Universal reference book for medicines
Product name: ABADJIO (ABADJIO)

Active substance: teriflunomide

Type: Immunosuppressive drug used for multiple sclerosis

Manufacturer: GENZYME EUROPE (Netherlands) manufactured by SANOFI WINTHROP INDUSTRIE (France)
Composition, form of production and packaging
The tablets covered with a film membrane of
pale blue color, pentagonal, on one side of the tablet it is stamped "14", on another the firm's logo is engraved.

1 tab.

teriflunomide 14 mg

Excipients: lactose monohydrate - 76 mg, corn starch - 38 mg, hydroxypropyl cellulose - 3.5 mg, microcrystalline cellulose - 10.5 mg, sodium carboxymethyl starch - 7.5 mg, magnesium stearate - 0.5 mg.

The composition of the film membrane: hypromellose - 3.607 mg, titanium dioxide E 171-0.902 mg, talcum 0.271 mg, macrogol 0.158 mg, aluminum lacquer based on indigocarmine E 132-0.062 mg

14 pcs.
- blisters of aluminum foil (2) - packages (1) of the "sleeve" type - packs of cardboard.
14 pcs.
- blisters of aluminum foil (2) - packages (3) such as "sleeve" - ​​packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2014.

PHARMACHOLOGIC EFFECT

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.
Thus, teriflunomide blocks the proliferation of stimulated lymphocytes, for which synthesis of pyrimidine de novo is required. The exact mechanism of action of teriflunomide in multiple sclerosis is not fully understood, but it may be due to 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, by less than 0.3 x 10%, as noted during the first 3 months of treatment.
The levels reached were maintained until the end of treatment.
Effect on the QT interval

In a placebo-controlled study involving healthy volunteers, teriflunomide at moderate equilibrium concentrations showed no potential for prolonging the QTcF interval compared with placebo: the largest mean difference between teriflunomide and placebo was 3.45 ms with an upper 90% confidence limit , equal to 6.45 ms.

Effects on tubular kidney function

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

The effectiveness of Abaggio was demonstrated in the study CFC6049 / TEMSO, which was devoted to the assessment of the daily intake of 7 mg and 14 mg geriffunomide in patients with relapsing multiple sclerosis (RRS).

One thousand eighty-eight patients with RRS were randomized to receive 7 mg (n = 366) or 14 mg (n = 359) of 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 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 results of the study are presented in Table I. A total of 1,169 patients with RRS were included in the TOWER study for 7 mg (n = 408) or 14 mg (n = 372) of 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 EDSS (Expanded Disability Status Scale) <5.5.
The average age of the patients studied was 37.9 years.
The majority of patients had relapsing 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. 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 I.
Table 1 - Main results (for the indicated dose, ITT population)

TEMSO Study The TOWER Study

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 Week 108 56.5% 45.6% 57.1% 46.8%

The odds ratio (CI 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%

The chanson ratio (CI 95 %) 0.75 (0.50, 1.11) 0.84 (0.53, 1.33)

MPT endpoint

Change of BOD of the week 108 1 0.72 2.21

Changes in placebo 67% ***

The average number of foci accumulating Gd on the scan in the week of 108 0.38 1.18

Changes in placebo ( 95 % CI) -0.80 (-1.20, -0.39) **** Not Measured

Number of unified active foci per scan 0.75 2.46

Changes in placebo ( 95 % CI) 69% (59%, 77%) ****

**** p <0.0001 *** p <0.001 ** p <0.01 * p <0.05 compared with placebo 1. BOD: total focal volume in ml (T2 and hypo-intensive T1)

The efficacy of teriflunomide was compared with the effectiveness 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. The number of patients permanently discontinued 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 for follow-up (0.9%). The number of patients who stopped treatment permanently 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-
Msyer was 41.1% against teriflunomide 14 mg compared with 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 mean T max in plasma is 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 calculated on the basis of the analysis of population pharmacokinetics (PorRK) using data on healthy volunteers and patients with multiple sclerosis, a slow approach to the equilibrium concentration (ie, approximately 100 days (3.5 months) up to 95% of equilibrium concentrations), and the estimated rate of accumulation of AUC exceeds the initial value by approximately 34 times.
Distribution

Teriflunomide actively binds to plasma proteins (> 99%), probably with albumin and, for the most part, is distributed in plasma.
V d after a single intravenous injection of the drug is low (11 L).
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.
T 1/2 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 2 times 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 3 times a day, you can use a dose of 4 g 3 times a day. Alternatively, activated charcoal may also be used (the preparation need not be taken 11 consecutive days unless there is a need for a rapid reduction in the concentrations of teriflunomide in the plasma).
INDICATIONS

- treatment of adult patients with relapsing-remitting multiple sclerosis.

