Fingolimod - instructions for use, dose, side effects, contraindications

Means for treating multiple sclerosis. Fingolimod modulates the sphingosine-1-phosphate receptors (S1P receptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite of phylogenide phosphate. In low nanomolar concentrations of phylogolimide, phosphate binds to S1P receptors of lymphocytes 1, 3, and 4 types and quickly penetrates into the central nervous system through the blood-brain barrier, binding to S1P receptors of nerve cells 1, 3, and 5 types. Binding the S1P receptors of lymphocytes, phylogolide phosphate blocks the ability of lymphocytes to leave the lymph nodes, which leads to a redistribution of lymphocytes in the body. At the same time, the total number of lymphocytes in the body does not decrease.

Redistribution of lymphocytes leads to a decrease in lymphocytic infiltration of the central nervous system, a decrease in the severity of inflammation and the degree of damage to the nervous tissue.

Pharmacokinetics:

A pharmacologically active metabolite is the (S) -enantiomer of phingolide phosphate.

If ingested, ≥ 85% of the dose is absorbed. Absorption fingolimoda occurs slowly (time to reach a maximum concentration of 12-16 hours). Fingolimod is absorbed slowly and to a large extent (≥ 85%). Absolute bioavailability with oral administration is 93%. Equilibrium concentration in blood plasma is achieved within 1-2 months of regular intake of the drug (1 time per day). Requilibrium concentration phyglylimide is approximately 10 times higher than its concentration after the first administration. After repeated administration of 500 μg or 1.25 mg once a day, the concentrations of phageolimode and phongolimide phosphate increase, probably in proportion to the dose. The intake of food does not affect the maximum concentration or systemic exposure of phylogolimide or phongolimide phosphate.

Fingolimod is significantly distributed in erythrocytes (fraction in blood cells is 86%). Fingolimoda phosphate has a lower ability to penetrate into blood cells (fraction in blood cells <17%). Fingolimod and phignolimide phosphate binds to a high degree with plasma proteins (> 99%).The binding of phageolide and phongolimod phosphate to proteins does not change in patients with impaired renal or hepatic function.

Fingolimod is largely distributed in the tissues of the body (the volume of distribution is about 1,200 ± 260 L).

In humans, the bi-transformation of figolimod occurs as a result of reversible stereoselective phosphorylation to the pharmacologically active (S) -enantiomer of phignolimod phosphate, and due to oxidative biotransformation, mainly through cytochrome P450 4F2 isoenzyme, and subsequent degradation similar to fatty acids to an inactive metabolite and the formation of pharmacologically inactive non-polar analogues of ceramide phylogenide.

After a single oral ingestion in the blood plasma, (for about 1 month) unchanged phingolimod (23%), phylogolide phosphate (10%)), inactive metabolites (M3 acidic carboxylic acid metabolite (8%), metabolites of ceramide M29 (9%) and M30 (7%)).

Plasma clearance of phylogenide is 6.3 ± 2.3 l / h, the average apparent half-life is 6-9 days. Reduction of the concentrations of phageolimod and phongolimod phosphate in blood plasma in the terminal stage occurs in parallel, so the values of the half-life are close.

After ingestion, about 81% of the dose is excreted in the urine as inactive metabolites. Unchanged phingolimod and phylogolide phosphate are not excreted in the urine, but are the main compounds in the stool (the amount of each <2.5% of the dose). Within 1 month, about 89% of the dose is excreted.

The use of the drug in patients with severe impairment of liver function (> 9 on the Child-Pugh scale) leads to an increase in systemic exposure by 103% and 29% for phylogolide and phylogolide phosphate, respectively. The elimination half-life is increased by 50%.

Indications:Remittent multiple sclerosis - to reduce the incidence of clinical exacerbations of the disease and reduce the risk of progression of disabilityti.

ICD-10

VI.G35-G37.G35 Multiple sclerosis

Contraindications:

Pregnancy.
Lactation period (breastfeeding).
Hypersensitivity to fingolimoda.
Syndrome of immunodeficiency.
Increased risk of opportunistic infections, including in immunocompromised patients receiving immunosuppressive therapy now or in the past.
Active phases of severe infections, chronic infections (hepatitis, tuberculosis).
Identified malignant neoplasms in the active phase, except for basal cell skin cancer.

Carefully:Use with caution in patients with severe impairment of liver function (> 9 on the Child-Pugh scale), with diabetes mellitus (risk of developing macular edema), history of uveitis, in patients 65 years of age or older (limited amount of data on application).

Pregnancy and lactation:Category by FDA - C. Contraindicated in pregnancy and lactation (breastfeeding).

Dosing and Administration:

The recommended dose is 500 μg orally 1 time per day, regardless of food intake. Treatment is long.

Patients with high degree of atrioventricular blockade or with syndrome of weakness of the sinus node with a low heart rate (<55 beats per minute) at rest or with simultaneous reception of beta-blockers should be monitored for 6 hours after the start of treatment to confirm the good tolerability of the drug.

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

At the termination of reception it is necessary to consider, that normalization of quantity of lymphocytes occurs in 1-2 months after last application финголимода. Since with the appointment of immunosuppressants within 1-2 months after discontinuation of phylogolide reception, an additional inhibitory effect on the immune system is possible, caution should be exercised when using immunosuppressants shortly after discontinuation of drug treatment.

