Expiration date: 03/2025

Active substance: Leflunomide

Description pharmaceutical form:

Tablets 10 mg: round, film-coated tablets, white or nearly white labeled «ZBN» on one side.

20 mg Tablets: triangular, lenticular, coated tablets, from pale yellow to pale brown labeled "ZBO" on one side.

Pharmacokinetics:

Leflunomide is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces were seen only trace amounts of unchanged leflunomide. The sole determining metabolite A771726 is responsible for the basic properties of the drug in vivo.

When administered is absorbed between 82 and 95% of the formulation. Cmax plasma A771726 determined from 1 to 24 hours after the dose once. Leflunomide may be taken with food. Because of the very long T1 / 2 A771726 (approximately 2 weeks) was used loading dose of 100 mg daily for 3 days. This has allowed to quickly reach an equilibrium state plasma concentrations of A771726. Without a loading dose to achieve equilibrium concentration would require a 2-month drug. In studies with multiple assignment A771726 drug pharmacokinetic parameters were dose-dependent within the dose range of 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and a daily dose of leflunomide. At a dose of 20 mg / day, average plasma concentration of A771726 at equilibrium have the value of 35 ug / ml.

The plasma is rapid binding A771726 albumin. Unbound fraction of A771726 is about 0.62%. Binding of A771726 more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

Leflunomide is metabolised to one primary (A771726) and several secondary metabolites, including 4-triflyuorometilalanin. The biotransformation of leflunomide to A771726 and subsequent metabolism of A771726 are controlled by several enzymes, and occur in microsomal and other cellular fractions. Interaction studies with cimetidine (non-specific inhibitor of cytochrome P450) and rifampicin (non-specific inducer of cytochrome P450) showed that in vivo CYP-enzymes involved in the metabolism of leflunomide only to a small extent.

Elimination of A771726 is slow and characterized by the body's clearance of 31 ml / h. Leflunomide is excreted in the feces (probably due to biliary excretion) and in the urine. T1 / 2 is about two weeks. The pharmacokinetics of A771726 in patients on chronic ambulatory peritoneal dialysis (CAPD), similar to that in healthy volunteers. A more rapid elimination of A771726 observed in patients on hemodialysis, which is not connected with the extraction of drug in the dialysate and displacing it from its association with the protein. Although A771726 clearance is increased to about 2 times the final T1 / 2 is similar to that in healthy individuals, as at the same time increases the amount of the distribution.

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

Pharmacokinetic characteristics in patients younger than 18 years have not been studied. In elderly patients (65 years and older) pharmacokinetic data correspond roughly to the middle age group.

Description of the pharmacological actions:

Arava belongs to a class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, anti-inflammatory and immunosuppressive properties. Active metabolite A771726 Leflunomide degidroorotatdegidrogenazu inhibits enzyme and possesses anti-proliferative activity. A771726 under in vitro inhibits mitogen-induced proliferation and DNA synthesis of T lymphocytes. A771726 manifests antiproliferative activity, apparently at the level of pyrimidine biosynthesis, since the addition of uridine in the cell culture inhibitory effect eliminates metabolite A771726. With the use of radioisotope ligand shown that A771726 selectively binds to the enzyme dehydrogenase degidroorotat than due to its property to inhibit this enzyme and lymphocyte proliferation in the G1 phase. Lymphocyte proliferation is one of the key stages in the development of rheumatoid arthritis.

Simultaneously A771726 inhibits expression of receptors for IL-2 (CB-25) and core antigens Ki-67 and PCNA, associated with the cell cycle.

The therapeutic effect of leflunomide was shown in several animal models of autoimmune diseases including rheumatoid arthritis.

Leflunomide decreases the symptoms and slow the progression of joint damage, with the active form of rheumatoid arthritis.

The therapeutic effect is usually seen after 4-6 weeks and may increase further over 4-6 months.

Testimony:

As a basic means for treating adult diseases, such as:

• rheumatoid arthritis (active form - to reduce symptoms and the delay of progression of structural damage of joints)
  
• psoriatic arthritis (active form).
  