DOSING MODE

The recommended dose of Abaggio is 14 mg per day.

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

SIDE EFFECT

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. According to the results of placebo-controlled studies, the most frequent adverse reactions in the group of patients taking teriflunomide 14 mg, relative to the placebo group were the following: influenza (11.8% vs. 9.3%), upper respiratory tract infection (10.8% vs. 9 , 0%), urinary tract infection (10.6% versus 9.5%), paresthesia (10.6% vs. 7.8%), diarrhea (17.3% vs 8.3%), increased ALT activity (14.0% against 7.1%), nausea (14.2% vs. 6.9%) and alopecia (14.7% vs. 4.3%). In general, diarrhea, nausea and alopecia were mild or moderate, passed quickly and occasionally led to discontinuation of therapy.
The adverse reactions noted with the admission of Abaggio at a dose of 14 mg per day 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); unknown (can not be determined from available data).
Infectious complications: very often - influenza, upper respiratory tract infections, urinary tract infections, laryngitis, foot mycosis;
often bronchitis, sinusitis, pharyngitis, cystitis, viral gastroenteritis, oral cavity herpes, periodontal infections.
From the hemopoietic system and lymphatic system: often - neutropenia, infrequently - anemia, thrombocytopenia of mild degree.

From the immune system: often - mild allergic reaction.

Mental disorders: often - anxiety.

From the nervous system: very often - paresthesia;
often - lumbosacral radiculitis, carpal tunnel disease, hyperesthesia, neuralgia, peripheral neuropathy.
From the cardiovascular system: often - hypertension.

From the respiratory system: interstitial lung diseases *.

From the digestive system: very often - diarrhea, nausea;
often - vomiting, toothache; very rarely - pancreatitis *.
From the skin and subcutaneous tissues : very often - alopecia, often - a rash, acne.

From the musculoskeletal system and connective tissue: often - musculoskeletal pain, myalgia.

From the kidneys and urinary tract: often - pollakiuria.

On the part of the reproductive system: often - mennoragia.

Reaction at the injection site, complications of the procedure: often - pain, post-traumatic pain.

Laboratory indicators: very often - an increase in the level of alanine aminotransferase;
often - 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.
Injuries, poisoning and complications of the procedure: often - 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 associated with or unrelated to changes in hair texture in 15.2% of patients taking tetramulomide at a dose of 14 mg compared with 4.3% of patients taking a 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 57 of 63 (90%) patients. 1.5% of participants discontinued therapy due to alopecia in the teriflunomide group compared with 0% 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 = 420) Triflunomide 14 mg (N = 413)

> 1 -? 3 VGN 124/420 (29.5%) 205/413 (49.6%)

> 3 - 5 VGN 15/420 (3.6%) 16/413 (3.9%)

> 3 VGN 26/420 (6.2%) 25/413 (6.1%)

> 5 UGN 11/420 (2.6%) 9/413 (2.2%)

> 10 VGN 6/420 (1.4%) 4/413 (1.0%)

> 5 -? 20 VGN 9/420 (2.1%) 7/413 (1.7%)

> 20 VGN 2/420 (0.5%) 2/413 (0.5%)

ALT> 3 VGN and 1 1

General.
bilirubin> 2 IUV
In the groups of patients receiving teriflunomide, an increase in ALT transaminase activity less than or equal to 3 UGN was observed more frequently compared with placebo.
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 varied from months to years.
Effect on blood pressure

In placebo-controlled studies, the following was established:

- systolic blood pressure was higher than 140 mm Hg.
Art. in 18.6% of patients who took teriflunomide at a dose of 14 mg per day compared with 17.8% in the placebo;
- systolic blood pressure was higher than 160 mm Hg.
Art. in 4.1% of patients taking teriflunomide at a dose of 14 mg per day, compared with 2.6% for placebo;
- The diastolic blood pressure was above 90 mm Hg.
Art. in 20.3% of patients who took teriflunomide at a dose of 14 mg per day compared with 17.1% in the placebo.
Infections

