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Instruction for use: Fingolimod

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Trade name of the drug – Gilenia, Nescler, Fingolimod hydrochloride

The Latin name of the substance Fingolimod

Fingolimodum (genus. Fingolimodi)

Chemical name

2-Amino-2- [2- (4-octylphenyl) ethyl] propane-1,3-diol (as hydrochloride)

Gross formula

C19H33NO2

Pharmacological group:

Immunosuppressive drugs

The nosological classification (ICD-10)

G35 Multiple Sclerosis: Disseminated Sclerosis; Multiple sclerosis; Recurrent multiple sclerosis; Secondary-progressive multiple sclerosis; Exacerbation of multiple sclerosis; Mixed forms of multiple sclerosis

CAS Code

162359-55-9

Pharmacology

Mode action - Immunosuppressive.

Pharmacodynamics

Fingolimod modulates sphingosine-1-phosphate receptors (S1P receptors). Fingolimod is metabolized by sphingosine kinase to the active metabolite of phylogenide phosphate. In nanomolar concentrations of phylogolimide, phosphate binds to type 1, 3 and 4 S1P receptors on the surface of lymphocytes and rapidly penetrates the CNS through the BBB, binding to S1P receptors 1, 3, and 5-type on the surface of neurons. Linking to S1P receptors of lymphocytes, phylogolide phosphate blocks the ability of lymphocytes to leave the lymph nodes, which leads to a redistribution of lymphocytes in the body, without decreasing the total number of lymphocytes.

Redistribution of lymphocytes leads to a decrease in lymphocytic infiltration of the central nervous system, incl. Inflammatory Th17 cells, 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 phylogolimidine in a dose of 0.5 mg, the amount of lymphocytes in the blood decreases to approximately 75% of the initial value. With a long daily application of phylogolimoid, the number of lymphocytes continues to decrease within 2 weeks, reaching a minimum of 500 cells / μl or approximately 30% of the initial value. 18% of patients had (at least once) a decrease in the number of lymphocytes below 200 cells / μl. With regular ingestion of phylogolimide, the decrease in the number of lymphocytes persisted. Since most T and B lymphocytes constantly pass through the lymphoid organs, the effect of phylogolide 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 the termination of reception of phylogolimoid in the blood there is an increase in the number of lymphocytes. Normalization of the number of lymphocytes occurs 1-2 months after discontinuation of treatment. Continuous reception of phylogolimide leads to a 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 (RRS) (mean EDSS (Expanded Disability Status Scale) - 2) phylogolimide in a dose of 0.5 mg reduced the incidence of clinical exacerbations by 54%. When taking phyngolimod, 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. When using phylogolimoda, the time to the onset of a 3-month and 6-month period of confirmed disability progression (estimated as an increase in the EDSS score from baseline) was significantly increased compared with placebo. The results of the MRI of the brain of patients with RRS on the background of treatment with phynolyimode confirm a significant decrease in the activity of the course of the disease (the intensity of the inflammatory process in the central nervous system, the size and number of foci of demyelination).

Pharmacokinetics

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

Absorption

When ingested, ≥85% of the dose is absorbed. Absorption of phylogenide is slow (Tmax - 12-16 h).

Absolute bioavailability with oral administration is 93%. Css in the blood plasma is achieved within 1-2 months of regular reception phongolimoda (1 time per day). Ńss phingolimoda is approximately 10 paz higher than its concentration after the first intake. After repeated intake of 0.5 mg once a day, the concentrations of phyglylim and phongolimide phosphate increase, probably in proportion to the dose.

Food does not affect Cmax or exposure (AUC) of phylogolimide or phongolimod phosphate.

Distribution

Fingolimod is significantly distributed in erythrocytes (fraction of phynogolimoda in blood cells - 86%). Fingolimoda phosphate has a lower ability to penetrate into blood cells (fraction in blood cells - <17%). Fingolimod and phongolimodo phosphate bind to high levels of plasma proteins (> 99%). The relationship between phignolimod and phignolimod phosphate with plasma proteins does not change in patients with impaired renal or hepatic function.

