NOVAGRA 50

INSTRUCTIONS for medical use of the medicinal product GILENYA (GILENYA)

GILENYA

(GILENYA)

Composition:

active substance: fingolimod;

1 capsule contains 0.5 mg of fingolimod (in the form of hydrochloride);

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

Pharmaceutical form.

Hard capsules.

Main physical and chemical properties:

capsules with a white opaque body and a bright yellow opaque cap; radial embossing with black ink "FTY 0.5 mg" on the cap and two radial stripes on the body, applied with yellow ink; capsule size: 3;

capsule contents: powder from white to almost white color.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Fingolimod is a sphingosine-1-phosphate receptor modulator. Fingolimod is metabolized by sphingosine kinase to its active metabolite, fingolimod phosphate. Fingolimod phosphate binds to sphingosine-1-phosphate (S1P) receptors of type 1, located on lymphocytes, at low nanomolar concentrations. It easily penetrates the blood-brain barrier to bind to S1P receptors of type 1, located on nerve cells in the central nervous system (CNS). Acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the ability of lymphocytes to exit lymphoid organs, causing redistribution, not depletion, of lymphoid tissue. Animal studies have shown that such redistribution reduces the penetration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, into the CNS, where they could participate in nerve inflammation and damage to nervous tissue. Animal studies and in vitro experiments also show that fingolimod may act through interaction with S1P receptors on nerve cells.

Pharmacodynamic effects

Within 4-6 hours after the first application of fingolimod at a dose of 0.5 mg, the number of lymphocytes in peripheral blood decreases to approximately 75% of the initial value. With continuous daily use, the number of lymphocytes continues to decrease over a 2-week period, reaching a minimum of approximately 500 cells/μl, or approximately 30% of the initial number. 18% of patients achieved a minimum number of less than 200 cells/μl at least once. Low lymphocyte levels are maintained with constant daily use. Most T- and B-lymphocytes regularly pass through lymphoid organs, and these cells are mainly affected by fingolimod. Approximately 15-20% of T-lymphocytes have an effector memory cell phenotype, which is important for controlling the peripheral immune system. Since this subgroup of lymphocytes usually does not regularly pass through lymphoid organs, they are not affected by fingolimod. An increase in the number of peripheral lymphocytes is observed within a few days after stopping treatment with fingolimod, and a characteristic normal number is achieved within 1-2 months. Continuous use of fingolimod leads to a slight decrease in the number of neutrophils, approximately to 80% of the initial number. Monocytes are not affected by fingolimod.

Pharmacokinetics.

Data on pharmacokinetics were obtained in healthy volunteers, patients with kidney transplants, and patients with multiple sclerosis.

The pharmacologically active metabolite is fingolimod phosphate.

Absorption

Absorption of fingolimod occurs slowly (Tmax 12-16 hours) and extensively (≥ 85%). The predicted absolute bioavailability after oral administration is 93% (95% confidence interval: 79-111%). Steady-state blood concentrations are reached within 1-2 months after administration of 1 dose per day and are approximately 10 times higher than after administration of the first dose.

Food intake does not affect Cmax or exposure (AUC) of fingolimod: Cmax of fingolimod phosphate was slightly increased (by 34%), and AUC did not change. Therefore, the drug GILENYA can be used regardless of food intake (see section "Method of administration and dosage").

Distribution

Fingolimod is intensively distributed in red blood cells with a fraction in blood cells of 86%. Fingolimod phosphate has a lower cell uptake ratio - <17%. Fingolimod and fingolimod phosphate are actively bound to proteins (> 99%).

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

Metabolism

The metabolism of fingolimod in humans occurs by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is excreted by oxidative biotransformation, which is mainly catalyzed by CYP4F2 and possibly other isoenzymes, and subsequent breakdown, similar to fatty acids, to inactive metabolites. The formation of pharmacologically inactive non-polar ceramide analogs of fingolimod was also observed. The main enzyme involved in the metabolism of fingolimod is partially identified: it may be either CYP4F2 or CYP3A4.

After a single oral administration of [14C] fingolimod, the main fingolimod-related components in the blood, determined by their share in the AUC of total radiolabeled components within 34 days after administration, are fingolimod (23%), fingolimod phosphate (10%), and inactive metabolites (metabolite M3 carboxylic acid (8%), ceramide metabolite M29 (9%), and ceramide metabolite M30 (7%)).

Excretion

The clearance rate of fingolimod from the blood is 6.3 ± 2.3 L/h, and the average apparent terminal half-life (T1/2) is 6-9 days. The levels of fingolimod and fingolimod phosphate decrease similarly in the terminal phase, resulting in a similar half-life.

After oral administration, approximately 81% of the dose is slowly excreted in the urine in the form of inactive metabolites. Fingolimod and fingolimod phosphate are not excreted in the urine in their intact form, but are the main components in the feces, where the amount of each is less than 2.5% of the dose. Within 34 days, 89% of the accepted dose is excreted.

Linearity

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

Characteristics in specific patient groups

Sex, ethnic origin, and renal impairment

The pharmacokinetics of fingolimod and fingolimod phosphate do not differ in men and women, in patients of different ethnic origin, and in patients with renal impairment from mild to severe.

Hepatic impairment

In patients with hepatic impairment of mild, moderate, or severe degree (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 decreased by 22%, and AUC did not change significantly. 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 and moderate hepatic impairment (see section "Method of administration and dosage").

Elderly patients

Clinical experience and pharmacokinetic study results in patients aged 65 and older are limited. The drug GILENYA should be used with caution in patients aged 65 and older.

