Leflunomide - instructions for use, dose, side effects, contraindications

Excipients: cellulose microcrystalline 81.9 mg, lactose monohydrate 44.6 mg, povidone (Kollidon 25 or Kollidon 30, Plasdon K-25, or Plasdon K-29/32) 3.0 mg, crospovidone 7.5 mg, silicon dioxide colloid 1 , 5 mg, magnesium stearate 1.5 mg;

Sheath: opadrai II (series 85) yellow 5,0 mg, containing in its composition polyvinyl alcohol, partially hydrolyzed 2.0 mg, talc 0.74 mg, macrogol 3350 (polyethylene glycol 3350) 1.01 mg, pigments: titanium dioxide 1, 2495 mg, aluminum lacquer based on quinoline yellow dye 0.0005 mg.

For the dosage of 20 mg:

One tablet, film-coated, contains:

Active substance: Leflunomide 20 mg;

Excipients: cellulose microcrystalline 163.8 mg, lactose

monohydrate 89.2 mg, povidone (Kollidon 25 or Kollidon 30, Plasdon K-25, or Plasdon K-29/32) 6.0 mg, crospovidone 15.0 mg, silicon dioxide colloid 3.0 mg, magnesium stearate 3.0 mg;

Sheath: opadrai II (series 85) yellow 10.0 mg, containing in its composition polyvinyl alcohol, partially hydrolyzed 4.0 mg, talc 1.48 mg, macrogol 3350 (polyethylene glycol 3350), 2.02 mg, coloring pigments: titanium dioxide 2, 4 mg, an aluminum varnish on the basis of a dye of quinoline yellow 0,1 mg.

Description:

For the dosage of 10 mg - film-coated tablets, almost white or white with a yellowish hue, round, biconvex.

For the dosage of 20 mg - film-coated tablets, yellow or yellow with a greenish hue, round, biconvex.

On the cross-section, the core of the tablets of both dosages is white or almost white Colour.

Pharmacotherapeutic group:Immunosuppressive remedy

ATX: & nbsp

L.04.A.A.13 Leflunomide

L.04.A.A Selective immunosuppressants

Pharmacodynamics:

A basic antirheumatic drug with antiproliferative, immunosuppressive and anti-inflammatory properties.The active metabolite leflunomide - teriflunomide (А771726), responsible for the basic properties of the drug in vivo, inhibits dehydroorotate dehydrogenase and exhibits antiproliferative activity. A771726 in vitro inhibits proliferation caused by mitogens and the synthesis of T-lymphocyte DNA. The antiproliferative activity of A771726 appears, apparently, at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the metabolite A771726. Using radioisotope ligands it was shown that A771726 selectively binds to dehydroorotate dehydrogenase, which explains its property to inhibit this enzyme and the proliferation of lymphocytes in stage G1. Proliferation of lymphocytes is one of the key stages in the development of rheumatoid arthritis.

At the same time, A771726 inhibits the expression of receptors for interleukin-2 (Cd-25) and antigens of the nucleus Ki-67 and PCNA, associated with the cell cycle.

The therapeutic effect usually manifests itself in 4-6 weeks and can grow further in 4-6 months.

Pharmacokinetics:

Leflunomide quickly turns into its active metabolite teriflunomide A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces trace amounts of unchanged leflunomide are found. The only detectable leflunomide metabolite is A771726.

Suction

When ingested absorbed from 82 to 95% of the drug. Taking leflunomide with food does not affect bioavailability.

Distribution

The maximum plasma concentrations of A771726 are determined from 1 to 24 hours after a single dose. Stable concentration in the plasma is achieved after about 7 weeks, if not assigned a loading dose. A long half-life of A771726 (about 2 weeks) allows to reach a stable concentration faster when using a saturating dose of 100 mg / day in the first 3 days of treatment.

When used as a maintenance dose of 20 mg / day, the average concentration of A771726 in the plasma stabilizes at approximately 35 mg / l.