Fingolimod is largely distributed in the tissues of the body (Vd about (1200 ± 260) L). Fingolimod penetrates the brain, which has been shown in a clinical study in healthy volunteers. In a study of 13 volunteers with PPC who received in equilibrium phlyngolimide at a dose of 0.5 mg, the amount of phngolimod (or phongolimide phosphate) in the seminal fluid was 10,000 times lower than the initial dose (0.5 mg).

Biotransformation

In humans, the biogransformation of figolimod occurs as a result of reversible stereoselective phosphorylation to the pharmacologically active (S) -enantiomer of phignolimod phosphate and due to oxidative biotransformation, mainly by the isoenzyme CYP4F2 and possibly other isoenzymes of CYP4F, followed by degradation similar to fatty acids to an inactive metabolite with the formation of pharmacologically Inactive nonpolar analogs of phynoglodimeramide.

After a single oral ingestion in the blood plasma, unchanged fingolimode (23.3%), phignolimodal phosphate (10.3%), inactive metabolites (M3 - acidic carboxylic metabolite (8.3%), conjugates of metabolites With ceramide M29 (8.9%) and M30 (7.3%).

Excretion

Plasma clearance of phylogenide - (6.3 ± 2.3) l / h, average apparent T1 / 2 - 6-9 days. Reduction of the concentrations of phylogolimide and phongolimod phosphate in the blood plasma in the terminal stage occurs in parallel, which leads to a similar T1 / 2.

After ingestion, about 81% of the dose is excreted by the kidneys in the form of inactive metabolites. Unchanged phylogolimide and phylogolimide phosphate 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 of phylogenide is excreted.

Individual patient groups

Sex and ethnicity do not affect the pharmacokinetics of phylogolide and phongolyimophosphate.

Impaired renal function. Violation of the function of the kidneys of a severe degree leads to an increase of Cmax and AUC of phylogolimide by 32 and 34% and by 25 and 14% of phignolimide phosphate, respectively.

Violation of the function of the liver. The use of phylogolimoda in patients with a mild, moderate and severe liver dysfunction (> 9 on Child-Pugh classification) leads to an increase in AUC phylogolimide by 12, 44 and 103%, respectively. In patients with impaired liver function, the mild degree of T1 / 2 remains unchanged, the average and severe degree increases by 49-50%. In patients with severe liver failure (class C according to the Child-Pugh classification) Cmax of phylogolide phosphate was reduced by 22%, and AUC increased by 38%. In patients with a malfunction of liver function of light and medium degree, the pharmacokinetics of phignolimide phosphate were not evaluated.

Elderly patients. The mechanism of phylogenide elimination 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.

Application of the substance Fingolimod

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

Contraindications

Hypersensitivity to fitolimodu; Identified immunodeficiency syndrome; Increased risk of opportunistic infections, incl. In immunocompromised patients receiving immunosuppressive therapy now or in the past; Active phases of severe infections, chronic infections (hepatitis, tuberculosis); Detected malignant neoplasms in the active phase, except for basal cell carcinoma of the skin; Violation of liver function of a serious degree (class C according to the Child-Pugh classification); pregnancy; The period of breastfeeding; Age to 18 years (efficiency and safety not established).

Restrictions on the use

Diabetes mellitus (risk of developing macular edema); The presence of uveitis in the anamnesis; Age over 65 years (limited amount of application data).

Bradyarrhythmia. Due to the risk of developing severe rhythm disturbances, phignolimod should not be used in patients with type II Mobits II AV blockade or higher, sinus node weakness syndrome, or sinoatrial blockade. Since severe bradycardia can be poorly tolerated in patients with IHD, history of myocardial infarction, CHF, history of heart failure, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea syndrome, phylogolimide should not be used in such patients. Since the use of phylogolimide leads to a decrease in heart rate, and so on. Prolongation of the QT interval, phylogolimide should not be used in patients with a significant QT interval prolongation (QTs> 470 ms (female) or> 450 ms (male).) If a phylogolymer is needed in patients in this category, a cardiologist should be consulted before starting therapy to select the optimal monitoring of the cardiac Activity, perhaps until the next morning.

Caution should also 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 use of β-blockers, with a history of fainting.

Application in pregnancy and lactation

The action category for fetus by FDA is C.

Before starting treatment with phignolyimide, a 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 caused by a long period of phylogenide induction and a continuing risk to the fetus.

