Expiration date: 11/2025

Dosage forms

• tablets 10mg
  
• tablets 20mg
  

Synonyms:

• Arava 
  
• Laplaud 
  
• The Leflunomide 
  
• Alara 
  

Group

Anti-inflammatory drugs of different groups 

International nonproprietary name

The Leflunomide

Composition

Active substance: Leflunomide 10 or 20 mg. 

Pharmacological action

The pharmacodynamics Leflunomide belongs to the class of basic Antirheumatic drugs and has antiproliferative, immunomodulatory, immunosuppressive and anti-inflammatory properties. The active metabolite of Leflunomide A771726 inhibits the enzyme dihydroorotatdehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogens-induced proliferation and the synthesis of deoxyribonucleic acid (DNA) of T-lymphocytes. Antiproliferative activity of A771726 is manifested, apparently, at the level of biosynthesis of pyrimidine, adding in uridine cell culture eliminates the inhibitory effect of metabolite A771726. