Leflunomid

General characteristics. Structure:

Active ingredient: 10 mg, 20 mg or 100 mg of a liflunamid in 1 tablet.

The drug rendering the expressed antirheumatic, immunodepressive, anti-proliferative, antiinflammatory effect.

Pharmacological properties:

Pharmacodynamics. The mechanism of action is caused by dihydroorotatedehydrogenase inhibition – the enzyme participating in synthesis of pyrimidines.

Pharmacokinetics. After intake лефлуномид is metabolized in an active metabolite A77 1726 (further designated as M1) which causes effect of the drug in vivo.

Leflunomid in a blood plasma comes to light in trace quantities therefore at pharmacokinetic researches concentration of M1 were defined.

After intake of Cmax  it is reached in 6–12 h. Semi-life time in plasma long (T1/2  about 2 weeks). For bystry achievement of equilibrium concentration of M1 in a blood plasma in clinical tests use of a load dose of drug on 100 mg within 3 days was used. It is shown that without preliminary load dose concentration of M1 in plasma reaches equilibrium values within 2 months. The resulting concentration of M1 in a blood plasma defined after reception of load and subsequent therapeutic doses of a leflunomid show that the plasmatic M1 levels are dozozavisimy.

Determination of the pharmacokinetic M1 parameters was carried out after intake of a leflunomid in daily doses of 5, 10 and 25 mg a day (preliminary load doses – 50, 100 and 100 mg respectively) at patients with a pseudorheumatism (n=54). In 24 h after a load dose of concentration of M1 made 4,0±0,6; 8,4±2,1 and 8,5±2,2 mkg/ml respectively; in 24 h after reception of therapeutic doses and in equilibrium state – 8,8±2,9; 18±9,6 and 63±36 mkg/ml.

Bioavailability of the tableted form of a leflunomid — 80%. Joint intake of tablets of a leflunomid and greasy food has no significant effect on the M1 level in a blood plasma.

M1 has the low volume of distribution (0,13l/kg) and high extent of linkng with plasmatic albumine (> 99,3%) at healthy patients. It is shown that linkng with proteins is linear at therapeutic concentration. Level of untied fraction M1 is slightly higher at patients with a pseudorheumatism and approximately doubles at patients with a chronic renal failure. The mechanism and value of these increases are unknown.

Leflunomid is metabolized to one main (M1) and several minor metabolites. From minor metabolites only 4 trifluoromethylalanine (TFMA) quantitatively are defined at some patients in low concentration. Related connections seldom are defined in plasma. Now specific places of metabolism of a leflunomid are not revealed. On the basis of the researches in vivo and in vitro it is possible to assume participation in this process of a gastrointestinal wall and a liver. Specific enzymes of metabolism of a leflunomid are not emitted, however participation of cytoplasmatic and microsomal fractions of cells of a liver in connection metabolism is shown.

The active metabolite of M1 is removed as by the subsequent metabolism and excretion by kidneys, and by means of direct removal with bile. In a 28-day research of ways of removal of connection (n=3), with use of a single dose it is radioactive marked drug, shown that about 43% of a radioactive dose are removed with urine and 48% — with excrements. The subsequent analysis of samples showed that the main metabolites in urine are glucuronides of a leflunomid and derivatives of M1. The main metabolite in excrements was M1. From these two ways removal with urine was more significant in the first 96 h then the second way of excretion dominated. With in/in introduction of M1 the clearance was equal in a research to 31 ml/h.

In small researches with use of absorbent carbon (n=1) and Colestyraminum (n=3) for simplification of removal of HP of T1/2 M1 value  from in vivo plasma decreased from more than 1 week to about 1 day. Similar decrease in T1/2  were observed at group of volunteers (n=96) participating in researches with kolestiraminovy loading. This fact gives the grounds to assume that repeated absorption from bile makes the main contribution to maintenance of long T1/2 M1  from plasma. The researches conducted at use of a hemodialysis and out-patient peritoneal dialysis show that M1 is not dialyzed from plasma and peritoneal liquid.

Dependence of parameters of pharmacokinetics on some factors. Reliable sexual and age distinctions in pharmacokinetics of M1 of in vivo are not revealed.

