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

Composition of hard gelatin capsules: capsule body - titanium dioxide 2.0000%, gelatin - up to 100%; capsule cap - titanium dioxide 2.0000%, gelatin - up to 100%.

Description:

Hard gelatin capsules №3, body and lid of white color. Contents of capsules: white or almost white powder.

Pharmacotherapeutic group:Immunosuppressive remedy. Means for treating multiple sclerosis

ATX: & nbsp

L.04.A.A.27 Fingolimod

Pharmacodynamics:

Fingolimod modulates the receptors of sphingosine-1-phosphate (SlPreceptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite of phignolyimophosphate. In nanomolar concentrations, phignolyimophosphate binds to S1P receptors of types 1, 3 and 4 on the surface of lymphocytes and quickly penetrates into the central nervous system (CNS) through the blood-brain barrier, S1P receptors are 1, 3 and 5 types on the surface of neurons. Communicating with S1 P-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 Th17, 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 decline 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 affected by phylogenide.

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.

In clinical trials, at the beginning of treatment with the drug, a transient decrease in heart rate (heart rate) and a decrease in atrioventricular conduction were noted at the recommended dose. At the same time, 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 chronotopic effect is achieved on the first day of use. The heart rate returned to the baseline within 1 month of regular use of the drug. Autonomous functions of the heart, incl.the circadian variability of the heart rate and the response to physical activity do not change under the influence of the phylogolide. At the beginning of the application of phylogolim, there is an increase in the number of atrial extrasystoles, not accompanied by increased frequency of atrial fibrillation / flutter, ventricular arrhythmia or ectopia. There was no effect of phylogolimoda on cardiac output reduction. The decrease in heart rate caused by phylogolimod can be stopped by the use of atropine, isoprenaline or salmeterol. A single and multiple application of phylogolimide in doses of 0.5 mg and 1.25 mg for two weeks was not associated with a detectable increase in airway resistance by the value of FEV1 and the mean volumetric flow rate of 25-75% of FVC. However, a dose-dependent increase in respiratory tract resistance was noted with a single application of phylogolimide in a dose exceeding 5 mg exceeding the recommended value by more than 10 times. Multiple application of phylogolimide in doses of 0.5 mg, 1.25 mg or 5 mg is not associated with a decrease in oxygenation, a decrease in oxygen saturation with physical exertion or an increase in the reactivity of the respiratory tract to methacholine.In patients who received phingolimod, there was a normal bronchodilator response to the use of inhaled beta-agonists.

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 scale rating EDSS of the 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.

Suction

When ingested, ≥85% of the dose is absorbed. Absorption of phylogolimide occurs slowly (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 (1 time per 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 area under the pharmacokinetic curve "concentration-time") phingolimod or phingolyimophosphate.

Distributive

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 relationship between phignolimod and phignolimophosphate with plasma 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 1200 ± 260 liters). Fingolimod penetrates the brain, which has been shown in a clinical study in healthy volunteers. In the study, 13 volunteers with remitting multiple sclerosis who received phingolimod in a dose of 0.5 mg in the equilibrium state, the amount of phngolimod (or phongolimophosphate) in the seminal fluid was 10,000 times less than the dose (0.5 mg).

Metabolism

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 the subsequent degradation similar to fatty acids to an inactive metabolite and the formation of pharmacologically inactive non-polar analogs of phynoglobin-ceramide.

After a single oral ingestion in the blood plasma, (for about 1 month) unchanged phingolimod (8.3%), conjugates of metabolites with ceramide M29 (8.9%), and MZO (7.3%)), in the absence of active metabolites (23.3%), phongolyimophosphate (10.3%), inactive metabolites (M3 - acidic carboxylic metabolite (8.3%)) .

Excretion

Plasma clearance of phngolimod 6.3 ± 2.3 l / h, average apparent half-life (T1 / 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 in the urine as inactive metabolites. Unchanged 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

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

Impaired renal function

Violation of the function of the kidneys of a serious degree leads to an increase in C_m_Oh and AUC phylogolimide by 32% and 34%, phygolyimophosphate by 25% and 14%.