It is necessary to exclude pregnancy before treatment with phylogolimide. If pregnancy is diagnosed during its use, therapy should be canceled. Available data suggest that the use of phylogolimoda 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 phylogolide on fertility is unlikely.

When phylogolimoda was used in experimental studies, reproductive toxicity was detected, including fetal death and organ developmental defects, especially the nephrosis of the arterial duct and defects of the interventricular septum. In addition, the sphingosine-1-phosphate receptors on which the phylogolimide acts are involved in the formation of vessels during embryogenesis. At present, there is no data on the effect of phylogolimoda on the formation of human SSS, data on its use during pregnancy are extremely limited. In clinical trials, 20 pregnancies were reported in patients receiving phylogolimide, but these data are insufficient to assess the safety of phylogolimoda in patients in this category.

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

In experimental studies, phynogolimide was excreted with the milk of lactating animals. Given the theoretical possibility of developing adverse reactions in infants receiving breast milk from women taking Fingolimod, breastfeeding should be discontinued or phyloglobin should be discontinued.

Side effects of the substance Fingolimod

Below are the undesirable phenomena (AEs), identified as a result of three clinical trials in 2,431 patients with RRS. When using phylogolimide in a dose of 0.5 mg, the following serious AEs were noted: infection, macular edema and transient AV blockade at the beginning of the treatment. The most common (frequency ≥10%) with phygolimod in a dose of 0.5 mg was headache, increased activity of hepatic transaminases, diarrhea, cough, flu, sinusitis and back pain. The most frequent cause (frequency> 1%) of cessation of therapy with phynolyimide at a dose of 0.5 mg was an increase in ALT activity (2.2%).

Below are the AEs according to the frequency of occurrence. To assess the frequency, the following criteria were used (according to WHO classification): very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000), including individual messages. Since in the post-marketing 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, which is why the frequency is unknown for these AEs: the frequency is unknown. AEs are grouped according to the classification of organs and systems of MedDRA organs, within each group of AEs are arranged in descending order of severity.

Infectious and parasitic diseases: very often - influenza, sinusitis; Often - bronchitis, infections caused by the herpes virus, for example, shingles, pityriasis; Infrequently pneumonia1.

On the part of the immune system: the frequency is unknown - hypersensitivity, rash.

On the part of the blood and lymphatic system: often - lymphopenia, leukopenia.

From the side of the psyche: often - depression; Infrequently - low mood.

From the nervous system: very often - headache; Often - dizziness, migraine; Rarely - a syndrome of reversible posterior encephalopathy1.

From the side of the organ of vision: often - blurred vision; Infrequently - macular edema.

From the heart: often - bradycardia, AV-blockade.

From the side of the vessels: an increase in blood pressure.

From the respiratory system, chest and mediastinum: very often - cough; Often - shortness of breath.

From the digestive tract: very often - diarrhea.

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

From the side of the musculoskeletal and connective tissue: very often - the pain of the back.

General disorders and disorders at the injection site: often - asthenia.

Laboratory and instrumental data: very often - increased activity of hepatic enzymes (ACT, GGT, ACT); Often - an increase in the concentration of triglycerides of blood; Infrequently - neutropenia.

1Y, whose connection with the reception of the phongolimod is regarded as probable.

Infections

When using phylogolimoda 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, patients receiving fingolimod were more likely to have bronchitis, shingles and pneumonia. The incidence of serious infections in the group receiving fingolimod 0.5 mg was 1.6%, in the placebo group 1.4%.

There are data on extremely rare deaths caused by infection with the Varicella Zoster virus in patients who were simultaneously receiving long-term GCS therapy (more than 5 days) in order to treat recurrences of RRS, but the causal relationship between treatment and death is not established. In clinical studies with phylogolimoda in patients with RRS who received short GCS courses (within 5 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 the cause-and-effect relationship between deaths and the use of phylogolimidine has not been established.

Neurological disorders

There are reports of rare cases of damage to the nervous system in patients receiving phylogolimide in high doses (from 1.25 to 5 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 ODEM (acute disseminated encephalomyelitis) -like conditions.

Vascular disorders

In the treatment with phylogolimide at 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 in a dose of 0.5 mg.