The population pharmacokinetic analysis in the Phase of the III researches shows that at smokers the clearance increases for 38% in comparison with non-smoking; however there are no distinctions in clinical performance (leflunomid) at smokers and non-smoking.

At the patients with a chronic renal failure needing a hemodialysis or laboratory peritoneal dialysis (n=6) after a single dose of HP significant influence on levels of the circulating M1 is not revealed. The fraction of untied M1 was almost doubled, but the mechanism of this increase is not known. In the light of the fact that kidneys participate in process of removal of drug and in the absence of adequate researches at use of a leflunomid for patients with a renal failure it is necessary to be careful at purpose of treatment by this drug.

Researches of influence of a liver failure on pharmacokinetics of M1 were not conducted. In view of metabolism of a leflunomid in active metabolites, a liver role in elimination and recirculation in an organism of drugs, the possible risk of increase of a hepatotoxic, use of a leflunomid for patients with a liver failure is not recommended.

Carcinogenicity, mutagenicity and influence on fertility. In two-year researches on rats carcinogenicity of a leflunomid was not revealed at peroral doses, up to the most transferable — 6 mg/kg (about 1/40 maximum system exposures of M1 at the person based on AUC). However in biennial researches on mice males increase in cases of formation of a lymphoma at the maximum studied peroral dosage of 15 mg/kg (1,7-fold exposure of M1 at the person based on AUC) was observed. In the same researches at mice females the combined, dozozavisimy increase in formation of bronchoalveolar adenomas and carcinomas at the increasing doses was observed, since 1,5 mg/kg (about 1/10 exposures of M1 at the person based on AUC). Value of these data on clinical use of a leflunomid is not defined.

Leflunomid did not show a mutagenicity in Ames's test, the test of unplanned synthesis of DNA and/or the test with гипоксантин-гуанинфосфорибозилтрансферазой cells of an ovary of the Chinese hamster. Also лефлуномид did not show clastogene properties in micronuclear test on mice of in vivo and in the cytogenetic test on cells of marrow of the Chinese hamsters of in vivo. However 4 trifluoromethylaniline (TFMA), a minor metabolite of a leflunomid, showed mutagen properties in Ames's test and in the test with гипоксантин-гуанинфосфорибозилтрансферазой cells of an ovary of the Chinese hamster and showed clastogene properties in the test of aberation chromosomes on cells of the Chinese hamster of in vitro. TFMA did not show clastogene properties in micronuclear test on mice in vivo or the cytogenetic test on cells of marrow of the Chinese hamster of in vivo.

Leflunomid does not influence fertility of males and females of rats at peroral dosages to 4,0 mg/kg (approximately 1/30 exposures of M1 at the person based on AUC).

Clinical tests. Efficiency of a leflunomid in treatment of the pseudorheumatism (P) was продемонстрированав 3 controlled tests. Simplification of symptomatology was estimated by means of Criterion of the answer of ACR20 which is a complex of clinical, laboratory and functional trials at RA (ACR20 Responder Index, ACR – American College of Rheumatology — the American board of rheumatologists). "ACR20 a responder" is the patient with RA at which 20% or more improvement are observed at assessment of number of the painful / inflamed joints of willows 3iz the following 5 criteria: the general assessment of a state the doctor, the general assessment of a state the patient, an invalidism indicator (under the modified questionnaire of assessment of health — MHAQ-Modified Health Assessment Questionnaire), a visual analog of a painful scale and an indicator of SOE or concentration of S-reactive protein. "ACR20 a responder in a final point" is the patient at whom at the time of the end of researches 20% or more improvement in the parameters stated above were observed. The delay in progressing of structural injuries of joints in comparison with control decided on the help of a scale of Sharp by the general calculation of regional erosion and narrowings of joint cracks of brushes/wrists and front department of feet.

At the beginning of clinical tests all patients to whom it was appointed лефлуномид accepted a load dose of 100 mg/day within 3 days.

In clinical tests of US301 in the USA there were randomizirovana 482 patients with the RA active form lasting not less than 6 months. Patients received лефлуномид in a dosage 20 mg/day (n=182), or a methotrexate with the increasing dosage from 7,5 to 15 mg in week (n=182), or placebo (n=118). All patients accepted folic acid on 1 mg twice a day. Time of treatment made 52 weeks.

