Femoriks - instructions for use, dosage, side effects, contraindications

Active substanceTeriflunomideTeriflunomide

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Abaggio®

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Genzyme Europe BV Netherlands

Femoriks®

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VALENTA PHARM, PAO Russia

Dosage form: & nbspfilm coated tablets

Composition:

Composition per one tablet

One tablet, film-coated, contains:

Active substance: teriflunomide - 14,00 mg;

Excipients: microcrystalline cellulose - 121,80 mg, sodium carboxymethyl starch - 3,50 mg, magnesium stearate - 0,70 mg.

Shell: hypromellose E6 - 2.40 mg, titanium dioxide - 1.00 mg, talcum - 0.19 mg, macrogol 6000 S - 0.67 mg.

Description:Round biconvex tablets covered with a film coat of white or almost white color. On the cross section, the core of the tablet is white or almost white in color.

Pharmacotherapeutic group:Selective immunosuppressant

ATX: & nbsp

L.04.A.A Selective immunosuppressants

L.04.A.A.31 Teriflunomide

Pharmacodynamics:

Teriflunomide is an immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydroorotate dihydrogenase (DHO-DH), which is necessary for the synthesis of pyrimidine de novo. In this way, teriflunomide blocks the proliferation of stimulated lymphocytes, which require the synthesis of pyrimidine de novo. The exact mechanism of action of teriflunomide in multiple sclerosis is not fully understood, but it can be caused by a decrease in the number of circulating lymphocytes.

Pharmacodynamic effects

The immune system

Effect on the number of immune cells in the blood: during placebo-controlled studies, the administration of teriflunomide at a dose of 14 mg once daily on average resulted in a slight decrease in the number of lymphocytes, less than 0.3 x 10⁹/ l, which was noted during the first 3 months of treatment. The levels reached were maintained until the end of treatment.

Influence on the interval QT

In a placebo-controlled study conducted with healthy volunteers, teriflunomide at average equilibrium concentrations did not demonstrate the potential for lengthening the interval QTcF compared with placebo: the largest average difference between teriflunomide and placebo was 3.45 ms with an upper 90% confidence limit of 6.45 ms.

Effect on renal tubule function

In placebo-controlled studies, there was a more pronounced decrease in serum uric acid concentration in the range of 20 to 30% in patients taking teriflunomide, compared with placebo.The average reduction in serum phosphorus was about 10% in the teriflunomide group compared with placebo. It is suggested that such effects are associated with an increase in tubular excretion and are not associated with changes in glomerular functions.

Clinical efficacy and safety

The effectiveness of teriflunomide was demonstrated in the course of studies EFC6049/TEMSO and TOWER, which were devoted to the assessment of daily reception of teriflunomide in a dose of 7 mg and 14 mg in patients with relapsing multiple sclerosis (RRS).

In total, 1088 patients with RRS were randomized to the study TEMSO for taking 7 mg (n= 366) or 14 mg (n= 359) teriflunomide or placebo (n= 363) for 108 weeks. All patients were diagnosed (based on the McDonald criteria (2001)) multiple sclerosis, recurrent course, with or without progression; In patients, at least 1 relapse occurred during the year preceding the study, or at least 2 relapses within 2 years preceding the study. When included in the study, the average score for the extended scale of disability EDSS (Expanded Disability Status Scale) was ≤ 5,5. The average age of the study population is 37.9 years.The majority of patients had a remitting form of multiple sclerosis (91.5%), subgroups of patients with secondary progressive (4.7%) or progressive-recurrent multiple sclerosis (3.9%) were also represented. The average number of exacerbations during the year before enrollment in the study was 1.4, while initially at 36.2 % patients had foci accumulating gadolinium contrast substance. Average point score EDSS - 2,50: initially in 249 patients (22,9%) points EDSS was more than 3.5. The average duration of the disease since the appearance of the first symptoms is 8.7 years. Most patients (73%) did not take drugs that change the course of multiple sclerosis (PITRS) for 2 years before enrolling in the study. The results of the study are presented in Table 1.

In total, 1169 patients with RRS were included in the study TOWER for taking 7 mg (n= 408) or 14 mg (n= 372) teriflunomide or placebo (n= 389). The duration of treatment was 48 weeks after the last patient was switched on. All patients had an established diagnosis of multiple sclerosis (based on the McDonald criterion (2001)), recurrent course, with or without progression,and suffered at least one episode of relapse a year before the study or at least 2 relapses two years before the study. At inclusion, patients had an evaluation on the extended scale of disability EDSS (Expanded Disability Status Scale) ≤ 5,5.