Macular edema

When phylogolimide 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 macular edema was observed without clinical manifestations (revealed during a routine ophthalmological examination), in some patients macular edema was accompanied by indistinctness or decreased visual acuity. At the termination of treatment 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 phignolyimide, the recommended dose was a transient decrease in heart rate and a slowing of AV conduction. At the same time, the maximum decrease in heart rate is observed within 6 hours after taking phylogolimoda (mean decrease by 12-13 bpm), and 70% of the negative chronotropic effect is achieved on the first day of use.

In clinical trials, 4.7% of patients (1.6% in the placebo group) were observed with fingolimide at a dose of 0.5 mg in patients with RRS of the first-degree AV blockade (prolongation of the ECG pulse time). AV-blockade of the 2nd degree was detected in less than 0.2% of patients receiving phylogolimide at the recommended dose. Conduction abnormalities observed in both clinical trials and post-marketing periods were generally transient and asymptomatic, did not require therapy, and were resolved within the first 24 hours after initiation of treatment. Some patients experienced symptoms such as a decrease in blood pressure, dizziness, fatigue and / or a feeling of palpitation, which were also resolved within 24 hours. In the post-marketing period, individual cases of complete AV blockade after receiving the first dose of phongolimoda, which were transient and Spontaneously resolved. Although in most cases, medical intervention was not required to arrest AEs, in one case in a clinical trial in a patient who received phylogolimide at the recommended dose, an asymptomatic AV block of the 2nd degree of the Mobits type I was stopped with isoprenaline.

Cases of asystole and unexplained sudden death after first ingestion of phynogolimoda were noted, but the relationship between the reception and these events is not proven.

Respiratory system

In the clinical study, after a first month of application of phylogolimide in a dose of 0.5 mg, there was a slight dose-dependent decrease in FEV values for the 1st second and diffusivity of the lungs by carbon monoxide (DLCO), and the values of these parameters were not subsequently changed. The abolition of therapy was accompanied by the normalization of indicators. The decrease in DLCO by the 24th month of application of phylogolimide in a dose of 0.5 mg was 3.3% compared with 2.7% in the placebo group.

Increased blood pressure

In clinical studies, when phylogolimidine was administered at a dose of 0.5 mg in patients with PPC, there was a small increase in the SAD by an average of 3 mm Hg. And DAD by 1 mm Hg. The increase in blood pressure was observed approximately 1 month after the start of treatment and was preserved with the continuation of therapy. Increased blood pressure was noted in 6.5% of patients who received finkolimod at the recommended dose (3.3% in the placebo group). According to post-registration observations, 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 phylogolimide, there was an increase in activity of hepatic transaminases (predominantly ALT). At a recommended dose of 0.5 mg, in 8% of cases, asymptomatic increase in ALT activity was observed ≥3 times higher than ULN and in 1.8% of cases it was ≥5 VGN compared to the placebo group where these indicators were 1.9 and 0, 9% respectively. In most cases, an increase in ALT activity was 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 blood plasma occurred approximately 2 months after the termination of phylogenide administration. In a small number of patients with elevated ALT activity ≥5 VGN who continued treatment, normalization of ALT activity occurred approximately after 5 months of therapy.

Lymphomas

According to clinical and post-registration studies, the patients receiving phylogolimide had 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, incl. Isolated cases of the development of cryptococcal meningitis.

Hemophagocyte syndrome

In the post-marketing period, patients receiving treatment with phygolimodome had very rare cases of hemophagocytic syndrome with a lethal outcome associated with an infectious disease. Hemophagocyte syndrome is a condition associated with infectious diseases, immunosuppression and a number of autoimmune diseases.

Interaction

Pharmacodynamic interaction

Considering the possibility of additional inhibitory effect on the immune system, caution should be exercised when using phongolimoda along with antitumor agents, immunosuppressants (including GCS), and immunomodulators.

Since GCS have an immunosuppressive effect, the duration of treatment and dose when used concomitantly with phyngolyimide should be adjusted based on clinical data. In clinical trials using phongolimod in patients with RCS who received short GCS courses (within five days), there was no increase in the incidence of infections.

It is necessary to use with caution fingolimod in patients who have received long-term drugs such as natalizumab, teriflunomide or mitoxantrone.