In placebo-controlled studies in the teriflunomide group, 14 mg of increased incidence of serious infections was not observed (2.2% compared with 2.1% in placebo).
Serious opportunistic infections were noted in 0.2% of cases in each group.
Hematological effects

The mean decrease in the number of leukocytes (<15% of the baseline, mainly a decrease in the number of penthophils and lymphocytes) was observed in placebo-controlled studies against the backdrop of the use of Abaggio.
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 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 incidence of peripheral neuropathy.
including polyyeuropathy, and mononeuropathy (the so-called carpal tunnel syndrome), in comparison with placebo. In the main placebo-controlled studies, peripheral polyneuropathy, confirmed by studies of nerve conduction, was noted in 2.2% of patients (15 of 685) in the group of teriflunomide 14 mg compared with 0.6% (4 patients out of 708) in the placebo group. Treatment was interrupted in 7 patients with peripheral neuropathy. Recovery after cessation of treatment was recorded in 2 of them.
Neoplasms are benign, malignant and indeterminate (including cysts and polyps)

In clinical studies against the background of taking teriflunomide, there was no increase in the risk of malignant tumors.
The risk of malignancies, namely lymphoproliferative diseases increases with the application of certain other drugs affecting the immune system.
CONTRAINDICATIONS

- hypersensitivity to the active agent or any of the excipients;
- severe hepatic insufficiency (class C by Child-Pugh);
- pregnancy (before treatment teriflunomide is necessary to exclude pregnancy), breast-feeding;
- Women with a stored childbearing potential not using reliable methods of contraception and teriflunomide plasma concentrations above 0,02 mg / l;
- severe immunodeficiency, such as AIDS;
- severe impairment of bone marrow hematopoiesis, including clinically significant anemia, leukopenia, neutropenia or thrombocytopenia;
- Severe renal failure requiring dialysis;
- severe active infection;
- severe hypoproteinemia;
- lactase deficiency, galactose intolerance, glucose-galactose malabsorption;
- up to age 18 years.
PREGNANCY AND LACTATION

Pregnancy
Data on the use of teriflunomide in pregnant women is limited. Studies in animals have shown reproductive toxicity.
Teriflunomide is not recommended during pregnancy. Pregnant women should be advised to take advantage of the accelerated clearance procedure for the rapid reduction of teriflunomide plasma concentration.
Women of childbearing age prior to treatment is necessary to evaluate the possible serious potential risk to the fetus and to use effective contraception during treatment with Abadzhiev and after discontinuation of therapy to achieve a concentration of the drug in the plasma is not more than 0.02 mg / liter (usually a period of 8 months ). In case of delay of menstruation in patients receiving teriflunomide is an urgent need to inform the doctor and perform a pregnancy test. In the case of a positive result the physician should discuss with the patient all the risks associated with pregnancy, to check residual concentration of teriflunomide. If the concentration exceeds 0.02 mg / l, it is recommended to repeat the procedure accelerated elimination.
Women seeking pregnancy should be advised to take advantage of the accelerated clearance procedure for the rapid reduction of teriflunomide plasma concentration. Due to individual variations in the clearance of the drug may require control of teriflunomide plasma concentrations within 2 years after the cessation of therapy. An accelerated withdrawal can also be used at any time after the cessation of therapy Abadzhiev. Accelerated elimination procedure:
• cholestyramine at a dose of 8 g of 3 times a day for 11 days, or in case of poor tolerability of this dose may be used 4g dose cholestyramine 3 times a day;
• alternatively can take on 50 g of activated charcoal every 12 hours for 11 days.
fertility
Animal studies have not shown any impact en fertility. Despite the absence of data for those effects on male and female fertility is unlikely.
Breastfeeding
Studies in animals have shown excretion of teriflunomide in breast milk. It is not known whether this medication passes into breast milk in women falls. Due to the fact that many drugs are allocated in breast milk, and in connection with the probability of serious adverse reactions associated with the action Abadzhiev, infants should decide the termination of breastfeeding or discontinuation of the drug to the extent necessary the drug to the mother.
Application men
Embriofetalnoy risk of toxicity by men as a result of teriflunomide therapy is considered to be low.
APPLICATION FOR FUNCTIONS OF THE LIVER

In patients with renal insufficiency, mild, moderate or severe, are not on dialysis, the dose adjustment is required.
Patients with severe renal insufficiency, hemodialysis, did not participate in clinical trials. Teriflunomide this group of patients is contraindicated.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

