Abadzhio - instructions for use, doses, 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:

1 tablet, film-coated *),

Ingredients	Amount, mg
*Active substance*
Teriflunomide	14,0
Excipients
Lactose Monohydrate	76,0
Corn starch	38,0
Hydroxypropylcellulose	3,5
Microcrystalline cellulose	10,5
Sodium carboxymethyl starch	7,5
Magnesium stearate	0,5
Nominal mass of the core of the tablet	150,0
Film coating ¹⁾
Hypromellose ²⁾	3,607
Titanium dioxide E 171 ²⁾	0,902
Talc ²⁾	0,271
Macrogol ²⁾	0,158
Aluminum lacquer indigo carmine E 132²⁾	0,062
Nominal tablet weight	5,00
Nominal weight of coated tablets	155,0

^*) In the preparation of coated tablets, purified water (EF, FSA / NF) is used for binding and film coating, which is removed during processing.

¹⁾ The film coating system is ready to use the mixture and tested according to the company's ND.

²⁾ These substances are part of the ready-to-use mixture: Opadray® coating system with film 03F20651 blue.

Description:

Pentagonal tablets covered with a film coat of pale blue; on one side of the tablet is printed "14", on the other is engraved the logo of the company.On the cross section, the nucleus 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, selectively and reversibly inhibiting the mitochondrial enzyme dihydroorotate dihydrogenase (DGO-DG), 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 receiving teriflunomide at a dose of 14 mg once a day 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 mean difference between teriflunomide and placebo was 3.45 ms with an upper 90% confidence interval equal to 6.45 ms.

Effect on renal tubule function

In the course of 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 Abagio® was demonstrated in the course of research EFC6049/TEMSO and TOWER, who were evaluating the daily intake of 7 mg and 14 mg of teriflunomide in patients with recurrent multiple sclerosis (RRS).

In total, 1088 patients with RRS were randomized to the TEM studySO for taking 7 mg (n= 366) or 14 mg (n= 359) teriflunomide or placebo (n= 363) in for a period of 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 recurrences in the 2 years preceding the study. When included in the study, the average score for the extended disability scale (EDSS) 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 was 1.4, while initially 36.2% of patients had foci accumulating gadolinium contrast substance. The mean baseline EDSS score was 2.50: initially, in 249 patients (22.9%), the EDSS score 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,changing the course of multiple sclerosis (PITRS) for 2 years before inclusion 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 were assessed on the Extended Disability Scale EDSS (Expanded Disability Status Scale) ≤ 5,5.

The average age of the patients studied was 37.9 years. The majority of patients had recurrent remitting multiple sclerosis (97.5%), but there were subgroups of patients with secondary progressive (0.8%) or progressively-relapsing multiple sclerosis (1.7%). The average number of relapses during the year before enrollment is 1.4. The average initial EDSS score is 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
Attitude chances (CI_95%)	- 0,17 (-0,26,- 0,08)***		-0,18 (-0,27,- 0,09)***
Without relapse Week 108	56,5 %	45,6%	57,1 %	46,8 %
Attitude chances (DI_95%)	0,72 (0,58, 0,89)**		0,63 (0,50, 0,79)***
Confirmed progression 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 disability for 6 months. weeks 108	13,8%	18,7%	11,7%	11,9%
Attitude chances (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% ***
Average number foci, accumulating Gd on the scan to the week of 108	0,38	1,18
Changes in placebo (DI_95%)	-0,80 (-1,20, -0,39)****		Not Measured
Number of unified active foci per scan	0,75	2,46
Changes in placebo (DI_95%)	69% (59%, 77%)****

****p<0,0001 ***p<0,001 **p<0,01 *p<0,05 in comparison with placebo

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

Efficacy in patients with high disease activity:

A significant effect of teriflunomide therapy was notedfor exacerbations and confirmed for 3 months progression of disability in a subgroup of patients with high disease activity in the TEMSO study (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. Such a subgroup analysis in the TEMSO trial was not carried out because no MRI data were obtained.

There are no data on patients who do not respond to a full and sufficient course of treatment (on average 1 year of therapy) with interferon beta, and have at least 1 relapse during the previous year on therapy, and at least 9 T2-hypertensive focal lesions on cranial nerve MRI or at least 1 focus, accumulating gadolinium, or about patients, in whom the rate of occurrence exacerbations did not change or decreased during the previous year when compared with the previous 2 years.

TOPIC is a double-blind, placebo-controlled study that evaluated once-daily doses of 7 mg and 14 mg of teriflunomide 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 were randomized to receive 7 mg (n = 205) or 14 mg (n = 216) 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).

The results obtained during the TOPIC study confirmed effectiveness of teriflunomide in remittent multiple sclerosis (including early remitting multiple sclerosis with the first clinical demyelinating episode and MRI foci of different prescription and localization).