Plasma rapidly binds A771726 to albumins. The unbound fraction of A771726 is approximately 0.62%. Binding of A771726 is more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Metabolism

Leflunomide is metabolized to one major (A771726) and several secondary metabolites, including 4-trifluoromethylaniline. Biotransformation of leflunomide in A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cell fractions. Investigations of interaction with cimetidine (nonspecific inhibitor of cytochrome P450) and rifampicin (nonspecific inducer of cytochrome P450) showed that in vivo CYP-enzymes are involved in the metabolism of leflunomide only in an insignificant degree.

Excretion

Excretion of A771726 from the body is slow and characterized by a clearance of 31 ml / h. Leflunomide is excreted with feces (probably due to biliary excretion) and with urine. The half-life (T1 / 2) is about 2 weeks.

The pharmacokinetics of A771726 in patients on chronic outpatient peritoneal dialysis is similar to that of healthy volunteers. A faster excretion of A771726 is observed in patients on hemodialysis, which is not due to the extraction of the drug into the dialysate, but to its removal from the bond with the protein. Although the clearance of A771726 increases approximately 2-fold, the terminal half-life is similar to that of healthy individuals,since at the same time the volume of distribution increases.

Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent.

Pharmacokinetic characteristics in patients under the age of 18 years have not been studied.

In elderly patients (65 years and older), the pharmacokinetic data roughly correspond to the average age group.

Indications:

As a basic drug for the treatment of adult patients with active form of rheumatoid arthritis in order to reduce the symptoms of the disease and delay the development of structural damage to the joints.

Active form of psoriatic arthritis.

Contraindications:

Hypersensitivity to leflunomide or other components of the drug, hepatic insufficiency, severe immunodeficiency (including AIDS), serious disturbance of bone marrow hematopoiesis or severe anemia, leukopenia (less than white blood cells 2,5x10⁹/ l), neutropenia (neutrophil count less than 1,5x10⁹/ l) or thrombocytopenia (platelet count less than 100x10⁹/ l), not associated with rheumatoid or psoriatic arthritis, severe, uncontrolled infections,moderate or severe renal failure (creatinine clearance less than 60 ml / min), severe hypoproteinemia (including nephrotic syndrome), leflunomide contraindicated in pregnancy, as well as women of reproductive age who do not exclude the possibility of becoming pregnant during the treatment period leflunomide, after completion of treatment with leflunomide, women should not become pregnant until the plasma concentration of the active metabolite remains above 0.02 mg / L (see section "Application during pregnancy and during breastfeeding"), lactation period (see " Application during pregnancy and during breastfeeding "), the age of 18 years, due to the lack of data on efficacy and safety in this group of patients.

Lactose intolerance, deficiency of lactase or glucose-galactose malabsorption.

Men receiving treatment with leflunomide should be warned about the possible toxic effects of the drug on spermatozoa. During the period of application of the drug, men need to take measures to protect their partner from pregnancy.

Carefully:

Patients with interstitial lung diseases due to an increased risk of interstitial lung injury (see section "Special instructions").

Patients with anemia, leukopenia, thrombocytopenia and impaired bone marrow hematopoiesis in the anamnesis; patients who have recently received or are receiving concomitantly with leflunomide medications with immunosuppressive or hematotoxic action; patients with unrelated to rheumatoid arthritis significant deviations from the norm of hematological parameters before treatment with leflunomide; with a white blood cell count less than 4х10⁹/ l, neutrophils 2х10⁹/ l, platelets 150x10⁹/ l. When treating leflunomide requires frequent hematological control, see section "Special instructions".

When using medicines (with the exception of non-steroidal anti-inflammatory drugs), which are metabolized by an isoenzyme CYP2C9, such as phenytoin, warfarin, tolbutamide, fenprokumone.

Patients aged more than 60 years, with the simultaneous use of other neurotoxic drugs and diabetes mellitus (due to the increased risk of peripheral neuropathy, see section "Special instructions").

Renal insufficiency of mild severity (creatinine clearance 60 - 80 ml / min) due to limited clinical experience.

Pregnancy and lactation:

The drug is contraindicated in pregnancy.It is necessary to inform women of childbearing age that the onset of pregnancy is possible only 2 years after stopping treatment with leflunomide.