Contraindications:

• leflunomide or hypersensitivity to any other component of the preparation
  
• liver function abnormalities
  
• severe immunodeficiency (eg AIDS)
  
• significant violations of medullary hematopoiesis, or significant anemia, leukopenia or thrombocytopenia due to other reasons (other than rheumatoid arthritis)
  
• severe, uncontrolled infections
  
• moderate or severe renal insufficiency (because of the small experience of clinical observation)
  
• severe hypoproteinemia (eg in nephrotic syndrome)
  
• in pregnancy or women of childbearing age who do not use reliable contraception during treatment with leflunomide and then as long as the plasma levels of the active metabolite remains above 0.02 mg / l (see. "Pregnancy and lactation"). Pregnancy must be excluded before starting treatment with leflunomide
  
• breastfeeding (see. "Pregnancy and lactation")
  
• men being treated with leflunomide should be warned about the possible foetotoxic effect of the drug (related to its possible impact on the father's sperm) and the need to use reliable contraception
  
• Arava is not recommended for use in patients under 18 years since data on the efficacy and safety in this group of patients no.
  

Application of pregnancy and breastfeeding:

Leflunomide should not be administered to pregnant women or women of childbearing age who are not using reliable contraception during treatment with leflunomide and for a while after this treatment (waiting period or abbreviated period of "laundering" - see below.). It must be ensured in the absence of pregnancy prior to treatment with leflunomide.

Patients should be informed that as soon as there comes a month or if the delay has another reason to assume pregnancy, they should immediately inform your doctor to do a pregnancy test in the case of pregnancy positive test, the physician should discuss with the patient the possible risk to this pregnancy . It is possible that the rapid decline in the level of the active metabolite in the blood with the help of the drug described below will launch the procedure at the first delay of menses to reduce the risk to the fetus from leflunomide.

Women who are taking leflunomide and want to become pregnant, it is recommended to follow one of the following procedures to make sure that the fetus is not exposed to toxic concentrations of A771726 (control concentration - less than 0.02 mg / L).

waiting Period

One would expect that A771726 plasma concentration may be higher than 0.02 mg / l for a long period. It is believed that the concentration can be less than 0.02 mg / l in 2 years after stopping the treatment with leflunomide.

First time A771726 plasma concentration is measured after 2 years of waiting period.

Thereafter A771726 necessary to measure the concentration in blood plasma for at least 14 days. If the value of both measurements below 0.02 mg / l, is not expected any teratogenic risk.

"Laundering" procedure

After the cessation of treatment leflunomide: cholestyramine at a dose of 8 g administered three times a day for 11 days alternatively - 50 g of activated carbon, pulverized, administered 4 times a day for 11 days.

Regardless of the procedure "laundering" is necessary to inspect two separate tests at intervals of at least 14 days and to wait six weeks from the moment when the concentration of drug in plasma is first recorded below 0.02 mg / l, up to the moment of fertilization.

It is necessary to inform women of childbearing period that must elapse 2 years after stopping treatment with leflunomide, before they can try to get pregnant. If a 2-year waiting period under reliable contraception seems unreasonable, it may be advisable to conduct a "laundering" the procedure as a preventive measure.

And colestyramine, and activated carbon can affect the absorption of estrogens and progestogens therefore reliable oral contraceptives do not give absolute guarantee during the "laundering" using activated charcoal or cholestyramine. It is recommended to use alternative methods of contraception.

Animal studies indicate that leflunomide or its metabolites pass into breast milk. Therefore, women who are breastfeeding should not take leflunomide.

Side effect:

The classification of the intended frequency of side effects: very often - often 1/10 & ge - & ge1 / 100 but <1/10 uncommon - & ge1 / 1000 but <1/100 rarely - & ge1 / 10,000, but <1/1000 rarely - < 1/10000 frequency is not known - on the basis of the available frequency can not be estimated data.

Cardiovascular system: often - a moderate increase in blood pressure is rare - marked increase of blood pressure.

Gastrointestinal tract, liver: often - diarrhea, nausea, vomiting, oral mucosal disorders (eg aphthous stomatitis, mouth ulceration), abdominal pain rarely - impaired sense of taste very rare - pancreatitis.