The efficacy of teriflunomide was compared with the efficacy of the subcutaneous form of interferon beta-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 is 114 weeks. The risk of ineffective therapy (confirmed relapse or complete cessation of treatment, regardless of what happened first) has become the primary endpoint. Number of patients, finally who discontinued treatment in the group teriflunomide 14 mg - 22 of 111 (19.8%).

The reasons were undesirable phenomena (10.8%), inefficiency (3.6%), other causes (4.5%) and loss for 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 failure to comply with 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 (PorRK) using data on healthy volunteers and patients with multiple sclerosis, there is a slow approach to the equilibrium concentration (ie, approximately 100 days (3.5 months) to reach 95% equilibrium concentrations) , and the assumed rate of accumulation AUC exceed the original approximately 34 times.

Distribution

Teriflunomide actively binds to plasma proteins (> 99%), probably with albumin and, for the most part, is distributed in plasma. The volume of distribution after a single intravenous injection of the drug is low (11 liters).

Biotransformation

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

Teriflunomide is released into 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 was 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 aimed at accelerating the release 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. With poor tolerance of colestyramine in a dose of 8 g three times a day, you can use a dose of 4 g three times a day. 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 concentrations of teriflunomide in the plasma).

Indications:Abaggio® is indicated for the 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 preserved reproductive potential, who do not use reliable methods of contraception and with a plasma concentration of teriflunomide above 0.02 mg / l.

Severe immunodeficiency, such as 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.

Deficiency of lactase, intolerance to galactose, glucose-galactose malabsorption.

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 should assess the possible serious potential risk to the fetus and use effective contraception during the treatment with Abaggio®, 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 about it and perform the pregnancy test immediately. 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 discontinuation of Abagio® therapy.

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 Abaggio® in infants, a decision should be made whether to stop breastfeeding or stop taking the medication taking into account the degree the 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:The recommended dose of Abaggio® is 14 mg per day.

Tablets should be taken whole, washed down with water, regardless of food intake.

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 average duration of the drug was approximately 672 days in four placebo-controlled studies 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 metabolite of leflunomide. 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, increased ALT, nausea and alopecia. In general, headache, diarrhea, nausea and alopecia were mild or moderate, transient and rarely led to discontinuation of treatment.

Unwanted reactions with a frequency of ≥ 1% than with placebo, noted with Abagio® at a dosage of 7 and 14 mg during placebo-controlled studies, are listed 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 unknown (can not be determined from available data).

Classes and systems of organs	Often	Often	Infrequently	Rarely	Rarely	Unknown
Infections		Influenza, upper respiratory tract infections, urinary tract infections, bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral herpes, dental infections, laryngitis, foot mycosis				Severe infections, including sepsis
						Severe infections, 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	Headache	Paresthesia, lumbosacral radiculitis, carpal tunnel syndrome	Hyperesthesia, neuralgia, peripheral neuropathy
Heart Disease		Palpitation
Vascular disorders		Hypertension
Disturbances from the respiratory system, chest and mediastinal organs					Interstitial diseases of the 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				Severe skin reactions
Disorders from the musculoskeletal system and connective tissue		Musculoskeletal pain, myalgia, arthralgia
Disorders from the kidneys and urinary tract		Pollakuria
Violations of the reproductive system, breast diseases
General violations and violations at the site of introduction		Pain
Research	An increase in the level of alanine aminotransferase (ALT)	An increase in the level of gamma-glutamyltransferases, an increase in the level of aspartate-transferase, a decrease in weight, a decrease in the number of neutrophils, a decrease in the number of leukocytes, an increase in the level of creatinine phosphorus kinase in the blood
Injury, poisoning and complication of the procedure			Post-traumatic pain

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

Description of individual adverse 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 at a dose of 14 mg compared with 5.1% of patients taking placebo. Most of the 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.

Undesirable reactions from the liver

In placebo-controlled studies, it was found that:

Increased ALT level (based on laboratory data) according to baseline status - Population of safety study in placebo-controlled trials
	Placebo (N = 997)	Teriflunomide 14 mg (N = 1002)
> 3 VGN	66/994 (6,6%)	80/999 (8,0%)
> 5 VGN	37/994 (3,7%)	31/999 (3,1%)
> 10 VGN	16/994(1,6%)	9/999 (0,9%)
> 20 VGN	4/994 (0,4%)	3/999 (0,3%)
ALT> 3 VGN and total bilirubin> 2 VGN	5/994 (0,5%)	3/999 (0,3%)

VGN - upper limit of norm In groups of patients who received teriflunomide, more often than in placebo, there was an increase in ALT transaminase activity less than or equal to 3 VGN.