Impaired liver function

A single application of phylogolimidine in a dose of 1 or 5 mg in patients with impaired hepatic, moderate and severe liver function (> 9 on the Child-Pugh scale) 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 a violation of the average and severe degree - increases by 49-50%. In patients with impaired hepatic function of a serious degree (class C according to the Child-Pugh classification) C_m_Oh phongolyimophosphate was reduced by 22%, a AUC increased by 38%. In patients with impaired liver function of mild to moderate severity, the pharmacokinetics of phignolyimophosphate were not evaluated.

Elderly patients

The mechanism of phylogenide induction and the results of population pharmacokinetic studies suggest that dose adjustment in elderly patients is not required. The clinical experience of using phyngolimoda in patients over the age of 65 is limited.

Patients under the age of 18 years

The safety and efficacy of phylogolimoda in patients younger than 18 years of age has not been studied. The use of the drug is not indicated in patients younger than 18 years.

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 immunocompromised patients who are receiving immunosuppression 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.

- Severe liver damage (Child-Pugh class C).

- Hypersensitivity to phylogolimide or any other component preparation.

- Pregnancy and the period of breastfeeding.

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

Carefully:

Caution is advised to prescribe the drug to patients aged> 65 years (limited amount of application data), with diabetes mellitus (risk of developing macular edema), and if uveitis is present in the anamnesis.

Bradyarrhythmia

In connection with the risk of developing serious rhythm disorders phingolimod It should not be used in patients with AV blockade of the 2nd degree of the Mobits type II or higher, a syndrome of weakness of the sinus node or a sinoatrial block.Because severe bradycardia can be poorly tolerated by patients with coronary heart disease, history of myocardial infarction, chronic heart failure, history of heart failure, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea syndrome, phingolimod should not be used in such patients. Since the use of phingleolim leads to a decrease in the heart rate and, thus, to the lengthening of the interval QT, Fingolimod 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 this category of patients, it is necessary to consult a cardiologist before starting therapy to select the optimal monitoring of cardiac activity probably before the next morning.

Caution should also be taken in patients with low heart rate (HR) at rest, less than 55 beats per minute (low heart rate, not associated with cardiac dysfunction), with simultaneous use of β-blockers, with a history of fainting.

Pregnancy and lactation:

Before beginning treatment with Limod, the doctor should inform women with the preserved reproductive potential of the serious risk for the fetus and the need for effective contraception within 2-3 months after the end of treatment, which is caused by a long period of drug withdrawal and a 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 pre-clinical studies, the negative effect of phylogolimide on fertility is unlikely.

When using the drug in studies in animals at a dose of 0.1 mg / kg, which corresponds to a twofold increase in exposure when applied in humans at the recommended dose of 0.5 mg, reproductive toxicity was found, including fetal death and organ developmental defects, especially the non-proliferation 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.

Well-controlled adequate studies of the use of the drug during pregnancy in humans have not been conducted. In a prospective observation of more than 300 cases of pregnancy, resulting in the birth of a live fetus, in patients with multiple sclerosis who received phingolimod during pregnancy, the frequency of serious congenital anomalies is similar to that in the general population. Studies conducted in Canada, the major EU countries and South America show that the incidence of birth defects in children in a population of patients with multiple sclerosis is similar to that in the general population. In the US, the risk of self-termination of pregnancy and stillbirth in a population of patients with multiple sclerosis corresponds to a similar indicator in the general population.

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

In preclinical studies phingolimod penetrated into the milk of lactating animals.There is no data on the effect of phylogolimoda on children receiving it with breast milk, as well as on the effect of phylogolimide therapy on human milk production. Given that many drugs are absorbed into breast milk, as well as the theoretical possibility of developing serious adverse reactions in infants receiving breast milk from women taking phingolimod, you should stop breastfeeding.

