Fingolimod (Capsules) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

Manufactured By

Pharmstandard-Lexredstva OJSC (Russia)

Or

Pharmstandard-UfaVITA OJSC (Russia)

Contact Information

BIOCAD JSC (Russia)

ATC Code

L04AA27 (Fingolimod)

Active Substance

Fingolimod (Rec.INN WHO registered)

Dosage Form

Fingolimod

Capsules 0.5 mg: 7, 28, or 98 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 1, with an opaque white body and an opaque light green cap; the capsule contents are a mixture containing granules and/or powder, white or white with a yellowish tint; the presence of lumps that disintegrate with light pressure from a glass rod is allowed.

Excipients: pregelatinized starch – 153.88 mg, magnesium stearate – 1.56 mg.

Capsule body composition: gelatin – sufficient quantity to 100%, titanium dioxide (E171) – 3%.
Capsule cap composition gelatin – sufficient quantity to 100%, titanium dioxide (E171) – 0.8%, quinoline yellow dye (E104) – 0.0176%, brilliant blue dye (E133) – 0.0193%.

7 pcs. – blister packs (1) – cardboard packs.
14 pcs. – blister packs (2) – cardboard packs.
14 pcs. – blister packs (7) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Mechanism of action

Fingolimod modulates sphingosine-1-phosphate receptors (S1P receptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate. At nanomolar concentrations, fingolimod phosphate binds to S1P receptors on the surface of lymphocytes, rapidly penetrates the CNS through the BBB and binds to S1P receptors on the surface of neurons. By binding to S1P receptors on lymphocytes, fingolimod phosphate blocks the ability of lymphocytes to leave the lymph nodes, leading to a redistribution of lymphocytes in the body, without a decrease in the total number of lymphocytes. The redistribution of lymphocytes leads to a decrease in lymphocytic infiltration of the CNS, including inflammatory Th17 cells, a reduction in the severity of inflammation and the degree of nerve tissue damage.

Animal studies and in vitro experiments show that the effects of fingolimod may also be due to its interaction with S1P receptors on nerve cells.

Pharmacodynamics

Within 4-6 hours after a single dose of 0.5 mg, the number of lymphocytes in the blood decreases to approximately 75% of the baseline value. With long-term daily use of fingolimod, the lymphocyte count continues to decrease over 2 weeks, reaching a minimum of 500 cells/µL or approximately 30% of the baseline value. In 18% of patients, at least one decrease in lymphocyte count below 200 cells/µL was noted. With regular use of the drug, the reduced lymphocyte count persisted. Since most T and B lymphocytes continuously circulate through lymphoid organs, the effect of fingolimod on these cells is most pronounced. However, about 15-20% of T lymphocytes, which are effector memory cells and play an important role in peripheral immune control, do not circulate through lymphoid organs and are not affected by fingolimod. Within a few days after discontinuation of the drug, an increase in the number of lymphocytes is noted in the blood. Normalization of the lymphocyte count occurs 1-2 months after discontinuation of treatment. Continuous use of fingolimod leads to a slight decrease in the number of neutrophils to approximately 80% of the baseline. Monocytes are not affected by fingolimod.

At the start of treatment with the recommended dose, a transient decrease in heart rate and slowing of AV conduction were noted. The maximum decrease in heart rate is observed within 6 hours after taking the drug, and 70% of the negative chronotropic effect is achieved on the first day of use. Heart rate returned to baseline within 1 month of regular use of the drug.

The decrease in heart rate caused by fingolimod can be relieved by the use of atropine or isoprenaline. Inhaled salmeterol has also been shown to produce a moderate positive chronotropic effect.

At the start of fingolimod use, an increase in the number of atrial extrasystoles is noted, not accompanied by an increase in the frequency of atrial fibrillation/flutter, ventricular arrhythmia or ectopy. No effect of fingolimod on the reduction of cardiac output was noted.

Autonomic functions of the heart, including circadian heart rate variability and response to physical activity, are not altered by fingolimod.

Single and multiple use of fingolimod at doses of 0.5 mg or 1.25 mg for 2 weeks was not associated with a detectable increase in airway resistance as measured by FEV₁ and mean forced expiratory flow between 25% and 75% of FVC. However, a dose-dependent increase in airway resistance was noted with a single dose of fingolimod ≥5 mg, which is 10 times the recommended dose. Multiple use of fingolimod at doses of 0.5 mg, 1.25 mg or 5 mg was not associated with decreased oxygenation, decreased saturation during exercise, or increased airway reactivity to methacholine. Patients receiving Fingolimod showed a normal bronchodilator response to inhaled beta-agonists.

When used in patients with relapsing-remitting multiple sclerosis (RRMS, mean EDSS score 2.0), Fingolimod at a dose of 0.5 mg reduced the frequency of clinical exacerbations of the disease by 54%. When taking the drug, 70% of patients had stable remission for 2 years (compared to 45.6% in the placebo group). Fingolimod significantly reduced the risk of disability progression. The use of the drug significantly increased the time to 3-month and 6-month confirmed disability progression (assessed as an increase in EDSS score from baseline) compared to placebo. MRI results of the brain of patients with relapsing-remitting multiple sclerosis during treatment with fingolimod confirm a significant reduction in disease activity (intensity of the inflammatory process in the CNS, size and number of demyelinating lesions).

Pharmacokinetics

Data on the pharmacokinetics of fingolimod were obtained from healthy volunteers, kidney recipients and patients with multiple sclerosis (MS).

The pharmacologically active metabolite is fingolimod phosphate.

Absorption

When taken orally, ≥85% of the dose is absorbed. The absorption of fingolimod is slow (T_max in plasma is 12-16 hours). The apparent absolute oral bioavailability is 93%. C_ss in plasma is reached within 1-2 months of regular use of the drug (once daily). The C_ss of fingolimod is approximately 10 times higher than its concentration after the first dose.

Food intake does not affect the C_max or exposure (AUC) of fingolimod. The C_max of fingolimod phosphate was slightly reduced (by 34%), and the AUC was unchanged. For this reason, Fingolimod can be taken regardless of meal times.

Distribution

Fingolimod is significantly distributed in erythrocytes (fingolimod fraction in blood cells 86%). Fingolimod phosphate has a lower ability to penetrate blood cells (fraction in blood cells <17%). Fingolimod and fingolimod phosphate are highly bound to plasma proteins (>99%).

Fingolimod is widely distributed in body tissues (V_d about 1200±260 L). Fingolimod penetrates the brain, as shown in a clinical study in healthy volunteers. In a study of 13 volunteers with MS taking Fingolimod 0.5 mg at steady state, the amount of fingolimod (or fingolimod phosphate) in seminal fluid was 10,000 times less than the administered dose (0.5 mg).