The average age of the patients studied was 37.9 years. Most patients had recurrent remitting multiple sclerosis (97.5%), but there were subgroups of patients with secondary progressive (0.8%) or progressively-recurrent multiple sclerosis (1.7%). The average number of relapses during the year before enrollment is 1.4. Average point score EDSS - 2.50. The average duration of the disease from the time of the onset of the first symptoms is 8 years.

The majority of patients (67.2%) did not take drugs that change the course of the disease, for 2 years before enrolling in the study. The results of the study are presented in Table 1.

Table 1. Main results (for the indicated dose, population ITT)

	Study TEMSO			Study TOWER
	Teriflunomide 14 mg		Placebo	Teriflunomide 14 mg	Placebo
N	358		363	370	388
Clinical outcomes
Number of relapses per year	0,37	0,54		0,32	0,50
The odds ratio (CI_{95 %})	-0,17(-0,26,-0,08)***			-0,18(-0,27, -0,09)***
No relapse a week ₁₀₈	56,5%	45,6%		57,1%	46,8%
Odds ratio (DI_{95 %})	0,72 (0,58, 0,89)**			0,63 (0,50, 0,79)***
Confirmed progression of disability for 3 months of the week ₁₀₈	20,2%	27,3%		15,8%	19,7%
The odds ratio (CI_{95 %)}	0,70 (0.51,0,97)*			0,68 (0,47, 1,00)*
Confirmed progression of disability for 6 months of the week ₁₀₈	13,8%	18,7%		11,7%	11,9%
Odds ratio (DI_{95 %})	0,75 (0,50, 1,11)			0,84 (0,53	, 1,33)
MRI endpoint
Change BOD weeks ₁₀₈¹	0,72	2,21
Changes in placebo	67%***
The average number of foci that accumulate Gd on a scan in the week ₁₀₈	0,38	1,18
Changes in placebo (CI_{95 %)}	-0,8 (-1,20, -0,39)****			Not Measured
Number of unified active foci per scan	0,75	2,46
Changes in placebo (CI_{95 %)}	69% (59%, 77%)****

****R_<0._>0001 *** p <0.001 ** p <0.01 * p <0.05 compared with placebo

1.BOD: total focal volume in ml (T2 and hypointense T1)

Efficacy in patients with high disease activity:

A significant effect of therapy with teriflunomide was observed with regard to exacerbations and a progression of incapacity for work confirmed in 3 months in a subgroup of patients with high disease activity in the study TEMSO (n= 127). In accordance with the design of the study, high activity of the disease was defined as 2 or more relapses during the year and the presence of one or more foci accumulating gadolinium on the MRI of the brain. Similar analysis of subgroups in the study TEMSO was not carried out because no MRI data were obtained. There are no data on patients who do not respond to complete and sufficient treatment (on average 1 year of therapy) with interferon beta,and having at least 1 relapse during the previous year on the background of therapy, and at least 9 T2-hypertensive foci on MRI of the cranial nerves or at least 1 foci accumulating gadolinium, or patients whose exacerbation rate did not change or decreased during previous year compared with the previous 2 years.

TOPIC a double-blind, placebo-controlled trial in which time-bound doses of 7 mg and 14 mg of teriflunomide were evaluated for 108 weeks for patients with the first clinical demyelinating episode (mean age 32.1 years). The main criterion for evaluation was the time until the second clinical episode (relapse). A total of 618 patients were randomized to receive 7 mg (n= 205) or 14 mg (n = 216) of teriflunomide or placebo (n= 197). The risk of a second clinical exacerbation for 2 years was 35.9% in the placebo group and 24.0% in the treatment group of teriflunomide at a dose of 14 mg (risk ratio: 0.57, 95% confidence interval: 0.38-0.87, p = 0.0087). Results obtained during the study TOPIC, confirmed the efficacy of teriflunomide in remitting multiple sclerosis (including early relapsing sclerosis with the first clinicaldemyelinating episode and MPT-frags of different prescription and localization). The efficacy of teriflunomide was compared with the effectiveness of the subcutaneous form of interferon runa-1a (at a recommended dose of 44 μg three times a week) in a study involving 324 patients (TENERE). The minimum duration of treatment was 48 weeks, the maximum - 114 weeks. The risk of ineffective therapy (confirmed relapse or complete cessation of treatment, regardless of what happened first) has become the primary endpoint. The number of patients who finally stopped treatment in the group of teriflunomide 14 mg - 22 of 111 (19.8%). The reasons were undesirable phenomena (10.8%), insufficient efficiency (3.6%), other causes (4.5%) and loss of follow-up (0.9%). The number of patients who finally stopped treatment in the interferon beta-1a group was 30 out of 104 (28.8%). The reasons were undesirable phenomena (21,2%), insufficient efficiency (1,9%), other reasons (4,8%) and non-fulfillment of protocol conditions (1%). Teriflunomide in a dose of 14 mg / day did not exceed interferon beta-1a on the effect on the primary endpoint. The percentage of patients with confirmed failure of therapy by the 96th week by the Kaplan-Meier method was 41.1% against the background of teriflunomide 14 mg compared to 44.4% against interferon beta-1a (p = 0.5953).