Women should be convinced of the absence of pregnancy before treatment with leflunomide. Before beginning treatment with leflunomide, patients should be explained a serious potential risk of exposure to the fetus. In case of suspicion of pregnancy it is necessary to immediately inform the doctor about it for the purpose of testing for pregnancy, and in case of a positive reaction the doctor should discuss with the patient the possible risk to which this pregnancy is exposed. Rapid reduction in the concentration of active metabolite in the blood in case of suspected pregnancy can be achieved through the procedure of "laundering" the drug (see below), this will help reduce the risk to which the fetus is exposed.

Women who take leflunomide and want to become pregnant, it is necessary to stop taking the drug and follow one of the procedures below to make sure that the fetus is not exposed to toxic concentrations of A771726 (control concentration below 0.02 mg / L).

Waiting period

It can be expected that the concentration of A771726 in the blood plasma can be above 0.02 mg / L for a long period. It is believed that the concentration of the metabolite can decrease below 0.02 mg / l only 2 years after the cessation of leflunomide treatment. At this time, it is necessary to abstain from conceiving a child.

After a two-year waiting period, the concentration of A771726 in the blood plasma is measured. The concentration of A771726 is then measured again with an interval of at least 14 days. If the value of both measurements is less than 0.02 mg / l, there is no risk of teratogenic effects.

The procedure for "laundering"

After stopping the drug, go through the procedure of "laundering":

- Colestyramine 8 g is administered 3 times a day for 11 days;

- as an alternative, 50 g of activated carbon powdered into powder is taken 4 times a day for 11 days.

After the procedure of "laundering" it is necessary to control the plasma concentration of metabolite A771726 less than 0.02 mg / l twice with an interval of at least 14 days. If the active metabolite A771726 content in blood serum is higher than 0.02 mg / l, consideration should be given to repeating the procedure for "laundering".

Regardless of the chosen procedure for removing leflunomide from the body, the onset of pregnancy is possible only after a two-fold (with an interval of 14 days) of testing the concentration of A771726. Fertilization is possible only 1.5 months after the concentration of the active metabolite is established below 0.02 mg / l.

After discontinuing leflunomide administration, it is recommended that all women of childbearing age undergo the procedure of "laundering" from the drug.

It is possible to reduce the contraceptive activity of oral contraceptive medications during the "washing" procedure with colestyramine or activated charcoal, which may affect the absorption of estrogens and progestogens. Thus, oral contraceptives do not guarantee the necessary contraception during the period of "laundering" from the drug.

Leflunomide and its metabolites penetrate into breast milk, so leflunomide contraindicated in breastfeeding.

Pediatric Use:

Leflunomide is not recommended for use in patients under 18 years of age, as there is no data on the efficacy and safety of the drug in this group of patients.

Dosing and Administration:

Tablets should be swallowed whole, with enough liquid. Eating does not affect the absorption of leflunomide.

Treatment with leflunomide should begin under the supervision of a physician with experience in the treatment of rheumatoid arthritis and psoriatic arthritis.

Recommendations for treatment control, see section "Special instructions".

Treatment of rheumatoid arthritis

Treatment of rheumatoid arthritis with leflunomide usually begins with a single dose within a day of ingestion of a shock dose of 100 mg (take 5 tablets with a dosage of 20 mg simultaneously) for 3 days. However, the exclusion of a loading dose may reduce the risk of side effects (especially from the gastrointestinal tract and the effect on the activity of "hepatic" enzymes in the blood). The recommended maintenance dose is 20 mg leflunomide once a day. When taking a maintenance dose of 20 mg once a day immediately after the start of treatment (that is, without taking a loading dose), the effectiveness of the drug in rheumatoid arthritis did not decrease. In the case of poor tolerability of a dosage of 20 mg, a dose reduction of up to 10 mg once a day is possible.

Treatment of psoriatic arthritis

Treatment with leflunomide psoriatic arthritis also begins with a loading dose of 100 mg (take 5 tablets with a dosage of 20 mg at a time) once a day for 3 days. The maintenance dose is 20 mg leflunomide once a day.