Metabolism

In humans, the biotransformation of fingolimod occurs as a result of reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate and through oxidative biotransformation, mainly by the CYP4F2 isoenzyme and possibly other CYP4F isoenzymes, followed by degradation similar to fatty acids to an inactive metabolite and by the formation of pharmacologically inactive non-polar analogues of fingolimod ceramide. The main enzyme responsible for the metabolism of fingolimod is partially identified: it may be CYP4F2 or CYP3A4. After a single oral dose, unchanged Fingolimod (23.3%), fingolimod phosphate (10.3%), inactive metabolites (M3 – acidic carboxylic metabolite (8.3%), ceramide conjugates of metabolites M29 (8.9%) and M30 (7.3%)) were detected in plasma (for approximately 1 month).

Excretion

The plasma clearance of fingolimod is 6.3±2.3 L/h, the mean apparent T_1/2 is 6-9 days. The decrease in plasma concentrations of fingolimod and fingolimod phosphate in the terminal phase occurs in parallel, resulting in a similar T_1/2.

After oral administration, about 81% of the dose is excreted by the kidneys as inactive metabolites. Unchanged Fingolimod and fingolimod phosphate are not excreted by the kidneys, but are the main compounds in feces (amount of each <2.5% of the dose). About 89% of the drug dose is excreted within 1 month.

Linearity

Concentrations of fingolimod and fingolimod phosphate increase proportionally to the dose after multiple doses of 0.5 mg or 1.25 mg once daily.

In pediatric patients, the concentration of fingolimod phosphate increases proportionally to the dose after multiple doses of 0.25 mg or 0.5 mg once daily.

Pharmacokinetics in special patient groups

Renal impairment. Renal impairment (mild to severe) does not affect the pharmacokinetics of fingolimod and fingolimod phosphate.

Hepatic impairment . A single dose of fingolimod 1 mg or 5 mg in patients with mild, moderate and severe hepatic impairment (Child-Pugh class A, B and C) leads to an increase in the AUC of fingolimod by 12%, 44% and 103%, respectively, with no effect on C_max noted. In patients with severe hepatic impairment (Child-Pugh class C), the C_max of fingolimod phosphate decreased by 22%, while the AUC value did not change significantly. In patients with mild and moderate hepatic impairment, the pharmacokinetics of fingolimod phosphate were not assessed.

In patients with mild hepatic impairment, T_1/2 remains unchanged; in patients with moderate and severe impairment, it increases by approximately 50%.

Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C). In patients with mild and moderate hepatic impairment, Fingolimod should be started with caution.

Patients under 18 years of age . The C_ss of fingolimod phosphate is similar in adults and children over 10 years of age. The safety and efficacy of fingolimod in patients under 10 years of age have not been studied.

Elderly patients . Clinical experience with fingolimod in patients over 65 years of age is limited. In patients aged 65 years and older, Fingolimod should be used with caution.

Gender and ethnicity . Gender and ethnicity do not affect the pharmacokinetics of fingolimod and fingolimod phosphate.

Indications

• Relapsing-remitting multiple sclerosis (RRMS) in adults and children over 10 years of age – to reduce the frequency of clinical exacerbations of the disease and reduce the risk of disability progression.

ICD codes

Dosage Regimen

Treatment should be initiated and conducted only under the supervision of a physician experienced in the treatment of MS.

The drug is taken orally, regardless of meals.

The recommended dose of the drug for adults and children and adolescents over 10 years of age with a body weight >40 kg is 0.5 mg (1 capsule) once daily.

The patient must be observed after the first dose of the drug, both at the start of treatment with Fingolimod and after taking the first dose, in case of interruption of therapy

• For 1 day or more during the first 2 weeks of therapy;
• For more than 7 days during the 3rd or 4th week of treatment;
• For more than 2 weeks after treatment has continued for more than a month.

If treatment is interrupted for a shorter period than indicated above, treatment should be continued with the next scheduled dose.

Discontinuation of fingolimod treatment

After discontinuation of fingolimod treatment, a 6-week treatment-free interval is required for the elimination of fingolimod from the bloodstream; this period is determined by the T_1/2 of the drug. When discontinuing the drug, it must be taken into account that normalization of the lymphocyte count occurs 1-2 months after the last use of fingolimod, although in some cases full recovery takes significantly longer. During this period, vigilance should be maintained for the development of infections. Patients should be instructed to immediately report all symptoms of infection to the physician for 2 months after discontinuation of fingolimod. Since the use of immunosuppressants within 1-2 months after discontinuation of fingolimod may have an additional suppressive effect on the immune system, caution should be exercised when using immunosuppressants shortly after discontinuation of the drug.

Caution when discontinuing fingolimod therapy should also be exercised due to the risk of relapse. If discontinuation of Fingolimod is necessary, patients should be monitored for signs of possible disease relapse during the period after discontinuation.

Special patient groups

In patients aged 65 years and older, Fingolimod should be used with caution due to lack of safety and efficacy data.

In key MS studies, the use of fingolimod in patients with renal impairment has not been studied. Based on clinical pharmacology studies, no dose adjustment of the drug is required in patients with renal impairment.

The use of Fingolimod in patients with severe hepatic impairment (Child-Pugh class C) is contraindicated. No dose adjustment of the drug is required in patients with mild and moderate hepatic impairment, however, caution should be exercised when starting the drug in patients of this group.

The efficacy and safety of fingolimod in children under 10 years of age have not been established.

Diabetes mellitus

No studies have been conducted on the use of fingolimod in patients with diabetes mellitus. Caution should be exercised when using the drug in patients of this category due to the risk of macular edema. In such patients, regular ophthalmological examinations should be performed to detect macular edema.

Adverse Reactions

Summary of the safety profile

Safety data for fingolimod were obtained from two placebo-controlled phase III clinical trials and a phase III clinical trial with active control in adult patients with relapsing RRMS. The total number of patients receiving Fingolimod at doses of 0.5 mg or 1.25 mg was 2431. The two-year placebo-controlled clinical trial D2301 (FREEDOMS) included 854 adult patients receiving Fingolimod and 418 adult patients receiving placebo. The two-year placebo-controlled clinical trial D2309 (FREEDOMS II) included 728 adult patients with MS receiving Fingolimod and 355 adult patients receiving placebo. In the pooled data from these two studies, the following serious adverse reactions (ARs) were noted with fingolimod 0.5 mg: infections, macular edema and transient AV block at the start of treatment. The most common (frequency ≥10%) with the drug at a dose of 0.5 mg were influenza, sinusitis, headache, diarrhea, back pain, increased liver enzyme activity and cough. The most common reason for discontinuation of therapy with the drug (at a dose of 0.5 mg) was increased ALT (2.2%). ARs in the one-year study D2302 (TRANSFORMS), which included 849 patients receiving Fingolimod (the comparator group used interferon beta-1a), were generally similar to the placebo-controlled studies, taking into account differences in study duration.