Clinical data on the efficacy and safety of teriflunomide in children aged 0 to 18 years are not available.

Pharmacokinetics:

Suction

The average period of maximum plasma concentrations is from 1 to 4 hours after repeated oral administration of teriflunomide with high bioavailability (approximately 100%).

Food has no clinically significant effect on the pharmacokinetics of teriflunomide. Based on the average predicted pharmacokinetic parameters based on the analysis of population pharmacokinetics (PORR) using data on healthy volunteers and patients with multiple sclerosis, a slow approach to the equilibrium concentration (ie, about 100 days (3.5 months) before reaching 95% of equilibrium concentrations), and the assumed rate of accumulation AUC exceeds the original by approximately 34 times.

Distribution

Teriflunomide actively binds to plasma proteins (> 99%), probably with albumin and, for the most part, is distributed in plasma.

Biotransformation

Teriflunomide is moderately metabolized and is the only component determined in plasma.

Teriflunomide is excreted in the gastrointestinal tract, mainly with bile, in unchanged form. The half-life after repeated intake is 19 days. After a single intravenous injection, the total clearance of teriflunomide from the body is 30.5 ml / h.

The removal of teriflunomide from the bloodstream can be accelerated by the appointment of colestyramine or activated charcoal, probably by interrupting the reabsorption process in the intestine. The concentrations of teriflunomide, measured during the 11-day procedure, directed to accelerate the excretion of teriflunomide by the administration of colestyramine at a dose of 4 g 3 times a day; Colestyramine 8 g 3 times a day or 50 g activated charcoal twice a day after discontinuation of treatment with teriflunomide indicate that these schemes led to a decrease in the concentration of teriflunomide in plasma by more than 98%. In this case, the effect of colestyramine was more rapid than that of activated charcoal. The choice between the three accelerated clearance procedures should depend on the patient's tolerability. If the tolerability of colestyramine is poor at a dose of 8 g three times a day, a dose of 4 g three times a day can be used.Alternatively, you can also use Activated carbon (the drug is not necessary to take 11 consecutive days, unless there is a need for a rapid decrease in the concentration of teriflunomide in the plasma).

Indications:Treatment of adult patients with relapsing-remitting multiple sclerosis.

Contraindications:

Hypersensitivity to the active substance or any of the excipients.

Severe form of hepatic insufficiency (class C on the Child-Pugh scale).

Pregnancy. Before starting therapy with teriflunomide, pregnancy should be excluded.

Lactation.

Women with a persistent reproductive potential who do not use reliable contraceptive methods, and with a plasma concentration of teriflunomide above 0.02 mg / l.

Severe immunodeficiency, for example, AIDS.

Severe disturbance of bone marrow hematopoiesis, including clinically significant anemia, leukopenia, neutropenia, or thrombocytopenia.

Severe renal failure requiring hemodialysis.

Severe active infections.

Severe hypoproteinemia.

Age to 18 years.

Pregnancy and lactation:

Pregnancy

Data on the use of teriflunomide by pregnant women are limited. Animal studies have demonstrated reproductive toxicity.

Teriflunomide is not recommended during pregnancy. Pregnant women should be encouraged to use an accelerated elimination procedure to rapidly reduce the concentration of teriflunomide in the plasma.

Women of childbearing age before the start of treatment need to assess the possible serious potential risk to the fetus and use effective contraception during the treatment with teriflunomide, and after discontinuation of therapy to achieve a drug concentration in the plasma of not more than 0.02 mg / l (usually a period of 8 months) . In case of delay in menstruation against the background of taking teriflunomide, it is necessary to inform the doctor immediately about this and to perform a pregnancy test. In case of a positive result, the doctor should discuss with the patient all the risks associated with pregnancy, check the residual concentration of teriflunomide. In case the concentration exceeds 0.02 mg / l, it is recommended to repeat the procedure of accelerated elimination.

Women seeking pregnancy should be encouraged to use an accelerated elimination procedure to rapidly reduce the concentration of teriflunomide in the plasma. In connection with individual deviations in the clearance of the drug, it may be necessary to monitor the concentrations of teriflunomide in the plasma for 2 years after discontinuation of therapy. The accelerated elimination procedure can also be used at any time after the termination of therapy with teriflunomide.

The procedure for accelerated elimination:

- Kolestiramin in a dose of 8 g 3 times a day for 11 days, or in case of poor tolerance of this dose, you can use a dose of 4 g of colestyramine 3 times a day.