The percentage of patients who had a rise in ALT above 3 VGN was comparable in all groups. The increase in ALT levels was noted mainly in the first six months of treatment. After cessation of treatment, the activity of the ALT enzyme returned to normal. The time to normalize the activity of the ALT enzyme ranged from several months to several years.

Effect on blood pressure

In placebo-controlled studies, the following was established:

- Increased 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;

- Increased 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.

Infections

In placebo-controlled studies in the group of teriflunomide, 14 mg, there was no increase in the incidence 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 infectious reactions were observed, including sepsis. In some cases, a fatal outcome was noted.

Hematological effects

In placebo-controlled studies against the backdrop of the use of Abaggio, 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 was noted during the first 6 weeks.Then, on the background of continuing treatment, the number of leukocytes 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 number of cases peripheral neuropathy, including polyneuropathy and mononeuropathy (carpal tunnel syndrome), in comparison with placebo. In the main placebo-controlled studies, peripheral polyneuropathy, confirmed by studies of nerve conduction, was noted 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. The treatment was interrupted in 5 patients with peripheral neuropathy who received teriflunomide in a dose of 14 mg. Recovery after cessation of treatment was recorded in 4 of these patients.

Neoplasms are benign, Malignant and vague (including cysts and polyps)

In clinical studies, amid the administration of teriflunomide, there is no increased risk of malignant tumors.Risk the occurrence 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 undesirable reactions corresponded to the safety profile of teriflunomide when administered to 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 inducer of carrier proteins, P-glycoprotein [P-gp] and resistance protein to breast cancer [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, as 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-intestinal cycles and / or gastrointestinal dialysis of teriflunomide.

Pharmacokinetic interactions of teriflunomide with other substances

Effects of teriflunomide on the substrate CYP2C8: repaglinide

An increase in the mean FROM_max and AUC for repaglinide (1.7 and 2.4 fold, respectively) after receiving 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 ethinylestradiol and 0.15 mg of levonorgestrel

After taking multiple doses of teriflunomide, an increase in the mean FROM_max and AUC_0-24 for ethinylestradiol (1.58 and 1.54-fold, respectively) and FROM_max and AUC_0-24 and levonoadrelals (1.33 and 1.41 times, respectively). While this interaction of teriflunomide should not adversely affect the efficacy of oral contraceptives, the type or dose of oral contraceptives used in conjunction with teriflunomide should be considered.

The effect of teriflunomide on the substrate of the isoenzyme CYP1A2: caffeine

Repeated doses of teriflunomide reduced the mean C_max and AUC for caffeine (substrate of the isoenzyme CYP1A2) by 18% and 55%, respectively, suggesting that teriflunomide to a lesser extent induces the isoenzyme CYP1A2 in vivo. Therefore, drugs metabolized by 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 S-warfarin, which shows that teriflunomide is not an isoenzyme inhibitor or inducer CYP2C9. 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 concentration FROM_max and AUC (1.43 and 1.54-fold, respectively) of cefaclor, after repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of PAA3 in vivo. Therefore, precautions should be taken if teriflunomide is assigned together with substrates POA3, such as cefaclor, benzylpenicillin, ciprofloxacin, indomethacin, ketoprofen, furosemide, cimetidine, methotrexate and zidovudine.

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

An increase in the value FROM_max 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 dose reduction of 50% is recommended for co-administration with teriflunomide. Other BCRP substances (for example, methotrexate, topotecan, sulfasalin, daunorubicin, doxorubicin) and the family of the OATP, especially HMG-CoA reductase inhibitors (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 treatment begins conduct the following studies:

- Blood pressure measurement

- Activity of alanine aminotransferase (ALT)

- A general blood test, including leukocyte formula, and 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 the case of new symptoms and signs (eg, infection) during treatment, it is necessary to perform a general blood test, including the leukocyte formula, and 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;

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

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

Patients of the older age group

Abaggio® should be given with caution to patients 65 years of age or older due to a lack of data on efficacy and safety in this age group.

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.

Children's population

The safety and efficacy of Abagio® 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.

Liver failure

In patients with hepatic insufficiency of mild or moderate degree, dose adjustment is not required.

Teriflunomide is contraindicated in patients with severe hepatic insufficiency.

In patients who took teriflunomide, there was an increase in activity liver enzymes. 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. The need for discontinuation of teriflunomide therapy 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.

Abaggio® should be administered with caution to patients, abusing alcohol.

Because the teriflunomide is highly associated with the protein, and since binding depends on the level of albumin, the concentration of unbound tetrylunomide in plasma can be increased in patients with hypoproteinemia, for example, with 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 the case of high blood pressure, appropriate antihypertensive therapy before and against treatment with teriflunomide.