Children

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

The concentration of fingolimod phosphate at steady state is approximately 25% lower in children (aged 10 and older) after daily administration of 0.25 mg or 0.5 mg of fingolimod compared to the concentration in adult patients who received fingolimod at a dose of 0.5 mg once daily.

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

Clinical characteristics.

Indications.

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

• Patient with high disease activity.
• Patient with rapidly evolving severe relapsing-remitting multiple sclerosis.

Contraindications.

Immunodeficiency syndrome.

Contraindicated in patients with an increased risk of opportunistic infections, including patients with weakened immunity (including patients undergoing immunosuppressive therapy or patients with weakened immunity due to therapy).

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 that occurred within the last 6 months.

Unstable angina.

Stroke. Transient ischemic attack.

Decompensated heart failure requiring hospitalization.

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

Expressed cardiac arrhythmia requiring simultaneous use with antiarrhythmic drugs of class Ia or III.

Existing or existing in the anamnesis atrioventricular block of II degree of Mobitz II type or atrioventricular block of III degree.

Sinus node weakness syndrome (if the patient does not have a functioning pacemaker).

Basic interval QTc ≥ 500 ms.

Contraindicated in pregnant women and women of reproductive age who do not use highly effective methods of contraception.

Hypersensitivity to the active substance or to any excipient.

Interaction with other medicinal products and other types of interactions.

Antineoplastic, immunosuppressive, or immunomodulatory treatment

Caution should be exercised when using antineoplastic, immunosuppressive, or immunomodulatory agents simultaneously due to the risk of an additive effect on the immune system (see sections "Contraindications" and "Special warnings and precautions for use").

Also, caution should be exercised when switching from long-acting treatments that affect the immune system, such as natalizumab or mitoxantrone (see section "Special warnings and precautions for use"). In clinical studies of multiple sclerosis, concomitant treatment with a short course of corticosteroids for relapse did not result in an increased frequency of infections.

Vaccination

Vaccination may be less effective during treatment with the drug GILENYA, as well as within 2 months after the end of treatment. The use of live attenuated vaccines may lead to a risk of infection and is therefore not recommended (see sections "Special warnings and precautions for use" and "Adverse reactions").

Drugs that induce bradycardia development

Treatment with fingolimod has been studied in combination with drugs that reduce heart rate, such as atenolol and diltiazem. When fingolimod is used with atenolol in interaction studies in healthy volunteers, an additional 15% decrease in heart rate is observed at the beginning of fingolimod treatment, which is not observed with diltiazem. Contraindicated in patients who are taking beta-blockers or other agents that may increase heart rate, such as antiarrhythmic drugs of class Ia and III, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, anticholinesterase agents, or pilocarpine, due to an additive effect on heart rate (see sections "Special warnings and precautions for use" and "Adverse reactions").

If combination therapy with the drug GILENYA is planned, it is recommended to consult a cardiologist regarding the transfer of the patient to drugs that do not reduce heart rate or regarding appropriate monitoring for the start of treatment. Monitoring is recommended for at least one night if the use of a drug that reduces heart rate cannot be stopped.

The administration of a single dose of fingolimod with isoprenaline or atropine did not change the effect of the drug. Additionally, the use of atenolol, diltiazem, and fingolimod did not change the pharmacokinetics of the latter.

Pharmacokinetic influence of other medicinal products on fingolimod

Fingolimod is metabolized mainly by CYP4F2. Other enzymes, such as CYP3A4, may also be involved in its metabolism, especially in the case of pronounced induction of CYP3A4. It is not expected that potent inhibitors of transport proteins will affect the distribution of fingolimod. Concomitant use of fingolimod with ketoconazole led to an increase in exposure to fingolimod and fingolimod phosphate (AUC) by 1.7 times due to inhibition of CYP4F2. Caution should be exercised when prescribing fingolimod simultaneously with agents that may inhibit CYP3A4 activity (protease inhibitors, antifungal agents of the azole group, some macrolide agents, such as clarithromycin or telithromycin).

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

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

The pharmacokinetics of potential interactions do not indicate a significant effect of fluoxetine, paroxetine (potent inhibitors of CYP2D6), and carbamazepine (potent inhibitor of the enzyme) on fingolimod and fingolimod phosphate. Additionally, 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.

Influence on laboratory tests

Since fingolimod reduces the number of lymphocytes in the blood due to their redistribution in secondary lymphoid organs, the content of lymphocytes in peripheral blood cannot be used to determine the state of lymphocytes.

Laboratory studies of circulating mononucleates require a large volume of blood due to the decrease in circulating lymphocytes.

Pharmacokinetic interactions of fingolimod with other substances

It is unlikely that fingolimod will interact with substances that are metabolized mainly by CYP450 enzymes or are substrates of major transport proteins.

When fingolimod was used concomitantly with cyclosporine, no changes in cyclosporine or fingolimod exposure were observed. Therefore, it is not expected that fingolimod will affect the pharmacokinetics of medicinal products that are substrates of the CYP3A4 isoenzyme.

As a result of concomitant use of fingolimod with oral contraceptives (ethinyl estradiol and levonorgestrel), no changes in exposure to oral contraceptive agents were detected. Studies of drug interactions with oral contraceptives containing other progestogens have not been conducted; however, it is not expected that fingolimod will affect their exposure.

Special warnings and precautions for use.

Bradycardia

The start of treatment with fingolimod is accompanied by a temporary decrease in heart rate, as well as may be associated with a delay in atrioventricular conduction, in particular, there are isolated reports of transient complete AV block, which spontaneously resolves (see section "Adverse reactions" and "Pharmacodynamics").

