Fingolimod (Capsules) Instructions for Use

ATC Code

L04AA27 (Fingolimod)

Active Substance

Fingolimod (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressive agent. Agent for the treatment of multiple sclerosis

Pharmacological Action

Agent for the treatment of multiple sclerosis. Fingolimod modulates sphingosine-1-phosphate receptors (S1P receptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate. At low nanomolar concentrations, fingolimod phosphate binds to S1P receptors of lymphocytes types 1, 3, and 4 and rapidly penetrates the CNS through the blood-brain barrier, binding to S1P receptors of nerve cells types 1, 3, and 5.

By binding to S1P receptors of lymphocytes, fingolimod phosphate blocks the ability of lymphocytes to leave the lymph nodes, leading to the redistribution of lymphocytes in the body. This does not result in a decrease in the total number of lymphocytes in the body.

The redistribution of lymphocytes leads to a reduction in lymphocyte infiltration of the CNS, a decrease in the severity of inflammation, and the extent of nerve tissue damage.

Pharmacokinetics

The pharmacologically active metabolite is the (S)-enantiomer of fingolimod phosphate.

When taken orally, ≥85% of the dose is absorbed. The absorption of fingolimod is slow (time to reach C_max 12-16 hours). Fingolimod is absorbed slowly and to a significant extent (≥85%). The absolute oral bioavailability is 93%. Steady-state plasma concentration (C_ss) is achieved within 1-2 months of regular drug intake (once daily). The C_ss of fingolimod is approximately 10 times higher than its concentration after the first dose. After multiple doses of 500 mcg or 1.25 mg once daily, the concentrations of fingolimod and fingolimod phosphate increase, likely proportionally to the dose. Food intake does not affect the C_max or AUC of fingolimod or fingolimod phosphate.

Fingolimod is significantly distributed in red blood cells (blood cell fraction 86%). Fingolimod phosphate has a lower ability to penetrate blood cells (blood cell fraction <17%). Fingolimod and fingolimod phosphate are highly bound to plasma proteins (>99%). The binding of fingolimod and fingolimod phosphate to proteins is not altered in patients with impaired renal or liver function.

Fingolimod is significantly distributed in body tissues (V_d approximately 1,200±260 L).

In humans, the biotransformation of fingolimod occurs through reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate, and through oxidative biotransformation, mainly via the cytochrome P450 4F2 isoenzyme, followed by degradation similar to fatty acids to an inactive metabolite and the formation of pharmacologically inactive non-polar analogues of fingolimod ceramide.

After a single oral dose, the following were detected in plasma (for approximately 1 month): unchanged Fingolimod (23%), fingolimod phosphate (10%), inactive metabolites (M3 acidic carboxylic metabolite (8%), ceramide metabolites M29 (9%) and M30 (7%)).

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, so the T_1/2 values are similar.

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

Use of the drug in patients with severe hepatic impairment (>9 points on the Child-Pugh scale) leads to an increase in AUC by 103% and 29% for fingolimod and fingolimod phosphate, respectively. T_1/2 is prolonged by 50%.

Indications

Relapsing-remitting multiple sclerosis – to reduce the frequency of clinical exacerbations of the disease and reduce the risk of disability progression.

ICD codes

Dosage Regimen

Capsules

The recommended dose is 500 mcg orally once daily, regardless of meals. Treatment is long-term.

Patients with high-degree AV block or sick sinus syndrome, with low heart rate (<55 beats/min) at rest, or with concurrent use of beta-blockers should be monitored for 6 hours after initiation of treatment to confirm good tolerability of the drug.

Patients previously treated with interferon-beta and glatiramer acetate, with good tolerability (absence of neutropenia), can be switched to treatment with fingolimod.

When discontinuing the drug, it should be taken into account that normalization of lymphocyte count occurs 1-2 months after the last use of fingolimod. Since the administration 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 treatment with the drug.

Adverse Reactions

Infections and infestations: Very common – influenza virus infections; Common – herpes virus infections, bronchitis, sinusitis, gastroenteritis, fungal infections; Uncommon – pneumonia.

Blood and lymphatic system disorders: Common – lymphopenia, leukopenia.

Psychiatric disorders: Common – depression; Uncommon – depressed mood.

Nervous system disorders: Very common – headache; Common – dizziness, paresthesia, migraine.

Eye disorders: Common – blurred vision, eye pain; Uncommon – macular edema.

Cardiac disorders: Common – bradycardia, increased blood pressure.

Respiratory, thoracic and mediastinal disorders: Very common – cough; Common – dyspnea.

Gastrointestinal disorders: Very common – diarrhea.

Skin and subcutaneous tissue disorders: Common – eczema, alopecia, pruritus.

Musculoskeletal and connective tissue disorders: Very common – back pain.

General disorders and administration site conditions: Common – asthenia, weight decreased.

