Leflunomid Kanon

General characteristics. Structure:

Dosage of 10 mg:
One tablet, film coated contains: Active agent: лефлуномид 10 mg.
Excipients: hypro rod (hydroxypropyl cellulose) of 4,6 mg, hydrophosphate calcium dihydrate of 48,2 mg, starch of corn 22,8 mg, croscarmellose sodium (primelloza) of 5 mg, magnesium stearate of 1 mg, cellulose of microcrystallic 28,4 mg.
Structure of a cover: Selekoat of AQ-02003 4 mg, including: gipromelloz (gidroksipropilmetiltsellyuloz) of 2,4 mg, macrogoal 6000 (polyethyleneglycol 6000) of 0,8 mg, titanium dioxide of 0,8 mg.
Dosage of 20 mg:
One tablet, film coated contains: Active agent: лефлуномид 20 mg.
Excipients: hypro rod (hydroxypropyl cellulose) of 6,7 mg, hydrophosphate calcium dihydrate of 72 mg, starch of corn 31,7 mg, croscarmellose sodium (primelloza) of 7,5 mg, magnesium stearate of 1,5 mg, cellulose of microcrystallic 40,6 mg.
Structure of a cover: Selekoat of AQ-02003 6 mg, including: gipromelloz (gidroksipropilmetiltsellyuloz) of 3,6 mg, macrogoal 6000 (polyethyleneglycol 6000) of 1,2 mg, titanium dioxide of 1,2 mg.
Dosage of 100 mg:
One tablet, film coated contains: Active agent: лефлуномид 100 mg.
Excipients: hypro rod (hydroxypropyl cellulose) of 7,5 mg, hydrophosphate calcium dihydrate of 90 mg, starch of corn 54,1 mg, croscarmellose sodium (primelloza) of 12,9 mg, magnesium stearate of 2,5 mg, cellulose of microcrystallic 43 mg.

Structure of a cover: Selekoat of AQ-02003 10 mg, including: gipromelloz (gidroksipropilmetiltsellyuloz)  of 6 mg, macrogoal 6000 (polyethyleneglycol 6000) of 2 mg, titanium dioxide of 2 mg.

Description: Tablets, film coated white or almost white color, round, biconvex. On cross section – almost white color.

Pharmacological properties:

Pharmacodynamics. Leflunomid belongs to a class of basic antirheumatic drugs and has anti-proliferative, immunomodulatory, immunosuppressive and antiinflammatory properties. The active metabolite of a leflunomid of A771726 inhibits enzyme to a degidroorotatdegidrogenaz and has anti-proliferative activity. A771726 in the conditions of in vitro slows down the proliferation caused by mitogens and synthesis of deoxyribonucleic acid (DNA) of T lymphocytes. Anti-proliferative activity of A771726 is shown, apparently, at the level of biosynthesis of a pyrimidine as addition in cellular culture of uridine eliminates the braking action of a metabolite of A771726. With use of radio isotope ligands it is shown that A771726 selectively contacts enzyme degidroorotatdegidrogenazy, than its property to brake this enzyme and proliferation of lymphocytes at G1 stage speaks. Proliferation of lymphocytes is one of key stages of development of a pseudorheumatism.
At the same time A771726 brakes an expression of receptors to interleykinu-2 (SV-25) and antigens of a kernel Ki-67 and PCNA connected with a cellular cycle.
Therapeutic action of a leflunomid was shown on several experimental models of autoimmune diseases, including a pseudorheumatism.
Leflunomid reduces symptoms and slows down progressing of damage of joints at an active form of a pseudorheumatism.
The therapeutic effect is usually shown in 4 - 6 weeks and can increase further for 4 - 6 months.

Pharmacokinetics. Leflunomid quickly turns into the active metabolite of A771726 (primary metabolism in an intestinal wall and a liver). In plasma, urine or Calais only trace quantities of not changed leflunomid were noticed. The only defined metabolite is A771726 responsible for the main properties of the drug in vivo.
At intake from 82 to 95% of drug are absorbed. The maximum plasma concentration of A771726 are defined from 1 to 24 hours after once accepted dose. Leflunomid can be accepted together with food. Because of very long elimination half-life (T1/2) A771726 (about 2 weeks) the load dose of 100 mg a day within 3 days was used. It allowed to reach quickly an equilibrium condition of plasma concentration of A771726. Without load dose achievement of equilibrium concentration would require 2-month administration of drug. In researches with repeated use of drug the pharmacokinetic A771726 parameters were dozozavisimy in the range of doses from 5 to 25 mg. In these researches the clinical effect was closely connected with plasma concentration of A771726 and a daily dose of a leflunomid. At a dose of 20 mg a day average plasma concentration of A771726 at an equilibrium state mattered 35 mkg/ml.
In plasma there is a bystry linkng of A771726 with albumine. The untied fraction A771726 makes about 0,62%. Binding of A771726 more variable and decreases at patients with a pseudorheumatism or a chronic renal failure a little.
Leflunomid is metabolized to one main (A771726) and several minor metabolites, including 4-triflyuorometilalanin. Biotransformation of a leflunomid in A771726 and the subsequent metabolism of the A771726 are controlled by several enzymes and happen in microsomal and other cellular fractions. Interaction researches with Cimetidinum (nonspecific inhibitor of P450 cytochrome) and rifampicin (the nonspecific inductor of P450 cytochrome) showed that in vivo CYP-enzymes are involved in metabolism of a leflunomid only in insignificant degree.
Removal of A771726 from an organism slow is also characterized by clearance of 31 ml/hour Leflunomid is brought with excrements (possibly, at the expense of biliary excretion) and with urine. (T1/2) makes about 2 weeks.
A771726 pharmacokinetics at the patients who are on the chronic out-patient peritoneal dialysis (COPPD) is similar that at healthy volunteers. More bystry removal of A771726 is observed at the patients who are on a hemodialysis that is connected not with extraction of drug in dialyzate, and with its replacement from communication with protein. Though the clearance of A771726 increases approximately twice, final (T1/2) is similar to that at healthy faces as distribution volume at the same time increases.
Data on drug pharmacokinetics at patients with a liver failure are absent.
Pharmacokinetic characteristics at patients more young were not studied than 18 years. At patients of advanced age (65 years are also more senior) pharmacokinetic data approximately correspond to an average age group.

Indications to use:

- As basic means for treatment of adult patients with an active form of a pseudorheumatism for the purpose of reduction of symptoms of a disease and an arrest of development of structural injuries of joints;
- Active form of psoriasis arthritis.

Route of administration and doses:

Treatment leflunomidy has to begin under observation of the doctor having experience of treatment of a pseudorheumatism and psoriasis arthritis.
Recommendations about control of treatment see the section "Special Instructions".
Pill needs to be taken regardless of meal, to swallow entirely, washing down with enough liquid.
Treatment leflunomidy begin with intake of a shock dose 100 mg once a day, within 3 days. As a maintenance dose at a pseudorheumatism reception from 10 mg to 20 mg of a leflunomid is recommended once a day, at psoriasis arthritis – 20 mg once a day.
The therapeutic effect is usually shown in 4 – 6 weeks and can increase further up to 4 – 6 months.
No correction of a dose for patients is required 65 years are more senior.

Features of use:

Leflunomid can be applied at patients only after careful medical examination.
Washings procedure
The washings procedure is carried out according to the following scheme:
- Colestyraminum of 8 g is entered 3 times a day within 11 days;
- as an alternative - 50 g of the absorbent carbon crushed in powder 4 times a day within 11 days are entered.