- Alternatively, you can take 50 g of activated carbon every 12 hours for 11 days.

Fertility

The results of animal studies did not show any effect on fertility. Despite the lack of data for people, the impact on male and female fertility is unlikely.

Breast-feeding

Studies in animals have demonstrated the isolation of teriflunomide in breast milk.It is not known whether this drug enters the breast milk of women. Due to the fact that many drugs are excreted in breast milk, and because of the likelihood of developing serious adverse reactions associated with the action of teriflunomide in infants, a decision should be made to stop Breastfeeding or discontinuation of medication taking into account the degree of need for a medicinal product for the mother.

Application in men

The risk of embryo-fetal toxicity from men as a result of therapy with teriflunomide is considered low.

Dosing and Administration:

Inside. Tablets should be taken whole, washed down with water, regardless of food intake. The recommended dose is 14 mg per day.

Side effects:

Security Profile Summary

A total of 2,267 patients took part in various studies of teriflunomide (1155 received teriflunomide in a dose of 7 mg and 1112 in a dose of 14 mg). The median duration of the drug was approximately 672 days in four placebo-controlled trials with patients with relapsing forms of multiple sclerosis (RRS).In placebo-controlled trials, 1045 and 1002 patients in groups of 7 and 14 mg of teriflunomide, respectively, participated, and 110 patients in each group in one study with an active reference drug. Teriflunomide is the main leflunomide metabolite. Information on the safety profile of leflunomide in patients with rheumatoid or psoriatic arthritis can be used in the administration of teriflunomide to patients with multiple sclerosis. Combined data from placebo-controlled studies were based on the experience of the use of teriflunomide once a day in 2,047 patients with relapsing forms of multiple sclerosis. Among these patients, the most frequently reported adverse reactions against the treatment with teriflunomide were: headache, diarrhea, elevated ALT levels. nausea and alopecia. In general, headache, diarrhea, nausea and alopecia were mild or moderate, transient and rarely led to discontinuation of treatment.

Undesirable reactions with a frequency> 1% than with placebo, noted with the administration of teriflunomide at a dosage of 7 and 14 mg during placebo-controlled studies, are given below.The frequency was determined as follows: very frequent (≥ 1/10); frequent (≥ 1/100, <1/10); infrequent (≥ 1/1000, <1/100); Rare (≥ 1/10000, <1/1000); very rare (<1/10000); frequency is unknown (can not be determined from available data).

Classes and systems of organs		Often	Often	Infrequently	Rarely	Very rarely	Unknown
Infections			Influenza, upper respiratory tract infections. Urinary tract infections. Bronchitis. Sinusitis. Pharyngitis. Cystitis. Viral gastroenteritis. Oral herpes. Infections of teeth. Laryngitis. Mycosis of feet.				Heavy infection, including sepsis
Blood and lymphatic system diseases			Neutropenia, anemia	Thrombocytopenia of mild degree (platelets <100x10⁹/ l)
Immune system disorders			Mixed allergic reactions of mild				Hypersensitivity reactions (immediate or delayed), including anaphylactic shock and Quincke's edema
Mental disorders			Anxiety
Disturbances from the nervous system		Head pain	Paresthesia, Lumbosacral sciatica, Carpal tunnel syndrome	Hyperesthesia, Neuralgia, Peripheral neuropathy
Heart Disease			Palpitation
Vascular disorders			Hypertension
Disturbances from the respiratory system, chest and mediastinal organs						Interstitial diseases lungs *
Disorders from the digestive tract	Diarrhea, nausea		Pain in the upper abdomen, vomiting, toothache				Pancreatitis, stomatitis
Disturbances from the skin and subcutaneous tissues	Alopecia		Rash, acne				Heavy dermal reactions
Disorders from the musculoskeletal system and connective tissue			Musculoskeletal pain, myalgia, arthralgia
disorders of the kidneys and urinary tract			pollakiuria
disorders of the reproductive system, breast diseases			menorrhagia
General violations and violations at the site of administration			pain
research	an increase in the level of alanine aminotransferase (alt)		an increase in the level of gamma-glutamyltransferase, an increase in the level of aspartate aminotransferase, weight reduction, a decrease in the number of neutrophils, a decrease in the number of leukocytes, an increase in the level of creatinine phosphokinase in the blood
trauma, poisoning and complication of the procedure				posttraumatic pain

* only on the basis of information on the safety profile of leflunomide

description of individual undesirable reactions

alopecia

alopecia has been described as thinning hair, reducing hair density, hair loss, whether or not associated with changes in hair texture in 13.9% of patients taking teriflunomide in a dose of 14 mg compared with 5.1% of patients taking placebo. most cases have been described as a diffuse or generalized lesion of the entire scalp (without complete loss of hair). in most cases this undesirable reaction was noted during the first 6 months, with spontaneous recovery in 121 of 139 (87.1%) patients. 1.3% of participants discontinued therapy due to the development of alopecia in the teriflunomide group compared with 0.1% in the placebo group.