Dosing and Administration:

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 phingolimod apply 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 phygolyimode are presented in the section "Special instructions". After taking the first dose of phylogolide, all patients should be followed for 6 hours, including: measurement of heart rate and blood pressure every hour, as well as electrocardiography before starting treatment with the drug and 6 hours after taking the first dose of the drug in order to early diagnosis of possible manifestations of bradyarrhythmia.

With the development of bradyarrhythmia against the background of the initiation of therapy with the drug, if necessary, appropriate measures should be taken to correct this disorder, and the patient should be monitored until this condition is relieved. If it is necessary to perform drug therapy during the monitoring period after the first dose, follow-up of the patient should be continued in the inpatient settings at least until the next morning. After applying the second dose of phylogolimoid in such patients, it is necessary to repeat all the measures, as well as after applying the first dose of the drug.

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

- if the heart rate after 6 hours after the first intake of the drug is <45 bpm, or is 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 QTc on the ECG is> 500 msec.

With the resumption of therapy with phylogolimide, 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 finkholimodom patients with violations of liver function in history 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 "liver" transaminases is recommended for 1, 3, 6, 9 and 12 months of treatment, and then periodically. An increase in the activity of "hepatic" transaminases> 5 VGN requires more frequent biochemical examination of blood serum, including the determination of the level of bilirubin and 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 phingolimod in patients with severe liver dysfunction (class C according to the Child-Pugh classification) is contraindicated.

Patients over 65 years of age

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

Diabetes

Studies on the use of phyngolimod in patients with diabetes mellitus have not been conducted. Care must be taken when using 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 carry out ophthalmic control.

Impaired renal function

Correction of the dose of the drug in patients with impaired renal function is not required. Patients under 18 years of age The efficacy and safety of phylogolimoda 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 of quantity of lymphocytes occurs in 1-2 months after last application финголимода.Since the use of immunosuppressants within 1-2 months after stopping phylogolimidine administration may further suppress the immune system, care must be taken when using immunosuppressants soon after discontinuation of treatment with the drug.

Side effects:

Below are the undesirable phenomena revealed in three clinical trials in 2,431 patients with relapsing-remitting multiple sclerosis. When using phylogolimide in a dose of 0.5 mg, the following serious adverse events (AEs) were noted: infection, macular edema and transient atrioventricular blockage at the beginning of treatment. Headache, diarrhea, cough, flu, sinusitis, back pain, increased activity of "liver" transaminases were observed most often (frequency> 10%) when the drug was administered at a dose of 0.5 mg. The most frequent cause (frequency of more than 1%) of discontinuation of drug therapy (at a dose of 0.5 mg) was an increase in activity of alanine aminotransferase (ALT) (3.8%).

Below are the undesirable phenomena (AE) in accordance with the frequency of occurrence. To estimate the frequency, the following criteria were used: 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. Within each group, the frequencies of HH are arranged in decreasing order of gravity.

Infections and invasions: very often - influenza, sinusitis; often - shingles, pityriasis, bronchitis; infrequently pneumonia *.

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

Disorders of the psyche: often - depression, infrequently - decreased mood.

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

Disorders from the side of the organ of vision: often - blurred vision, pain in the eyes; infrequently - macular edema.

Heart Disease: often - bradycardia, increased blood pressure, atrioventricular blockade.

Vascular disorders increase in blood pressure.

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

Disorders from the gastrointestinal tract: very often - diarrhea.

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

Disturbances from the musculoskeletal and connective tissue: very often - back pain.

Immune system disorders: frequency unknown - hypersensitivity, rash.

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

Laboratory and instrumental data: very often - increased activity of "liver" enzymes (ACT, GGT, ACT); often - increased 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 in the placebo group. However, in patients who received phingolimod, bronchitis, shingles and pneumonia were more common. 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 received long-term glucocorticosteroid therapy (more than five days) for the purpose of treatment of RRS retsedivov, however, the causal relationship between treatment and death was not established.In clinical trials with fngolimod in patients with PPC 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, however, the cause-and-effect relationship between fatal outcomes is not established using phylogenide.