Investigations: Very common – increased ALT; Common – increased GGT, increased blood triglycerides.

Contraindications

Pregnancy, lactation (breastfeeding), hypersensitivity to fingolimod.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Use with caution in patients with severe hepatic impairment (>9 points on the Child-Pugh scale), with diabetes mellitus (risk of macular edema), history of uveitis, and in patients aged 65 years and older (limited data on use).

Since the safety of therapy in patients with pathological bradycardia due to second- or third-degree AV block (current or history) or with sick sinus syndrome has not been studied, in this category of patients Fingolimod should be used only if the expected benefit of therapy outweighs the potential risk (possibility of severe arrhythmias) and under monitoring of the patients’ condition.

Caution is also needed in patients with low resting heart rate – less than 55 beats/min (low heart rate not associated with cardiac dysfunction), as well as with concurrent use of beta-blockers.

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

Since there may be an increased risk of infections during use, effective diagnostic and therapeutic measures should be carried out in patients with symptoms of an infectious process during treatment with fingolimod. 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.

If severe infections develop during therapy with fingolimod, treatment should be discontinued. Treatment should be resumed only in cases where the benefit of therapy outweighs the possible risk.

Since macular edema may develop during the first 3-4 months of use, an ophthalmological examination is recommended. Patients with a history of uveitis, as well as patients with concomitant diabetes mellitus, have an increased risk of developing macular edema. Since use in patients with relapsing-remitting multiple sclerosis and concomitant diabetes mellitus has not been studied, patients with diabetes mellitus or a history of uveitis are recommended to undergo ophthalmological examination before starting and during therapy with fingolimod.

If patients develop visual disturbances during therapy with fingolimod, an examination of the fundus, especially the macular area, should be performed. If macular edema develops, treatment should be discontinued. The risk of recurrent macular edema upon resumption of therapy has not been studied. Treatment should be resumed only if the benefit of therapy outweighs the possible risk.

If bradyarrhythmia develops during therapy with the drug, appropriate measures should be initiated if necessary, and the patient should be monitored until this disorder resolves.

Considering the possible effect of fingolimod on heart rate and AV conduction after discontinuation of treatment, all precautions regarding cardiac dysfunction should be observed for 2 weeks after the last dose of fingolimod.

If symptoms suggesting the development of liver dysfunction (vomiting of unknown etiology, jaundice) appear, liver enzyme tests should be performed, and if liver damage is detected, fingolimod should be discontinued.

Use in pediatrics

The efficacy and safety of use in children and adolescents under 18 years of age have not been established.

Effect on ability to drive vehicles and operate machinery

Patients who experience dizziness and visual disturbances while using fingolimod should not drive vehicles or operate machinery until these side effects completely disappear.

Drug Interactions

Given the possibility of an additional suppressive effect on the immune system, caution is required when using fingolimod together with antineoplastic agents, immunosuppressants, or immunomodulators, as well as in patients who have received drugs that suppress the immune system for a long time, such as natalizumab or mitoxantrone.

In clinical studies, the use of fingolimod in patients with relapsing-remitting multiple sclerosis receiving short courses of corticosteroids did not show an increase in the frequency of infections.

Fingolimod can be used in combination with drugs that reduce heart rate, such as atenolol and diltiazem. When fingolimod was used with atenolol, an additional 15% reduction in heart rate was observed at the beginning of treatment. In patients receiving Fingolimod together with diltiazem, no additional reduction in heart rate was observed. Given the possible additional suppressive effect on heart rate, caution should be exercised when prescribing fingolimod together with beta-blockers (especially at the beginning of treatment).

The use of fingolimod in patients receiving class IA antiarrhythmic drugs (e.g., quinidine, procainamide) or class III antiarrhythmic drugs (e.g., amiodarone, sotalol) has not been studied. Since class IA and III antiarrhythmic drugs can cause bradyarrhythmia, these combinations should not be used.

The primary metabolism of fingolimod occurs with the participation of the CYP4F2 isoenzyme, as well as with significant participation of the CYP2D6, 2E1, 3A4, and 4F12 isoenzymes. The involvement of a large number of CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod and fingolimod phosphate will not be subject to significant inhibition in the presence of one specific CYP isoenzyme inhibitor.

Concomitant use of fingolimod with ketoconazole led to a moderate (1.7-fold) increase in the exposure of fingolimod and fingolimod phosphate (AUC assessment).

In clinical studies in patients with relapsing-remitting multiple sclerosis, no significant effect of fluoxetine and paroxetine (potent CYP2D6 inhibitors) and carbamazepine (a potent inducer of the isoenzyme) on the concentration of fingolimod or fingolimod phosphate was observed.

The following also did not have a clinically significant effect on the concentration (<20%) of fingolimod and fingolimod phosphate: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteroids, oral contraceptives.

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.