Respiratory system and mediastinal disorders: rarely - interstitial pulmonary process (including interstitial pneumonitis), which can be fatal.

Disorders of metabolism: often - increase in creatine phosphokinase (CPK), rarely - hypokalemia, hyperlipidemia, hypophosphataemia rarely - increased levels of lactate dehydrogenase (LDH) with unknown frequency - hypouricemia.

Nervous system: often - headache, dizziness, paresthesia uncommon - anxiety is very rare - peripheral neuropathy.

Musculoskeletal System: often - tenosynovitis rare - tendon rupture.

Leather and derivatives: typical - increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin rarely - urticaria, very rarely - toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome.

Immune system: often - mild allergic reactions are very rare - severe anaphylactic / anaphylactoid reactions, vasculitis, including cutaneous necrotizing vasculitis.

Infections and infestations: rare - the development of serious infections, including opportunistic and sepsis, which can be fatal. It may increase the number of possible infections (in particular, rhinitis, bronchitis and pneumonia).

hematopoietic system and lymphatic system: often - leukopenia (leukocytes> 2000 cells / mm), rarely - anemia, slight thrombocytopenia (platelets <100,000 / mm), rarely - pancytopenia (probably by antiproliferative action), leukopenia (leukocytes <2000 / L) eosinophilia, rarely - agranulocytosis. Recent, concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of hematological effects.

Hepato-biliary system: often - increase in liver transaminases (especially ALT, at least - GGT and alkaline phosphatase), hyperbilirubinemia, rarely - hepatitis, jaundice / cholestasis very rarely - severe liver injury such as liver failure, acute hepatic necrosis that may be fatal.

General changes: often - anorexia, weight loss (usually insignificant), asthenia.

Reproductive system: with unknown frequency - a slight decrease in sperm concentration, total sperm count and motility.

On the part of the kidney and urinary tract: with unknown frequency - renal failure.

Other: the risk of cancer, especially lymphoproliferative diseases increases with some immunosuppressive agents.

Drug Interactions:

Increased side effects may occur in case of recent or concomitant use of hepatotoxic (including alcohol) or gematotoksichnosti and immunosuppressive drugs or when taking these drugs is started after treatment with leflunomide procedure without "money" (see. "Special Instructions").

In rheumatoid arthritis patients, there was no pharmacokinetic interaction between the leflunomide (10-20 mg / day) and methotrexate (10-25 mg weekly).

Patients receiving leflunomide, it is recommended not to give colestyramine or active carbon, because it leads to rapid and substantial reduction in the concentration of A771726 (active metabolite of leflunomide) in the blood plasma. It is believed that this is due to violation of the A771726 recirculation in the liver and small intestine and / or violation of its gastrointestinal dialysis.

If a patient is already taking NSAIDs and / or corticosteroids, you can continue to take after the start of treatment with leflunomide.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known. In vivo studies of its interaction with cimetidine (non-specific cytochrome P450 inhibitor) showed no significant interaction.

After concomitant administration of a single dose of leflunomide subjects who received multiple doses of rifampicin (non-specific inducer of cytochrome P450), A771726 peak levels increased by approximately 40%, whereas the area under the concentration-time curve is not significantly changed. The mechanism of this effect is not clear.

Studies in vitro have shown that A771726 inhibits cytochrome R4502S9 (CYP2C9). In clinical trials, there was not any problems with the co-administration of leflunomide and NSAIDs metabolized CYP2C9.

Special care should be given leflunomide with other medications, non-NSAIDs metabolized by means of CYP2C9, such as phenytoin, warfarin and tolbutamide.

It reported an increase in PV, while the appointment of leflunomide and warfarin.

In a study in which leflunomide was given to healthy volunteers female together with three-phase oral contraceptive containing 30 mcg ethinyl estradiol, contraceptive effect is no reduction of tablets were found, and A771726 pharmacokinetics completely fit into the prescribed range.