Below are the ARs identified in clinical trials. The following criteria were used to assess frequency: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), unknown (cannot be estimated from the available data).

Infections and parasitic diseases very common – influenza, sinusitis; common – herpes virus infections, bronchitis, tinea versicolor; uncommon – pneumonia; unknown – progressive multifocal leukoencephalopathy (PML)**, cryptococcal infections**.

Benign, malignant and unspecified neoplasms (including cysts and polyps) common – basal cell carcinoma; uncommon – malignant melanoma****; rare – lymphoma***, squamous cell carcinoma****; very rare**** – Kaposi’s sarcoma****; unknown – Merkel cell carcinoma***.

Blood and lymphatic system disorders common – lymphopenia, leukopenia; uncommon – thrombocytopenia.

Immune system disorders frequency unknown – hypersensitivity reactions, including rash, urticaria and angioedema at the start of treatment***.

Psychiatric disorders common – depression; uncommon – depressed mood.

Nervous system disorders very common – headache; common – dizziness, migraine; uncommon – seizures; rare – posterior reversible encephalopathy syndrome*; unknown – severe worsening of the disease after drug withdrawal.

From the organ of vision:often – blurred vision; infrequently – macular edema.

From the cardiovascular systemoften – bradycardia, AV block, increased blood pressure; very rarely – T wave inversion***.

From the respiratory systemvery often – cough; often – dyspnea.

From the digestive systemvery often – diarrhea; infrequently – nausea***.

From the skin and subcutaneous tissuesoften – eczema, alopecia, skin pruritus.

From the musculoskeletal systemvery often – back pain; unknown – myalgia, arthralgia.

General disorders and administration site conditionsoften – asthenia; unknown – peripheral edema***.

Laboratory and instrumental datavery often – increased activity of hepatic enzymes (ALT, GGT, AST); often – increased blood triglycerides concentration; infrequently – neutropenia; unknown – decreased body weight.

* Not reported in the FREEDOMS, FREEDOMS II, TRANSFORMS studies. Frequency is calculated per 10,000 patients who received Fingolimod in all clinical studies.

** PML and cryptococcal infections (including cryptococcal meningitis) were reported in the post-marketing period.

*** Adverse reactions reported from spontaneous reports and literature.

**** Frequency category and risk estimate are based on >24,000 patients who received Fingolimod at a dose of 0.5 mg in clinical studies.

Description of selected adverse reactions

Infections

In clinical studies at a dose of 0.5 mg in patients with MS, the overall frequency of infections (65.1%) was similar to that in the placebo group. However, patients receiving Fingolimod more frequently had lower respiratory tract infections, primarily bronchitis, and to a lesser extent, infections caused by the herpes virus and pneumonia.

Several cases of disseminated herpes, including fatal cases, were reported during treatment with the drug at a dose of 0.5 mg.

Cases of HPV infection, including papilloma, dysplasia, and HPV-associated cancer, were observed in the post-marketing period of the drug’s use.

In the post-marketing period, cases of opportunistic infections caused by viruses (e.g., Varicella zoster virus (VZV), John Cunningham virus (JCV), Herpes simplex virus (HSV)), fungi (e.g., cryptococci, including cryptococcal meningitis), or bacteria (e.g., atypical mycobacteria), including fatal cases, were reported.

Macular edema

In clinical studies in patients with MS, the frequency of macular edema with the drug at a dose of 0.5 mg was 0.5%, and with a higher dose of 1.25 mg – 1.1%. In most cases, macular edema developed within 3-4 months after starting treatment. In some cases, macular edema was asymptomatic (detected during routine ophthalmological examination), in some patients macular edema was accompanied by blurred vision or decreased visual acuity. Upon discontinuation of the drug, in most cases, the severity decreased or spontaneous resolution of this condition occurred. The risk of recurrence after resuming therapy has not been studied.

The frequency of macular edema development increased with a history of uveitis (17% among patients with a history of uveitis and 0.6% without). The use of fingolimod has not been studied in patients with MS and diabetes mellitus, which is characterized by a high risk of macular edema. In clinical studies in patients with kidney transplantation, which also included patients with diabetes mellitus, the use of the drug at doses of 2.5 mg and 5 mg led to a doubling of the frequency of macular edema.

Bradyarrhythmia

In clinical studies in patients with MS, at the beginning of treatment with the drug at the recommended dose, a transient decrease in heart rate and slowing of AV conduction were observed, with the maximum decrease in heart rate observed within 6 hours after taking the drug at a dose of 0.5 mg (mean decrease of 12-13 beats/min). Heart rate less than 40 beats/min in adults and less than 50 beats/min in children with the drug at a dose of 0.5 mg was rare. Heart rate returned to baseline within 1 month of regular drug use. Bradycardia was generally asymptomatic, but some patients developed mild to moderate symptoms, including arterial hypotension, dizziness, increased fatigue, and/or palpitations. These symptoms resolved within the first 24 hours after starting treatment.

In clinical studies in patients with multiple sclerosis, at the beginning of therapy, first-degree AV block (prolonged PR interval on ECG) was observed in 4.7% of patients receiving Fingolimod 0.5 mg, in 2.8% of patients receiving interferon beta-1a, and in 1.6% in the placebo group. Second-degree AV block was detected in less than 0.2% of adult patients receiving Fingolimod 0.5 mg. In the post-marketing period, cases of transient, spontaneously resolving complete AV block within the first 6 hours after the first dose of fingolimod were reported. Symptoms resolved spontaneously. Conduction disturbances observed both in clinical studies and in the post-marketing period were generally transient, asymptomatic, and resolved within the first 24 hours after starting treatment. One patient with asymptomatic second-degree AV block type Mobitz I received isoprenaline, but most patients did not require medical intervention.

In the post-marketing period, isolated delayed cases of transient asystole and unexplained sudden death within 24 hours after the first dose of the drug against the background of concomitant use of other drugs and/or comorbidities have been described, but a causal relationship between fingolimod intake and these events has not been proven.

Blood pressure

In clinical studies with the drug at a dose of 0.5 mg in patients with MS, a slight increase in systolic blood pressure by an average of 3 mmHg and diastolic blood pressure by 1 mmHg was observed. The increase in blood pressure was observed approximately 1 month after starting treatment and persisted with continued therapy. Increased blood pressure was noted in 6.5% of patients receiving Fingolimod 0.5 mg (3.3% in the placebo group). According to post-marketing data, cases of increased blood pressure were reported during the first month of treatment and on the first day of drug use, and in some cases, the use of antihypertensive agents or interruption of fingolimod treatment was required.

