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

shell capsules: ferric iron oxide yellow (E 172) 0,164 mg, titanium dioxide (E 171) 1.022 mg, gelatin 46.81 mg, printing ink black; shellac (E 904), propylene glycol, potassium hydroxide, iron dye oxide black; printing inks are yellow: shellac (E 904), propylene glycol, iron dye oxide yellow, titanium dioxide, dimethicone.

Description:

Capsules 0.5 mg - Hard gelatin capsules No. 3 with a white opaque case and a bright yellow opaque lid, printed with black ink ”FTY 0,5 mg” on the lid and two radial strips printed on the body with yellow ink.

The contents of the capsules are white or almost white powder.

Pharmacotherapeutic group:Multiple sclerosis remedy

ATX: & nbsp

L.04.A.A.27 Fingolimod

Pharmacodynamics:

Fingolimod modulates the sphingosine-1-phosphate receptors (S1P-receptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite of phignolyimophosphate. In nanomolar concentrations, phignolyimophosphate binds to S1Preceptors 1, 3, and 4 g of suture on the surface of lymphocytes and quickly penetrates into the central nervous system (CNS) through the blood-brain barrier, SlP-receptors 1, 3, and 5 types on the surface of neurons. Communicating with S1P receptors of lymphocytes, phignolyimophosphate blocks the ability of lymphocytes to leave the lymph nodes, which leads to a redistribution of lymphocytes in the body, while the total number of lymphocytes does not decrease.

Redistribution of lymphocytes leads to a decrease in lymphocytic infiltration of the central nervous system, incl. inflammatory cells Thl7, a decrease in the severity of inflammation and the degree of damage to the nervous tissue.

Within 4-6 hours after a single dose of 0.5 mg, the amount of lymphocytes in the blood decreases to approximately 75% of the initial value. With prolonged daily use of the drug, the number of lymphocytes continues to decrease within 2 weeks, reaching a minimum of 500 cells / μl or approximately 30% of the original value. 18% of patients had (at least once) a decrease in the number of lymphocytes below 200 cells / μl.With regular administration of the drug, the decrease in the number of lymphocytes was preserved. Since most T and B lymphocytes constantly pass through the lymphoid organs, the effect of phylogolimod on these cells is most pronounced. However, about 15-20% of T-lymphocytes, which are effector cells of memory and play an important role in peripheral immune control, do not pass through the lymphoid organs and are not exposedMr.s impact on the phyllolimod.

Within a few days after discontinuation of the drug in the blood, there is an increase in the number of lymphocytes. Normalization of the number of lymphocytes occurs 1-2 months after the cessation of treatment. The constant reception of phyngolimod leads to a slight decrease in the number of neutrophils to about 80% of the baseline. Monocytes are not affected by phylogenide.

When used in patients with relapsing multiple sclerosis (mean score on the disability scale, EDSS, 2,0) phingolimod in 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 with 45.6% in the placebo group). Fingolimod significantly reduced the risk of progression of disability. With the use of the drug, the time elapsed before the onset of the 3-month and 6-month period of confirmed disability progression (estimated as an increase in the EDSS score from baseline) compared with placebo. The results of magnetic resonance imaging (MRI) of the brain of patients with relapsing multiple sclerosis on the background of treatment with phyngolimod confirm a significant decrease in the activity of the disease (intensity of the inflammatory process in the central nervous system, the size and number of foci of demyelination).

Pharmacokinetics:

A pharmacologically active metabolite is (S) -enantiomer of phignolyimophosphate.

Absorption

When ingested, ≥85% of the dose is absorbed. Absorption fingolimoda occurs slowly (the time to reach the maximum concentration in the blood plasma, t_max, 12-16 hours). Absolute bioavailability with oral administration is 93%. Equilibrium concentration in blood plasma is achieved within 1-2 months of regular intake of the drug (I once a day). The equilibrium concentration of phingolimod is approximately 10 times higher than its concentration after the first administration.After repeated intake of 0.5 mg once a day, the concentrations of phyngolimod and phignolyimophosphate increase, probably in proportion to the dose.

Food does not affect the maximum concentration (C_m_Oh) or exposure (AUC - the area under the pharmacokinetic curve "concentration-time") phingolimoda or phingolyimophosphate.

Distribution

Fingolimod is significantly distributed in erythrocytes (fingolimoda fraction in blood cells 86%). Finkolimodfosfat has less ability to penetrate into blood cells (fraction in blood cells <17%). Fingolimod and phignolyimophosphate binds to a high degree with blood plasma proteins (> 99%). The association between phignolimod and phignolimophosphate with plasma proteins does not change in patients with impaired renal function or liver.

Fingolimod is largely distributed in the tissues of the body (the volume of distribution is about 1200 ± 260 liters). Fingolimod penetrates the brain, which has been shown in a clinical study in healthy volunteers. In a study of 13 volunteers with remitting multiple sclerosis, who received the Gilenia® preparation at a dose of 0.5 mg in equilibrium, the amount of phylogolimide (or phongolimophosphate) in the seminal fluid was 10,000 times lower than the initial dose of 0.5 mg).