There is currently no information on the joint use of leflunomide with antimalarials used in rheumatology (eg chloroquine and gidroksihlorina), preparations of Au (V / m or orally), the D-penicillamine, azathioprine and other immunosuppressive drugs (with the exception of methotrexate). Unknown risks associated with carrying out a comprehensive therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) are undesirable. A recent concomitant or subsequent use of potentially myelotoxic agents may be associated with greater risk of haematological effects. Immunosuppressive drugs increase the risk of infections and malignancies, especially lymphoproliferative disorders.

Vaccination. There are no clinical data on the efficacy and safety of vaccinations under leflunomide treatment. However, it is not recommended to be vaccinated with live vaccines. Keep in mind a long T1 / 2 of the drug Arava when planning vaccination with live vaccine after its cancellation.

Dosage and administration:

Inside, swallowing a whole, drinking plenty of fluids. Food intake has no effect on the absorption of leflunomide.

leflunomide treatment should start under the supervision of a physician who is experienced in the treatment of rheumatoid and psoriatic arthritis.

According See "Special Instructions" section regarding recommendations for treatment for control.

leflunomide treatment begins with receiving a single bolus dose of 100 mg over three days. As maintenance dose for rheumatoid arthritis is recommended intake of 10-20 mg of leflunomide 1 times a day, in psoriatic arthritis - 20 mg 1 time per day.

The therapeutic effect is usually seen after 4-6 weeks and may increase further to 4-6 months.

There are no recommendations regarding the dosage of the drug for patients suffering from renal insufficiency mild.

It does not require any dose adjustment for patients older than 65 years.

Overdose:

Symptoms: There were reports of chronic overdose in patients treated with leflunomide at a dose up to 5 times the recommended daily dose, and reports of acute overdose in adults and children. In most cases of overdose not reported the development of adverse events. Emerging adverse events were comparable to the safety profile of leflunomide. The most frequently observed: diarrhea, abdominal pain, leukopenia, anemia, and increase performance tests of the functional state of the liver.

Treatment: In case of overdose or toxicity is recommended to take cholestyramine or activated charcoal, to accelerate the cleansing of the body. Cholestyramine, three healthy volunteers received orally with 8 g of 3 times a day for 24 h, reduced levels of A771726 in plasma by about 40% - 24 h and at 49-65% - after 48 h demonstrated that the introduction of the activated. carbon (powder converted into a slurry) or oral gavage (50 g every 6 hours during the day) reduced the concentration of the active metabolite A771726 plasma by 37% - 24 hours, and 48% - 48 hours.

These procedures are "laundering" can be repeated as clinically indicated. Studies with hemodialysis and CAPD indicate that A771726, the main metabolite of leflunomide, is not able to be displayed by dialysis.

Special instructions:

Arava can be administered to patients only after careful medical examination.

Before starting treatment with Arava should be aware of a possible increase in the number of side effects in patients previously treated with other basic facilities for the treatment of rheumatoid arthritis, which have a hepato-and haematological effects.

The active metabolite of leflunomide - A771726 characterized by long T1 / 2, usually from 1-4 weeks. Due to the long T1 / 2 of the active metabolite of leflunomide - A771726, even when stopping treatment with leflunomide may arise or persist serious adverse effects (eg hepatotoxicity, gematoksichnost or allergic reactions - see below.). "Laundering" the procedure should be carried out in this case. The procedure can be repeated as clinically indicated. For suspected severe immunological / allergic reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis conduct full "laundering" the procedure is necessary.

Therefore, in the event of such cases of toxicity or in the transition to receiving another reference drug (eg methotrexate) after treatment with leflunomide is necessary to carry out the procedure "money" (see. Below).

liver reactions. Since the active metabolite of Leflunomide, A771726, bound to proteins and excreted by hepatic metabolism and secretion of bile, it is assumed that the level of A771726 in plasma may be increased in patients with hypoproteinemia. The drug Arava is contraindicated in patients with severe hypoproteinaemia or impairment of liver function (see. "Contraindications").

It was reported about rare cases of severe liver injury, in some cases fatal, in the treatment with leflunomide.

Most of these cases were observed within the first six months of treatment. Although not established a causal relationship between these adverse events with leflunomide, and in most cases there are several other suspicious factors, the exact implementation of the recommendations on the treatment of control is considered mandatory.