In patients with mild hepatic impairment, moderate to severe dose adjustment is required.
Teriflunomide is contraindicated in patients with liver failure and severe.
APPLICATION FOR CHILDREN

The safety and efficacy Abadzhiev in children under the age of 18 years have not been established. Teriflunomide is not appointed for children under the age of 10 years for the treatment of multiple sclerosis.
APPLICATION IN ELDERLY PATIENTS

Abadzhiev should be prescribed with caution in patients aged 65 years and over due to insufficient number of efficacy and safety data in this age group.
SPECIAL INSTRUCTIONS

Treatment should be under the supervision of a physician who has experience in treating patients with multiple sclerosis.
Monitoring
Prior to treatment should be carried out the following studies:
• Blood pressure measurement;
• alanine aminotransferase activity (ALT);
• Complete blood analysis, including leukocyte formula, and determining the number of thrombocytes in the blood.
During treatment with teriflunomide following parameters should be checked regularly:
• Blood pressure;
• alanine aminotransferase activity (ALT);
• In the case of new symptoms and signs (e.g., infection) during treatment is necessary to perform a complete blood analysis, including leukocyte formula, and determining the number of thrombocytes in the blood.
Accelerated clearance procedure
Teriflunomide slowly cleared from the plasma: plasma concentrations reach values below 0.02 mg / l on average for 8 months, although due to individual variations in excretion of drugs it may last up to 2 years.
Excretion of the drug can be accelerated by any of the procedures described below, leading to a reduction of more than 98% of the level of teriflunomide plasma concentrations:
- reception of cholestyramine at a dose of 8 grams every 8 hours for 11 days. When poor tolerability cholestyramine at a dose of 8 g of 3 times a day can reduce the dose to 4 g three times a day;
- reception of activated charcoal (50 grams) every 12 hours for 11 days (daily intake of poor portability is not required).
Accelerated removal procedure may be used at any time after discontinuation teriflunomide.
Patients older age group
Abadzhiev should be prescribed with caution in patients aged 65 years and over due to insufficient number of efficacy and safety data in this age group.
Renal insufficiency
In patients with renal insufficiency, mild, moderate or severe, are not on dialysis, the dose adjustment is required.
Patients with severe renal insufficiency, hemodialysis, did not participate in clinical trials. Teriflunomide this group of patients is contraindicated.
Pediatric population
The safety and efficacy Abadzhiev in children aged 10 to 18 years has not been established. Teriflunomide is not appointed for children under the age of 10 years for the treatment of multiple sclerosis.
Effect on the liver
in patients with mild hepatic impairment, moderate to severe dose adjustment is required.
Teriflunomide is contraindicated in patients with liver failure and severe. In patients treated with teriflunomide, there was an increase in liver enzymes. These undesirable reactions occurred mainly during the first 6 months of treatment. Liver enzymes must be checked before starting therapy teriflunomide, then every two weeks for the first 6 months of treatment and every 8 weeks thereafter, or related clinical signs and symptoms, such as nausea, vomiting, abdominal pain, fatigue, loss of appetite or jaundice and / or dark urine. For ALT increase is acceptable, fold 2-3 upper limit of normal, the monitoring should be carried out weekly. Teriflunomide therapy should be withdrawn if there is suspicion of liver disease.Consider the need to stop treatment when teriflunomide confirmed increases in liver enzymes (more than 3 times the ULN). Patients with a history of liver disease included in the group of liver disease risk patients receiving teriflunomide. In this group of patients, symptoms of liver disease should be monitored closely.
Abadzhiev should be prescribed with caution in patients who abuse alcohol.
Since teriflunomide highly bound to protein, and since the binding is dependent on the level of albumin, the concentration of unbound teriflunomide plasma can be increased in patients with hypoproteinemia, for example, in the nephrotic syndrome. Teriflunomide should not be administered to patients with severe hypoproteinaemia.
Arterial pressure
on the background of teriflunomide can be marked increase in blood pressure. It is necessary to control the blood pressure before treatment teriflunomide, and periodically thereafter. In the case of a blood pressure increase is necessary to carry out appropriate antihypertensive therapy before and during treatment teriflunomide.
infection
Initiation of treatment is necessary to postpone teriflunomide in patients with severe active infections until complete recovery.