Biotransformation

In humans, the biogransformation of phylogolimide occurs as a result of reversible stereoselective phosphorylation to pharmacologically active (S) -enantiomer of phignolyimophosphate, and due to oxidative biotransformation, mainly by isoenzyme CYP4F2 and possibly other isoenzymes CYP4F, with subsequent degradation similar to fatty acids to an inactive metabolite with the formation of pharmacologically inactive non-polar analogs of phynoglobin-ceramide.

After a single oral ingestion in the blood plasma, (for about I month), the unchanged phingolimod (8.3%), conjugates of metabolites with ceramide M29 (8.9%), and M30 (7.3%)), and in particular, .

Excretion

Plasma clearance of phylogolimide 6.3 ± 2.3 l / h, mean apparent half-life (T_1/2) - 6-9 days. Reduction of phylogenide concentrations and phignolimophosphate in the blood plasma in the terminal stage occurs in parallel, which leads to a similar half-life.

After ingestion, about 81% of the dose is excreted by the kidneys in the form of inactive metabolites. Notaltered phingolimod and phongolimophosphate are not excreted by the kidneys, but are the main compounds in the feces (the amount of each <2.5% of the dose). Within 1 month, about 89% of the dose is withdrawn.

Pharmacokinetics in some cases

Gender and ethnicity do not affect the pharmacokinetics of phignolimod and phignolyimophosphate.

Severe renal dysfunction leads to an increase in C_ma_x and AUC phylogolimide by 32% and 34%, by 25% and by 14% by phignolimophosphate.

Application of the drug in patients with impaired liver function mild, moderate and severe (> 9 on the Child-Pugh classification) leads to an increase AUC phongolimoda by 12%, 44% and 103% respectively. In patients with impaired liver function of mild severity, the half-life period remains unchanged, with an average and severe disorder, increases by 49-50%. In patients with impaired hepatic function of a serious degree (class C according to the Child-Pugh classification) FROM_ma_x phongolyimophosphate was reduced by 22%, and the AUC increased by 38%. In patients with impaired liver function of mild to moderate severity, the pharmacokinetics of phignolyimophosphate were not evaluated. The mechanism of phylogolimin elimination and the results of population pharmacokinetic studies suggest that,that dose adjustment in elderly patients is not required.

Clinical experience with phylogolimoda in patients over the age of 65 years is limited.

Indications:

Remitting Multiple Sclerosis (RRS) - to reduce the frequency of clinical exacerbations of the disease and reduce the risk of progression of disability.

Contraindications:

Identified immunodeficiency syndrome.

An 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, with the exception of basal cell carcinoma of the skin.

Violation of the liver function of a serious degree (class C according to the Child-Pugh classification).

Hypersensitivity to phylogolimide or any other component of the drug.

Pregnancy and the period of breastfeeding.

The effectiveness and safety of Gilenia® in children and adolescents under the age of 18 years have not been established.

Carefully:

Caution should be used in patients aged ≥ 65 years (limitednumber of application data), patients with diabetes mellitus (risk of developing macular edema), as well as in the presence of uveitis in an anamnesis.

Bradyarrhythmia

Due to the risk of serious arrhythmias Gilenia® drug should not be used in patients with AV block 2 degrees slime Mobitts II or higher, sick sinus syndrome and sinoatrial blockade. Since bradycardia may be poorly tolerated by patients with coronary heart disease, myocardial infarction, congestive heart failure, heart failure in the history of cerebrovascular disease, uncontrolled hypertension or severe untreated sleep apnea syndrome, Gilenia® drug should not be used in these patients. Since the use of the drug Gilenia® leads to a decrease in heart rate, reduction (HR) and, thus, to lengthen the interval QT, Gilenia® should not be used in patients with significant lengthening of the interval QT (QTc > 470 ms (female) or> 450 ms (male)). If it is necessary to use the drug in patients in this category, it is necessary to consult a cardiologist before starting therapy to choose the optimal monitoring of cardiac activity, possibly before the next morning.

Also, care should be taken in patients with low heart rate at rest, less than 55 beats per minute (low heart rate, not associated with cardiac dysfunction), with simultaneous application β- adrenoblockers, with a history of fainting.

Pregnancy and lactation:

Before starting treatment with Gilenia^® the doctor should inform women of childbearing age about the serious risk to the fetus and the need for effective contraception within 2-3 months after the end of treatment, which is due to the long period of drug withdrawal and the continuing risk to the fetus.

It is necessary to exclude pregnancy before treatment with phylogolimide. If the pregnancy is diagnosed during the use of the drug, therapy should be canceled. Available data suggest that the use of the drug in men is not associated with an increased risk of developing toxic effects on the fetus. According to the results of experimental studies, the negative effect of Fingolimod on fertility is unlikely.