There is limited experience with phongolimod in patients receiving concomitant therapy with β-blockers, CCKs that lower heart rate (such as verapamil, diltiazem or ivabradine), or other drugs that can reduce heart rate (eg digoxin). The use of these drugs in combination with fingolimod 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 heart rate, phylogolimide is not recommended for patients who are currently receiving these drugs. If treatment with phylogolimide is contemplated, a cardiologist should be consulted regarding the possibility of switching to drug therapy that does not reduce heart rate, or appropriate monitoring.

The use of phongolimod in patients receiving antiarrhythmic drugs of class IA (eg, quinidine, procainamide) or class III (eg amiodarone, sotalol) has not been studied. Since the use of antiarrhythmic drugs IA and III classes may develop bradyarrhythmias, phylogolimide should not be used together with these antiarrhythmic drugs.

Pharmacokinetic interaction

Fingolimod is primarily metabolized with cytochrome P450 4F2 and, possibly, other CYP4F isoenzymes. In vitro in hepatocytes in the case of significant induction, the isoenzyme CYP3A4 can also participate in the metabolism of phylogolimide. In view of the foregoing, the effect of phageolimod and phongolimod phosphate on the clearance of drugs metabolized with the help of basic isoenzymes of CYP is unlikely.

The effect of phylogolimide and phongolimod phosphate on the metabolism of concomitantly used drugs

In vitro studies have shown that phylogolimide and phignogolimode phosphate 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, is clinically unlikely in the presence of phylogolide and phongolimide phosphate.

The ability of phageolimod and phongolimod phosphate to induce its own metabolism and / or metabolism of concomitantly used drugs

In in vitro studies, fingolimode did not induce the mRNA of cytochrome 3A4, 1A2, 4F2 and ABCB1 (P-gp) isoenzymes, as well as the activity of cytochrome 3A, 1A2, 2B6, 2C8, 2C9, 2C19, 4F2 isoenzymes; Phongolimodo phosphate 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 is unlikely.

Transport proteins

Fingolimod 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 in the case of a single or multiple application did not change.

Oral contraceptives

Simultaneous use of phylogolimide in a dose of 0.5 mg / 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 finiolimod is not expected.

Ketoconazole

In the case of concomitant use of ketoconazole (200 mg twice a day before reaching the equilibrium state) and phingolimod (5 mg once), a slight increase in the AUC of phignolimod and phongolimide phosphate (1.7-fold) was observed.

Isoprenaline, atropine, atenolol and diltiazem

Simultaneous use of isoprenaline or atropine did not affect the exposure of phylogolimide and phongolimide phosphate. Simultaneous use of atenolol and diltiazem did not affect the pharmacokinetics of phingolide or phongolimide phosphate.

Carbamazepine

Simultaneous application of carbamazepine 600 mg twice a day in the equilibrium state and 2 mg phingolimode had a weak effect on the AUC of phignolimod and phingolimide phosphate once with a decrease of about 40%. Simultaneous use of carbamazepine with phylogolimide can reduce the effectiveness of the latter.

Potential interactions

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

Vaccination

Since the use of live attenuated vaccines may increase the risk of infection, phylogolide should not be immunized with live attenuated vaccines. During therapy with phygolyimide, and also within 2 months after discontinuation of treatment, vaccination may be less effective.

Overdose

Symptoms: healthy volunteers satisfactorily tolerated a single dose of phylogolimide in a dose of 40 mg (a dose 80 times higher than the recommended daily dose), while 5 out of 6 volunteers showed slight airway obstruction, accompanied by a feeling of slight tightness in the chest or a feeling of discomfort.

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

Treatment: in case of an overdose, when taking the first dose of phongolimoda, it is important to identify the manifestations of bradycardia, and monitoring may be required until the next morning. It is necessary to regularly measure heart rate and blood pressure, and also conduct ECG. If the heart rate is <45 bpm after the first reception, or if the ECG signs of the ≥2th degree of the AV blockade appear, or if the QT interval is ≥500 msec, prolong monitoring overnight until the signs of cardiac dysfunction disappear Rhythm. 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 is not removed from the body by dialysis and plasmapheresis.

Routes of administration

Inside.

Precautions for the substance Fingolimod

The key pharmacodynamic effect of fingolimod 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.

Since fingolimod reduces the number of lymphocytes in the blood, the number of lymphocytes in the peripheral blood cannot be used to evaluate the different populations of lymphocytes in patients receiving treatment.