In the researches MN301 in Europe there were randomizirovana of 358 patients with the RA active form receiving or лефлуномид 20 mg/day (n=133), either Sulfasalazinum of 2,0 g/day (n=133), or placebo (n=92). Treatment duration – 24 weeks. Clinical tests of MN303 in Europe were additional 6-month placebo - uncontrollable continuation of the researches MN301 which result was a comparison of efficiency of a leflunomid and Sulfasalazinum within 12 months.

In clinical tests of MN302 in Europe there were randomizirovana of 999 patients with the RA active form receiving or лефлуномид on 20 mg/day (n=501), or a methotrexate in the increasing dosage from 7,5 to 15 mg in a week (n=498). 10% of patients in addition accepted folic acid. Time of treatment made 52 weeks.

Results of clinical tests. According to Criterion of the answer of ACR20 in a final point, the quantity of sick RA with improvements at treatment leflunomidy was statistically reliable above in comparison with the answer to placebo: 41% and 18% respectively in the US301 group, 49% and 28% respectively in the MN301/303 groups. On this modification of Criterion of the answer of ACR20 efficiency of treatment was stable eventually and made in 6 months 41%, and in 12 months — 49%. Reliable distinctions in efficiency of treatment between leflunomidy and a methotrexate and between leflunomidy and Sulfasalazinum are not revealed.

Statistically significant effect of treatment leflunomidy at the US301 group in comparison with placebo was determined by the main modification of ACR20 in 1 month after the beginning of therapy (38 and 20% respectively), reached a maximum and was stabilized for 3–6 months (50–55 and 26–30% respectively) and practically did not change within the next 6 months.

According to X-ray inspections of structural damages of the joints estimated on Sharp's scale treatment leflunomidy in comparison with placebo statistically authentically slows down the speed of progressing of RA. At patients of the US301 group this parameter made 0,5 units a year at a speed of 2,2 units in case of placebo, and in the researches MN301/303 process stabilization whereas at placebo reception the speed of radiological progressing was 5,5 units a year was observed. Reliable distinctions at treatment leflunomidy both a methotrexate or leflunomidy and were not observed by Sulfasalazinum.

Indications to use:

According to Physician Desk Reference (2005), лефлуномид it is shown at adults for treatment of active RA, decrease in objective symptoms and improvement of a subjective condition of patients, a delay of formation of regional erosion of joints and narrowings of the joint cracks revealed roentgenoscopic. Treatment by acetylsalicylic acid, NPVS and/or low doses of corticosteroids can be continued at therapy leflunomidy. The combined use of a leflunomid with antimalarial drugs, gold drugs for intramuscular introduction or intake, Penicillaminum, Azathioprinum and a methotrexate is rather not investigated.

Route of administration and doses:

Inside. Load dose. Bystry achievement of the necessary therapeutic M1 level in a blood plasma, at the beginning of therapy leflunomidy requires use of a load dose of HP. Further, in connection with long T1/2  from M1 plasma and the recommended dosing interval (24 h), there is enough performing therapy by smaller doses. It is recommended to initiate therapy leflunomidy a load dosage on 100 mg a day within 3 days.

Maintenance therapy. The daily dose no more than 20 mg is recommended to patients with RA for treatment. At a small number of patients (n=104) receiving 25 mg/day more side reactions were revealed: baldness, loss of weight, rise in activity of liver enzymes. Doses higher than 20 mg a day are not recommended. If the dosage is not transferred to 20 mg/day clinically well, it can be lowered to 10 mg a day.

Level of activity of enzymes of a liver should be controlled and, if necessary, to carry out correction of a dosage (see. "Restrictions to use. Hepatotoxic"). Due to the prolonged time of semi-life of an active metabolite of a leflunomid, patients have to be observed carefully after a dose decline since there can pass several weeks before decrease in levels of a metabolite.