When using the drug in experimental studies, reproductive toxicity was detected,including death of the fetus and malformations of the organs, especially the nephrosis of the arterial duct and defects of the interventricular septum. In addition, the sphingosine-1-phosphate receptors on which phingolimod, are involved in the formation of vessels during embryogenesis. AT Currently, there is no data on the influence of phylogolimoda on the formation of the cardiovascular system of a person, data on the use of the drug during pregnancy are extremely limited. AT clinical trials reported 20 pregnancies in patients who received phingolimod. but these data are insufficient to assess the safety of Gilenia® in patients in this category.

There is no data on the effect of phylogolimod on generic activity and the outcome of labor.

In experimental studies phingolimod stood out with the milk of lactating animals. Given the theoretical possibility of developing unwanted reactions in infants receiving breast milk from women taking phingolimod, it follows that stop breastfeeding or cancel the drug.

Dosing and Administration:

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

The recommended dose of the drug is one capsule of 0.5 mg orally once a day, regardless of the time of ingestion. In case of missed admission, the next day the drug Gilenia^® take at the usual time. The drug is intended for long-term treatment.

Recommendations for the replacement of therapy with other drugs modifying the course of the disease for treatment with Gilenia® are given in the section "Special instructions".

After taking the first dose of Gilenia®, all patients should be followed for 6 hours, including: measurement of heart rate and blood pressure (BP) every hour, as well as electrocardiography (ECG) before starting treatment with the drug and 6 hours after the first dose preparation with the aim of early diagnosis of possible manifestations of bradyarrhythmia.

When development of bradyarrhythmia against the background of initiation of therapy with the drug, if necessary, appropriate measures should be taken to correct this Mr.aRthe patient is monitored until this condition is reduced. If it is necessary to carry out drug therapy during the monitoring period after taking the first doseMonitoring of the patient should be continued in the hospital at least until the next morning. After receiving the second dose of Gilenia® in such patients, it is necessary to repeat all the activities as and after taking the first dose of the drug.

Additional monitoring up to the resolution of the state is also required at following cases:

- if the heart rate after 6 hours after the first intake of the drug: is <45 bpm or the lowest value for the entire observation period;

- when a newly arisen AV blockade of degree 2 or higher is detected by the ECG data at 6 hours after the first administration of the drug;

- if the interval QTs on the ECG is ≥500 msec.

When the therapy with Gilenia® is resumed, it is necessary to monitor the activity of the cardiovascular system, as well as after taking the first dose, in case of interruption of therapy:

- at least 1 day during the first 2 weeks of therapy;

- more than 7 days at the 3rd or 4th week of treatment;

- more than 2 weeks after the treatment lasted more than a month.

Impaired liver function

Correction of the dose of the drug in patients with impaired liver function of mild and moderate severity is not required.Treatment with Gilenia® for patients with a history of liver failure should be done with caution. It is recommended to control the activity of "liver" transaminases during the 6 months preceding the initiation of therapy with the drug. In the absence of clinical manifestations of liver damage, the activity of "hepatic" transaminases is recommended to be performed at 1, 3, 6, 9 and 2 months of treatment, and then periodically. Increased activity of "hepatic" transaminases ≥5 of the upper limit of the norm (VGN) requires more frequent biochemical examination of blood serum, including determination of bilirubin concentration and activity of alkaline phosphatase. When symptoms appear that suggest a violation of liver function (vomiting and nausea of unknown etiology, jaundice, abdominal pain, fatigue, anorexia, dark urine), it is necessary to determine the activity of "liver" enzymes. If liver damage is detected, treatment with the drug should be discontinued.

The use of Gilenia® in patients with severe liver failure (class C according to the Child-Pugh classification) is contraindicated.

Patients older than 65years old

Correction of the dose of the drug in patients of this category is not required, but treatment should be conducted with caution because of the lack of clinical experience in the use of the drug in patients older than 65 years.

Diabetes

Studies on the use of the drug Gilenia® in patients with diabetes mellitus have not been conducted. Care should be taken when using the drug in patients of this category because of the risk of developing macular edema, to exclude the development of which it is required to regularly perform ophthalmic control.

Impaired renal function

Correction of the dose of the drug in patients with impaired renal function is not required.

Patients under the age of 18 years

The effectiveness and safety of Gilenia® in children and adolescents under the age of 18 years have not been established.

Discontinuation of drug treatment

At the termination of treatment by a preparation it is necessary to consider, that normalization the number of lymphocytes occurs 1-2 months after the last dose of Gilenia®. Since with the use of immunosuppressants within 1-2 months after discontinuation of Gilenia®, 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:

Below are the undesirable phenomena revealed in three clinical trials in 2,431 patients with relapsing-remitting multiple sclerosis. When using the drug Gilenia® at a dose of 0.5 mg, the following serious adverse events (AEs) were noted: infections, macular edema and transient atrioventricular blockade at the beginning of treatment. Most often (frequency ≥10%) with atChanges in the dose of 0.5 mg were observed in headache, increased activity of "liver" transaminases, diarrhea, cough, flu, sinusitis and back pain. The most frequent cause (frequency of more than 1%) of discontinuation of therapy with the drug (0.5 mg dose) was an increase in the activity of alanine aminotransferase (ALT) (2,2%).