adverse reactions from the liver

in placebo-controlled studies it was found:

an increase in the level of alt (based on laboratory data) in accordance with the initial status - the population of safety studies in placebo-controlled studies
	placebo (n = 997)	teriflunomide 14 mg (n = 1002)
> 3 hrs	66/994 (6,6%)	80/999 (8,0%)
> 5 hrs	37/994 (3,7%)	31/999(3,1%)
> 10 hrs	16/994(1,6%)	9/999 (0,9%)
> 20 hrs	4/994 (0,4%)	3/999 (0,3%)
alt> 3 meters and commonly. bilirubin> 2 hrs	5/994 (0,5%)	3/999 (0,3%)

vgn - the upper limit of the norm

in the groups of patients who received teriflunomide, more often than in placebo, there was an increase in the transaminase activity of the ALT of less than or equal to 3 volts. the percentage of patients who had an increase in alt levels above 3 hrs was comparable in all groups. Elevated alt levels were noted mainly in the first six months of treatment. after the cessation of treatment, the activity of the enzyme ALT returned to normal. The time to normalize the activity of the enzyme ALT varied from several months to several years.

effect on blood pressure

in placebo-controlled trials, the following was established:

an increase in systolic blood pressure above 140 mm Hg. Art. 19.9% of patients who took teriflunomide in a dose of 14 mg per day compared with 15.5% in the placebo;

increased systolic blood pressure above 160 mm Hg. Art. was noted in 3.8% of patients taking teriflunomide at a dose of 14 mg per day compared with 2.0% for a placebo;

an increase in diastolic blood pressure above 90 mm Hg. Art. 21,4% of patients who took teriflunomide in a dose of 14 mg per day compared with 13.6% in the placebo.

infection

in placebo-controlled studies inthe group of teriflunomide 14 mg did not show an increase in the number of serious infections (2.7% compared with 2.2% in the placebo group). Serious opportunistic infections were noted in 0.2% of cases in each group.

Serious infections, including sepsis, were observed. in some cases a death was reported.

hematological effects

in placebo-controlled studies against the background of teriflunomide, there was a moderate decrease in the number of leukocytes (<15% of the baseline, mainly a decrease in the number of neutrophils and lymphocytes). at the same time, in some patients there was a more pronounced decrease in the number of leukocytes. this undesirable reaction occurred during the first 6 weeks. then, on the background of continuing treatment, the number of white blood cells stabilized at the achieved level (<15% decrease from the baseline level). the effect on the number of erythrocytes (<2%) and platelets (<10%) was less pronounced.

peripheral neuropathy

in placebo-controlled studies in groups of 14 mg teriflunomide, there was an increase in the incidence of peripheral neuropathy, including polyneuropathy and mononeuropathy (carpal tunnel syndrome), compared with placebo.in the main placebo-controlled studies, peripheral polyneuropathy, confirmed by studies of nerve conduction, was observed in 1.9% of patients (17 of 898) in the group of teriflunomide 14 mg compared with 0.4% (4 patients out of 898) in the placebo group. treatment was interrupted in 5 patients with peripheral neuropathy who received teriflunomide at a dose of 14 mg. recovery after discontinuation of treatment was recorded in 4 of these patients.

neoplasm of benign, malignant and vague (including cysts and polyps)

in clinical studies against the background of receiving teriflunomide there was no increase in the risk of malignant tumors. the risk of malignant tumors, namely lymphoproliferative diseases, increases with the use of some other drugs that affect the immune system.

Overdose:

Symptoms

There is no information on overdose or intoxication of teriflunomide in humans. Teriflunomide in a dose of 70 mg daily was taken by healthy participants for 14 days. The observed adverse reactions corresponded to the safety profile of teriflunomide when taken by patients with multiple sclerosis.

Treatment

In case of a significant overdose or toxicity for accelerated elimination, it is recommended colestramine or Activated carbon. The recommended procedure is the reception of colestyramine in a dose of 8 g 3 times a day for 11 days, or, in case of poor tolerance of this dose, you can reduce the dose of colestyramine to 4 g. Alternatively, you can take 50 g of activated carbon every 12 hours for 11 days .

Interaction:

Pharmacokinetic interactions with other substances with the administration of teriflunomide

The primary pathway of biotransformation of teriflunomide is hydrolysis; The secondary path is oxidation.