After administration of the first dose, a decrease in heart rate begins within 1 hour and reaches a maximum approximately 6 hours later. This effect after administration persists for several subsequent days, although symptoms are usually milder and pass within a few weeks. With continued use of the drug, heart rate usually returns to baseline within 1 month, although in some patients it may not return to baseline until the end of the first month. Pathological changes in conduction were generally temporary and asymptomatic. These changes usually did not require treatment and disappeared within the first 24 hours of continued treatment. In case of need to decrease heart rate induced by fingolimod, it can be stopped by intravenous administration of atropine or isoprenaline.

Before administration of the drug and at the end of the 6-hour period after administration of the first dose, all patients should undergo electrocardiography and measurement of blood pressure. It is recommended to monitor all patients with hourly measurement of pulse and blood pressure for 6 hours to detect symptoms of bradycardia. 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 daily dose of 0.25 mg to a daily dose of 0.5 mg.

In case of development of symptoms after dose bradycardia, if necessary, appropriate treatment should be prescribed, and the patient should be monitored until the symptoms disappear. If there is a need for medical intervention during the monitoring period after the first administration of the drug, monitoring should be continued for at least one night in a medical facility, as well as after the second administration of the drug GILENYA.

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

The effect of the drug on heart rate and atrioventricular conduction may recur when treatment with fingolimod is resumed and depends on the duration of the break and the time since the start of treatment. Monitoring of the first dose of the drug, as well as at the beginning of treatment, is recommended in case of interruption of treatment (see section "Method of administration and dosage").

Very rarely, reports of T-wave inversion have been received in adult patients who received treatment with fingolimod. In case of T-wave inversion, the doctor should ensure that there are no associated signs or symptoms of myocardial ischemia. If there is a suspicion of myocardial ischemia, it is recommended to consult a cardiologist.

Due to the risk of developing serious cardiac arrhythmias or severe bradycardia, the drug GILENYA is contraindicated in patients with sinoatrial block, symptomatic bradycardia, or recurrent loss of consciousness in the anamnesis, cardiac arrest in the anamnesis, and patients with significant prolongation of the QT interval (QTc > 470 ms (adult women), QTc > 460 ms (children of the female sex), or > 450 ms (adult and children of the male sex)), uncontrolled hypertension, or severe sleep apnea (see also section "Contraindications").

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

It is recommended to consult a cardiologist before starting treatment regarding proper monitoring and to perform extended monitoring for at least one night (see also section "Interaction with other medicinal products and other types of interactions").

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

Experience with the use of the drug GILENYA in patients who are receiving concomitant therapy with beta-blockers, calcium channel blockers that reduce heart rate (such as verapamil or diltiazem), or other agents that reduce heart rate (such as ivabradine, digoxin, anticholinesterase agents, or pilocarpine) is limited. Since a decrease in heart rate was also observed at the beginning of treatment with fingolimod (see also section "Adverse reactions", Bradycardia), concomitant use of these agents during the start of treatment may be accompanied by the development of severe bradycardia and heart block. Due to the possible additive effect on heart rate, treatment with the drug GILENYA is not recommended in most cases for patients who are receiving concomitant therapy with these agents (see also section "Interaction with other medicinal products and other types of interactions"). The appointment of the drug GILENYA to these patients is possible only if the expected benefit outweighs the risk. When prescribing the drug GILENYA, it is recommended to consult a cardiologist regarding the transfer of the patient to drugs that do not reduce heart rate. If treatment with drugs that reduce heart rate cannot be stopped, it is recommended to consult a cardiologist regarding proper monitoring and to perform extended monitoring for at least one night (see also section "Interaction with other medicinal products and other types of interactions").

Prolongation of the QT interval

In a thorough study of the effect of fingolimod at doses of 1.25 or 2.5 mg on the QT interval at steady state, when the negative chronotropic effect of fingolimod was still observed, treatment with this agent led to a prolongation of the QTc interval with an upper limit of 90% CI ≤ 13.0 ms. There is no dependence of QTc interval prolongation on the dose of fingolimod or exposure/response. A signal indicating an increased frequency of QTc interval deviations, if this is an absolute change or a change compared to the baseline level, associated with the use of fingolimod, is absent.

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

The use of medicinal products that can lead to QTc interval prolongation is best avoided in patients with relevant risk factors, such as hypokalemia or congenital QT interval prolongation.

Immunosuppression

Fingolimod has an immunosuppressive effect, which increases the risk of developing infections, including opportunistic ones, which can be life-threatening, as well as the risk of developing lymphomas and other malignant neoplasms, particularly on the skin. Doctors should carefully monitor the condition of patients, especially patients with concomitant diseases or known factors, such as previous immunosuppressive therapy. If there is a suspicion of such a risk, the doctor should consider the possibility of stopping treatment in each individual case (see also sections "Special warnings and precautions for use", Infections, and Neoplasms on the skin; and section "Adverse reactions", Lymphoma).

Infections

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

Before starting treatment with the drug GILENYA, the results of the last general blood test (i.e., performed within the last 6 months or after stopping the previous course of therapy) should be available. A general blood test is also recommended to be performed periodically during treatment, on the third month of therapy, and at least annually thereafter, as well as in case of symptoms of an infectious disease. If the absolute number of lymphocytes is confirmed to be <0.2 × 10^9/L, treatment should be temporarily stopped until the indicator is normalized, since in clinical studies, treatment with fingolimod was temporarily stopped in patients with an absolute number of lymphocytes <0.2 × 10^9/L.