Below are the undesirable phenomena (AE) in accordance with the frequency of occurrence. The following criteria were used to estimate the frequency (according to the classification of the World Health Organization (WHO)): very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1,000, <1/100); rarely (≥1 / 10,000, <1 / 1,000); very rarely (<1 / 10,000), including individual messages.Since the post-release period reports of AEs are received voluntarily from a population of an undefined number, it is not possible to estimate the frequency of their occurrence, and for this reason ND data are indicated: "frequency is unknown". AEs are grouped according to the classification of organs and systems of organs MedDRA, Within each group, the frequencies of the NW are arranged in decreasing order of gravity.

Infectious and parasitic diseases: Often - influenza, sinusitis; often - bronchitis, infections caused by the herpes virus, for example, herpes zoster; pityriasis lichen; infrequently pneumonia *.

Immune system disorders: frequency unknown - hypersensitivity, rash.

Violations from the blood and lymphatic system: often - lymphopenia, and leukopenia.

Disorders of the psyche: often - Depression; infrequently - low mood.

Impaired nervous system: Often - headache; often - dizziness, migraine; rarely - syndrome of reversible posterior encephalopathy *.

Disturbances on the part of the organ of sight: often - blurred vision; infrequently - macular edema.

Heart Disease: often - bradycardia, atrioventricular block.

Vascular disorders: increased blood pressure.

Disturbances from the respiratory system, chest and mediastinal organs: Often - cough; often - shortness of breath.

Infringements from gastrointestinal tract: Often - diarrhea.

Disturbances from the skin and subcutaneous tissues: often - eczema, alopecia, itching.

Disturbances from musculoskeletal and connective tissue: Often - pain in blue.

General disorders and disorders at the site of administration: often - asthenia.

Laboratory and instrumental data: Often - Increased activity of "liver" enzymes (ALT, YYT, ACT); often - increase in the concentration of triglycerides of blood; infrequently - neutropenia.

* AE, the relationship of which with taking the drug is regarded as "probable".

Infections

When the drug was used in clinical trials at the recommended dose (0.5 mg once a day) in patients with RRS, the overall incidence of infections (65.1%) was similar to that of the placebo group. However, patients receiving Gilenia® were more likely to have bronchitis, shingles and pneumonia.The incidence of serious infections in the group of patients receiving phingolimod in a dose of 0.5 mg, was 1.6%, in the placebo group, 1.4%.

There are data on extremely rare deaths caused by infection with the virus Varicella Zoster, in patients who simultaneously received long-term therapy with glucocorticosteroids (more than five days) in order to treat relapses of the RRS, but the cause-and-effect relationship between treatment and death is not established. In clinical trials using phylogolimod in patients with RRS who received short courses of glucocorticosteroids (within five days), there was no increase in the incidence of infections compared with the placebo group.

There are also data on other extremely rare deaths caused by infection with the herpes virus, but a causal link between deaths and the use of Gilenia® has not been established.

Neurological disorders

There are reports of rare cases of damage to the nervous system in patients receiving phingolimod in high doses (from 1.25 mg before 5.0 mg), with development ischemic and hemorrhagic attacks, as well as a syndrome of reversible posterior encephalopathy.There have also been cases of development of atypical neurologic lesions, such as ODEM (acute disseminated encephalomyelitis) -like conditions.

Vascular disorders

In the treatment with phylogolimide in a dose of 1.25 mg occlusion of peripheral arteries was noted. There are isolated reports of the development of the syndrome of reversible posterior encephalopathy, as well as ischemic and hemorrhagic stroke with phylogolimide at a dose of 0.5 mg.

Macular edema

When the drug was administered at the recommended dose in clinical trials, the incidence of macular edema was 0.54% in patients with RRS. In most cases, the development of macular edema was observed within 3-4 months after initiation of treatment. In some cases, edema of the macula without clinical manifestations with a routine ophthalmological examination), some patients Macular edema was accompanied by blurred vision or decreased visual acuity. At the termination of treatment with the drug, in most cases there was a decrease in severity or spontaneous resolution of this condition. The incidence of macular edema was increased with a history of uveitis.

Bradyarrhythmia

In clinical trials at the beginning of treatment with the drug at the recommended dose, there was a transient decrease in heart rate and a slowing of atrioventricular conduction. In this case, the maximum decrease in heart rate is observed within 6 hours after taking the medication (mean decrease by 12-13 beats per minute), and 70% of the negative chronotropic effect is achieved on the first day of use.