ALT levels should be checked before the start of leflunomide treatment and then every 2 weeks for the first 6 months of treatment, followed by a test once every 6-8 weeks.

The following recommendations for the correction of a regimen of dosage or discontinuation of the drug, depending on the severity and persistence increased ALT.

If confirmed by a 2-3 fold excess upper limit of normal ALT dose reduction from 20 to 10 mg / day may be allowed to continue receiving leflunomide with careful monitoring of this indicator.

If the 2-3-fold excess of the upper limit of normal ALT persists, or if there is a confirmed rise in ALT levels above the upper limit of normal in more than 3 times, taking leflunomide should be discontinued and should begin the process of "laundering".

Due to the possible additional hepatotoxic effects, it is recommended to abstain from alcohol during treatment with leflunomide.

Hematologic reactions. Full blood count, including the determination of leukocyte and platelet counts should be performed prior to initiating treatment with leflunomide and every 2 weeks during the first 6 months of treatment and then every 6-8 weeks.

Patients with previously took place anemia, leukopenia and / or thrombocytopenia as well as in patients with impaired bone marrow function or at risk of developing such disorders increases the risk of haematological disorders. If you have this kind of phenomena should be used "laundering" the procedure to reduce the A771726 plasma levels.

In the case of severe haematological reactions, including pancytopenia, Arava need to stop taking the drug and any other concomitant medication that suppresses bone marrow blood, and begin the process of "laundering".

The combined use with other treatments. Currently there is no information yet on the joint use of leflunomide with antimalarials used in rheumatology (eg chloroquine and hydroxychloroquine), introduced into / m or oral gold preparations, D-penicillamine, azathioprine and other immunosuppressive agents (with the exception of methotrexate). Not known risk associated with the appointment of combination therapy, particularly after prolonged treatment. Since this type of therapy can lead to the development of additional or even synergistic toxicity (eg hepato- or gematotoksichnosti), the combination of this drug with other DMARDs (eg methotrexate) is not advisable.

Switching to other treatments. Since leflunomide persists in the body for a long time, the transition to receiving another reference drug (eg methotrexate) without proper carrying out of "laundering" the procedure may increase the possibility of additional risk, even long after the transition (ie kinetic interaction, organotoksichnost).

Similarly, recent treatment of hepatotoxic or gematotoksichnosti drugs (eg methotrexate) may result in 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 the intake of this drug.

Skin reactions. In the case of ulcerative stomatitis should stop taking leflunomide.

It was reported about rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis in patients treated with leflunomide. In case of skin reactions and / or reactions on the part of the mucous membranes need to stop taking the drug Arava and any other associated preparation and immediately begin the process of "laundering". It is necessary to achieve complete excretion of the drug. In such cases, the re-appointment of the drug is contraindicated.

Infection. It is known that drugs like leflunomide and having immunosuppressive properties, making patients more susceptible to various infections, including opportunistic infections (infections caused by fungi and microorganisms capable of causing infection only in reducing immune). Arisen infections occur, usually hard and require early and intensive treatment. In the event of severe infection may need to interrupt leflunomide treatment and begin the process of "laundering".

It is necessary to carefully monitor patients with a positive reaction to the tuberculin due to the risk of reactivation of tuberculosis.

airway responsiveness. In the treatment with leflunomide it was noted rare cases of interstitial pulmonary process. Symptoms such as cough and dyspnoea may cause discontinuation of leflunomide.

HELL. Before starting treatment with leflunomide and periodically after the start should be controlled blood pressure.

Interactions. You should be careful in the appointment of drugs metabolized by the action of CYP2C9 (phenytoin, warfarin, tolbutamide), except NSAIDs.

Advice for men. There are no data on the risk of fetotoxicity (related to the toxic effects of the drug on the father's sperm) when using leflunomide men. The experimental data in this area have been conducted. To minimize the potential risk men when planning a baby must stop taking the use of leflunomide and colestyramine 8 g 3 times a day for 11 days or 50 g of pulverized activated carbon 4 times a day for 11 days.