Features of use:

Need for drug removal. The active metabolite of a leflunomid is slowly brought out of plasma. In cases of manifestation of high toxicity of a leflunomid and/or hypersensitivity, use of a technique of removal of drug is necessary for more bystry decrease in concentration of HP in plasma after the therapy termination leflunomidy. The prolonged reception of Colestyraminum or absorbent carbon is necessary for achievement of bystry and sufficient removal, duration of reception can change depending on the clinical status of the patient. Colestyraminum accepted inside in a dosage of 8 g 3 times a day during 24 h by three healthy volunteers reduced the plasmatic M1 levels during 24 h approximately by 40%, and during 48 h – for 49–65%. It was shown that reception of absorbent carbon () inside or through a gastric tube (on 50 g each 6 h during 24 h) leads powder in the form of suspension to decrease in plasmatic concentration of an active metabolite of M1 by 37% for 24 h and for 48% for 48 h. These procedures of removal of drug can be repeated in case of clinical need.

Renal failure. In researches with a single dose of a leflunomid it was shown that at the patients who underwent the procedure of a hemodialysis, concentration of free M1 in plasma doubles. However there are no clinical data on use of a leflunomid for patients with renal disturbances. Therefore it is necessary to use with care drug at this group of patients.

Vaccination. Clinical data on efficiency and safety of vaccination during treatment leflunomidy are absent. However vaccination by live vaccines is not recommended. It is necessary to consider duration of time of semi-life of a leflunomid at intention of introduction of a live vaccine after the therapy termination leflunomidy.

Laboratory researches. Level of activity of ALT is the main diagnostic indicator of a hepatotoxic and has to be controlled monthly, and then, at stabilization, be determined by an individual clinical situation.

At patients with the increased risk of manifestation of a gematotoksichnost more careful control, including hematologic has to be guaranteed (see. "Restrictions to use. Possibility of an immunosuppression").

In connection with specific action on a brush border of renal proximal tubules, лефлуномид causes acceleration of removal of uric acid (uricosuric effect). At some patients the hypophosphaturia is separately observed. These effects jointly are not observed and are not alternative each other.

Use for men. Available information does not give the grounds for the assumption that use of a leflunomid increases risk of fetalis toxicity, dependent on the man. Experiments on the animals devoted to assessment of this specific risk were not conducted. For minimization of any possible risk of the man, wishing to become fathers, have to interrupt treatment leflunomidy and accept Colestyraminum inside po8 3 times daily within 11 days.

Use in pediatrics. Safety and efficiency of a leflunomid at use for children is not investigated. Use of a leflunomid by patients more young is not recommended than 18 years.

Geriatrics. At patients 65 years are more senior correction of dosing of a leflunomid is not required.

The possibility of abuse and dependence on a leflunomid is not revealed.

Information for patients. It is necessary to discuss with patients — women of childbearing age — probability of the increased risk of inborn defects at a fruit. Women at visit of the doctor need to explain that they will be in group of the increased risk of the birth of the child with inborn defects if to begin to accept лефлуномид during pregnancy, to become pregnant during passing of a course of treatment or before interruption of treatment and holding a procedure of removal of drug. The men wishing to become fathers have to interrupt treatment leflunomidy.

Patients have to be warned about a possibility of rare, but serious skin reactions, about need of urgent contact with the doctor in case of skin rash or damage of mucous membranes.

Patients have to be informed on possible hepatotoxic effects of a leflunomid and need of control of activity of enzymes of a liver.

Patients who receive immunodepressive therapy together with reception of a leflunomid or finished this therapy before treatment leflunomidy, or have essential hematologic pathology in the anamnesis, have to be informed on possible development of a pancytopenia and need of frequent hematologic control. They have to be instructed about the immediate notice of the doctor in case of detection of symptoms of a pancytopenia (easy formation of hypodermic hematomas, predisposition to infections, pallor and increased fatigue).

Side effects:

The side reactions connected using a leflunomid at treatment of RA include: diarrhea, increase in activity of liver enzymes (ALT and nuclear heating plant), alopecia and rash. The side reactions revealed during controlled tests (irrespective of causality) and observed with a frequency of 3% at least in one of the studied groups (tab. 4) are given below.