With both indications (rheumatoid and psoriatic arthritis), the therapeutic effect usually manifests itself after 4 weeks and can then increase to 4-6 months.

Therapy is usually carried out for a long time.

Special patient groups

Patients with impaired hepatic function

Recommendations for dose adjustment or drug withdrawal depending on the severity or persistence of alanine aminotransferase elevation on the background of taking the drug, see "Special instructions".

Patients with impaired renal function

The current experience is not enough to give special recommendations on the dosing regimen in patients with impaired renal function. It should be taken into account that the active metabolite leflunomide A771726 has a high affinity for proteins.

Elderly patients

Do not require dose adjustment in patients older than 65 years.

Side effects:

Classification of the alleged frequency of side effects:

very frequent (more than 1/10), frequent (more than 1/100, but less than 1/10), infrequent (more than 1/1000, but less than 1/100), rare (more than 1/10000, but less than 1/1000) , very rare (less than 1/10000), unknown frequency (based on the available data to estimate the incidence of side effects is not possible).

From the cardiovascular system:

Frequent: moderate increase in blood pressure.

Rare: significant increase in blood pressure.

From the gastrointestinal tract:

Frequent: diarrhea, nausea, vomiting, decreased appetite, erosive and ulcerative lesions of the oral mucosa (aphthous stomatitis, ulceration of the oral mucosa), abdominal pain.

Infrequent: a violation of taste.

Very rare: pancreatitis.

On the part of the respiratory system and mediastinal disorders:

Rare: interstitial lung diseases (including interstitial pneumonia), with a possible fatal outcome.

Metabolic disorders:

Frequent: a slight increase in creatine phosphokinase.

Infrequent: hypokalemia, insignificant hyperlipidemia, insignificant hypophosphatemia.

The frequency is unknown: a slight increase in lactate dehydrogenase activity, hypo-uricemia due to the uricuric effect.

From the nervous system:

Frequent: headache, dizziness, paresthesia.

Infrequent: anxiety.

Very rare: peripheral neuropathy.

From the side of the musculoskeletal and connective tissue:

Frequency unknown: tendosynovitis and rupture of tendons (causal relationship with leflunomide treatment not established).

From the skin and subcutaneous tissues:

Frequent: increased hair loss, eczema, itching, dry skin.

Infrequent: hives.

Very rare: toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome (currently causal relationship with leflunomide treatment has not been established, but it can not be ruled out).

Unknown frequency: discoid lupus erythematosus, pustular psoriasis or exacerbation of psoriasis.

From the immune system:

Frequent: mild allergic reactions, including maculopapular rash and other types of rash.

Very rare: severe anaphylactic / anaphylactoid reactions, vasculitis, including, skin necrotic vasculitis (due to the underlying disease, the causal relationship with leflunomide treatment can not be established).

Infectious and parasitic diseases:

Rare: development of severe infections and sepsis, which can be fatal.

Drugs with immunosuppressive action can make a patient more susceptible to infections, including opportunistic infections.

May increase the number of possible infections (in particular, rhinitis, bronchitis and pneumonia).

From the hemopoietic system and lymphatic system:

Frequent: leukopenia (leukocytes more 2,0x10⁹/ l).

Infrequent: anemia, minor thrombocytopenia (platelets less than 150x10%).

Rare: pancytopenia (probably due to antiproliferative action), leukopenia (leukocytes less 2,0x10%), eosinophilia.

Very rare: agranulocytosis.

The recent, concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematological effects.

From the liver and bile ducts:

Frequent: increase activity of "liver" transaminases (special alanine aminotransferase, less often - gamma-glutamyltranspeptidase and alkaline phosphatase), hyperbilirubinemia.

Rare: hepatitis, jaundice / cholestasis.

Very rare: severe liver damage, such as hepatic insufficiency, acute liver necrosis, which can be fatal.

Metabolic and nutritional disorders:

Frequent: weight loss, asthenia.

Very rarely: anorexia.

On the part of the reproductive system:

The frequency is unknown: in men, a slight decrease in the concentration of sperm, the total number of spermatozoa and their mobility.