Side reactions:
Before an initiation of treatment drug Leflunomid Kanon it is necessary to remember possible increase in number of side reactions at the patients who were earlier receiving other basic means for treatment of a pseudorheumatism which possess gepato-and gematotoksichesky actions. The active metabolite of a leflunomid of A771726, is characterized by the long T1/2 which is usually making from 1st to 4 weeks. Owing to a long elimination half-life of an active metabolite of a leflunomid even at the treatment termination leflunomidy serious undesirable effects can arise or remain. In this case it is necessary to carry out the washings procedure for the above-stated scheme. The procedure can be repeated according to clinical indications. At suspicion on heavy immunological/allergic reactions like Stephens's syndrome – Johnson or a Lyell's disease holding the full washings procedure is obligatory.
At emergence of similar cases of toxicity or upon transition to reception of other basic drug (for example, a methotrexate) after treatment leflunomidy it is necessary to carry out the washings procedure (see above).

Reactions of a liver:
As the active metabolite of a leflunomid of A771726 is connected with proteins and is removed by means of hepatic metabolism and biliary secretion, it is supposed that the level of contents A771726 in a blood plasma can increase at patients with a hypoproteinemia. Leflunomid is contraindicated to patients with a heavy hypoproteinemia or abnormal liver functions (see the section "Contraindications"). Reception of a leflunomid is not recommended to patients with the previous acute or chronic disease of a liver, and also to patients at whom the ALT level before an initiation of treatment exceeds the upper bound of norm twice.
It was reported about exceptional cases of development of severe damage of a liver, in some cases from the death, at treatment leflunomidy. The majority of these cases was observed within the first six months of treatment. Though the causal interrelation of these undesirable phenomena with leflunomidy is not established, and in most cases there were several accessory suspicious factors, exact implementation of recommendations about control of treatment is considered obligatory.
The ALT level has to be checked before therapy leflunomidy, and then each 2 weeks within the first 6 months of treatment, with the subsequent check once each 6 – 8 weeks. There are following recommendations about correction of the mode of dosing or to the termination of administration of drug depending on expressiveness and firmness of increase in the ALT level. At the confirmed 2-3 multiple exceeding of the upper bound of norm of ALT the dose decline from 20 mg to 10 mg a day is able to afford to continue reception of a leflunomid on condition of careful control of this indicator. If 2-3 multiple exceeding of the upper bound of norm of ALT remain or if there is a confirmed rise in the ALT level exceeding the upper bound of norm more than by 3 times, reception of a leflunomid has to be stopped and it is necessary to begin the washings procedure.
Because of possible additional hepatotoxic effects Leflunomid Kanon is recommended to refrain from alcohol intake at treatment by drug.

Hematologic reactions:
Full clinical blood test, including definition of a leukocytic formula and quantity of thrombocytes, has to be carried out prior to treatment leflunomidy, and also each 2 weeks within the first 6 months of treatment and then each 6-8 weeks.
At patients with the anemia which was earlier taking place, a leukopenia and/or thrombocytopenia, and also at patients with dysfunctions of marrow or with risk of development of such disturbances, danger of emergence of hematologic disturbances increases. At emergence of this sort of the phenomena it is necessary to use the washings procedure for decrease in the A771726 level in a blood plasma.
In case of development of serious hematologic reactions, including a pancytopenia, it is necessary to stop administration of drug Leflunomid Kanon and any other accompanying drug suppressing a marrowy hemopoiesis and to begin the washings procedure.

Combined use with other types of treatment:
There are no data of rather combined use of a leflunomid with the antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), entered intramusculary or orally, gold drugs, D-Penicillaminum, Azathioprinum and other immunodepressive means except for a methotrexate now. The risk connected using a combination therapy, especially at prolonged treatment is not known. As such therapy can lead to development of additional or even synergistic toxicity (for example, gepato-or gematotoksichnost), combinations of this drug with other basic drugs (for example, a methotrexate) are not desirable.

Transition to other types of treatment:
As лефлуномид in an organism, transition to reception of other basic drug long remains (for example, a methotrexate) without the corresponding holding the washings procedure can increase possibility of additional risk even later a long time after transition (for example, kinetic interaction, an organotoksichnost).
Similarly recent treatment by gepatotoksichny or gematotoksichny drugs (for example, a methotrexate) can lead to increase in number of by-effects therefore, beginning treatment leflunomidy, it is necessary to consider carefully all positive and negative aspects connected with reception of this drug.