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 to 5.0 mg), with the development of ischemic and hemorrhagic attacks, as well as the syndrome of reversible posterior encephalopathy. There have also been cases of development of atypical neurologic lesions, such as ODE (acute disseminated encephalomyelitis) - like state.

Violation of the vessels

When treating patients with phylogolimide at a dose of 1.25 mg occlusion of peripheral arteries was noted. There are single observations on the development of the syndrome of reversible posterior encephalopathy, as well as ischemic and hemorrhagic stroke with phylogolimide in a dose of 0.5 mg.

Macular edema

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

Bradyarrhythmia

In clinical trials, at the start of treatment with the drug, a transient reduction in the number of cardiac contractions (HR) and a decrease in atrioventricular conduction were noted at the recommended dose. At the same time, the maximum decrease in heart rate was observed during the first 4-5 hours after taking the medication (an average decrease of 8 beats per minute), and 70% of the negative chronotropic effect was achieved on the first day of use.After a second dose of 0.5 mg, a further slight decrease in heart rate is possible. Reduction in heart rate below 40 beats per minute was noted in rare cases. With continued treatment, heart rate returned to the baseline within 1 month. The majority of patients are asymptomatic bradycardia, however, in some cases, the patients showed clinical manifestations of mild to moderate, including dizziness, fatigue and palpitations, which resolved without medical intervention within 24 hours after initiation of therapy.

At the beginning of the drug was also observed increased incidence of premature atrial contractions, but the incidence of atrial fibrillation / flutter, ventricular arrhythmias or ventricular ectopic not increased. Fingolimod had no effect on cardiac output, changes in autonomic functions of the heart, including diurnal fluctuations in heart rate, response to physical exertion.

In clinical trials at the beginning of therapy fingolimod 0.5 mg in patients with RRMS atrioventricular (AV block) I degree (elongation at the time of the pulse electrophotographic study ECG) was observed in the 4.7% (1.6% in the placebo group ), AV block of II degree was detected in less than 0.2% of patients who received phingolimod in the recommended dose. Conduction abnormalities, as a rule, were transient and asymptomatic, did not require therapy, and passed within the first 24 hours after initiation 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. At the postmarketing stage, individual cases of complete AV blockade after receiving the first dose of phongolimod, which were transient and spontaneously resolved, were 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 phingolimod in the recommended dose, the asymptomatic AV block of the II degree of the Mobitz II type 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 phongolimoda 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-dependentdecrease in expiratory forced expiratory volume in 1 second (FEV1) and diffusivity of lungs on 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 studies, the use of the drug in a dose of 0.5 mg in patients with RRS was noted a slight increase in blood pressure (BP) on average by 1 mm.rt. The increase in blood pressure was observed approximately 2 months after the start of treatment and persisted with the continuation of therapy. Increased blood pressure was noted in 6.5% of patients who received phingolimod in the recommended dose (3.3% in the placebo group).

Impaired liver function

In clinical studies in patients treated with phylogolimide, increased activity of "liver" transaminases (mainly, ALT). At the recommended dose of 0.5 mg, in 8.0% of cases asymptomatic increase in ALT activity was observed> 3 times higher than the upper limit of the norm (VGN) and in 1.8% of cases it was> 5 VGN. compared with the placebo group, where these rates were 1.9% and 0.9%, respectively.In most cases, an increase in ALT activity is observed 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-marketing research, in patients who received phingolimod, there was a development of lymphoma in both B-cell and T-cell lymphomas.

The frequency of lymphomas is 3 cases per 10,000 person-years (versus 1.9 cases per 10,000 person-years in the general population).

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:

There are no data on drug overdose in patients with RRS.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:

Pharmacodynamic interaction

Taking into account the possibility of an additional inhibitory effect on the immune system, caution should be exercised when using phongolimoda along with antitumor agents, immunosuppressants (incl. 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 RRS who received short courses of glucocorticosteroids (up to 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.