Infections

Initiation of treatment with teriflunomide it is necessary to postpone in patients with serious active infections until complete recovery.

In placebo-controlled trials, no significant infection was noted with the use of teriflunomide. However, taking into account the immunomodulatory effect of Abaggio, if the patient develops a serious infection, it is necessary to consider the need for suspension of treatment with the drug, and before the resumption of therapy it is necessary to evaluate the possible advantages 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 taking the drug Abaggio® should immediately report symptoms of infection to the doctor. Patients with active acute and chronic infections should not begin treatment with Abagio® beforecomplete cure. The safety of Abaggio® 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 test at screening should receive appropriate treatment before starting Abaggio®.

Respiratory reactions

In clinical trials teriflunomide of cases of interstitial lung diseases is not fixed.

However, such potentially lethal diseases were reported against leflunomide. On the background of therapy, interstitial lung diseases can develop rapidly. Risk is increased in patients with such diseases in history of the leflunomide treatment.

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

Hematological effects

A moderate decrease is observed the number of white blood cells less than 15% of the baseline. As a precaution before initiating therapy with Abaggio, it is necessary perform a general clinical blood test with the definition of the leukocyte formula and the number of platelets. On the background of Abaggio® therapy, it is necessary to perform a general clinical blood test according to 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 are at risk of suppression of bone marrow hematopoiesis, the risk of hematological diseases with Abaggio® 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 severe hematologic reactions, including pancytopenia, the use of Abaggio® and any other myelosuppressive drug should be discontinued. It is necessary to consider the expediency of carrying out the procedure for accelerated excretion.

Skin Reactions

Cases of severe skin reactions (including Stevens-Johnson syndrome and toxic epidermal necrolysis).

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

If ulcerative stomatitis occurs, the treatment with teriflunomide should be discontinued. If severe generalized skin reactions (Stevens-Johnson syndrome or toxic epidermal necrolysis - Lyell's syndrome) are suspected during 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

Patients taking Abaggio® had cases of peripheral Neuropathy. 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 receiving Abaggio® is diagnosed with peripheral neuropathy,should consider the possibility of stopping the reception of Abaggio® and carrying out an accelerated elimination procedure.

Vaccination

Two clinical studies have shown that vaccination with inactivated Neoantigen (first vaccination) or sensitizing antigen (stimulation) were safe and effective during drug treatment Abaggio®. 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.

A joint treatment with antineoplastic or immunosuppressive drugs used to treat multiple sclerosis has not been studied. Safety Studies in which teriflunomide was administered concomitantly with interferon beta or with glatiramer acetate for one year, there were no safety problems, but a higher incidence of undesired reactions compared with teriflunomide monotherapy was observed. The safety of this combination with long-term administration for the treatment of multiple sclerosis has not been investigated.

Switch to or from Abaggio®

Based on the 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 therapy with teriflunomide 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 therefore simultaneous exposure to the immune system, can occur if Abaggio® therapy is started within 2-3 months after discontinuing natalizumab. Therefore, precautions should be taken when switching from natalizumab therapy to Abaggio.

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 Abaggio®.

When PC median t_1/2was approximately 19 days after repeated doses of 14 mg. If a decision was made to stop Abaggio® treatment during the interval of 5 half-lives (approximately 3.5 months, although in some patients it may be longer), the start of another therapy will lead to simultaneous exposure with Abaggio®. This can lead to additive effect on the immune system, which requires mandatory compliance with measures precautions.

Lactose

Since Abagio® tablets contain lactose, patients with lactose intolerance problems, deficiency lactases Lapp or glucose-galactose malabsorption, this medication should not be taken.

Effect on the ability to drive transp. cf. and fur:Abadzhio® 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, you should refrain from driving and other potentially hazardous activities.

Form release / dosage:Tablets, film-coated 14 mg.

Packaging: (specified only with Sanofi Wintrop Industry packaging):

For 14 tablets are placed in a blister of aluminum foil. Two blisters, sealed in a cardboard "pocket", are placed in a sleeve-type package. For 1 or 3 packages of the "sleeve" type, together with the instruction, they are placed in a pack of cardboard. On each opening side of a pack of cardboard paste an anti-counterfeit sticker (tamper control).

Or (indicated only for the packaging of ZAO ORTAT, Russia or ZAO R-Pharm, Russia):

For 14 tablets are placed in a blister of aluminum foil. Two blisters of aluminum foil with instructions for use are put in a cardboard box. On each opening side of a pack of cardboard paste an adhesive control sticker.

Storage conditions:

Store at temperatures between 2 and 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002520

Date of registration:04.07.2014 / 07.07.2016

Expiration Date:04.07.2019

The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands

Manufacturer: & nbsp