Table 4. Side effects of a leflunomid

Systems of an organism	Frequency of side reactions, %
	All researches	Placebo-controlled researches				Placebo-uncontrollable researches
		MN301 and US301				MN 302
	Leflunomid, n=13391	Leflunomid, n=315	Placebo, n=210	Sulfasalazinum, n=133	Methotrexate, n=182	Leflunomid, n=501	Methotrexate, n=498
Organism in general
Allergic reactions	2	5	2	0	6	1	2
Adynamy	3	6	4	5	6	3	3
Influenzal syndrome	2	4	2	0	7	0	0
Infections	4	0	0	0	0	0	0
Accidental injury	5	7	5	3	11	6	7
Pain	2	4	2	2	5	1
Abdominal pain	6	5	4	4	8	6	4
Dorsodynia	5	6	3	4	9	8	7
Cardiovascular
Gipertenziya2	10	9	4	4	3	10	4
Stethalgia	2	4	2	2	4	1	2
Gastrointestinal
Anorexia	3	3	2	5	2	3	3
Diarrhea	17	27	12	10	20	22	10
Dyspepsia	5	10	10	9	13	6	7
Gastroenteritis	3	1	1	0	6	3	3
Increase in a liver	5	10	2	4	10	6	17
Nausea	9	13	11	19	18	13	18
Gastrointestinal/abdominal pain	5	6	4	7	8	8	8
Ulcers in a mouth	3	5	4	3	10	3	6
Vomiting	3	5	4	4	3	3	3
Metabolism
Hypopotassemia	1	3	1	1	1	1
Weight reduction	4	2	1	2	0	2	2
Skeletal and muscular
Arthralgia	1	4	3	0	9		1
Spasms of legs	1	4	2	2	6	0	0
Diseases of joints	4	2	2	2	2	8	6
Synovitis	2		1	0	2	4	2
Tendosinovit	3	2	0	1	2	5	1
Nervous
Dizziness	4	5	3	6	5	7	6
Headache	7	13	11	12	21	10	8
Paresthesia	2	3	1	1	2	4	3
Respiratory
Bronchitis	7	5	2	4	7	8	7
Strengthening of cough	3	4	5	3	6	5	7
Respiratory infections	15	21	21	20	32	27	25
Pharyngitis	3	2	1	2	1	3	3
Pneumonia	2	3	0	0	1	2	2
Rhinitis	2	5	2	4	3	2	2
Sinusitis	2	5	5	0	10	1	1
Skin and appendages (skin)
Baldness	10	9	1	6	6	17	10
Eczema	2	1	1	1	1	3	2
Itch	4	5	2	3	2	6	2
Rash	10	12	7	11	9	11	10
Xeroderma	2	3	2	2	0	3	1
Urogenital
Infections of urinary tract	5	5	7	4	2	5	6

All patients of the US301 group accepted folic acid; in the MN301 group folic acid was not accepted; only 10% of patients of the MN302 group accepted folic acid.

^{1 -} including all controlled and not controlled tests with leflunomidy.

^{2 -} hypertensia as the state which arose prior to tests was present at all groups on a research of action of a leflunomid in the III phase of tests. The analysis of cases of again arisen hypertensia shows lack of distinctions among the studied groups.

The side reactions observed at patients from RA undergoing treatment leflunomidy in controlled clinical tests with a frequency from 1% to are presented to addition

Organism in general: abscess, cyst, fever, hernia, indisposition, pain, neck pain, pelvic pain.

Cardiovascular system: stenocardia, migraine, heartbeat, tachycardia, varicosity of veins, vasculitis, vazodilatation.

Gastrointestinal system: cholelithiasis, colitis, lock, esophagitis, meteorism, gastritis, ulitis, melena, candidiasis of a mucous membrane of an oral cavity, pharyngitis, increase in sialadens, stomatitis (or aphthous stomatitis), diseases of teeth.

Endocrine system: diabetes mellitus, hyperthyroidism.

Hemopoietic and lymphatic systems: anemia (including an iron deficiency anemia), an ecchymoma.

Metabolism: increase in activity of a kreatininfosfokinaza, hyperglycemia, lipidemia, peripheral hypostasis.

Skeletal and muscular system: arthrosis, bone necrosis, bone pain, bursitis, muscular spasms, mialgiya, rupture of a sinew.