Liver function impairment

In clinical studies in adult patients with MS treated with fingolimod, an increase in hepatic enzyme activity was observed. At the recommended dose of 0.5 mg, asymptomatic elevation of ALT ≥3×ULN was noted in 8.0% of cases and ≥5×ULN in 1.8% of cases. In some patients, upon resumption of therapy, a repeated increase in hepatic transaminase activity was noted, confirming the association with the drug. In clinical studies, increased hepatic aminotransferase activity could occur at any time during treatment, but in most cases it occurred within the first 12 months. Normalization of plasma ALT activity occurred approximately 2 months after discontinuation of the drug. In a small number of patients with elevated ALT ≥5×ULN (10 in the 1.25 mg group, 2 in the 0.5 mg group) who continued treatment with the drug, normalization of ALT activity occurred within approximately 5 months of therapy.

Neurological disorders

There are reports of rare cases of nervous system damage in adult patients receiving Fingolimod at high doses (1.25 mg or 5.0 mg), including the development of ischemic and hemorrhagic strokes and atypical neurological disorders such as acute disseminated encephalomyelitis (ADEM)-like conditions.

Vascular disorders

During treatment with fingolimod at a dose of 1.25 mg, peripheral arterial occlusions were rarely reported.

Respiratory system

In a clinical study, after 1 month of drug use, a slight dose-dependent decrease in FEV₁ and carbon monoxide diffusing capacity (DLCO) was observed; subsequently, the achieved values of these parameters did not change. By month 24, the decrease in predicted FEV₁ as a percentage of the initial value was 2.7% with fingolimod 0.5 mg and 1.2% in the placebo group; this difference disappeared after discontinuation of therapy. The decrease in DLCO by month 24 with fingolimod 0.5 mg was 3.3% compared to 2.7% in the placebo group.

Seizures

Cases of seizures, including status epilepticus, in adults have been reported with the use of fingolimod in clinical studies and in the post-marketing period. In clinical studies in adults, the frequency of seizures was 0.9% in patients receiving Fingolimod versus 0.3% in the placebo group. It is unknown whether these phenomena are related only to the course of MS, only to fingolimod, or to their combination.

Lymphomas

According to clinical and post-marketing studies, the development of various types of lymphomas has been observed in patients receiving Fingolimod. Non-Hodgkin’s lymphoma was the most common, including B-cell and T-cell lymphomas, including a fatal case of Epstein-Barr virus-positive B-cell lymphoma. The frequency of lymphoma (B- and T-cell) in clinical studies was higher than expected in the general population. In the post-marketing period, isolated cases of cutaneous T-cell lymphoma (mycosis fungoides) have also been reported.

Hemophagocytic syndrome

In the post-marketing period, very rare cases of hemophagocytic syndrome with fatal outcome associated with an infectious disease have been reported in patients treated with fingolimod. Hemophagocytic syndrome is a condition associated with infectious diseases, immunosuppression, and a number of autoimmune diseases.

Patients over 10 years of age

In controlled clinical studies in children and adolescents (10-18 years) with the drug at a dose of 0.25 mg or 0.5 mg once daily, the overall safety profile was comparable to that in adult patients.

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

If any of the side effects listed in the instructions worsen or any other side effects not listed in the instructions are noted, the patient should inform the doctor.

Contraindications

• Diagnosed immunodeficiency syndrome;
• Increased risk of opportunistic infections, including in immunocompromised patients (including those currently receiving immunosuppressive therapy or immunocompromised due to prior therapy);
• Severe active infection, active chronic infection (hepatitis, tuberculosis);
• Diagnosed active malignancies;
• Severe liver impairment (Child-Pugh class C);
• Myocardial infarction, unstable angina, stroke/transient ischemic attack (TIA), decompensated heart failure (requiring hospitalization), NYHA class III-IV heart failure within the last 6 months;
• Severe cardiac arrhythmia requiring treatment with class IA or III antiarrhythmic drugs;
• Second-degree AV block type Mobitz II, third-degree AV block, sick sinus syndrome – in the absence of a pacemaker;
• Baseline QTc interval ≥500 ms;
• Pregnancy;
• Breastfeeding period;
• Women of childbearing potential not using effective contraception;
• Hypersensitivity to fingolimod or any other component of the drug.

The efficacy and safety of fingolimod in children under 10 years of age have not been established.

Use in Pregnancy and Lactation

Women of childbearing potential, contraception in women

Before starting fingolimod, a negative pregnancy test result should be obtained and women of childbearing potential should be informed about the serious risk to the fetus and the need to use effective contraception throughout the entire time of drug use and for about 2 months after the end of treatment, due to the long elimination period of the drug and the persistent risk to the fetus.

Pregnancy

Available post-marketing data and information from the pregnancy registry suggest that treatment with fingolimod is associated with an increased prevalence of major congenital malformations compared to the general population.

Reliable methods of contraception should be used throughout the entire time of drug use and pregnancy should be avoided. If pregnancy is diagnosed during drug use, discontinuation of the drug should be considered, taking into account the results of an individual benefit-risk assessment for both the mother and the fetus. A medical opinion on the risks of adverse effects of the drug on the fetus should be provided, and a follow-up examination (e.g., ultrasound) should be performed. The risk of severe disease exacerbation in women who discontinue fingolimod due to pregnancy or planned pregnancy should also be taken into account, so patients should discuss alternative treatment options with their doctor.

Animal studies have revealed reproductive toxicity, including fetal death and organ malformations, in particular patent ductus arteriosus and ventricular septal defects. Furthermore, it is known that the receptor targeted by Fingolimod (sphingosine 1-phosphate receptor) is involved in vascular formation during embryogenesis. Data on the use of fingolimod in pregnant women are limited.

Women planning pregnancy should discontinue the drug 2 months before conception. In a prospective assessment of more than 600 pregnancy cases resulting in live birth, stillbirth, or termination of pregnancy due to fetal developmental abnormalities as a result of maternal exposure to fingolimod during gestation, registered in the post-marketing period, the proportion of major congenital malformations was approximately 5%. The prevalence of major congenital malformations in the general population is 2 to 4%. The pattern of developmental abnormalities registered during treatment with fingolimod is similar to that in the general population, with frequent major malformations being

• Congenital heart defects, e.g., atrial and ventricular septal defects, tetralogy of Fallot;
• Renal abnormalities;
• Musculoskeletal abnormalities.

There is no evidence of clustering of specific structural abnormalities associated with fingolimod treatment.