Simultaneous long-term use (600 mg once daily for 22 days) of rifampicin (inductor of the isoenzyme CYP2B6, 2C8, 2C9, 2C19, 3A), as well as the inducer of carrier proteins, P-glycoprotein [P-gp] and cancer resistance protein (BCRP), and teriflunomide (a single dose of 70 mg) led to a decrease in the effect of teriflunomide by approximately 40%. Rifampicin and other known inducers of CYP and carrier proteins, such as carbamazepine, phenobarbital, phenytoin and St. John's wort should be administered with caution in the presence of teriflunomide therapy.

Kolestyramine or activated charcoal

The simultaneous administration of teriflunomide and colestyramine or activated charcoal is not recommended, since this leads to a rapid and significant reduction in the concentration of teriflunomide in plasma, except when accelerated excretion is necessary. The mechanism of accelerated excretion is probably the interruption of hepatic cycles and / or gastrointestinal dialysis of teriflunomide.

Pharmacokinetic interactions of teriflunomide with other substances

Effects of teriflunomide on the substrate CYP2C8: repaglinide

There was an increase in the mean Cmax and AUC for repaglinide (1.7 and 2.4 fold, respectively) after taking multiple doses of teriflunomide, suggesting that teriflunomide acts as an inhibitor of the isoenzyme CYP2C8 in vivo.

Therefore, against the background of the appointment of teriflunomide drugs metabolized by the isoenzyme CYP2C8, such as repaglinide, paclitaxel, pioglitazone or rosiglitazone, should be used with caution.

The effect of teriflunomide on oral contraceptives: 0.03 mg of ethinyl estradiol and 0.15 mg of levonorgestrel

After taking multiple doses of teriflunomide, an increase in the average value of Cmax and AUC0-24 for ethinyl estradiol (1.58-1.54-fold, respectively) was observed;and Cmax and AUC0-24 levonorgestrel (1.33 and 1.41 fold, respectively). While this interaction of teriflunomide should not adversely affect the effectiveness of oral contraceptives, the type and dose of oral contraceptives used in conjunction with teriflunomide should be considered.

Interaction of teriflunomide on the substrate of the isoenzyme CYP1A2: caffeine

Repeated doses of teriflunomide reduced the mean Cmax and AUC for caffeine (the substrate of the isoenzyme CYP1A2) by 18% and 55%, respectively, suggesting that teriflunomide to a lesser degree, induces the isoenzyme CYP1A2 in vivo. Therefore, drugs metabolized under the action of the CYP1A2 isoenzyme (such as duloxetine, alosetron, theophylline and tizanidine) during treatment with teriflunomide should be used with caution, as this may lead to a decrease in the effectiveness of these products.

Effects of teriflunomide on warfarin

Repeated doses of teriflunomide did not affect the pharmacokinetics of S-warfarin, indicating that teriflunomide is not an inhibitor or inducer of the CYP2C9 isoenzyme.Nevertheless, there was a 25% decrease in the peak international normalized ratio (INR) with simultaneous administration of teriflunomide and warfarin, compared with the introduction of warfarin alone. Therefore, with simultaneous administration of warfarin and teriflunomide, careful follow-up and current monitoring of INR is recommended.

The effect of teriflunomide on the substrates of carriers of organic anions 3 (PAA3)

There is an increase in the concentration of Cmax and AUC (1.43 and 1.54-fold, respectively) of cefaclor after repeated doses of teriflunomide, indicating that teriflunomide is a PAASE inhibitor in vivo. Therefore, caution should be exercised if teriflunomide is assigned together with PAAS substrates, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate and zidovudine.

The effect of teriflunomide on BCRP and / or organic anions, transporting substrates of polypeptides B1 and B3 (OATP1B1 / B3)

There was an increase in the value of Cmax and AUC (2.64 and 2.51-fold, respectively) of rosuvastatin after the administration of repeated doses of teriflunomide. However, there was no apparent effect of this increase in rosuvastatin exposure in plasma on the activity of HMG-CoA reductase.For rosuvastatin, a 50% dose reduction is recommended for joint administration with teriflunomide. Other BCRP substances (eg, methotrexate, topotecan, sulfasalin, daunorubicin, doxorubicin) and the family of the OATP, especially inhibitors of HMG-CoA reductase (eg, simvastatin, atorvastatin, pravastatin, methotrexate, nateglinide, repaglinide, rifampicin) concomitantly with teriflunomide should be administered with caution. Patients should be carefully monitored for signs and symptoms of excessive exposure to drugs and, if necessary, reduce the dose.

Special instructions:

Treatment should be conducted under the supervision of a physician with experience in treating patients with multiple sclerosis.

Monitoring

Before the start of treatment should be the following studies:

- Blood pressure measurement

- Activity of alanine aminotransferase (ALT)

- A general blood test, including the leukocyte formula and the determination of the number of platelets in the blood

During treatment with teriflunomide, the following parameters should be monitored regularly

- Arterial pressure

- Activity of alanine aminotransferase (ALT)

In case of new symptoms and signs (for example, infection) during treatment, it is necessary to perform a general blood test, including the leukocyte formula, and the determination of the number of platelets in the blood.