Nervous system: alarm, a depression, dryness in a mouth, an insomniya, neuralgia, neuritis, a sleep disorder, the increased perspiration, dizziness.

Respiratory system: asthma, short wind, nasal bleeding, diseases of lungs.

Skin and appendages of skin: eels, contact dermatitis, fungal dermatitis, change of hair-dyeing and skin color, a hematoma, the herpes simplex surrounding herpes, papular rash, diseases of nails, skin diseases, skin small knots, hypodermic small knots, skin ulcers.

Sense bodys: sight illegibility, cataract, conjunctivitis, diseases of eyes, food faddism.

Urinogenital system: albuminuria, cystitis, dysuria, hamaturia, menstrual frustration, prostate diseases, increase of an urination, vaginal candidiasis.

Even more rare side reactions observed in clinical tests included the following: 1 case of anaphylactic reaction which happened during researches in the Phase II during the repeated beginning of testing of drug after interruption of treatment because of emergence of rash; small tortoiseshell; eosinophilia; tranzitorny thrombocytopenia (seldom); leukopenia ³ (seldom). In post-market researches separate cases of a pancytopenia, Stephens's syndrome — Johnson, a toxic epidermal necrolysis and a mnogoformny erythema were observed.

Interaction with other medicines:

In in vivo researches on interaction of HP insignificant interaction between leflunomidy and three-phase contraceptives for internal use, and Cimetidinum is revealed.

In vitro of a research of linkng of HP with proteins showed lack of impact of warfarin on binding by proteins of an active metabolite of M1. At the same time it was shown that M1 increases by 13–50% the maintenance of free fractions of diclofenac, an ibuprofen and Tolbutamidum in concentration of clinical range. In vitroissledovaniya of metabolism of a leflunomid showed that M1 inhibits CYP2C9 which is responsible for metabolism of NPVS. It is shown that M1 inhibits education 4 hydroxydiclofenacs from in vitro diclofenac. The clinical importance of these data is not known, however in clinical tests the accompanying use of NPVS and similar effects was widely used not observed.

Reception of Colestyraminum or absorbent carbon by patients (n=13) and volunteers (n=96) leads to bystry and reliable decrease in M1 plasma (see. "Precautionary measure").

Methotrexate. 30 patients have a joint reception of a leflunomid (100 mg/day within 2 days, further – 10–20 mg/day) and a methotrexate (10–25 mg/week with folic acid) showed lack of pharmacokinetic interaction between drugs. However joint reception increases risk of a hepatotoxic.

Gepatotoksichny drugs. Increase of side effects can be shown at joint reception of a leflunomid and gepatotoksichny connections. It needs to be taken into account when such drugs are used right after treatment leflunomidy without preliminary use of the procedure of removal of a leflunomid. In a small research (n=30) at combined use of a leflunomid and methotrexate at 5 of 30 patients 2-3-fold rises in activity of enzymes of a liver were observed. These rises decreased: in 2 cases — at continuation of reception of both drugs, in 3 cases — after cancellation of a leflunomid. More than 3-fold increase was observed at other 5 patients. These rises decreased: at 2 patients – at continuation of reception of both drugs, at the 3rd — after cancellation of a leflunomid.

Rifampicin. At joint reception of a single dose of a leflunomid and repeated doses of rifampicin the M1 levels increased approximately by 40% in comparison with their value without rifampicin reception. Therefore in connection with a possibility of increase in levels of a leflunomid at its repeated use, when sharing with rifampicin, it is necessary to show care.

Contraindications:

Hypersensitivity, pregnancy.

Restrictions to use. Possibility of an immunosuppression. Leflunomid is not recommended to patients with heavy immunodeficiencies, a marrow dysplasia, heavy, uncontrollable infections.

In not numerous messages it was indicated identification of a pancytopenia at reception of a leflunomid. In the majority of these cases patients received joint treatment by a methotrexate or other immunodepressive drugs, or therapy by these connections was cancelled before a research; in certain cases at patients in the anamnesis essential hematologic disturbances were revealed. At treatment of such patients leflunomidy therapy has to be carried out with care and under constant clinical and hematologic control. Use of a leflunomid in a combination therapy with a methotrexate in controlled researches adequately is not studied.