In patients receiving fingolimod, the determination of the number of mononuclear cells requires the collection of large volumes of blood (due to a decrease in the number of circulating lymphocytes). Before the initiation of therapy with fingolimod, you should obtain a result of a general clinical blood test with a leukocyte formula performed during the last 6 months preceding the initiation of therapy, or after the abolition of previous therapy.

Infections

It is necessary to postpone the initiation of treatment with fingolimod in patients with severe infectious disease in the active phase prior to resolution of this condition. Since the use of fingolimod may increase the risk of developing infections, including. Opportunistic, during the treatment in patients with symptoms of the infectious process it is necessary to carry out effective diagnostic and therapeutic measures.

Removal of fingolimod 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 fingolimod therapy should be instructed to immediately notify the physician of all symptoms of the infection.

With the development of severe infections with therapy, treatment with fingolimod should be discontinued. Renewal treatment should be only if the benefits of therapy exceed the possible risk.

In the post-marketing period, cases of development of progressive multifocal leukoencephalopathy (PML) were noted. PML is an opportunistic infectious disease caused by the JC virus, with a possible fatal outcome or development of severe disability. Development of PML is possible only with infection with JC virus. When carrying out the analysis for the presence of JC virus, it is necessary to take into account that the effect of lymphopenia on the accuracy of the results of testing for the presence of antibodies to the JC virus in patients receiving fingolimod therapy has not been studied. It should also be noted that a negative test result for the presence of a JC virus does not exclude the possibility of developing JC infection in the future. Before the appointment of fingolimod, it is necessary to obtain the results of MRI for the preceding first application of fingolimod for 3 months. When conducting routine MRI studies, the frequency of which is determined by the standards for the diagnosis and monitoring of multiple sclerosis, care should be taken with regard to data that allow suspected PML. Thus, MRI is considered a priority diagnostic method in patients with a high risk of developing PML. If a PML is suspected, a diagnostic MRI should be performed immediately and the treatment with fingolimod should be stopped before the diagnosis of PML is excluded.

In the post-marketing period, cases of development of cryptococcal meningitis were noted. 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 varicella or a complete vaccination against the Varicella zoster virus (VZV) should be screened for antibodies to VZV before starting therapy. In the absence of antibodies to the VZV virus, a full course of vaccination should be conducted before the initiation of therapy with fingolimod. In this case, the start of treatment should be postponed for 1 month to develop a full immune response to vaccination.

Macular edema

Since fingolimod therapy in 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 ophthalmologic examination 3-4 months after the initiation 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 fingolimod in patients with PPC and concomitant diabetes mellitus has not been studied, in patients with diabetes or uveitis in an anamnesis it is recommended that an ophthalmological examination be conducted before and during the treatment with fingolimod.

When visual disturbances are detected against the background of fingolimod therapy, examination of the fundus, especially of the macular area, is necessary. In the case of edema of the macula, treatment with fingolimod should be stopped. The resumption of therapy with fingolimod after development of macular edema has not been studied. The risk of developing a repeated edema of the macula during the resumption of therapy with fingolimod has not been studied. Renewal treatment should only occur if the benefit of therapy exceeds the possible risk to the patient.

Diabetes

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

Bradyarrhythmia

Due to the risk of developing serious cardiac arrhythmias, fingolimod should not be used in patients with type II Mobits II AV blockade or higher, sinus node weakness or sinoatrial blockade. Since pronounced bradycardia can be poorly tolerated in patients with coronary artery disease, history of myocardial infarction, CHF, history of heart failure, cerebrovascular disease, uncontrolled increase in blood pressure, or severe untreated sleep apnea syndrome, fingolimod should not be used in such patients. Since the use of phyngolimoda leads to a decrease in heart rate and, thus, To the prolongation of the QT interval, it should not be used in patients with a significant QT interval prolongation (QTc> 470 ms (female) or> 450 ms (male).) If a phylogolymer is to be used in patients in this category, a cardiologist should be consulted before starting therapy to select the optimal Monitoring of cardiac activity, it is possible until the next morning.

After taking the first dose of fingolimod, it is recommended to observe patients for 6 hours, including a measurement of heart rate and blood pressure every hour, to eliminate manifestations of bradycardia. All patients should undergo an ECG examination before taking fingolimod and during the 6-hour monitoring period.