There is limited experience with phongolimod in patients receiving concomitant therapy with beta-blockers, blockers of "slow" calcium channels, which reduce the heart rate (such as verapamil, diltiazem), or other drugs that can reduce the heart rate (eg, ivabradine or digoxin). The use of these drugs in combination with Limod's preparation may 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 heart rate, Lymoda is not recommended for use in patients currently receiving these medications. If treatment with Limod is required. It is necessary to consult a cardiologist about the possibility of switching to therapy with drugs that do not reduce heart rate, or conducting appropriate monitoring (prolonged observation in a hospital at least until the morning of the next day after taking the first dose of the drug).

The use of Limod in patients receiving antiarrhythmic drugs IA class (for example, quinidine, procainamide) or class III (for example, amiodarone, sotalol), has not been studied. When using antiarrhythmic drugs IA and III classes in patients with bradycardia, there were cases of development of pirouette tachycardia (torsade des pointes). In connection with the development of bradycardia at the beginning of treatment with Limod, it should not be used concurrently with these antiarrhythmic drugs.

Pharmacokinetic interaction

Fingolimod is primarily metabolized with cytochrome P450 4F2 and, possibly, other isoenzymes CYP4F. In vitro in hepatocytes in the case of significant induction of isoenzyme CYP3A4 can also participate in phylogenide metabolism. In connection with the foregoing, the effect of phageolimod and phignolyimophosphate clearance of preparations metabolized by basic isozymes CYP, it is unlikely. It is not expected that powerful inhibitors of carrier proteins will affect the distribution of phylogolimide when they are used simultaneously.

The ability of phngolimod and phignolyimophosphate to inhibit the metabolism of concomitantly used drugs

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, 206, 2E1, 3A4 / 5 or 4A9 / 11). Thus, the decrease in clearance of drugs metabolized mainly by the main isoenzymes of cytochrome P450 in the presence of phingolimod and phignolyimophosphate is 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 the mRNA of cytochrome 3A4, 1A2, 4P2 and ABCB1 (P-glycoprotein) isoenzymes, as well as the activity of cytochrome isoenzymes 3A, 1A2, 2B6, 2C8, 2C9, 2C19, 4P2; 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 phylogolimide in therapeutic concentrations 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

The pharmacokinetics of phylogolimide and cyclosporine did not change in the case of single or repeated use.Thus, changes in the pharmacokinetics of preparations that are substrates of the isoenzyme are not expected CYP3A4, under the influence of the phongolimod.

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 exposure of oral contraceptives. Despite the lack of research, exposure to oral contraceptives containing other progestogens is not expected to affect the exposure of the phylogenide.

Ketoconazole

In the case of simultaneous use of ketoconazole (at a dose of 200 mg twice a day until the equilibrium state is reached) and phingolimod (5 mg once) there was a moderate increase AUC phinolimidine and phongolimophosphate (1.7-fold) due to inhibition of the isoenzyme CYP4F2.

Isoprenaline, atropine, atenolol and diltiazem

Simultaneous use of a single dose of phylogolimide with isoprenaline or artopine did not influence the exposure of phingolimod and phignolyimophosphate.

The pharmacokinetics of atenolol and diltiazem in the equilibrium state and the pharmacokinetics of a single dose of phignolimod and phignolimophosphate with simultaneous administration with these drugs did not change.

Carbamazepine

Simultaneous application of carbamazepine at a dose of 600 mg twice a day and 2 mg phingolimoda once had little effect on AUC phylogolimide and phignolyimophosphate, with a decrease of about 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 phingolimod or phongolyimophosphate. 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:

The key pharmacodynamic effect of the drug is a dose-dependent decrease in the number of lymphocytes in the peripheral blood to 20-30% of their initial amount, due to a reversible redistribution of lymphocytes in the lymphoid tissues. Because the phingolimod reduces the number of lymphocytes in the blood, the number of lymphocytes in the peripheral blood can not be used to assess the different populations of lymphocytes in patients receiving treatment with the drug. In patients receiving phingolimod, to determine the number of mononuclear cells requires the collection of large volumes 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

It is necessary to postpone the initiation of drug treatment in patients with severe infectious disease in the active phase prior to resolution of this condition. Since the use of the drug may increase the risk of infection, including.opportunistic infections, it is necessary to conduct effective diagnostic and therapeutic measures during treatment with Lymoda preparation in patients with symptoms of the infectious process.