The start of treatment with the drug GILENYA should be postponed for patients with an acute infectious disease in the active stage until its completion.

The effect of the drug GILENYA on the immune system may increase the risk of developing infections, including opportunistic ones (see section "Adverse reactions"). Therefore, effective diagnostic and treatment methods should be used for patients with symptoms of an infectious disease that occurred during treatment. When evaluating a patient with a suspected infection that may be serious, it is recommended to consult a doctor who has experience in treating such infections. During treatment with the drug GILENYA, patients should be informed about the need to immediately report to the doctor about symptoms of infectious diseases.

It is recommended to consider temporary discontinuation of the drug GILENYA in case of development of a serious infectious disease in a patient, as well as to conduct an assessment of the benefit/risk ratio before resuming therapy.

After stopping treatment, the elimination of fingolimod from the body may take up to two months, so during this period, monitoring for infection detection should be continued. Patients should be informed about the need to report to the doctor about symptoms of infectious diseases during the period up to 2 months after stopping treatment with fingolimod.

Herpesvirus infection

Serious, life-threatening, and sometimes fatal cases of encephalitis, meningitis, or meningoencephalitis caused by herpes simplex and varicella-zoster viruses have been observed at any time during treatment with the drug GILENYA. In case of suspected herpesvirus encephalitis, meningitis, or meningoencephalitis, the use of the drug GILENYA should be stopped, and appropriate treatment of the corresponding infection should be prescribed.

Before starting therapy with the drug GILENYA, it is recommended to assess the immune status of patients to varicella (chickenpox). It is recommended that patients who have no history of confirmed chickenpox or no documented complete course of varicella-zoster virus (VZV) vaccination undergo a test for VZV antibodies. It is recommended that patients with negative test results for VZV antibodies receive a complete course of varicella vaccination before starting treatment with the drug GILENYA. The start of treatment with fingolimod should be postponed for 1 month until the development of a full effect of vaccination.

Cryptococcal meningitis

There have been reports of cases of cryptococcal meningitis (fungal infection), sometimes fatal, during the post-marketing period after approximately 2-3 years of treatment, although the exact link with the duration of treatment is unknown (see section "Adverse reactions"). Patients with symptoms and signs corresponding to cryptococcal meningitis (e.g., with headache accompanied by changes in mental status, such as confusion, hallucinations, and/or changes in personality) should undergo thorough diagnostic examination. In case of diagnosis of cryptococcal meningitis, treatment with fingolimod should be stopped, and adequate therapy should be started. Consultations with other doctors (e.g., an infectious disease specialist) should be conducted if resumption of treatment with fingolimod is necessary.

Progressive multifocal leukoencephalopathy (PML)

During the post-marketing period, cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with fingolimod (see section "Adverse reactions").

PML is an opportunistic infection caused by the JC virus, which can lead to death or severe disability. Cases of PML have been reported after 2-3 years of monotherapy without prior use of natalizumab, although the exact link with the duration of treatment is unknown. Additional cases of PML have been reported in patients who previously received natalizumab, whose use is known to be associated with PML. PML can develop exclusively in the presence of JC virus infection. When conducting a test for JC virus, it should be remembered that the effect of lymphopenia on the reliability of the test for JC virus antibodies in patients receiving fingolimod has not been studied. It should also be taken into account that a negative result of the test for JC virus antibodies does not exclude the possibility of developing JC virus infection in the future. Before starting treatment with fingolimod, it is necessary to have the results of an MRI scan at the baseline level (usually, an MRI scan is performed no earlier than 3 months before starting treatment). The results of the MRI scan may indicate the presence of the disease before clinical symptoms or signs. During a standard MRI scan (in accordance with national and local recommendations), doctors should pay particular attention to lesions that may indicate the presence of PML. An MRI scan can be considered as one of the comprehensive measures for monitoring patients who are at risk of developing PML. There have been reports of asymptomatic PML based on MRI results and a positive test for JC virus DNA in cerebrospinal fluid in patients who used fingolimod.

In case of suspected PML, an MRI scan should be performed for diagnostic purposes, and therapy with fingolimod should be suspended until the suspected PML is ruled out.

Human papillomavirus (HPV)

There have been reports of the development of human papillomavirus (HPV) infection, including papilloma, dysplasia, warts, and HPV-related cancer, during treatment with fingolimod in post-marketing conditions (see section "Adverse reactions"). Due to the immunosuppressive properties of fingolimod, vaccination against HPV should be considered before starting treatment with fingolimod, taking into account vaccination recommendations. Screening for cancer, including a Pap test, is recommended according to standards of care.

Macular edema

In 0.5% of patients who received treatment with fingolimod at a dose of 0.5 mg, macular edema with or without the development of symptoms from the organs of vision was reported. Macular edema was observed in most cases within the first 3-4 months of treatment (see section "Adverse reactions").

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

In patients with uveitis in the anamnesis, as well as in patients with diabetes, the risk of developing macular edema is increased (see section "Adverse reactions"). The use of fingolimod in patients with multiple sclerosis and concomitant diabetes has not been studied. Patients with multiple sclerosis and diabetes or uveitis in the anamnesis are recommended to undergo ophthalmological examination before starting treatment and periodically during treatment.

The continuation of fingolimod treatment in patients with macular edema has not been evaluated.

In case of development of macular edema in a patient, it is recommended to stop treatment. When deciding on the resumption of therapy after the disappearance of macular edema, the potential benefits and risks for each individual patient should be taken into account.