Side effects:

Infections and infestations: infections caused by the influenza virus; infections caused by the herpes virus, bronchitis, sinusitis, gastroenteritis, fungal infections; pneumonia.

From the side system of hematopoiesis and lymphatic system: lymphopenia, and leukopenia.

Mental disorders: depression; worsening of mood.

From the side nervous system: headache; dizziness, paresthesia, migraine.

From the side organ of vision: blurred vision, pain in the eyes; macular edema.

From the side of cardio-vascular system: bradycardia, increased blood pressure.

From the side respiratory system: cough, shortness of breath.

From the side digestive system: diarrhea.

Dermatological reactions: eczema, alopecia, itching.

From the side musculoskeletal system: backache.

Common violations: asthenia, weight loss.

From the side laboratory indicators: increased ALT activity; increased GGT activity, increased triglyceride levels in the blood.

Overdose:

There are no data on drug overdose in patients with multiple sclerosis. Healthy volunteers satisfactorily transferred single dose of the drug in a dose of 40 mg (dose 80 times the recommended daily), with 5 of 6 volunteers small airway obstruction was identified, accompanied by a sense of tightness in the lung or chest discomfort.

Fingolimod is not removed from the body through dialysis and plasmapheresis.

Interaction:

Amiodarone. Since the use of amiodarone may cause bradyarrhythmia, phingolimod should not be administered together with amiodarone.

Atenolol. When using phongolimoda with atenolol, an additional 15% reduction in heart rate at the beginning of treatment was noted; combined application.

Diltiazem. In patients who received phingolimod together diltiazem, an additional reduction in heart rate was not observed; combined application.

Ketoconazole. Simultaneous application of phylogolimide with ketoconazole resulted in a moderate increase (1.7-fold) in exposure of phylogolimide and phongolimide phosphate (systemic exposure assessment).

Mitoxantrone. It is necessary to appoint with caution phingolimod patients who received long-term treatment mitoxantrone (suppresses the immune system).

Procainamide. Since the use of procainamide, it is possible to develop bradyarrhythmia, phingolimod Do not administer together with procainamide.

Quinidine. Since the use of quinidine may develop bradyarrhythmia, phingolimod should not be administered together with quinidine.

Special instructions:

Since the safety of therapy in patients with pathological bradycardia due to atrioventricular blockade of II and III degree (current or in history) or with syndrome of weakness of the sinus node not studied, in this category of patients phingolimod should be used only if the expected benefit of therapy exceeds the potential risk (the possibility of developing severe arrhythmias) and under the control of the patients' condition.

Caution is also necessary in patients with low heart rate at rest - less than 55 beats per minute (low heart rate, not related to cardiac dysfunction), and also with the simultaneous use of beta-blockers.

Because the phingolimod reduces the number of lymphocytes in the blood (by redistributing them in the secondary lymphoid organs), the number of lymphocytes in the peripheral blood can not be used to evaluate the different types of lymphocytes in patients receiving the drug. In patients receiving phingolimod, to determine the number of mononuclear cells requires the collection of large amounts of blood (due to a decrease in the number of circulating lymphocytes).

Because of the possible increase in the risk of developing infections during treatment with phignolyimide in patients with symptoms of the infectious process, effective diagnostic and therapeutic measures are necessary. Withdrawal of phylogolimidine after cessation of treatment can occur within 2 months, therefore for this period it is necessary to remain alert about the development of infections.

When developing severe infections with phygolyimide therapy, treatment should be discontinued. Renew the treatment should be only in cases where the benefit of therapy exceeds the possible risk.

Since the therapy may develop edema of the macula in the first 3-4 months of admission, it is recommended to conduct an ophthalmological examination. In patients with uveitis in the history, as well as in patients with concomitant diabetes mellitus, there is an increased risk of developing macular edema. Since the use in patients with relapsing multiple sclerosis and concomitant diabetes mellitus has not been studied in patients with diabetes or uveitis in an anamnesis, it is recommended that an ophthalmological examination be carried out before and during therapy with phylogolimide.

When detecting visual impairment in patients with phinoglobin therapy, it is necessary to examine the fundus, especially the macular area. Treatment should be stopped if the macular edema develops. The risk of developing a repeated macular edema during the resumption of therapy has not been studied. Renewal treatment should only be if the benefits of therapy exceed the possible risk.

When bradyarrhythmia develops against the background of therapy with the drug, if necessary, appropriate measures should be initiated, and the patient should be monitored until this disturbance is stopped.

Given the possible impact of phylogolide on heart rate and atrioventricular conduction after cessation of treatment, all precautions for cardiac dysfunction should be observed within 2 weeks after the last ingestion of phylogolimoda.

When symptoms appear that suggest the development of violations of the liver (vomiting of unknown etiology, jaundice), it is necessary to conduct a study of the activity of hepatic enzymes, and if liver damage is detected, stop taking phylogenide.

Use in pediatrics.

Efficacy and safety of use in children and adolescents under the age of 18 years are not established.

Impact on the ability to drive vehicles and manage mechanisms.

Patients who have dizziness and visual impairment when using phongolimo should not drive vehicles or work with mechanisms until these side effects disappear completely.

Instructions

Fingolimod (Fingolimodum)