Accelerated release procedure

Teriflunomide is slowly excreted from the plasma: plasma concentrations reach values below 0.02 mg / l on average for 8 months, although due to individual deviations in the process of excretion of drugs it can last up to 2 years.

Excretion of the drug can be accelerated by any of the procedures described below, resulting in a decrease in more than 98% of the plasma level of teriflunomide in the plasma:

- taking colestyramine at a dose of 8 g every 8 hours for 11 days. With poor tolerance of colestyramine in a dose of 8 g 3 times a day, you can reduce the dose to 4 g three times a day;

- Activated carbon reception (50 g powder) every 12 hours for 11 days (daily intake is not necessary if there is no need for a rapid decrease in the concentration of teriflunomide in the plasma).

The accelerated elimination procedure can be used at any time after the discontinuation of teriflunomide administration.

Patients of the older age group

Terrylunomide should be administered with caution to patients 65 years of age or older due to insufficient data on efficacy and safety in this age group.

Children's population

The safety and efficacy of teriflunomide in children aged 10 to 18 years is not established. Teriflunomide is not prescribed for children under 10 years of age for the treatment of multiple sclerosis.

Renal insufficiency

In patients with mild, moderate or severe renal failure not on hemodialysis, dose adjustment is not required.

Patients with severe renal insufficiency who were on hemodialysis did not take part in clinical studies. Teriflunomide this group of patients is contraindicated.

Liver failure

In patients with mild to moderate hepatic insufficiency, dose adjustment is not required.

Teriflunomide is contraindicated in patients with severe hepatic insufficiency.

In patients who took teriflunomide, an increase in the activity of liver enzymes was observed.These adverse reactions occurred mainly in the first 6 months of treatment.

The activity of hepatic enzymes should be checked before starting therapy with teriflunomide, then every two weeks during the first 6 months of treatment and every 8 weeks thereafter, or with appropriate clinical signs and symptoms such as nausea, vomiting, abdominal pain, fatigue, loss of appetite or jaundice and / or darkening of urine. For ALT, it is permissible to increase by a factor of 2-3 to the upper limits of the norm, while monitoring should be carried out weekly. Therapy with teriflunomide should be discontinued if there is a suspicion of liver damage. Consideration should be given to the need to discontinue therapy with teriflunomide with a confirmed increase in hepatic enzyme activity (more than 3 times that of UGN). Patients with a history of liver disease are at a risk of worsening liver function when taking teriflunomide. In this group of patients, the symptoms of liver damage should be carefully monitored.

Terrylunomide must be administered with caution to patients who abuse alcohol.

Because teriflunamide is highly protein bound, and since binding depends on the level of albumin, the concentration of unbound tetrylunomide in plasma can increase in patients with hypoproteinemia, for example, in a nephrotic syndrome. Teriflunomide Do not administer to patients with severe hypoproteinemia.

Arterial pressure

Against the background of the use of teriflunomide, there may be an increase in blood pressure. It is necessary to check blood pressure before beginning treatment with teriflunomide and periodically afterwards. In case of high blood pressure, appropriate antihypertensive therapy should be performed before and during the treatment with teriflunomide.

Infections

The beginning of treatment with teriflunomide should be postponed in patients with serious active infections, until complete recovery.

In placebo-controlled trials, when receiving teriflunomide, there was no increase in the incidence of serious infections. However, taking into account the immunomodulatory effect of teriflunomide, in the case of a serious infection in the patient, it is necessary to consider the need for suspension of drug treatment, and before resumption of therapy evaluate possible benefits and risks.In connection with the long half-life of the drug, it is necessary to consider the need for accelerated elimination with the help of colestyramine or activated charcoal.

Patients receiving teriflunomide, should immediately report symptoms of infection to the doctor. Patients with active acute and chronic infections should not begin treatment with teriflunomide until complete cure.

The safety of teriflunomide in persons with latent tuberculosis infection is unknown. Screening for tuberculosis in clinical studies has not been systematically performed. Patients who have a positive tuberculosis screening test should receive appropriate treatment before taking teriflunomide.

Respiratory reactions

In clinical studies, teriflunomide cases of interstitial lung diseases have not been documented. However, such potentially lethal diseases were reported against leflunomide. On the background of therapy, interstitial lung diseases can develop rapidly. The risk is increased in patients with such a history of the disease, identified with leflunomide treatment.

Pulmonary symptoms, such as persistent cough and shortness of breath, can lead to discontinuation of therapy and further examination.