Liver damage

There have been reports of increased levels of liver enzymes, particularly alanine aminotransferase (ALT), as well as gamma-glutamyltransferase (GGT) and aspartate aminotransferase (AST), in patients with multiple sclerosis who received fingolimod. There have also been reports of some cases of acute liver failure requiring liver transplantation and clinically significant liver damage. Signs of liver damage, including significantly elevated liver enzyme levels in serum and elevated total bilirubin levels, were observed as early as 10 days after the first dose and also after prolonged use. During clinical trials, in 8% of patients who received treatment with fingolimod at a dose of 0.5 mg, an increase in ALT levels more than 3 times the upper limit of normal (ULN) was observed, compared to 1.9% of patients who received a placebo. A 5-fold increase in ULN was observed in 1.8% of patients who received fingolimod and in 0.9% of patients who received a placebo.

In clinical trials, treatment with fingolimod was stopped if the level of liver transaminases exceeded 5 times the ULN. Repeated increases in liver transaminase levels were observed when treatment with fingolimod was resumed in some patients, which confirms the link between this adverse event and the use of fingolimod. In clinical trials, increases in transaminase levels occurred at any time during treatment, although most cases were observed within the first 12 months. Elevated levels of transaminases in serum returned to normal approximately within 2 months after stopping treatment with fingolimod.

Fingolimod has not been studied in patients with severe pre-existing liver dysfunction (Child-Pugh class C). The drug GILENYA is contraindicated in these patients (see section "Contraindications").

Due to the immunosuppressive properties of fingolimod, the start of treatment should be postponed for patients with viral hepatitis in the active stage until its completion.

Recent (i.e., obtained within the last 6 months) results of tests for transaminase and bilirubin levels should be available before starting treatment. In the absence of clinical symptoms, monitoring of liver transaminase activity and bilirubin levels in serum should be performed during 1, 3, 6, 9, and 12 months of treatment and then periodically up to 2 months after stopping the drug GILENYA. In the absence of clinical symptoms, if liver transaminase levels exceed the ULN by >3 but <5 times without an increase in bilirubin levels in serum, more frequent monitoring, including measurement of bilirubin and alkaline phosphatase (ALP) in serum, is necessary to determine whether further increases will occur and to determine whether there is an alternative etiology of liver dysfunction. If liver transaminase levels exceed the ULN by ≥5 times or ≥3 times with any increase in bilirubin levels in serum, the use of the drug GILENYA should be stopped. Monitoring of liver function should be continued. In case of normalization of transaminase levels in serum (including if an alternative cause of liver dysfunction is detected), the use of the drug GILENYA may be resumed based on a careful assessment of the benefit/risk ratio 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 enzymes and bilirubin should be checked immediately, and in case of confirmed significant liver damage, treatment should be stopped.

Treatment should not be resumed if it is not possible to establish a likely alternative etiology of signs and symptoms of liver damage.

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

Influence on blood pressure

Patients with arterial hypertension whose control is not achieved by drug treatment and who were not allowed to participate in pre-marketing clinical trials should be treated with caution when taking the drug GILENYA.

In clinical trials of multiple sclerosis, in patients who received fingolimod at a dose of 0.5 mg, an increase in average systolic blood pressure by approximately 3 mmHg and diastolic blood pressure by approximately 1 mmHg was observed, which was first noted approximately 1 month after the start of treatment. Such an increase persisted with continued treatment. In a 2-year placebo-controlled study, the development of hypertension as an adverse event was reported in 6.5% of patients who received fingolimod at a dose of 0.5 mg and in 3.3% of patients who received a placebo. Therefore, regular monitoring of blood pressure is recommended during treatment.

Respiratory effects

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

Reversible posterior encephalopathy syndrome (PRES)

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

Previous treatment with immunodepressants or immunomodulators

No studies have been conducted to evaluate the efficacy and safety of fingolimod when switching patients from teriflunomide, dimethyl fumarate, or alemtuzumab to the drug GILENYA. When switching patients from another disease-modifying therapy to the drug GILENYA, it is necessary to take into account its half-life and mechanism of action to avoid an additive immune effect and, at the same time, minimize the risk of disease reactivation. A general blood test is recommended before starting treatment with the drug GILENYA to ensure that the effect of previous therapy on the immune system (i.e., cytopenia) has already been eliminated.

Interferon beta, glatiramer acetate, or dimethyl fumarate

Usually, treatment with the drug GILENYA can be started immediately after stopping the use 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 treatment with the drug GILENYA.

Natalizumab or teriflunomide

Due to the long half-life of natalizumab, its washout period usually lasts up to 2-3 months after stopping its use.

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

Caution should be exercised regarding potential concomitant effects on the immune system when switching patients from natalizumab or teriflunomide to the drug GILENYA. A careful assessment of the start of treatment is recommended in each individual case.

Alemtuzumab

Alemtuzumab has a profound and long-lasting immunosuppressive effect. Since the actual duration of this effect is unknown, it is not recommended to start treatment with the drug GILENYA after the use of alemtuzumab, except in cases where the benefit of such treatment clearly outweighs the risks for a particular patient.

The decision to concomitantly administer a prolonged course of corticosteroids should be carefully weighed.

Concomitant use of potent CYP450 inducers

Caution should be exercised when using fingolimod in combination with potent CYP450 inducers. Concomitant use of St. John's wort is not recommended (see section "Interaction with other medicinal products and other types of interactions").