From the side of the kidneys and urinary tract:

Frequency unknown: renal failure.

Benign, malignant and unspecified neoplasms:

It is known that using some immunosuppressive drugs increases the risk of malignancy, especially the risk of developing lymphoproliferative diseases.

Overdose:

There have been reports of chronic overdose in patients receiving leflunomide in a dose up to five times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases, overdose has not been reported on the development of adverse events. The arising undesirable phenomena were comparable with the safety profile of leflunomide. The most frequently observed adverse events were diarrhea, abdominal pain, leukopenia, anemia and increased activity of "hepatic" enzymes.

Treatment

In case of overdose or toxic reactions, it is recommended to take colestramine or Activated carbon, to accelerate the cleansing of the body. Kolestyramine, taken orally 8 g 3 times a day during the day, reduces the A771726 plasma content by about 40% after 24 hours and at 49-65% after 48 hours.

It has been shown that the administration of activated carbon (as a suspension) orally or through a gastric tube (at a dose of 50 g every 6 hours during the day) reduces the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and 48%

These procedures for "laundering" can be repeated according to clinical indications. Studies with hemodialysis and chronic outpatient peritoneal dialysis indicate that A771726, the main leflunomide metabolite, is not able to be eliminated by dialysis.

Interaction:

In patients with rheumatoid arthritis, no pharmacokinetic interaction was observed between leflunomide (10-20 mg per day) and methotrexate (10-25 mg per week).

Patients receiving leflunomide, it is recommended not to assign colestramine or Activated carbon, as this leads to a rapid and significant decrease in the concentration of A771726 (the active metabolite leflunomide) in the blood plasma.It is believed that this is due to a violation of intestinal hepatic recirculation A771726 and / or a violation of its gastrointestinal dialysis.

If the patient is already taking non-steroidal anti-inflammatory drugs and / or glucocorticosteroids, they can continue to be taken after the start of treatment with leflunomide.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. Clinically significant interaction with cimetidine (nonspecific inhibitor of cytochrome P450) is absent. After the concomitant administration of a single dose of leflunomide against a background of multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), the maximum concentrations in the blood plasma (Cmah) A771726 increased by about 40%, while the area under the concentration-time curve (AUC) has not changed significantly. The mechanism of this effect is not clear.

Research in vitro showed that A771726 depresses the activity of the isoenzyme CYP2C9. Drugs metabolized by isoenzyme CYP2C9 are the phenytoin, warfarin, tolbutamide, non-steroidal anti-inflammatory drugs. In clinical studies, there were no problems with co-administration of leflunomide and non-steroidal anti-inflammatory drugs,metabolized by isoenzyme CYP2C9. With extreme caution should be given leflunomide together with phenytoin and tolbutamide, since it is impossible to exclude the possibility of their interaction with leflunomide at the level of metabolism, although there is no clinical data on such an interaction. An increase in prothrombin time was reported with the simultaneous use of leflunomide and warfarin.

There is no reduction in the contraceptive effect when combined with three-phase oral contraceptive medications containing 30 μg of ethinylestradiol, while the pharmacokinetics of A771726 did not change.

Currently, there is no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (intramuscularly or orally), Dpenicillamine, azathioprine and other immunosuppressive drugs (with the exception of methotrexate, see above). The risk associated with complex therapy is unknown, especially with long-term treatment.Since this type of therapy may lead to the development of additional or even synergistic toxicity (eg, hepatotoxicity or hematotoxicity), combinations of this drug with other basic drugs (eg methotrexate) are undesirable.

The recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects.

Immunosuppressants increase the risk of infections, as well as malignant, especially lymphoproliferative, diseases.

There is no data on the efficacy and safety of vaccination against leflunomide treatment. However, vaccination with live vaccines is not recommended. When planning vaccination with live vaccine, the long half-life of the drug should be taken into account after its elimination.

Special instructions:

The drug should be given after a thorough medical examination.

Increased side effects may occur in the case of recent or concomitant use of hepatotoxic (including alcohol) or hematotoxic and immunosuppressive drugs,or when the administration of these medicines begins after treatment with leflunomide without the procedure for "laundering" described in the section on "Application during pregnancy and during breastfeeding".