Data on the effect of fingolimod on uterine contractility and labor are lacking.

Breastfeeding

Fingolimod is excreted into the milk of lactating animals. Given the potential for serious adverse reactions in breastfed infants, women taking Fingolimod should discontinue breastfeeding.

Fertility

Preclinical data do not indicate an increased risk of impaired fertility with fingolimod use.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

Dosage adjustment in patients with mild to moderate hepatic impairment is not required, but caution should be exercised when initiating the drug in these patients.

Use in Renal Impairment

The use of fingolimod in patients with renal impairment has not been studied. Based on clinical pharmacology data, dosage adjustment in patients with renal impairment is not required.

Pediatric Use

The efficacy and safety of fingolimod in children under 10 years of age have not been established.

Geriatric Use

Fingolimod should be used with caution in patients aged 65 years and older.

Special Precautions

Bradyarrhythmia

At the initiation of fingolimod treatment, a transient decrease in heart rate is observed, which may be accompanied by delayed AV conduction, including isolated cases of transient complete AV block that resolves spontaneously.

Heart rate begins to decrease within 1 hour after the first dose, and the maximum decrease is observed approximately 6 hours later. This post-dose effect persists on subsequent days, although generally to a milder degree; it usually subsides over the following weeks. With continued treatment, the average heart rate returns to baseline within 1 month. However, in some patients, heart rate may not return to baseline by the end of the first month. Conduction disturbances were generally transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours of drug use. If necessary, heart rate reduced due to fingolimod can be increased by parenteral administration of atropine and isoprenaline.

All patients should have an ECG and blood pressure measured before starting the drug and 6 hours after the first dose. All patients should be observed for 6 hours for signs and symptoms of bradycardia, measuring heart rate and blood pressure every hour. Continuous (real-time) ECG monitoring is recommended during the 6-hour period.

If symptoms of bradyarrhythmia develop during therapy with the drug, appropriate measures should be initiated, and the patient should be monitored until this condition resolves. If drug therapy is required during the monitoring period after the first dose, monitoring should be extended at least until the next morning, and an examination similar to the monitoring after the first dose should be repeated after taking the second dose of Fingolimod.

If 6 hours after the first dose the heart rate is at its minimum (indicating that the pharmacodynamic effect on the heart may not have peaked yet), monitoring should be extended for at least another 2 hours or until the heart rate increases again. Furthermore, if the heart rate 6 hours after taking the drug is <45 beats/min in adults, or <55 beats/min in children over 12 years, or <60 beats/min in children from 10 to 12 years, or if newly occurring second-degree or higher AV block is present on ECG 6 hours after taking the drug, or if the QTc interval on ECG is ≥500 ms, additional monitoring should be performed (at least until the next morning or until the abnormalities resolve). Third-degree AV block, whenever it occurs, also requires extended monitoring (at least until the next morning).

Very rare cases of T wave inversion on ECG have been reported in patients treated with fingolimod. If T wave inversion is detected, the presence of other signs of myocardial ischemia should be excluded. If myocardial ischemia is suspected, consultation with a cardiologist is recommended.

Due to the risk of serious cardiac arrhythmias, Fingolimod should not be used in patients with sinoatrial block, symptomatic bradycardia, or a history of recurrent syncope, with significant prolongation of the QT interval (female: QTc >470 ms (over 18 years), QTc >460 ms (10-18 years); male: QTc >450 ms (over 10 years)). Since tolerance to severe bradycardia may be reduced in patients with a history of cardiac arrest, uncontrolled arterial hypertension, or severe sleep apnea syndrome, Fingolimod should not be used in such patients. In such patients, the use of the drug is possible only if the expected benefit outweighs the potential risk. If it is necessary to use the drug in these patients, consultation with a cardiologist should be conducted before starting therapy to determine the optimal cardiac monitoring, at least until the next morning.

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 drugs has not been studied. Cases of torsades de pointes tachycardia have been observed in patients with bradycardia while using Class IA or Class III antiarrhythmic drugs. Since a decrease in heart rate is observed at the start of fingolimod use, Fingolimod should not be used concomitantly with these drugs.

Experience with fingolimod in patients receiving concomitant therapy with beta-blockers, heart rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other drugs that can reduce heart rate (e.g., ivabradine, digoxin, cholinesterase inhibitors, or pilocarpine) is limited. Since heart rate also decreases at the start of fingolimod use, the use of these drugs at the beginning of fingolimod treatment may lead to severe bradycardia and AV block. Due to the potential additional effect on heart rate, Fingolimod should not be initiated in patients who are simultaneously taking these drugs. The use of Fingolimod in such patients should only be considered if the anticipated benefit outweighs the potential risks. If drug use is being considered, a cardiologist should be consulted before initiation regarding switching the patient to medications that do not lower heart rate. If discontinuation of the heart rate-lowering drug is not possible, a cardiologist should be consulted regarding appropriate monitoring after the first dose; extended monitoring until at least the next morning is recommended. Upon resumption of therapy with Fingolimod, the effects on heart rate and AV conduction may reappear depending on the duration of prior therapy and the time of therapy interruption.

Monitoring, as after the first dose, is necessary in case of therapy interruption

• For 1 day or more during the first 2 weeks of therapy;
• For more than 7 days in the 3rd or 4th week of treatment;
• For more than 2 weeks after treatment has continued for more than a month.

If treatment is interrupted for a shorter period than specified above, treatment should be continued with the next scheduled dose.

QT Interval

When using fingolimod at doses of 1.25 mg or 2.5 mg after reaching steady state, but while a negative chronotropic effect was still observed, a prolongation of the QTcI interval (QT interval corrected for heart rate based on individual patient data) compared to baseline was noted, with an upper limit of the 90% CI ≤13.0 ms. No dose-dependent or therapy duration-dependent relationship for the occurrence of QTcI interval prolongation was identified. No increased incidence of abnormal QTcI interval lengths (assessed by absolute or percentage changes from baseline) was found with fingolimod use.

The clinical significance of these findings is unknown. In MS studies, no clinically significant effects on QTc interval length were observed; however, patients at risk for QT interval prolongation were not included in clinical studies.

In patients with significant risk factors, such as hypokalemia or congenital long QT syndrome, the use of drugs that can prolong the QTc interval should be avoided.

Immunosuppressive Effect

Fingolimod has an immunosuppressive effect, resulting in an increased risk of infections (including opportunistic infections that can be fatal) and an increased risk of developing lymphomas and other malignancies, especially skin cancers. Patients should be carefully monitored, especially in the presence of comorbidities or risk factors, such as prior immunosuppressive therapy. If such a risk is suspected, the physician should individually consider discontinuing therapy.