Skin reactions:
In case of development of a stomacace it is necessary to stop reception of a leflunomid.
It was reported about very exceptional cases of emergence of a syndrome of Stephens – Johnson or a toxic epidermal necrolysis at the patients receiving лефлуномид. In case of skin reactions and/or reactions from mucous membranes it is necessary to cancel administration of drug Leflunomid Kanon and any other related drug and to immediately begin the washings procedure. It is necessary to reach full removal of drug from an organism. In similar cases repeated purpose of drug is contraindicated.

Infections:
It is known that drugs, similar to a leflunomid and having immunosuppressive properties, do patients more sensitive to different infections, including opportunistic infections (the infection caused by the fungi and microorganisms capable to cause infections only in the conditions of decrease in immunity). The arisen infectious diseases proceed, as a rule, hard and demand early and intensive treatment. When developing a serious infectious disease treatment interruption leflunomidy and the beginning of the washings procedure can be necessary.
It is necessary to watch carefully patients with positive reaction to tuberculine because of risk of reactivation of tuberculosis.

Reactions of respiratory tracts:
At therapy leflunomidy exceptional cases of intersticial pulmonary process were celebrated. Such symptoms as cough and диспноэ can serve as the reason of the termination of reception of a leflunomid.

Arterial pressure:
Before an initiation of treatment leflunomidy and periodically after its beginning it is necessary to control the level of arterial pressure.

Interactions:
It is necessary to be careful at use of the drugs which are metabolized under the influence of CYP2C9 (Phenytoinum, warfarin, Tolbutamidum) except for NPVP.

Recommendations for men:
There is no emergence of the fetotoksichnost connected with toxic influence of drug on the father's spermatozoa given about risk at use of a leflunomid by men. For the maximum reduction of possible risk men when planning appearance of the child need to stop reception of a leflunomid and to carry out the washings procedure.

Use at renal failures:
Use at a moderate or heavy renal failure is contraindicated (because of insignificant experience of clinical observations). There are no special recommendations concerning a dosage at patients with a renal failure of easy degree.

Influence on ability of control of vehicles and mechanisms:
Administration of drug can be followed by a headache, dizziness. In this regard the patients accepting лефлуномид should show care at management of dangerous mechanical means, including the car.

Side effects:

Frequency of side effects is specified in the following gradation: very often (more than 1/10); often (more than 1/100, less than 1/10); infrequently (more than 1/1000, less than 1/100); seldom (more than 1/10000, less than 1/1000); very seldom (less than 1/10000), including separate messages.
From cardiovascular system
Often: moderate increase in arterial pressure; Seldom: the expressed increase in arterial pressure;
Frequency is unknown: stenocardia, migraine, heart consciousness, tachycardia, varicosity, vasculitis, vazodilatation.
From digestive tract
Often: diarrhea, nausea, vomiting, diseases of a mucous oral cavity (for example, aphthous stomatitis, ulceration of lips), abdominal cavity pains; Infrequently: disturbance of flavoring feelings; Very seldom: pancreatitis; Frequency is unknown: ulitis, candidiasis of an oral cavity, esophagitis, gastritis, gastroenteritis, dyspepsia, colitis, lock, meteorism, melena.
From gepato-biliary system
Often: increase in activity of "hepatic" transaminases (alaninaminotranspherase (ALT), gamma глутамилтранспептидазы (GGT), alkaline phosphatase (AP), hyperbilirubinemia;
Seldom: hepatitis, cholestasia, jaundice, cholelithiasis; Very seldom: severe damages of a liver (including a liver failure, an acute necrosis of a liver) which can be fatal.
From a respiratory organs
Often: respiratory upper respiratory tract infections, cough; Seldom: intersticial pulmonary process (including intersticial pneumonia and pulmonary fibrosis) with a possible lethal outcome; Frequency is unknown: asthma, short wind, nasal bleeding.
Disbolism and food
Often: increase in a kreatinfosfokinaza (KFK); Infrequently: hypopotassemia, lipidemia, hypophosphatemia;
Seldom: increase in level of a lactate dehydrogenase; Frequency is unknown: hypolithemia, diabetes mellitus, hyper thyroidism, peripheral hypostases.
From a nervous system
Often: headache, dizziness, paresthesias; Infrequently: concern; Very seldom: peripheral neuropathy;
Frequency is unknown: uneasiness, a depression, dryness of a mucous membrane of an oral cavity, a sleep disorder, neuralgia, neuritis, the increased sweating.
From a musculoskeletal system
Often: tendovaginitis; Infrequently: rupture of sinews; Frequency is unknown: arthralgia, synovitis, muscular spasms, arthrosis, bone necrosis, bursitis, mialgiya.
From skin and hypodermic cellulose
Often: the strengthened hair loss, an alopecia, eczema, skin rash (including makulopapulezny), a skin itch, a xeroderma; Infrequently: small tortoiseshell; Very seldom: toxic epidermal necrolysis (Lyell's disease), multiformny erythema, Stephens-Johnson's syndrome; Frequency is unknown: acne, contact dermatitis, fungal dermatitis, discoloration of hair, herpes simplex, shingles, damage of nails, disturbance of a xanthopathy, skin ulceration.

From immune system
Often: allergic reactions; Very seldom: serious anaphylactic/anaphylactoid reactions, Quincke's disease.
Infections and invasions
Seldom: heavy infections (including opportunistic and sepsis) which can be fatal;
The risk of developing of infectious diseases, in particular, of rhinitis, bronchitis and pneumonia is increased.
System of a hemopoiesis and lymphatic system
Often: leukopenia (leukocytes> 2000/mkl); Infrequently: anemia, thrombocytopenia of easy degree (thrombocytes> 100 000/mkl);
Seldom: a pancytopenia (apparently due to anti-proliferative action), an eosinophilia, a leukopenia (leukocytes <2000/mkl); Very seldom: agranulocytosis.
The recent, accompanying or subsequent use of potentially miyelotoksichny agents can be associated with a bigger risk degree of hematologic effects.
From reproductive system
Frequency is unknown: insignificant decrease in concentration of sperm, total quantity of spermatozoa and their mobility.
From kidneys and urinary system
Frequency is unknown: infections of an urinary system, a renal failure, an albuminuria, cystitis, a dysuria, a hamaturia, damage of a prostate gland, the speeded-up urination, vaginal candidiasis.
From sense bodys
Frequency is unknown: illegibility of visual perception, cataract, conjunctivitis, taste disturbances.
The general
Often: anorexia, loss of body weight (usually insignificant), adynamy; Frequency is unknown: fever, weakness.
Other
The risk of emergence malignant, especially limfoproliferativny, diseases increases when using some immunodepressive drugs.

Interaction with other medicines:

Strengthening of side effects can take place in case of the recent or accompanying use gepatotoksichny (including alcohol) or gematotoksichny and immunosuppressive drugs or when reception of these drugs is begun after treatment leflunomidy without the washings procedure (see. "Special instructions").
At patients with a pseudorheumatism no pharmacokinetic interaction between leflunomidy (10 – 20 mg a day) and a methotrexate was revealed (10 – 25 mg a week).
The concomitant use of Colestyraminum or absorbent carbon as it leads to bystry and considerable decrease in concentration of A771726 in a blood plasma is not recommended to the patients accepting лефлуномид. It is considered that it is caused by disturbance of recirculation of A771726 in a liver and a small bowel and/or disturbance of its gastrointestinal dialysis.
If the patient already accepts non-steroidal anti-inflammatory drugs (NPVP) and/or corticosteroids, they can continue to be accepted after an initiation of treatment leflunomidy.
The enzymes participating in metabolism of a leflunomid and its metabolites are definitely not known. The research in vivo of its interaction with Cimetidinum (nonspecific inhibitor of P450 cytochrome) showed lack of essential interaction. After the accompanying introduction of a single dose of a leflunomid to the subjects receiving repeated doses of rifampicin (the nonspecific inductor of P450 cytochrome), the peak A771726 levels increased approximately for 40% whereas the area under a curve "concentration time" significantly did not change. The mechanism of this effect is not clear.
The researches in vitro showed that A771726 oppresses activity of P4502C9 (CYP2C9) cytochrome. In clinical trials no problems at combined use of a leflunomid and NPVP which are metabolized CYP2C9 were observed. With extra care it is necessary to apply лефлуномид together with other drugs which are not NPVP which are metabolized by means of CYP2C9 such as Phenytoinum, warfarin and Tolbutamidum. It was reported about increase in an indicator of a prothrombin time at simultaneous use of a leflunomid and warfarin.
In a research in which лефлуномид gave to female healthy volunteers together with the three-phase peroral contraceptives containing 30 mkg of ethinylestradiol of any decrease in contraceptive effect of contraceptives it was revealed not, and A771726 pharmacokinetics completely corresponded to the provided range.
Now there are no data of rather combined use of a leflunomid with the antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold drugs (intramusculary or orally), D-Penicillaminum, Azathioprinum and other immunodepressive medicines (except for a methotrexate). The risk connected with carrying out a combination therapy, especially at prolonged treatment is unknown. As such therapy can lead to development of additional or even synergistic toxicity (for example, gepato-or gematoksichnost), combinations of this drug with other basic drugs (for example, a methotrexate) are undesirable. The recent accompanying or subsequent use of potentially miyelotoksichny agents can be connected with a bigger risk degree of hematologic influences. Immunodepressants increase risk of development of infections, and also malignant, especially limfoproliferativny diseases.
Vaccination
There are no clinical data on effectiveness and safety of vaccination in the conditions of treatment leflunomidy. Nevertheless, it is not recommended to carry out vaccination by live vaccines. When planning vaccination by a live vaccine it is necessary to consider long T1/2 of a leflunomid after drug withdrawal.

Contraindications:

Hypersensitivity to a leflunomid or any other component of drug;
- Abnormal liver functions;
- Heavy immunodeficiency (including, acquired immunodeficiency syndrome);
- Considerable disturbances of a marrowy hemopoiesis or the expressed anemia, a leukopenia or thrombocytopenia as a result of other reasons (except a pseudorheumatism);
- Heavy, uncontrollable infections;
- A moderate or heavy renal failure (clearance of creatinine less than 60 ml/min., in view of small experience of clinical observation);
- A heavy hypoproteinemia (for example, at a nephrotic syndrome);
- At pregnant women or women of childbearing age who are not using methods of reliable contraception during treatment leflunomidy and until the plasma level of an active metabolite remains higher than 0,02 mg/l (see the section "Use during Pregnancy and during Breastfeeding"). Pregnancy has to be excluded before an initiation of treatment leflunomidy;
- During breastfeeding (see the section "Use during Pregnancy and during Breastfeeding");
- Children's age (18 years are younger), due to the lack of data on efficiency and safety.
The men receiving treatment leflunomidy have to be warned about the possible fetotoksichesky effect of drug (connected with its possible influence on the father's spermatozoa) and about need of use of well-tried remedies of contraception;