When bradyarrhythmia develops against the background of therapy with phygolymodoma, if necessary, appropriate measures should be initiated, the patient is ensured observation up to the reduction of this disturbance. 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 fingolimod.

Additional monitoring is also required in the following cases:

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

- at the first occurrence of AV-blockade of the 2nd degree or higher, according to ECG data, 6 hours after ingestion of the fingolimod;

- if the interval QTc on the ECG is ≥500 ms.

When resumption of therapy with fingolimod, it is necessary to monitor the activity of the CAS, 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 for 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 fingolimod in patients with risk factors for prolonging the QT interval, in particular hypokalemia, hypomagnesemia, or congenital QT interval elongation.

All patients need to conduct an ECG study before the initiation of therapy with phylogolimide and at the end of the 6-hour monitoring period.

In patients treated with fingolimod, 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 in the patient. When suspected of myocardial ischemia, it is recommended to seek advice from a cardiologist.

QT Interval

When using fingolimod in doses of 1.25 or 2.5 mg in the equilibrium state, the QTcI interval (the adjusted QT interval according to the pulse rate based on the data of the individual patient) was extended to 90% (CI: ≤13 ms). There was no dependence of the occurrence of QTcI interval elongation on the dose of fingolimod and duration of therapy. The use of drugs extending the QTc interval should be avoided in patients with hypokalemia or congenital QT interval elongation.

Syndrome of reversible posterior encephalopathy

In clinical and postregistration studies, rare cases of the development of the syndrome of reversible posterior encephalopathy were observed with fingolimod at 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 the syndrome of reversible posterior encephalopathy is suspected, the fingolimod should be discontinued.

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

When replacing therapy with other drugs that modify the course of the disease for treatment with fingolimod, one should take into account the mechanism of action of the previously used drug, and take into account its T1 / 2 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 the initiation of therapy with fingolimod, the result of a general clinical blood test with a leukocyte formula performed after the abolition of previous therapy should be obtained in order to be convinced of the cessation 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 fingolimod can be started immediately after the termination of the use of the above drugs.

Natalizumab and teriflunomide

In connection with prolonged T1 / 2 natalizumab and teriflunomide, care should be taken when changing therapy with drugs for treatment with phylogolimide because of the risk of developing a total oppressive effect on the immune system. Before starting phongolimoda after the end of 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 2-3 months from the moment of discontinuation of therapy is required. Withdrawal of teriflunomide from the blood plasma is slow and can take from several months to 2 years without an accelerated elimination procedure.

Alemtuzumab

Due to the mechanism of the action of alemtuzumab and its immunosuppressive effect, the use of phylogolide after the cessation of alemtuzumab therapy is not recommended, unless the expected benefit exceeds the possible risk for a particular patient.

Termination of treatment with fingolimod

After the abolition of treatment with fingolimod, a 6-week interval without treatment is needed to remove the fingolimod from the bloodstream. At the termination of reception fingolimod it is necessary to consider, that normalization of quantity of lymphocytes occurs in 1-2 months after last application fingolimod. Since the application of immunosuppressants within 1-2 months after the termination of fingolimod administration may further suppress the immune system, care must be taken when using immunosuppressants shortly after the termination of treatment with fingolimod.

Dysfunction of the liver

It is recommended to monitor the activity of hepatic transaminases and bilirubin concentrations during the 6 months preceding the initiation of therapy with fingolimod. In the absence of clinical manifestations of liver damage, the activity of hepatic transaminases is recommended for 1, 3, 6, 9 and 12 months of treatment, and then periodically. Increased activity of hepatic transaminases ≥5 VGN requires more frequent biochemical studies of serum, including the determination of bilirubin concentration and activity of AP. When symptoms appear that suggest a violation of liver function (vomiting and nausea of unknown etiology, jaundice, abdominal pain, fatigue, anorexia, dark color of urine), it is necessary to conduct a study of hepatic enzyme activity, and if liver damage is detected, stop taking phylogolide.

Respiratory system

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

Influence on the ability to drive vehicles and mechanisms. Patients who have such undesirable effects as dizziness and visual impairment when using fingolimod should not be controlled by 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 reception of the fingolimod before starting the control of vehicles.

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