Infections

A key pharmacodynamic effect of the drug is a dose-dependent reduction in peripheral blood lymphocyte count to 20-30% of baseline, due to reversible redistribution of lymphocytes to lymphoid tissues.

Before starting therapy, the results of a complete blood count with differential, performed within the last 6 months prior to initiation or after discontinuation of prior therapy, should be obtained. A complete blood count is also recommended periodically during therapy, at 3 months and then at least once a year, and in the presence of signs of infection. If a confirmed absolute lymphocyte count is <0.2×10⁹/L, the drug should be discontinued until this parameter recovers, as in clinical studies, therapy with fingolimod was discontinued in patients with an absolute lymphocyte count <0.2×10⁹/L.

In patients with a severe active infectious disease, the initiation of treatment should be postponed until the condition resolves.

Before starting Fingolimod, patients should be assessed for immunity to varicella. Patients without a documented history of chickenpox or a complete vaccination course against Varicella zoster virus (VZV) should be tested for VZV antibodies before starting therapy. If antibodies to VZV are absent, a full course of vaccination should be completed before starting therapy. In this case, the start of treatment should be delayed for at least 1 month to allow for the development of a full immune response to vaccination.

Due to the effect of Fingolimod on the immune system, the risk of developing infections, including opportunistic ones, may increase. During treatment with Fingolimod, effective diagnostic and therapeutic measures should be carried out in patients with symptoms of an infectious process.

When assessing a patient with suspected infection that may be serious, referral to a physician experienced in treating infections should be considered. Patients receiving Fingolimod should be warned to report any symptoms of infection during treatment to their doctor.

If serious infections develop, temporary discontinuation of Fingolimod should be considered. Treatment with Fingolimod should be resumed only after assessing the benefit-risk ratio.

In the post-marketing period, cases of cryptococcal meningitis (a fungal infection), sometimes fatal, have been observed after 2-3 years of treatment, although the exact relationship with therapy duration has not been established. If symptoms suggestive of this condition develop (e.g., headache accompanied by mental disorders such as confusion, hallucinations, and/or personality changes), appropriate diagnostic measures should be performed immediately. If the diagnosis is confirmed, Fingolimod should be temporarily discontinued and appropriate treatment initiated. If resumption of fingolimod therapy is required, consultation with physicians of different specialties (in particular, an infectious disease specialist) should be conducted.

In the post-marketing period, cases of progressive multifocal leukoencephalopathy (PML) have been observed. PML is an opportunistic infectious disease caused by the JC virus, which can be fatal or cause severe disability. Cases of PML were noted approximately 2-3 years after using fingolimod as monotherapy in patients who had not previously received natalizumab. Although the presumed risk increases with the cumulative amount of drug taken over time, the exact relationship with therapy duration is unknown.

Additional reports of PML development in patients previously treated with natalizumab, for which an association with PML is already known, have also been received.

PML development is only possible upon infection with the JC virus. When testing for the JC virus, it must be considered that the effect of lymphopenia on the accuracy of JC virus antibody test results in patients treated with Fingolimod has not been studied. It is also worth noting that a negative JC virus test result does not rule out the possibility of subsequent JC virus infection. Before using fingolimod, an MRI examination should generally be performed, usually no earlier than 3 months before starting therapy. During routine MRI examinations (the frequency of which is determined by national guidelines), which are performed according to the standards for diagnosing and monitoring the course of MS, vigilance should be maintained for findings that may suggest PML. Thus, performing MRI can be considered an element of increased vigilance in patients at high risk for PML. If PML is suspected, diagnostic MRI should be performed immediately and treatment with Fingolimod should be suspended until PML is ruled out.

MRI changes characteristic of PML may appear earlier than clinical signs or symptoms. In patients treated with drugs for MS for which an association with PML has been established, including Fingolimod, cases of PML have been diagnosed based on MRI data, as well as on the detection of JC virus DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms characteristic of PML.

Elimination of fingolimod after discontinuation of treatment may take up to 2 months, so vigilance regarding the development of infections should be maintained during this period. Patients should be instructed to immediately report all symptoms of infection to their doctor within 2 months after discontinuing fingolimod.

In the post-marketing period of fingolimod use, cases of human papillomavirus (HPV) infection have been observed, including papilloma, dysplasia, warts, and HPV-associated cancer. Since Fingolimod has an immunosuppressive effect, before starting fingolimod therapy, HPV vaccination should be considered, taking into account vaccination recommendations. Cancer screening, including Pap smear, is also recommended according to standard medical care.

Macular Edema

Since macular edema with/without clinical symptoms was observed in 0.5% of patients during therapy with fingolimod at the recommended dose, mainly in the first 3-4 months of treatment, an ophthalmological examination is recommended 3-4 months after starting therapy. If patients develop visual disturbances while using the drug, a fundus examination, including the macular area, should be performed.

Patients with a history of uveitis, as well as patients with concomitant diabetes mellitus, have an increased risk of developing macular edema. Since the use of the drug in patients with MS and concomitant diabetes mellitus has not been studied, an ophthalmological examination is recommended before starting and during therapy with Fingolimod in patients with diabetes mellitus or a history of uveitis.

The consequences of continuing fingolimod therapy in patients with macular edema have not been studied. If macular edema develops, treatment with Fingolimod should be discontinued. The risk of recurrent macular edema upon resumption of fingolimod therapy has not been studied. The decision to resume therapy after resolution of macular edema should be made taking into account the potential benefit and risk associated with the drug use in the specific patient.

Liver Function Impairment

In MS patients treated with Fingolimod, cases of increased liver enzyme activity, especially ALT, as well as GGT and AST, have been observed. In clinical studies, an increase in ALT to levels ≥3×ULN was observed in 8.0% of patients receiving Fingolimod 0.5 mg, compared to only 1.9% of patients receiving placebo. An increase to levels ≥5×ULN was observed in 1.8% of patients receiving Fingolimod and 0.9% of patients receiving placebo. In clinical studies, Fingolimod was discontinued if ALT activity increased to levels >5×ULN. Upon resumption of fingolimod therapy, liver aminotransferase activity increased again in some patients, supporting an association with fingolimod use. In clinical studies, increased aminotransferase activity could occur at any time during treatment, but in most cases it occurred within the first 12 months. Normalization of serum liver aminotransferase activity occurred approximately 2 months after discontinuation of fingolimod.

The use of fingolimod in patients with severe liver impairment at the start of therapy (Child-Pugh class C) has not been studied. The use of fingolimod in such patients is contraindicated.