Withdrawal of phylogolim after cessation of treatment can occur within 2 months, therefore during this period it is necessary to remain cautious about the development of infections. Patients receiving drug therapy should be instructed to immediately inform the doctor of all symptoms of the infection.

With the development of severe infections with therapy, treatment with Limod should be stopped. Renewal treatment with Limod should only be done if the benefit of therapy exceeds the possible risk.

In the post-marketing period, cases of development of progressive multifocal leukoencephalopathy (PML) were noted. PML-opportunistic infectious disease caused by JCvirus, with a possible fatal outcome or development of severe disability. The condition developed after 2-3 years of treatment with the drug, the exact relationship with the duration of therapy is not established.Additional reports were also received on the development of PML in patients who had previously received natalizumab therapy, for which association with PML is known.

Development of PML is possible only with infection JCvirus. When conducting an analysis for availability JC-virus should be taken into account that the effect of lymphopenia on the accuracy of test results for the presence of antibodies to JC-virus in patients treated with phylogolimide, was not studied. It should also be noted that the negative result of the analysis for the presence JC-virus does not exclude the possibility of development JC-infection in the future. Before using phongolimod, it is necessary to obtain the results of MRI for the previous 3-month use of the drug. When conducting planned MPTstudies, the frequency of which is determined by the standards for the diagnosis and control of multiple sclerosis, should be kept alert to data that can be suspected PML. Thus, MRI is considered a priority diagnostic method in patients with a high risk of developing NML. If a PML is suspected, a diagnostic MRI should be performed immediately and the Lymod drug should be stopped before the diagnosis of PML is excluded.

In the post-marketing period, cases of development of cryptococcal meningitis after 2-3 years of treatment with a drug have been noted, an exact relationship with the duration of therapy has not been established. With the development of symptoms that make it possible to suspect the development of this condition, appropriate diagnostic measures should be carried out immediately. 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. In the absence of antibodies to the virus VZV A full course of vaccination should be performed before the drug is started. In this case, the beginning of treatment with the drug should be postponed for 1 month to develop a full immune response to vaccination.

Macular edema

Since the development of Lymoda with the recommended dose in 0.5% of patients showed the development of edema of the macula with / without clinical symptoms mainly in the first 3-4 months of treatment, it is recommended to conduct an ophthalmological examination 3-4 months after the start of therapy.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 of the drug in patients with PPC and concomitant diabetes mellitus has not been studied, in patients with diabetes or uveitis in an anamnesis it is recommended to conduct an ophthalmological examination before and during therapy with Limod. When detecting visual disturbances against the background of 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 resumption of therapy with the drug after the development of edema of the macula has not been studied. The risk of developing a repeated edema of the macula during the resumption of therapy with Limod was not studied. The resumption of treatment with Limod should only occur if the benefit of therapy exceeds the possible risk to the patient.

Diabetes

Studies on the use of Limod in patients with diabetes mellitus have not been conducted. Care must be taken when using 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 carry out ophthalmic control.

Bradyarrhythmia

Due to the risk of developing serious cardiac arrhythmias, Limod should not be used in patients with type 2 Mobits II AB blockade or higher, sinus node weakness syndrome, or sinoatrial blockade. Since tolerability of severe bradycardia can be reduced in patients with coronary heart disease, history of myocardial infarction, chronic heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled increase in blood pressure, or severe untreated sleep apnea syndrome, Limod's drug should not be used in such patients . Since the use of Limod leads to a decrease in heart rate and, thus, to the lengthening of the interval QT, Limod's drug 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, it is necessary to consult a cardiologist before starting therapy to choose the optimal monitoring of cardiac activity, possibly before the next morning.