In clinical trials at the beginning of therapy with Gilenia® at a dose of 0.5 mg in patients with RRS, atrioventricular blockade (AV blockade) of the 1st degree (prolongation of the pulse time in ECG) was observed in 4.7% of patients (1.6% in the group and that sky). AB blockade of the 2nd degree was detected in less than 0.2% of patients receiving the Gilenia® preparation at the recommended dose. Conductivity disorders, observed both in clinical trials and post-marketing period, were usually transient and asymptomatic, did not require therapy, and were resolved within the first 24 hours after the start of treatment. Some patients experienced symptoms such as lowering blood pressure, dizziness, fatigue, and / or palpitations, which were also resolved on their own within 24 hours.In the post-registration period individual cases of complete AV blockade after the first dose of Gilenia®, which were of a transient nature and spontaneously resolved, are described. Although in most cases no medical intervention was required to relieve AEs, in one case in a clinical trial in a patient who received Gilenia® at the recommended dose, an asymptomatic AV block of type II Mobits I was stopped with isoprenaline.

There have been cases of asystole and unexplained sudden death after the first administration of the drug, but the connection between the administration of Gilenia® and these events has not been proven.

Respiratory system

In the clinical study, after the first month of application of the drug at a dose of 0.5 mg, there was a slight dose-dependent decrease in the volume of forced expiratory volume in the first second (FEV₁) and the diffusivity of light per carbon monoxide (DLCO), In the future, the achieved values of these parameters did not change. The abolition of therapy was accompanied by the normalization of indicators. Decrease DLCO by the 24th month of the use of phylogolimidine in a dose of 0.5 mg was 3.3% compared with 2.7% in the placebo group.

Increased blood pressure

In clinical trials with a 0.5 mg dose, a small increase in blood pressure was observed in patients with PPC, an average of 3 mm Hg. Art. - systolic, at 1 mm Hg. Art. - diastolic. The increase in blood pressure was observed approximately 1 month after the start of treatment and was maintained with the continuation of therapy. Increased blood pressure was noted in 6.5% of patients who received the drug Gilenia® at the recommended dose (3.3% in the placebo group). According to post-registration data, arterial hypertension was noted during the first month of treatment and in some cases required the use of antihypertensive drugs or interruption of treatment.

Impaired liver function

In clinical studies in patients treated with Gilenia®, there was an increase in the activity of "liver" transaminases (predominantly ALT). When recommended dose of 0.5 mg in 8,0% cases of asymptomatic increase in ALT activity in ≥3 times higher UGN and in 1.8% of cases - in ≥5 IUG compared with the placebo group, where these indicators were 1.9% and 0.9%, respectively. In most cases, an increase in ALT activity is observed at during the first 6-9 months of therapy.In some patients, a second increase in ALT activity was noted after the resumption of therapy with phylogolimide.

Normalization of ALT activity in the blood plasma occurred approximately 2 months after discontinuation of the drug. In a small number of patients with increased ALT activity ≥5 VGN who continued treatment with the drug, the normalization of ALT activity occurred after approximately 5 months of therapy,

Lymphomas

According to clinical and post-registration studies, patients with Gilenia® received lymphomas, both B-cell and T-cell lymphomas. The incidence of lymphoma is 3 cases per 10,000 person-years (versus 1.9 cases per 10,000 person-years in the general population).

In the post-marketing period, cases of development of cryptococcal infections are noted, including number of isolated cases of development of cryptococcal meningitis.

Hemophagocytic syndrome

In the post-marketing period, patients treated with phylogolimide were found to have very rare cases of hemophagocytic syndrome with a lethal outcome associated with an infectious disease.Hemophagocytic syndrome is a condition associated with infectious diseases, immunosuppression and a number of autoimmune diseases.

Overdose:

Healthy volunteers satisfactorily tolerated a single dose of the drug at a dose of 40 mg (a dose 80 times higher than the recommended daily dose), while 5 out of 6 volunteers showed a slight obstruction of the airways, accompanied by a feeling of slight tightness in the chest or a sense of discomfort.

Fingolimod can cause the development of a bradycardia. The decrease in heart rate is usually noted within one hour after taking the first dose and reaches a maximum within 6 hours. There are reports of slowing of atrioventricular conduction and individual reports of transient cases of AV blockade with spontaneous resolution.

In case of an overdose, when taking the first dose of Gilenia, it is important to identify the manifestations of bradycardia, and monitoring may be required until the next morning. It is necessary to regularly measure the heart rate and blood pressure, as well as conduct an ECG. If, after 6 hours after the first reception, the heart rate is <45 beats / min or if there are ECG signs II and above of the degree of the AV blockade, or QT-interval amounted to ≥500 msec, then prolong monitoring overnight until the signs of cardiac arrhythmias disappear. If there is an AV blockade of the third degree at any time of the day, it is necessary to ensure monitoring during the night. Fingolimod It is not removed from the body by dialysis and plasmapheresis.

Interaction:

Pharmacodynamic interaction

Given the possibility of an additional inhibitory effect on the immune system, caution should be exercised when using phongolimoda along with antitumor drugs agents, immunosuppressants (including glucocorticosteroids) or immunomodulators. Since glucocorticosteroids have an immunosuppressive effect, the duration of treatment and their dose with simultaneous application with phylogolimide should be adjusted based on clinical data.

In clinical trials with phylogolimoda in patients with PPC who received short courses of glucocorticosteroids (within five days), there was no increase in the incidence of infections.