Hematological effects

There is a moderate decrease in the number of white blood cells by less than 15% of the baseline level. As a precaution before starting therapy with teriflunomide, it is necessary to perform a general clinical blood test with the definition of the leukocyte formula and the number of platelets. Against the background of therapy with teriflunomide, a general clinical blood test should be performed according to the indications when there are clinical symptoms and signs (for example, with infections).

In patients with existing anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or who have the risk of suppression of bone marrow hematopoiesis, the risk of hematological diseases with teriflunomide therapy is increased. In case of development of these undesirable reactions, it is necessary to consider the possibility of using an accelerated elimination procedure to reduce the concentration of teriflunomide in plasma.

In cases of pronounced hematological reactions, including pancytopenia, the administration of teriflunomide and any other myelosuppressive drug should be discontinued. It is necessary to consider expediency of carrying out of procedure of the accelerated youateating.

Skin Reactions

Severe skin reactions have been reported (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

In patients who received leflunomide, also reported very rare cases of drug interactions, manifested by eosinophilia and systemic symptoms (DRESS-syndrome).

If ulcerative stomatitis occurs, the treatment with teriflunomide should be discontinued. If severe generalized skin reactions (Stephen-Johnson syndrome or toxic epidermal necrolysis-Lyell syndrome) are suspected in the development of reactions from the skin and / or mucous membranes, the use of teriflunomide and any other drugs potentially causing such reactions should be discontinued, and should immediately begin accelerated elimination procedure. In such cases, patients should not be reassigned teriflunomide.

Peripheral Neuropathy

In patients who took teriflunomide, cases of peripheral neuropathy were documented. After discontinuation of the drug, the condition of most patients improved, in some patients peripheral neuropathy regressed completely, and in some patients the intensity of symptoms did not change. If the patient who took teriflunomide, peripheral neuropathy is diagnosed, the possibility of stopping teriflunomide administration and conducting an accelerated elimination procedure should be considered.

Vaccination

Two clinical studies have shown that vaccination with inactivated neoantigen (first vaccination) or sensitizing antigen (stimulation) was safe and effective during treatment with teriflunomide.

The use of live attenuated vaccines may be associated with a risk of infection and should therefore be avoided.

Immunosuppressive and immunomodulatory therapy

Because the leflunomide is the starting compound for teriflunomide, the simultaneous administration of teriflunomide with leflunomide is not recommended.

Joint use with anginaoplastic or immunosuppressive drugs used to treat multiple sclerosis has not been studied.Safety Studies in which teriflunomide was administered concomitantly with interferon beta or glatiramer acetate for one year, did not reveal any safety problems, but a higher incidence of adverse reactions was observed compared to monotherapy with teriflunomide. The safety of this combination with long-term admission for the treatment of multiple sclerosis has not been investigated.

Transition to or from teriflunomide

Based on clinical data relating to the simultaneous administration of teriflunomide with interferon beta or with glatiramer acetate, it can be said that there is no need for a waiting period for the initiation of teriflunomide therapy after interferon beta or glatiramer acetate, or when initiating therapy with interferon beta or glatiramer acetate after teriflunomide .

Due to the long half-life of natalizumab, simultaneous exposure and, consequently, simultaneous exposure to the immune system can occur if therapy with teriflunomide is started within 2-3 months after discontinuation of natalizumab. Therefore, precautions should be taken when switching from natalizumab therapy to teriflunomide.

Taking into account the half-life of phylogenide, a 6-week interval without therapy is necessary to eliminate circulating substances from the body. From 1 to 2 months is necessary to return the number of lymphocytes to the norm after stopping the reception of phylogolimoda. This can lead to a combined effect on the immune system. Therefore, precautions should be taken when switching from phylogolimide therapy to teriflunomide.

When PC median t _{1 / 2z} was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with teriflunomide during an interval of 5 half-lives (approximately 3.5 months, although some patients may be longer), the onset of another therapy will result in simultaneous exposure with teriflunomide. This can lead to an additive effect on the immune system, which requires mandatory precaution.

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

Teriflunomide does not have or has little effect on the ability to drive or use machinery. However, if there are undesirable phenomena from the nervous system, for example, dizziness,should refrain from driving and other potentially hazardous activities.

Form release / dosage:

Tablets, film-coated, 14 mg.

Packaging:

For 10 or 14 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 3 or 5 contour cell packs of 10 tablets or 2, 6 or 10 contiguous cell packs of 14 tablets together with the instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004143

Date of registration:13.02.2017

Expiration Date:13.02.2022

The owner of the registration certificate:VALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Manufacturer: & nbsp

OBNINSKAYA CHEMICAL - PHARMACEUTICAL COMPANY, CJSC Russia

Information update date: & nbsp24.03.2017

Illustrated instructions

Instructions

Femoriks® (Femorix)