Malignant neoplasms

Neoplasms on the skin

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 who received the drug GILENYA (see section "Adverse reactions"). Enhanced surveillance for the development of skin lesions is recommended, as well as a medical evaluation of the skin at the start of treatment and every 6-12 months, taking into account the clinical assessment. In case of detection of suspicious lesions, the patient should be referred to a dermatologist.

Since there is a potential risk of tumor growth, patients who take fingolimod should be warned about the risks associated with exposure to sunlight without protection. These patients are contraindicated for concomitant UV-B phototherapy or PUVA therapy (photochemotherapy).

Lymphomas

There have been cases of lymphoma development of various types in clinical trials and during post-marketing use (see section "Adverse reactions"). The reported cases were non-uniform in nature, mainly non-Hodgkin's lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have been observed. A fatal case of B-cell lymphoma, positive for the Epstein-Barr virus (EBV), has also been reported. In case of suspected lymphoma, treatment should be stopped.

Tumefactive lesions

Rare cases of tumefactive lesions associated with multiple sclerosis relapse have been reported in post-marketing conditions. In case of severe relapses, an MRI scan should be performed to rule out tumefactive lesions. Stopping treatment should be considered by the doctor in each individual case, taking into account the individual benefits and risks.

Rebound effect after stopping treatment with fingolimod

In the post-marketing period, rare cases of severe disease exacerbation have been observed in some patients who stopped taking fingolimod. This usually occurred within 12 weeks after stopping fingolimod, but also occurred within a period of up to 24 weeks after stopping the drug. Caution is also indicated when stopping treatment with fingolimod. If stopping fingolimod is considered necessary, the possibility of a rebound effect of extremely high disease activity should be considered. Therefore, the condition of patients should be monitored for corresponding signs and symptoms, and if necessary, appropriate treatment should be started.

Stopping treatment

In case of a decision to stop treatment with the drug GILENYA, a 6-week interval without medication is necessary, taking into account the half-life of the drug, to remove fingolimod from the bloodstream (see section "Pharmacokinetics"). In most patients, the number of lymphocytes usually returns to the normal range of values within 1-2 months after stopping treatment (see section "Pharmacodynamics"), but complete recovery to the normal range may take significantly longer in some patients. Resumption of treatment during this period will lead to concomitant exposure to fingolimod. The use of immunosuppressants soon after stopping the drug GILENYA may lead to an additive effect on the immune system, so caution is necessary.

Interference with serological tests

Since fingolimod reduces the number of lymphocytes in the blood by redistributing them in secondary lymphoid organs, the content of lymphocytes in peripheral blood cannot be used to determine the state of lymphocytes.

Laboratory studies of circulating mononucleates require a large volume of blood due to the decrease in circulating lymphocytes.

Children

The safety profile in pediatric patients is similar to that in adults, so the special warnings and precautions for use for adults also apply to children.

In particular, when prescribing the drug GILENYA to children, the following should be noted:

• Caution should be exercised during the administration of the first dose (see "Bradycardia"). 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 a controlled pediatric study D2311, cases of seizures, anxiety, depressed mood, and depression were reported with a higher frequency of occurrence in patients who received fingolimod compared to patients who received interferon beta-1a. Caution is necessary when using this subgroup (see section "Adverse reactions", Children).
• A mild isolated increase in bilirubin has been observed in children who use the drug GILENYA.
• Pediatric patients are recommended to undergo all vaccinations according to the current vaccination recommendations before starting therapy with the drug GILENYA (see "Infections").
• There are very limited data on the use of the drug GILENYA in children aged 10-12 with a body weight of less than 40 kg or at Tanner stage <2 (see sections "Adverse reactions" and "Pharmacodynamics"). The use of the drug GILENYA in this subgroup requires caution due to very limited data available in clinical trials.
• Data on the safety of long-term use in children are not available.

Use during pregnancy or breastfeeding.

Women of childbearing age / contraception in women

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

Before starting treatment with Gilenya, women of childbearing age should be informed about the serious risk to the fetus and the need for effective contraception during treatment with the drug and receive a negative pregnancy test result.

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

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

Pregnancy

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

The most commonly reported major defects were:

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

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

In animal studies, reproductive toxicity has been demonstrated, including fetal loss and organ malformations, in particular, the common arterial trunk and ventricular septal defect. Additionally, the receptor affected by fingolimod

(sphingosine-1-phosphate receptor) is involved in vascular formation during embryogenesis.

As a result, fingolimod is contraindicated during pregnancy (see "Contraindications" section). The use of fingolimod should be stopped 2 months before planning pregnancy.

If a woman becomes pregnant while taking Gilenya, it is recommended to stop taking the drug. Medical counseling on the risk of adverse effects on the fetus associated with treatment and ultrasound examination should be provided.

Breastfeeding period

Fingolimod penetrated into the milk of animals that were given the drug during the lactation period, in concentrations that were 2-3 times higher than the concentrations in the plasma of maternal individuals. Due to the possibility of serious adverse reactions to fingolimod in infants, women should stop breastfeeding during the use of the drug.

Fertility

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

Ability to affect reaction rate when driving vehicles or operating other mechanisms.

Fingolimod does not affect or has a negligible effect on the ability to drive vehicles and operate other mechanisms.

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

Method of administration and dosage.

Treatment should be started and carried out under the supervision of a doctor who has experience in treating multiple sclerosis.

Dosage

The recommended dose of fingolimod for adults is 1 capsule of 0.5 mg orally once a day.

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

• for children with a body weight of ≤ 40 kg, 1 capsule of 0.25 mg (if such dosing is possible) orally once a day;
• for children with a body weight of ≥ 40 kg, 1 capsule of 0.5 mg orally once a day.