It is necessary to use caution phingolimod in patients who received long-lasting drugs such as natalizumab, teriflunomide or mitoxantrone.

Limited experience in the use of the drug Gilenia® in patients receiving concomitant therapy with beta-blockers, blockers of "slow" calcium channels, which reduce the heart rate (such as verapamil, diltiazem or ivabradine), or other drugs that can reduce the heart rate (eg, digoxin). The use of these drugs in combination with the preparation Gilenia® can be accompanied by the development of severe bradycardia and cardiac blockade. When taking phyngolimoda in combination with atenolol heart rate is further reduced by 15% (when taken with diltiazem this effect is not observed). Due to the powerful combined effect on the heart rate, Gilenia® is not recommended for use in patients currently receiving these medicines. If treatment with Gilenia® is contemplated, a cardiologist should be consulted about the possibility of switching to therapy that does not reduce the heart rate, or appropriate monitoring.

Application drug Gilenia® in patients, receiving antiarrhythmic drugs IA class (for example, quinidine, procainamide) or class III (for example, amiodarone, sotalol), has not been studied. Since the use of antiarrhythmic drugs IA and III classes may develop bradyarrhythmias, the drug Gilenia® should not be used together with these antiarrhythmic drugs.

Pharmacokinetic interaction

Fingolimod is primarily metabolized with the participation of cytochrome P450 4F2 and possibly other isoenzymes CYP4F. In vitro in hepatocytes in the case of significant induction of the isozyme CYP3A4 can also participate in the metabolism of phylogenide. In connection with the foregoing, the effect of phygnolimod and phignolimophosphate on the clearance of drugs metabolized by basic isoenzymes CYP, unlikely.

Effect of phylogolimide and phignolimophosphate on metabolism concomitant medications

Research in vitro showed that phingolimod and phignolyimophosphate are almost or completely unable to suppress the activity of human cytochrome P450 isoenzymes (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 / 5 or 4A9 / 11). Thus, the decrease in the clearance of drugs metabolized mainly by the main isoenzymes of cytochrome P450 in the presence of phingolimod and phignolyimophosphate is clinically unlikely.

The ability of phngolimod and phignolyimophosphate to induce its own metabolism and / or metabolism of concomitantly used drugs

In studies in vitro Fingolimode did not induce mRNA of cytochrome 3A4, 1A2,4F2 isoenzymes and ABCB1 (P-glycoprotein), as well as the activity of cytochrome isoenzymes 3A, 1A2, 2B6, 2C8, 2C9, 2C19, 4F2; phongolyimophosphate did not possess an inducing action with respect to cytochrome isoenzymes. Thus, an increase in the activity of various isoenzymes of cytochrome P450 and ABCB1 in the presence of phingolimode is unlikely.

Transport proteins

The drug probably does not interfere with the absorption and excretion of drugs and other substances that are substrates of the main transport proteins.

Cyclosporin

Pharmacokinetics phingolimoda and cyclosporine in the case of a single or repeated application did not change.

Oral contraceptives

Simultaneous use of phylogolimide in a dose of 0.5 mg per day and oral contraceptives (ethinyl estradiol and levonorgestrel) does not lead to a change in the effects of oral contraceptives. Despite the lack of research, the effect of oral contraceptives containing progestogens on phingolimod not expected.

Ketoconazole

In the case of concomitant use of ketoconazole (200 mg twice a day until equilibrium was reached) and phingolimod (5 mg once), there was a moderate increase AUC phylogolimide and phignolimophosphate (1.7-fold).

Isoprenaline, atropine, atenolol and diltiazem

Simultaneous application isoprenaline or atropine had no effect on the exposure of phylogolimide and phignolyimophosphate. Simultaneous use of atenolol and diltiazem did not affect the pharmacokinetics of phylogolimide or phignolyimophosphate.

Carbamazepine

Simultaneous application of carbamazepine 600 mg twice a day and 2 mg phylogolimide did not significantly affect AUC phylogolimide and phignolyimophosphate, reducing them by approximately 40%. Simultaneous use of carbamazepine with phylogolimide can reduce the effectiveness of the latter.

Potential drug interactions

In clinical studies in patients with PPC, there was no significant effect of fluoxetine and paroxetine (potent inhibitors of isoenzyme CYP2D6) on the concentration of phylogolimide or phignolyimophosphate. Baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalinum, glucocorticosteroids and oral contraceptives did not have a clinically significant effect on the concentration (≤20%) of phignolimod and phignolyimophosphate.

Vaccination

Since the use of live attenuated vaccines may increase the risk of infection, the use of the drug should not be immunized with live attenuated vaccines. During therapy with the drug, as well as within 2 months after the termination of treatment with phygolimide, vaccination may be less effective.

Special instructions:

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 assess the different populations 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). Before starting therapy with the drug, you should get a result of a general clinical blood test with a leukocyte formula performed during the last 6 months preceding the start of therapy, or after the abolition of previous therapy.