In the placebo-controlled studies were observed when receiving teriflunomide increasing the frequency of serious infections. However, in view of the immunomodulatory effects Abadzhiev, in the event of serious infection in a patient should consider the need for the suspension of treatment, and before resuming therapy is necessary to assess the possible benefits and risks. Due to the long half-life of the drug is necessary to consider the need for accelerated elimination using activated charcoal or cholestyramine.
Patients taking the drug Abadzhiev, must immediately inform the doctor about the symptoms of infection. Patients with active acute or chronic infections should not start treatment with Abadzhiev until complete healing.
Abadzhiev safety of the drug in patients with latent tuberculosis infection is unknown. Screening for tuberculosis in a clinical trial are not systematically carried out. Patients with a positive test for tuberculosis screening is necessary to pass the appropriate treatment Abadzhiev before taking the drug.
respiratory reactions
In clinical studies of teriflunomide interstitsnalnyh cases of lung disease have been recorded. However, for such diseases are potentially fatal, has been reported during treatment with leflunomide. The therapy may develop interstitial lung disease. The risk is increased in patients who develop such disease during treatment with leflunomide.
Pulmonary symptoms, such as persistent cough and shortness of breath, can cause discontinuation of therapy and conducting further investigations.
hematologic effects
There is a decrease in average number of white blood cells is less than 15% of the original level. As a precaution, before starting therapy with Abadzhiev must perform common clinical blood analysis with determination of leukocyte and platelet counts. The therapy is necessary to perform overall Abadzhiev CBC when certain symptoms and signs (e.g., infections).
In patients with existing anemia, leucopenia and / or thrombocytopenia as well as in patients with impaired bone marrow function or at risk of suppression of bone marrow blood, the risk of haematological disorders during therapy Abadzhiev upgraded. In the case of these undesired reactions is necessary to consider the possibility of applying the accelerated excretion tsriflonomida procedure for reducing the plasma concentration.
In case of a hematological reactions, including pancytopenia. reception Abadzhiev and any other mielosupressiruyuschey therapy should be discontinued, and the need to consider the expediency of the accelerated clearance procedure.
skin reactions
In clinical studies of teriflunomide cases of severe skin reactions were recorded. In patients treated with leflunomide. It reported rare cases of Stevens-Dzhonsopa syndrome or toxic epidermal necrosis. In case of ulcerative stomatitis receiving teriflunomide should be discontinued. If skin and / or mucosal reactions are observed with an increase in suspicions of serious generalized skin reaction (Stevens-Johnson syndrome or toxic eiidermalny necrosis - Lyell's syndrome), receiving teriflunomide and any other possibly related drugs should be stopped, and should immediately begin the process of an accelerated withdrawal. In such cases, patients should not be re-appoint teriflunomide.
peripheral neuropathy
Patients taking Abadzhiev, cases of peripheral neuropathy have been fixed. After discontinuation severity of adverse reactions in most patients decreased. However, in some patients, peripheral neuropathy disappeared completely, but some symptoms remain. If patients taking Abadzhiev has confirmed peripheral neuropathy. should consider discontinuation Abadzhiev and an expedited clearance procedures.
Vaccination
In clinical studies, patients taking teriflunomide had a normal immune response to the seasonal flu vaccine, corresponding to a normal response to a booster vaccination. In these patients, antibody titers sufficient to ssroprotektsii been made. Data on the efficacy and safety of primary vaccination neopatogenov not. The use of live attenuated vaccines may be associated with the risk of infection and should therefore be avoided.
Immunomodulatory and immunosuppressive therapy
Since lefluiomid is the starting compound for teriflunomide. co-administration of teriflunomide with leflunomide is not recommended.
Co-administration with antinsoplasticheskimi or immunosuppressive drugs used to treat multiple sclerosis, has not been studied. Safety studies in which tsriflunomid simultaneously injected with interferon beta or glatiramer acetate for one year, did not reveal any problems with safety, but there was a higher incidence of adverse reactions in comparison with monotherapy teriflunomide. The safety of this combination with chronic administration for the treatment of multiple sclerosis has not been investigated.
Daylight or Abadzhiev
Based on the clinical data related to the simultaneous reception of teriflunomide to interferon beta or glatiramer acetate, it can be said that there is no need for a waiting period at the beginning of therapy teriflunomide after interferon beta or glatiramer acetate, or at the beginning of therapy with interferon running or glatiramer acetate after teriflunomide .
Due to the long half-life natalizuma

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