Children who start taking capsules of 0.25 mg (if such dosing is possible) and subsequently reach a stable body weight above 40 kg should be switched to taking capsules of 0.5 mg.

When switching from a daily dose of 0.25 mg (if such dosing is possible) to a dose of 0.5 mg, it is recommended to repeat the monitoring of the first dose, as at the start of treatment.

The drug is intended for oral administration.

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

Monitoring of the first dose of the drug, as at the start 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 1 month of treatment.

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

Dosage for individual patient groups

Elderly patients

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

Kidney function disorders

The use of fingolimod in patients with multiple sclerosis and kidney function disorders has not been studied in basic studies. The results of clinical pharmacology studies indicate that there is no need to adjust the dose for patients with kidney function disorders from mild to severe.

Liver function disorders

Gilenya is contraindicated in patients with severe liver function disorders (Child-Pugh class C) (see "Contraindications" section). Although there is no need to adjust the dose for patients with liver function disorders from mild to moderate, such patients should be started on therapy with caution (see "Special Instructions" and "Pharmacokinetics" sections).

Children

The safety and efficacy of fingolimod in children under the age of 10 have not been established. There are no data.

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

Overdose.

Single doses that are 80 times higher than the recommended dose (0.5 mg) were well tolerated by healthy volunteers. Regarding the dose of 40 mg, 5 out of 6 people reported mild chest tightness or discomfort, which was clinically consistent with minor reactivity of the airways.

Fingolimod may induce the development of bradycardia at the start of treatment. The heart rate usually begins to decrease within one hour after the first dose of the drug, and the maximum decrease is observed within 6 hours. The negative chronotropic effect of Gilenya persists for more than 6 hours and gradually decreases over the next few days of treatment. There have been reports of slow atrioventricular conduction along with isolated reports of the development of temporary complete atrioventricular block, which resolved spontaneously (see "Special Instructions" and "Adverse Reactions" sections).

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

In addition, if after 6 hours the heart rate is less than 45 beats per minute in adults, less than 55 beats per minute in children aged 12 years and older, or less than 60 beats per minute in children aged 10 to 12 years, or if an AV block of the second degree or higher is detected on the ECG 6 hours after taking the first dose, or if the QTc interval is ≥ 500 ms, monitoring should be extended and performed for at least one night and until the detected symptoms disappear. The occurrence of a third-degree AV block at any time also requires extended monitoring, including monitoring during the night.

Dialysis or plasma replacement does not lead to the elimination of fingolimod from the body.

Adverse reactions.

Summary of safety profile

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

List of adverse reactions in table form

Description of individual adverse reactions

Infections

In clinical trials of multiple sclerosis, the overall frequency of infections (65.1%) at a dose of 0.5 mg was similar to that with placebo. However, lower respiratory tract infections, mainly bronchitis and to a lesser extent, herpes virus infections, and pneumonia, were more common in patients taking fingolimod.

Several cases of disseminated herpes infection, including fatal cases, have been observed even at a dose of 0.5 mg.

In the post-marketing period, cases of infections caused by opportunistic microorganisms, 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 "Special Instructions" section), have been reported.

There have been reports of human papillomavirus (HPV) infection, including papilloma, dysplasia, warts, and HPV-related cancer, during treatment with fingolimod in post-marketing conditions (see "Special Instructions" section). Due to the immunosuppressive properties of fingolimod, vaccination against HPV should be considered before starting treatment with fingolimod, taking into account vaccination recommendations. Screening for cancer, including the Pap test, is recommended according to standards of care.

Macular edema

In clinical trials of multiple sclerosis, macular edema was observed in 0.5% of patients who received treatment at the recommended dose of 0.5 mg and in 1.1% of patients who received treatment at the maximum dose of 1.25 mg. Most cases were observed within the first 3-4 months of treatment. In some patients, blurred vision or decreased visual acuity developed, but in other patients, the symptoms were asymptomatic and diagnosed during routine ophthalmological examination. Macular edema usually decreased or disappeared spontaneously after discontinuation of therapy. The risk of recurrence after re-administration of the drug was not assessed.

The frequency of macular edema is increased in patients with multiple sclerosis and uveitis in their history (17% with uveitis in their history compared to 0.6% without uveitis in their history). The use of Gilenya in patients with multiple sclerosis and diabetes, a disease associated with an increased risk of macular edema, has not been studied. In kidney transplant studies, which included patients with diabetes, treatment with Gilenya at a dose of 2.5 mg and 5 mg was associated with a twofold increase in the frequency of macular edema.

Bradycardia

The start of treatment with fingolimod is associated with a temporary decrease in heart rate, as well as may be associated with delayed atrioventricular conduction. In clinical trials of multiple sclerosis, the maximum decrease in heart rate was observed 6 hours after the start of treatment, with a decrease in average heart rate of 12-13 beats per minute during the use of fingolimod at a dose of 0.5 mg. A heart rate of less than 40 beats per minute in adults and less than 50 beats per minute in children was rarely observed in patients taking Gilenya at a dose of 0.5 mg. On average, the heart rate returned to normal within 1 month of continuous treatment. Bradycardia was usually asymptomatic, but in some patients, symptoms of mild or moderate severity, including arterial hypotension, dizziness, weakness, and/or palpitations, occurred, which disappeared within the first 24 hours after the start of treatment (see "Special Instructions" and "Pharmacodynamics" sections).