Before starting treatment, it is necessary to remember about the possible increase in the number of side effects in patients who received earlier basic medicines for the treatment of rheumatoid arthritis, which have hepato- and hematotoxic effects.

The active leflunomide metabolite A771726 is characterized by a long half-life, usually ranging from one to four weeks. Due to the long half-life of the active metabolite leflunomide, even with the cessation of leflunomide treatment, serious undesirable effects (eg, hepatotoxicity, hematotoxicity or allergic reactions) may occur and persist. If a serious undesirable phenomenon develops, or if rapid removal from the body of A771726 is required for any other reason, colestramine or Activated carbon, as described in the "laundering" procedure in the section "Use during pregnancy and during breastfeeding".The procedure for "laundering" can be repeated according to clinical indications.

If suspicion of severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome is required to achieve rapid and effective cleansing of the metabolite, a longer-term administration of colestyramine or activated charcoal may be required.

Due to the long half-life of the active metabolite leflunomide, when switching to another basic drug (for example, methotrexate), after treatment with leflunomide, it is necessary to carry out the "laundering" procedure.

Reactions of the liver

Since the active metabolite leflunomide, A771726 has a high affinity for proteins and is excreted by hepatic metabolism and secretion of bile, it is suggested that the concentration of A771726 in the blood plasma may increase in patients with hypoproteinemia. Leflunomide contraindicated in patients with severe hypoproteinemia or impaired liver function (see "Contraindications"). It is not recommended to use leflunomide in patients with liver diseases in the anamnesis, as well as patients in whom the activity of alanine aminotransferase before the start of treatment is 2 times higher than the upper limit of the norm.

There have been reports of rare cases of development of severe liver damage, in some cases with a fatal outcome, in the treatment with leflunomide. Most of these cases were observed in the first 6 months of treatment. Although there is no causal relationship between these undesirable phenomena and leflunomide, and in most cases there were several additional risk factors. It is necessary to strictly follow the recommendations for monitoring patients during treatment.

Before the start of treatment, and at least 1-2 times a month during the first 6 months of treatment, and after every 6-8 weeks, the activity of alanine aminotransferase in the blood should be checked.

Recommendations for correcting the dosage regimen or stopping the drug depending on the severity and persistence of increased activity of alanine aminotransferase: with a confirmed 2-3 fold excess of the upper limit of alanine aminotransferase, a dose reduction from 20 mg to 10 mg per day may allow leflunomide administration to be continued, provided that the indicator is closely monitored.

If a 2-3 fold excess of the upper limit of the alanine aminotransferase norm is maintained,or if there is an increase in activity of alanine aminotransferase exceeding the upper limit of the norm by more than 3 times, leflunomide intake should be discontinued. To reduce the concentration of A771726 more quickly, a procedure for "laundering" should be carried out (see the section on "Application during pregnancy and during breast-feeding").

Because of the possible additional hepatotoxic effects, it is recommended to refrain from taking alcohol while treating leflunomide.

Hematologic and immune reactions

In patients with previous anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or risk of suppression of bone marrow function, the risk of hematological disorders increases.

A complete clinical blood test, including the definition of the leukocyte formula and the number of platelets, must be performed before the leflunomide treatment, and 1-2 times a month for the first 6 months of treatment and then every 6-8 weeks.

Frequent monitoring of hematologic parameters (general blood test, including leukocyte count and platelet count) should be performed in the following cases:

- in patients with recent or concomitant use of immunosuppressive or hematotoxic drugs, as well as with the administration of these drugs after the end of treatment with leflunomide without a period of "laundering";

- in patients with an anamnesis of the corresponding deviations from the blood;

- in patients with corresponding changes in blood tests prior to treatment, not associated with inflammatory joint diseases.

In case of serious hematologic reactions, including pancytopenia, it is necessary to stop taking the drug Leflunomide and any other concomitant drug suppressing bone marrow hematopoiesis, and begin the procedure of "laundering".