After taking the first dose of Limod, it is recommended to observe patients for 6 hours, including a measurement of heart rate and blood pressure every hour, to eliminate manifestations of bradyarrhythmia.All patients should undergo an ECG examination before taking the drug and within a 6-hour period. When bradyarrhythmia develops against the background of drug therapy, if appropriate, appropriate measures should be initiated, and the patient should be monitored until the disturbance is stopped. If a drug therapy is necessary during the monitoring period after 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 Limod's drug. Additional supervision is also required in 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 resuming therapy with Limod, monitoring of the cardiovascular system is necessary, 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. It is advisable to avoid the use of Limod in patients with risk factors for lengthening the interval QT, in particular hypokalemia, hypomagnesemia or congenital lengthening of the interval QT.

In patients treated with phylogolimide, very rare cases of inversion of the T wave on the ECG were recorded. In case of inversion of the T wave, it is necessary to exclude the presence of other signs of myocardial ischemia. When suspected of myocardial ischemia, it is recommended to seek advice from a cardiologist.

Interval QT

When phylogolimide was used in doses of 1.25 mg or 2.5 mg in the equilibrium state, the lengthening of the interval QTcI (adjusted interval QT by pulse rate based on patient-specific data) to the upper 90% CI boundary <13.0 ms. There was no dependence of the occurrence of lengthening of the interval QTcI 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.

Syndrome of reversible posterior encephalopathy

In clinical and postgraduate studiesthere were rare cases of the development of the syndrome of reversible posterior encephalopathy with the use of the preparation Limod in a dose of 0.5 mg with the following symptoms: an 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, Limod 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, Lymod drug treatment should take into account the mechanism of action of the previously used drug, and also take into account its half-life in order to avoid the development of a total oppressive effect on the immune system. In this case, the risk of reactivation of the disease should be considered. Before starting therapy with Limod, you should get the result of a general clinical blood test with a leukocyte formula performed after the abolition of previous therapy,to be convinced of the termination of its depressing effect on the immune system (eg, cytopenia).

Interferon-beta and glatiramer acetate

In patients who received prior treatment with interferon-beta or glatiramer acetate, treatment with Lymoda 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 medications for treatment with Limod's drug because of the risk of developing a total oppressive effect on the immune system. Before beginning the use of Limod, after completing the therapy with natalizumab or teriflunomide, a thorough individual assessment of the condition of each patient is required.

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 Limod's drug after the cessation of therapy with alemtuzumab is not recommended, 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 be taken into account that the normalization of the number of lymphocytes occurs 1-2 months after the last application of Limod's preparation. Since the application of immunosuppressants within 1-2 months after stopping the preparation of Limod is possible additional inhibitory effect on the immune system, care must be taken when using immunosuppressants soon 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 activity of "hepatic" transaminases is recommended to be performed at 1, 3, 6. 9 and 12 months of treatment, and then periodically.Increased activity of "hepatic" 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, against the background of the drug phingolimod there are such undesirable phenomena as dizziness and visual impairment, do not drive vehicles or mechanisms until these side effects disappear completely. 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:

Primary packaging of medicinal product.

For 7 or 14 capsules in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

By 7, 28, 98 capsules in a polymer jar with a cover pulled with the control of the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.

Secondary packaging of medicinal product.

1 contour pack of 7 capsules together with the instructions for use are placed in a pack of cardboard. For 2 or 7 contour packs of 14 capsules together with the instructions for use are placed in a pack of cardboard.

On 1 bank together with the instruction on application place in a pack from a cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.

Shelf life:

2 years. Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004512

Date of registration:27.10.2017

Expiration Date:27.10.2022

The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Information update date: & nbsp04.12.2017

Illustrated instructions

Instructions

Modena (Modena)