At identification of oppression of marrow at the patient accepting лефлуномид treatment by this drug has to be stopped, and for bystry decrease in a blood plasma of concentration of an active metabolite of a leflunomid it is necessary to use Colestyraminum or absorbent carbon (see. "pharmacology. Pharmacokinetics", "Precautionary measures. Need for drug removal").

In case the decision of replacement of a leflunomid with other antirheumatic drug with the known gematodepressivny properties is made, is reasonable to continue to control a gematotoksichnost because of possible mutual imposing of systemic action of both drugs. Removal of a leflunomid by means of Colestyraminum or absorbent carbon can reduce this risk, but can worsen a condition of the patient susceptible to treatment leflunomidy.

Skin reactions. There are messages on separate cases of emergence of a syndrome of Stephens — Johnson and a toxic epidermal necrolysis for the patients accepting лефлуномид. In case of development in the patient accepting лефлуномид, one of these states, it is necessary to interrupt therapy leflunomidy and to carry out the recommended procedure of removal of drug (see. "pharmacology. Pharmacokinetics", "Precautionary measures. Need for drug removal").

Hepatotoxic. In clinical tests treatment leflunomidy at a certain number of patients was connected with increase in activity of liver enzymes, first of all ALT and nuclear heating plant; these effects in most cases were reversible. The majority of increases in activity of transaminases was an average (the ≤2-fold upper bound of norm, VGN) and usually decreased at treatment continuation. Essential increases (> 3-fold VGN) came to light infrequently and were reversible at decrease in a dosage or interruption of treatment. The data on increase in activity of liver enzymes which were defined at clinical tests monthly are presented in table 3. It should be noted that lack of use of folic acid in clinical tests of MN302 is associated with the bigger frequency of increase in activity of liver enzymes at treatment by a methotrexate.

Preclinical stage of a disease of a liver. Due to the fact of probable risk of strengthening of toxic action on a liver, a liver role in activation, removal and recirculation of drugs, use of a leflunomid is not recommended at patients with essential disturbance of functions of a liver or infected with viruses of the hepatitis B or C.

 

Malignancy. The risk of a malignancy, especially limfoproliferativny diseases, increases using some HP with an immunodepressive effect. Leflunomid has potential of an immunodepressive effect. In clinical tests using a leflunomid increase in frequency of a malignancy or developing of limfoproliferativny diseases was not observed, however more wide-ranging and long studies are necessary for determination of possible risk of manifestation of these processes.

Drug removal technique. The following technique of removal of drug allowing to reach it the level (less than 0,02 mg/l or 0,02 mkg/ml) which is not determined in plasma after the treatment termination leflunomidy is recommended:

 

1) reception of Colestyraminum po8 g3 once a day within 11 days (it is optional to accept Colestyraminum strictly 11 days in a row if there is no need of bystry decrease in the M1 level for plasma);

2) to control smaller than 0,2 mg/l (0,2 mkg/ml) the M1 levels in plasma 2 independent tests of at least 14 days. If plasma levels are higher than 0,02 mg/l, additional reception of Colestyraminum is necessary.

Without use of a technique of removal the plasmatic M1 level can not reach values less than 0,02 mg/l within 2 years, depending on individual variations of clearance.

 

 

 

Overdose:

The data concerning overdose of a leflunomid at its use for people no. In acute toxicological experiments on mice and rats 200–500 mg/kg and 100 mg/kg, respectively were the minimum toxic doses at oral administration of a leflunomid (is approximately more than 350 times higher than the maximum dose recommended to the person). In case of considerable overdose or manifestation of toxicity, for drug removal acceleration, reception of Colestyraminum or absorbent carbon is recommended (see. "Precautionary measures. Need for drug removal").

Storage conditions:

To store at a temperature of 15-25 °C, in dry, protected from light and the place, unavailable to children. Period of validity 3 years. Not to use after the expiry date specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets of 10 mg, 20 mg and 100 mg. 20 tablets in each blister, on one, two or three blisters together with the application instruction in cardboard packaging.