Use during pregnancy and during breastfeeding:
Leflunomid pregnant women or women of childbearing age who do not use reliable contraception at treatment leflunomidy and certain time after this treatment (the period of expectation or the reduced period of "washing" cannot apply; see below). Prior to treatment Leflunomid Kanon it is necessary to be convinced by drug of lack of pregnancy.
Patients need to be informed that as soon as there comes the delay monthly or if there is other reason to assume pregnancy approach, they have to report immediately about it to the doctor to make the test for pregnancy. In case of positive test for pregnancy the doctor has to discuss about sick possible risk to which this pregnancy is exposed. It is possible that bystry decrease in level of maintenance of an active metabolite in blood by means of the procedure of removal of drug described below will help monthly to reduce risk to which the fruit from a leflunomid is exposed at the first delay.
To women who accept лефлуномид and want to become pregnant, it is recommended to follow one of stated below procedures to be confident that the fruit will not be subject to influence of toxic concentration of A771726 (control concentration lower than 0,02 mg/l).
Expectation period
It is possible to expect that concentration of A771726 in a blood plasma can be higher than 0,02 mg/l during the long period. It is considered that its concentration can become less than 0,02 mg/l in 2 years after the treatment termination leflunomidy.
The first time concentration of A771726 is measured in a blood plasma after the two-year period of expectation.
After that it is necessary to measure concentration of A771726 in a blood plasma, at least, in 14 days. If the size of both measurements is lower than 0,02 mg/l, no teratogenic risk is expected.
Washings procedure
- Colestyraminum of 8 g is entered 3 times a day within 11 days;
- as an alternative 50 g of the absorbent carbon crushed in powder are entered 4 times a day within 11 days.
Irrespective of the chosen washings procedure it is necessary to carry out an inspection two separate tests with an interval, at least, in 14 days and to wait one and a half months since that moment when concentration of drug in plasma is for the first time recorded lower than 0,02 mg/l, until fertilization.
It is necessary to inform women of the genital period on what has to pass 2 years after the treatment termination leflunomidy before they can try to become pregnant. If the 2-year period of expectation at reliable contraception seems unreasonable, it is possible to advise to carry out the washings procedure in the preventive purposes.
Both Colestyraminum and absorbent carbon can influence absorption of estrogen and progestogens therefore well-tried peroral contraceptives do not give an absolute guarantee during "washing" by means of Colestyraminum or absorbent carbon. It is recommended to use alternative methods of contraception.
Researches on animals showed that лефлуномид or its metabolites pass into breast milk therefore the women nursing should not accept drug.

Overdose:

Symptoms
The patients receiving лефлуномид in a dose up to five times had messages on chronic overdose the exceeding recommended daily dose, and also messages on acute overdose for adults and children. In most cases the overdose was not reported about development of side reactions. The arising side reactions were comparable to a profile of safety of a leflunomid. Diarrhea, abdominal pains, a leukopenia, anemia and increase in indicators of tests of a functional condition of a liver were the most often observed side reactions.
Treatment
In case of overdose or toxicity it is recommended to accept Colestyraminum or absorbent carbon to accelerate clarification of an organism.
Colestyraminum accepted orally on 8 g 3 times a day within a day reduces the maintenance of A771726 in plasma approximately by 40% in 24 hours, and for 49-65% in 48 hours. Administration of absorbent carbon (in the form of suspension) orally or through a gastric tube (to 50 g there are each 6 hours within a day) reduces concentration of an active metabolite of A771726 in plasma by 37% in 24 hours, and for 48% in 48 hours. These procedures can be repeated according to clinical indications.
Researches with a hemodialysis and HAPD specify that A771726, the main metabolite of a leflunomid, is not capable to be removed by dialysis.

Storage conditions:

In the dry, protected from light place at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity: 2 years. Not to apply after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated on 10 mg, 20 mg or 100 mg.
For tablets dosage of 10 mg and 20 mg: on 10, 20 or 30 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 3, 6, 10 blister strip packagings on 10 tablets or on 3, 5 blister strip packagings on 20 tablets or on 1, 2, 3, 4 blister strip packagings on 30 tablets together with the application instruction place in a pack from a cardboard.
For tablets dosage of 100 mg: on 3 or 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.
On 1 blister strip packaging on 3 tablets or on 1 blister strip packaging on 10 tablets together with the application instruction place in a pack from a cardboard.