In clinical trials of multiple sclerosis, atrioventricular block of the first degree (prolonged pulse interval on ECG) occurred after the start of treatment in 4.7% of patients with Gilenya at a dose of 0.5 mg, in 2.8% of patients with interferon beta-1a for intramuscular administration, and in 1.6% of patients who received placebo. Atrioventricular block of the second degree was observed in less than 0.2% of patients with fingolimod at a dose of 0.5 mg. According to post-marketing observations, isolated cases of temporary complete atrioventricular block, which resolved spontaneously, were observed 6 hours after taking the first dose of Gilenya. Patients recovered without symptomatic treatment. The conduction disorders observed in clinical trials and during post-marketing surveillance were mostly temporary, asymptomatic, and disappeared within the first 24 hours after the start of treatment. Although the condition of most patients did not require medical intervention, one patient who took fingolimod at a dose of 0.5 mg was prescribed isoproterenol for asymptomatic atrioventricular block of the second degree, type Mobitz I.

During post-marketing surveillance, isolated delayed events, including temporary asystole and a fatal case of unknown cause, occurred within 24 hours after taking the first dose. In these cases, concomitant medications and/or patients had other diseases. The relationship between such events and the use of Gilenya is not established.

Arterial pressure

In clinical trials of multiple sclerosis, the use of fingolimod at a dose of 0.5 mg was associated with a slight increase, approximately 3 mmHg, in the average systolic blood pressure and approximately 1 mmHg in diastolic blood pressure, which was observed approximately 1 month after the start of treatment. Such an increase persisted with continued treatment. Arterial hypertension was observed in 6.5% of patients who took fingolimod at a dose of 0.5 mg and in 3.3% of patients who received placebo. During post-marketing surveillance, cases of arterial hypertension were reported during the first month after the start of treatment and on the first day of treatment, which may have required treatment with antihypertensive drugs or discontinuation of Gilenya (see also "Special Instructions" section).

Liver function

Increased liver enzyme levels have been reported in patients with multiple sclerosis who received Gilenya. In clinical trials of multiple sclerosis, in 8.0% and 1.8% of patients who took fingolimod at a dose of 0.5 mg, there was an asymptomatic increase in serum ALT levels more than 3 times and more than 5 times the upper limit of normal, respectively. Repeated increases in liver transaminase levels were observed in some cases when treatment was restarted, confirming the relationship between this phenomenon and the use of the drug. In clinical trials, increased transaminase levels were observed at any time during treatment, although in most cases, they were observed within the first 12 months. ALT levels returned to normal within approximately 2 months after stopping therapy. In a small number of patients (N = 10 for 1.25 mg, N = 2 for 0.5 mg) in whom ALT levels increased more than 5 times the upper limit of normal and who continued to receive fingolimod, ALT levels returned to normal within approximately 5 months (see also "Special Instructions" and "Liver damage" sections).

Nervous system disorders

In clinical trials, rare cases of nervous system disorders were observed in patients who received Gilenya at high doses (1.25 or 5.0 mg), including ischemic and hemorrhagic stroke and atypical neurological disorders, such as events similar to acute disseminated encephalomyelitis (ADEM).

There have been reports of seizures, including status epilepticus, with the use of fingolimod in clinical trials and post-marketing conditions.

Vascular reactions

In patients who took Gilenya at higher doses (1.25 mg), obstructive disease of the peripheral arteries rarely developed.

Respiratory system

Mild dose-dependent decreases in forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) were observed with the use of Gilenya in the first month of treatment and remained stable thereafter. At 24 months of treatment, the percentage decrease in predicted FEV1 values was 2.7% for patients who received fingolimod at a dose of 0.5 mg and 1.2% for patients who received placebo, with a difference in that this phenomenon disappeared after treatment was stopped. Regarding the DLCO value, the decrease at 24 months was 3.3% for patients who received fingolimod at a dose of 0.5 mg and 2.7% for patients who received placebo.

Lymphomas

There have been cases of lymphoma of various types in clinical trials and post-marketing use, including a fatal case of EBV-positive B-cell lymphoma. In clinical trials and post-marketing studies, the likelihood of developing lymphoma (B-cell and T-cell) was higher than expected in the general population.

In post-registration studies, cases of T-cell lymphoma (mycosis fungoides) have also been reported (see also "Special Instructions" and "Lymphomas" sections).

Hemophagocytic syndrome

Very rare cases of hemophagocytic syndrome (HPS) with a fatal outcome have been reported in patients who received fingolimod, with the development of infection. HPS is a rare disease that has been described in association with the development of infections, immunosuppression, and various autoimmune diseases.

Children

In a controlled pediatric study D2311, the safety profile in children aged 10 to 18 years who received 0.25 mg or 0.5 mg of fingolimod daily was generally similar to that in adult patients. However, there were more neurological and psychiatric disorders. The use of this subgroup requires caution due to very limited data obtained in the clinical study.

In the pediatric study, cases of seizures were registered in 5.6% of patients who received fingolimod and in 0.9% of patients who received interferon beta-1a.

As is known, depression and anxiety occur with increased frequency in patients with multiple sclerosis. Depression and anxiety have also been reported in children who received fingolimod.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after the registration of a medicinal product is important. This allows for the continued monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions through national reporting systems for undesirable reactions.

Shelf life.

2 years.

Storage conditions.

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

Packaging.

7 capsules in a blister pack; 1 blister pack in a carton.

14 capsules in a blister pack; 2 blister packs in a carton.

Release category.

By prescription.

Manufacturer.

Novartis Pharma Stein AG.

Manufacturer's location and address.

Schaffhauserstrasse, 4332 Stein, Switzerland.