Infections

Since the use of the drug may increase the risk of infection, during the treatment with the drug Gilenia® in patients with symptoms of the infectious process, it is necessary to conduct effective diagnostic and therapeutic measures. Withdrawal of phylogolimidine after discontinuation of treatment can occur within 2 months, therefore, during this period it is necessary to remain cautious about the development of infection. Patients receiving drug therapy should be instructed to immediately inform the doctor of all symptoms of the infection,

When the development of severe infections during therapy with Gilenia® should be discontinued. Renewal treatment with Gilenia® should only occur if the benefits of therapy exceed the possible risk.

In the post-marketing period, cases of development of cryptococcal meningitis are noted. With the development of symptoms that make it possible to suspect the development of this condition, appropriate diagnostic measures should be taken. When the diagnosis is confirmed, appropriate treatment should be started.

Patients who do not have a history of documented evidence of a chickenpox transferred or a complete course of vaccination against the virus Varicella zoster (VZV), before the start of therapy should be examined for the detection of antibodies to VZV. If necessary, the vaccination is carried out 1 month before the start of therapy for the prevention of post-vaccination complications.

Macular edema

Because the on the background of therapy with Gilenia®, it is possible to develop edema of the macula in the first 3-4 months of treatment, it is recommended to conduct an ophthalmological examination. Have patients with uveitis in the anamnesis, as well as in patients with concomitant diabetes mellitus, there is an increased risk of developing macular edema. Since the use of the drug in patients with PPC and concomitant diabetes mellitus has not been studied, in patients with diabetes mellitus or uveitis in an anamnesis, an ophthalmological examination is recommended before and during therapy with Gilenia®.

When detecting visual disturbances in patients with drug therapy, it is necessary to examine the fundus, especially the macular area. If the edema of the macula develops, the drug should be discontinued.The risk of developing a repeated edema of the macula with the resumption of drug therapy Gilenia® has not been studied. Renewal treatment with Gilsnia® should only be made if the benefit of therapy exceeds the possible risk for the patient.

Diabetes

Research on the use of the drug Gilenia® in patients with diabetes mellitus not carried out. Care must be taken when prescribing the drug in this category of patients because of the risk of developing macular edema, in order to exclude the development of which it is required to regularly perform ophthalmic control.

Bradyarrhythmia

In connection with the risk of developing serious rhythm disorders, the drug Gilenia® It should not be used in patients with type 2 Mobbit AV blockade II or higher, sinus node weakness syndrome, or sinoatrial blockade. Since severe bradycardia can be poorly tolerated in patients with coronary heart disease, history of myocardial infarction, chronic heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled rise in blood pressure, or severe untreated sleep apnea syndrome, the drug Gilenia® should not be used in such patients. Since the use of the drug Gilenia® leads to a decrease in the heart rate and, thus, to the lengthening of the interval QT, a drug Gilenia® should not be used in patients with significant lengthening of the interval QT (QTc > 470 ms (female) or> 450 ms (male)). If it is necessary to use the drug in patients of this category should consult a cardiologist before starting therapy to choose the optimal monitoring of cardiac activity, possibly before the next morning.

Also, care should be taken in patients with low heart rate at rest - less than 55 beats per minute (low heart rate, not associated with impaired cardiac function), with simultaneous application β-adrenoblockers, with a history of fainting.

After taking the first dose of Gilenia®, it is recommended to monitor the patient for 6 hours, including a measurement of heart rate and blood pressure every hour, to eliminate manifestations of bradyarrhythmia. All patients should receive an ECG study before taking the drug and during the 6-hour monitoring period.

With the development of bradyarrhythmia against the background of drug therapy, if necessary, appropriate measures should be initiated, the patient is monitored until the violation is overcome. If a drug therapy is necessary during the monitoring period after taking the first dose, it is necessary to prolong the observation at least until the morning of the next day and repeat the examination after taking the second dose of the drug Gilenia®.

Additional follow-up is also required for the following cases:

- if the heart rate after 6 hours after taking the drug is <45 bpm, or is the smallest value for the entire observation period;

- at the first occurrence of AB-blockade of the 2nd degree or higher according to the ECG data 6 hours after taking the drug;

- if the interval QTc by ECG is> 500 msec.

When the resumption of therapy with Gilenia® requires the monitoring of the cardiovascular system, as well as after the first dose, in the event of interruption of therapy:

- at least 1 day during the first 2 weeks of therapy;

- more than 7 days at the 3rd or 4th week of treatment;

- more than 2 weeks after the treatment lasted more than a month.

It is advisable to avoid the use of Gilenia® in patients with risk factors for lengthening the interval QT, in particular hypokalemia, hypomagnesemia or congenital lengthening of the interval QT.

The decision to use Gilenia® in patients with recurrent syncope or symptomatic bradycardia should be based on an assessment of the benefit-risk relationship.

All patients need to carry out an ECG study before starting therapy with Gilenia® and at the end of the 6-hour monitoring period.