Since Fingolimod has an immunosuppressive effect, in patients with active viral hepatitis, initiation of therapy should be postponed until the condition resolves. Monitoring of liver transaminase activity and bilirubin concentration is recommended for the 6 months preceding the start of therapy. In the absence of clinical manifestations of liver damage, determination of liver transaminase activity is recommended at 1, 3, 6, 9, and 12 months of treatment and then periodically. An increase in liver transaminase activity ≥5×ULN requires more frequent testing of liver enzymes, including bilirubin concentration and ALP activity. Upon repeated confirmation of this result (liver aminotransferase activity >5×ULN), Fingolimod should be discontinued and therapy resumed only after liver aminotransferase activity returns to normal.

If symptoms suggesting liver function impairment appear (nausea of unknown etiology, vomiting, abdominal pain, increased fatigue, anorexia, jaundice and/or dark urine), liver enzyme activity should be analyzed. If significant liver damage is detected (e.g., liver aminotransferase activity >5×ULN and/or increased serum bilirubin level), treatment with the drug should be discontinued. The decision to resume treatment will depend on whether another cause of liver damage is identified, as well as the balance between the benefit of resuming treatment and the risk of recurrent liver function impairment.

There are no data indicating that patients with pre-existing liver disease receiving Fingolimod have an increased risk of elevated liver function tests. Nevertheless, Fingolimod should be used with caution in patients with a history of severe liver disease.

Effect on Serological Test Results

Since Fingolimod reduces the lymphocyte count in the blood (by redistributing them to secondary lymphoid organs), the peripheral blood lymphocyte count cannot be used to assess the counts of various lymphocyte subsets in patients receiving Fingolimod. In patients receiving Fingolimod, larger blood volumes are required to determine mononuclear cell counts (due to the reduced number of circulating lymphocytes).

Effect on Blood Pressure

Patients with uncontrolled arterial hypertension were not included in pre-marketing clinical studies, so special caution is required if fingolimod is used in patients with uncontrolled arterial hypertension.

In clinical studies in MS patients, the mean increase in systolic blood pressure with fingolimod 0.5 mg was approximately 3 mmHg, and diastolic blood pressure approximately 1 mmHg; this effect appeared approximately 1 month after starting treatment and persisted with continued treatment. In a 2-year placebo-controlled study, hypertension was reported as an adverse event in 6.5% of patients taking Fingolimod 0.5 mg and 3.3% of patients taking placebo. Blood pressure should be monitored regularly during therapy with Fingolimod.

Respiratory System

One month after starting fingolimod, a slight and dose-dependent decrease in FEV1 and diffusing capacity of the lungs for carbon monoxide (DLCO) was observed; subsequently, the achieved values of these parameters did not change. Fingolimod should be used with caution in patients with severe respiratory disease, pulmonary fibrosis, and chronic obstructive pulmonary disease.

Posterior Reversible Encephalopathy Syndrome

Rare cases of posterior reversible encephalopathy syndrome have been observed in clinical and post-marketing studies with fingolimod 0.5 mg, with the following symptoms: intense headache with sudden onset, nausea, vomiting, impaired consciousness, visual disturbance, and seizures. The condition is generally reversible but can worsen, including leading to ischemic or hemorrhagic stroke. Delay in diagnosis and treatment can lead to permanent neurological sequelae. If posterior reversible encephalopathy syndrome is suspected, Fingolimod should be discontinued.

Prior Treatment with Immunosuppressants and Disease-Modifying Therapies

No studies have been conducted to evaluate the efficacy and safety of fingolimod in patients switched from teriflunomide, dimethyl fumarate, and alemtuzumab. When switching therapy from other disease-modifying drugs to Fingolimod, the mechanism of action of the previously used drug, as well as its T_1/2, should be taken into account to avoid a cumulative suppressive effect on the immune system. The risk of disease reactivation should also be considered. Before starting therapy with Fingolimod, the results of a complete blood count with differential, performed after discontinuation of prior therapy, should be obtained to ensure the cessation of its suppressive effect on the immune system (e.g., cytopenias).

In patients previously treated with interferon or glatiramer acetate, treatment with Fingolimod can be started immediately after discontinuation of the aforementioned drugs.

If switching from dimethyl fumarate, Fingolimod should only be started after a washout period sufficient for blood parameters to recover.

Typically, complete elimination of natalizumab requires 2-3 months from the cessation of therapy. Elimination of teriflunomide from plasma is slow and can take from several months to 2 years without an accelerated elimination procedure.

It is recommended to resort to the accelerated elimination procedure described in the teriflunomide prescribing information. In the absence of this procedure, the washout period should be at least 3.5 months. When switching patients from natalizumab or teriflunomide to Fingolimod, caution should be exercised and the possibility of an additional effect on the immune system should be considered.

Alemtuzumab has a profound and prolonged immunosuppressive effect. Since the actual duration of such an effect is unknown, the use of Fingolimod after discontinuation of alemtuzumab therapy is not recommended, except in cases where the expected benefit outweighs the possible risk for the specific patient.

The decision regarding long-term use of corticosteroids as concomitant medications should be made after careful assessment.

Concomitant use with potent inducers of CYP450 isoenzymes

Caution should be exercised when using fingolimod concomitantly with potent inducers of CYP450 isoenzymes. Concomitant use of St. John’s wort is not recommended.

Malignancies

Skin malignancies. Development of basal cell carcinoma and other skin neoplasms, including malignant melanoma, squamous cell carcinoma, Kaposi’s sarcoma, and Merkel cell carcinoma, has been observed in patients treated with the drug. Vigilance should be maintained for skin neoplasms, and a medical examination with skin inspection is recommended at the start of treatment. Subsequently, such an examination is recommended every 6-12 months at the discretion of the treating physician. If suspicious lesions are found, the patient should be referred to a dermatologist.

Considering the risk of skin malignancies, patients receiving Fingolimod should be advised on the need to use protection against UV radiation. During treatment with fingolimod, patients should not receive phototherapy with UV-B radiation or PUVA photochemotherapy.

Lymphomas. Cases of lymphoma have been observed in clinical studies and during the post-marketing period of the drug. The described cases were heterogeneous in nature, with non-Hodgkin’s lymphoma being the most common, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have occurred.

Return of active disease (rebound) after discontinuation of fingolimod therapy

In the post-marketing period, cases of severe disease exacerbation have been reported in patients who discontinued Fingolimod. Typically, the worsening occurred within 12 weeks, but cases of worsening within 24 weeks or more after discontinuation of therapy with the drug have also been noted. Therefore, caution should be exercised when discontinuing therapy with Fingolimod. If discontinuation of the drug is necessary, patients should be monitored for the development of relevant symptoms and signs and provided with necessary treatment.

