which were fatal (see section "Special precautions for use").

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

Macular edema

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

The incidence of macular edema is increased in patients with multiple sclerosis and a history of uveitis (17% with a history of uveitis compared to 0.6% without uveitis). The use of Aralaptan in patients with multiple sclerosis and diabetes mellitus, a condition associated with an increased risk of macular edema, has not been studied. In kidney transplant studies involving patients with diabetes mellitus, treatment with Aralaptan 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 atrioventricular conduction delay. In clinical trials of multiple sclerosis, the maximum decrease in heart rate occurred 6 hours after initiation of treatment, with a mean decrease in heart rate of 12–13 beats per minute during treatment with fingolimod 0.5 mg. Heart rates below 40 beats per minute in adults and below 50 beats per minute in children were rarely observed in patients treated with Aralaptan 0.5 mg. On average, heart rate returned to baseline within 1 month of continuous treatment. Bradycardia was usually asymptomatic, but some patients experienced mild or moderate symptoms, including hypotension, dizziness, weakness, and/or palpitations, which resolved within the first 24 hours after initiation of treatment (see sections "Pharmacodynamics" and "Special precautions for use").

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

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

Blood pressure

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

Liver function

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

Nervous system disorders

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

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

Vascular reactions

Peripheral arterial occlusive disease was rarely observed in patients treated with Aralaptan at higher doses (1.25 mg).

Respiratory system

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

Lymphomas

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

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

Hemophagocytic syndrome

Very rare cases of hemophagocytic syndrome (HPS) with fatal outcome have been reported in patients treated with 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 treated with 0.25 mg or 0.5 mg of fingolimod daily was generally similar to that in adult patients. However, a higher incidence of neurological and psychiatric disorders was observed. Use of the drug in this subgroup requires caution due to very limited data from clinical trials.

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

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

Mild isolated elevations in bilirubin have been observed in children treated with fingolimod.

Reporting of adverse reactions

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

Shelf life. 2 years.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

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

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

Prescription status.

Prescription only.

Manufacturer.

Manufacturer responsible for batch release:

Pharmasell International Betriebsgesellschaft mbH.

Manufacturer's address and site of operations.

Ernst-Melichor-Gasse 20, 1020 Vienna, Austria.