Interval QT

When applying phingolimoda in doses of 1.25 mg or 2.5 mg at rest there was an elongation of the interval QTcl (adjusted interval QT by pulse rate based on the data of the individual patient) to 90% (CI <13.0 ms). There was no dependence of the occurrence of lengthening of the interval QTcl from the dose of the drug and the duration of therapy. Do not use drugs that extend the interval QTc, In patients with hypokalemia or congenital lengthening of the interval QT.

Increased blood pressure

In clinical studies, the use of the drug at a dose of 0.5 mg in patients with RRS showed a slight increase in blood pressure by an average of 3 mm Hg. Art. - systolic, per 1 mm pt. Art. - diastolic. The increase in blood pressure was observed approximately 1 month after the start of treatment and was maintained with the continuation of therapy.Increased blood pressure was noted in 6.1% of patients who received Gilenia® at the recommended dose (3.8% in the placebo group). According to the post-registration observation, hypertension was noted during the first month of treatment and may require the use of antihypertensive drugs or interruption of treatment.

Syndrome of reversible posterior encephalopathy

In clinical and post-research studies have noted rare cases of development sindroma reversible encephalopathy with the use of the drug Gilenia® at a dose of 0.5 mg with the following symptoms: intense headache with a sudden onset, accompanied by nausea and vomiting, impaired consciousness, visual disturbances and seizures. The condition is usually reversible, but can lead to ischemic or hemorrhagic stroke, so belated diagnosis and postponement of the onset of correction of the condition can lead to neurological consequences. If you suspect a syndrome of reversible posterior encephalopathy, the drug Gilenia® should be discontinued.

Previously conducted treatment with immunosuppressants and drugs that modify the course of the disease

When replacing therapy with other drugs modifying the course of the disease for treatment with Gilenia®, attention should be paid to the mechanism of action of the previously used drug, and also to take into account the half-life of the drug, in order to avoid the development of a total depressant effect on the immune system. In this case, the risk of reactivation of the disease should be considered.

Interferon-beta and glatiramer acetate

In patients who received prior treatment with interferon-beta, glatiramer acetate or dimethyl fumarate, with good tolerability (no cytopenia), treatment with Gilenia® can be started immediately after the discontinuation of the use of the above drugs.

Natalizumab and teriflunomide

Due to the long half-life of natalizumab and teriflunomide, care should be taken when changing the therapy with these drugs for treatment with Gilenia® because of the risk of developing a total oppressive effect on the immune system.

As a rule, for complete elimination of natalizumab, it takes two to three months from the moment of discontinuation of therapy.

Withdrawal of teriflunomide from the blood plasma is slow, and can take from several months to two years without an accelerated elimination procedure.

Alemtuzumab

In connection with the mechanism of action of alemtuzumab and its immunosuppressive effect, the use of the drug Gilenia® after the cessation of therapy with alemtuzumab is not recommended, for except when the expected benefit exceeds the possible risk for a particular patient.

Termination of treatment with phygolyimode

After the withdrawal of treatment with phylogolimide, a 6-week interval without treatment is needed to remove phyloglymide from the bloodstream. When discontinuing the drug should take into account that the normalization of the number of lymphocytes occurs 1-2 months after the last application of the drug Gilenia®. Since the use of immunosuppressants within 1-2 months after discontinuation of the Gilenia® drug may further suppress the immune system, care must be taken when using immunosuppressants shortly after discontinuation of treatment with the drug.

Dysfunction of the liver

It is recommended to control the activity of "liver" transaminases during the 6 months preceding the initiation of therapy with the drug. In the absence of clinical manifestations of liver damage, the determination of the activity of "hepatic" transaminases is recommended in 1, 3, 6,9 and 12 months of treatment, and then periodically. Increased activity of "liver" transaminases ≥5 VGN requires more frequent biochemical examination of blood serum, including the determination of the concentration of bilirubin and alkaline phosphatase. With the appearance of symptoms suggesting a violation of liver function (vomiting and nausea of unknown etiology, jaundice, abdominal pain, fatigue, anorexia, dark urine), it is necessary to carry out a study of the activity of "liver" enzymes, and when detecting liver damage, stop taking the drug.

Respiratory system

Patients with suspected development of disturbances from the respiratory system are recommended to perform spirometry.

Effect on the ability to drive transp. cf. and fur:

Patients who, with Gilenia®, experience undesirable effects such as dizziness and visual impairment, do not drive vehicles or mechanisms until these side effects have completely disappeared. It is necessary to monitor the patient's condition in the first 6 hours after the first intake of the drug before starting the management of vehicles.

Form release / dosage:

Capsules, 0.5 mg.

Packaging:

By 7 or 14 capsules in a blister of PVC / PVDC.

For 2 or 7 blisters for 14 capsules (calendar packing); 1 blister pack of 7 capsules (perforated blister), along with the instruction, is placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-008272/10

Date of registration:17.08.2010

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

ORTAT, CJSC Russia

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp25.09.2015

Illustrated instructions

Instructions

Gilenia® (GILENIA®)