Tumefactive demyelinating lesions

Rare cases of tumefactive demyelinating lesions associated with MS exacerbation have been identified in the post-marketing period. In case of a severe exacerbation, an MRI should be performed to rule out tumefactive lesions. The treating physician should consider discontinuing Fingolimod on an individual basis, taking into account the benefit and risks for the specific patient.

Discontinuation of fingolimod treatment

After discontinuation of fingolimod treatment, a 6-week treatment-free interval is required for the elimination of fingolimod from the bloodstream; this period is determined by the drug’s T_1/2. When discontinuing the drug, it should be taken into account that lymphocyte count normalization occurs 1-2 months after the last use of fingolimod, although in some cases complete recovery takes significantly longer. Since the use of immunosuppressants within 1-2 months after discontinuation of fingolimod may have an additional suppressive effect on the immune system, caution is required when using immunosuppressants shortly after discontinuation of treatment with the drug.

Pregnancy, fetal risk, and contraception

Due to the potential serious risk to the fetus, pregnancy must be excluded in women of reproductive potential before starting Fingolimod. The healthcare professional should explain the risk of adverse effects of the drug on the fetus.

Pregnancy should be avoided during therapy with Fingolimod, and effective methods of contraception should be used throughout the entire therapy period and for 2 months after discontinuation of therapy. If pregnancy occurs during therapy with Fingolimod, discontinuation of Fingolimod should be considered, taking into account the results of an individual benefit-risk assessment for both the mother and the fetus.

Patients aged 10-18 years

Before starting treatment with Fingolimod, all vaccinations recommended by the local immunization schedule should be completed.

Effect on ability to drive vehicles and operate machinery

Patients who experience adverse reactions such as dizziness and drowsiness during treatment with Fingolimod should not drive vehicles or operate machinery until these side effects have completely resolved. The patient’s condition should be monitored during the first 6 hours after the first dose before starting to drive vehicles.

Overdose

Symptoms

Healthy volunteers tolerated a single dose of the drug of 40 mg (a dose 80 times the recommended daily dose) satisfactorily, with 5 out of 6 volunteers noting a sensation of mild tightness or discomfort in the chest, which clinically corresponded to mild airway reactivity.

At the start of use, Fingolimod may cause bradycardia. A decrease in heart rate is usually observed within one hour after the first dose and occurs most sharply within 6 hours. The negative chronotropic effect of fingolimod persists beyond 6 hours, but gradually weakens over the subsequent days of treatment. There are reports of slowed AV conduction and isolated reports of transient cases of complete AV block with spontaneous resolution.

Treatment

In case of overdose upon taking the first dose of fingolimod, the patient’s condition should be monitored for at least 6 hours, including real-time ECG monitoring and hourly measurement of heart rate and blood pressure.

If 6 hours after the first dose the heart rate is <45 bpm in adults or <55 bpm in children over 12 years, or <60 bpm in children from 10 to 12 years, or ECG signs of second-degree or higher AV block appear, or the QT interval is ≥500 ms, monitoring should be extended at least until the next morning or until the abnormalities resolve. If third-degree AV block occurs at any time of the day, observation should also be provided at least until the next morning.

Fingolimod is not removed from the body by dialysis or plasmapheresis.

Drug Interactions

Antineoplastic drugs, immunomodulators, and immunosuppressants

Given the possibility of an additional suppressive effect on the immune system, Fingolimod should not be used together with antineoplastic agents, immunosuppressants, or immunomodulators.

Caution should be exercised when switching to Fingolimod in patients who have previously received long-acting drugs that affect the immune system, such as natalizumab, teriflunomide, or mitoxantrone. In clinical studies, the use of fingolimod in MS patients receiving short courses of corticosteroids did not show an increase in the frequency of infections.

Vaccination

During therapy with the drug, as well as for 2 months after discontinuation of fingolimod treatment, vaccination may be less effective. Since the use of live attenuated vaccines may increase the risk of infections, immunization with live attenuated vaccines should not be carried out during treatment with the drug and for 2 months after discontinuation of fingolimod treatment.

Substances causing bradycardia

The use of fingolimod in combination with atenolol and diltiazem has been studied. In a drug interaction study in healthy volunteers, the use of fingolimod with atenolol resulted in an additional 15% reduction in heart rate at the start of fingolimod use. This effect was not observed in patients receiving Fingolimod together with diltiazem. Therapy with fingolimod should not be initiated in patients receiving beta-blockers or other drugs that may reduce heart rate, such as class IA or III antiarrhythmic agents, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin, cholinesterase inhibitors, or pilocarpine, due to the risk of an additional suppressive effect on heart rate. If treatment with fingolimod is planned for such patients, consultation with a cardiologist is necessary regarding the possibility of switching to therapy with drugs that do not reduce heart rate or performing appropriate monitoring (extended observation in a hospital setting at least until the next morning).

Pharmacokinetic effects of other drugs on Fingolimod

Fingolimod is metabolized mainly by the CYP4F2 isoenzyme. Other cytochrome isoenzymes, such as CYP3A4, may also participate in its metabolism, especially if there is significant induction.

No effect of potent transporter protein inhibitors on the pharmacokinetics of fingolimod is expected. Concomitant use of fingolimod with ketoconazole led to a 1.7-fold increase in the exposure (AUC) of fingolimod and fingolimod-phosphate due to inhibition of the CYP4F2 isoenzyme. Caution should be exercised when using fingolimod concomitantly with drugs that can inhibit CYP3A4 (protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

Concomitant use of carbamazepine at a dose of 600 mg twice daily at steady state and a single 2 mg dose of fingolimod had a weak effect on the AUC of fingolimod and fingolimod-phosphate, reducing this parameter by approximately 40%.

Other inducers of the CYP3A4 isoenzyme, such as rifampicin, phenobarbital, phenytoin, efavirenz, and St. John’s wort, can reduce the AUC of fingolimod and its metabolite to approximately the same extent. Since this may reduce the effectiveness of fingolimod, these drugs should be used concomitantly with caution. Concomitant use of St. John’s wort, however, is not recommended.

Pharmacokinetic effects of fingolimod on other drugs

Interaction of fingolimod with substances whose clearance is mainly dependent on cytochrome P450 isoenzymes, or with substrates of major transporter proteins, appears unlikely.

The pharmacokinetics of fingolimod and cyclosporine did not change when used concomitantly. Thus, no change in the pharmacokinetics of drugs that are substrates of the CYP3A4 isoenzyme under the influence of fingolimod is expected.

Concomitant use of fingolimod and oral contraceptives (ethinylestradiol and levonorgestrel) does not lead to a change in the exposure of oral contraceptives. Despite the lack of interaction studies with oral contraceptives containing other progestogens, no effect of fingolimod on their exposure is expected.

Storage Conditions

The drug should be stored in the original packaging, out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.