Despite the lack of clinical data, due to the potential for immunosuppression, leflunomide is not recommended for patients who have the following diseases:

- severe immunodeficiency (eg AIDS);

- pronounced impairment of bone marrow function;

- severe infection.

Joint application with other types of treatment

At present, there is still no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example,chloroquine and hydroxychloroquine), administered intramuscularly or orally with gold preparations, Dpenicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate). There is no known risk associated with the appointment of complex therapy, especially with long-term treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (for example, hepatotoxicity or hematotoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are not desirable.

Transition to other types of treatment

Because the leflunomide long remains in the body, switching to another basic drug (for example, methotrexate) without an appropriate procedure for "laundering" can increase the possibility of additional risk even after a long time after the transition (for example, kinetic interaction, organotoxicity).

Similarly, the recent treatment with hepatotoxic or hematotoxic drugs (eg methotrexate) may lead to an increase in the number of side effects, so starting leflunomide treatment,it is necessary to carefully consider all the positive and negative aspects associated with taking this drug.

Skin Reactions

If ulcerative stomatitis develops, Leflunomide should be discontinued.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrosis have been reported in patients who received leflunomide. In case of skin reactions and / or reactions from the mucous membranes, it is necessary to cancel the administration of leflunomide and any other drug associated with it and immediately begin the procedure of "washing". It is necessary to achieve complete removal of the drug from the body. In such cases, the repeated administration of the drug is contraindicated.

Infections

It is known that drugs like leflunomide and possessing immunosuppressive properties increase the risk of developing various infections, including opportunistic infections (infections caused by fungi and microorganisms that can cause infections only in conditions of decreased immunity). Emerging infectious diseases occur, as a rule, hard and require early and intensive treatment.In the event of a serious infectious disease, it is necessary to interrupt treatment with leflunomide and begin the procedure of "laundering".

It is necessary to carefully monitor patients with severe tuberculin reactivity because of the risk of reactivation of tuberculosis.

Respiratory system reactions

In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. The risk of occurrence increases in patients with a history of interstitial lung diseases. Interstitial lung diseases are diseases with a potential fatal outcome, which can be acute in patients receiving treatment. Symptoms such as cough and shortness of breath can cause the cessation of leflunomide and further examination if necessary.

Peripheral Neuropathy

There were reports of cases of peripheral neuropathy in patients treated with leflunomide, which in most patients after discontinuation of the drug was eliminated, but in some patients the symptomatology persisted. Age over 60 years, the concomitant use of neurotoxic drugs and diabetes mellitus may increase the risk of peripheral neuropathy.In the development of peripheral neuropathy in a patient receiving leflunomide, consideration should be given to discontinuing treatment with this drug and conducting a "laundering" procedure.

Arterial pressure

Before the start of treatment with leflunomide and periodically after its onset, it is necessary to monitor the indices of arterial pressure, since during treatment with leflunomide it is possible to increase it.

Recommendations for men

There is no evidence of an increased risk of fetotoxic action (associated with the toxic effect of the drug on the father's spermatozoa) when leflunomide is used by men. To minimize the possible risk to men, when planning the appearance of a child, it is necessary to stop taking leflunomide and undergo the procedure of "laundering" described in the section "Use during pregnancy and during breastfeeding".

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

Taking the drug may be accompanied by a headache, dizziness. During the treatment period, care must be taken when driving vehicles and performing work that requires an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Tablets, film-coated 10 mg and 20 mg.

Packaging:

10 tablets per contour cell package; 3 contour packagings along with instructions for use are placed in a cardboard box.

For 30 or 100 tablets per can of polymer. Each bank along with the instruction for use is placed in a cardboard box.

Storage conditions:

In a dry, protected from light place at a temperature of no higher than 25 ° C.

Keep out of the reach of children!

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002401

Date of registration:17.03.2014

The owner of the registration certificate:Berezovsky Pharmaceutical Plant, ZAO Berezovsky Pharmaceutical Plant, ZAO Russia

Manufacturer: & nbsp

Berezovsky Pharmaceutical Plant, ZAO Russia

Information update date: & nbsp13.11.2015

Illustrated instructions

Instructions

Leflunomide (Leflunomide)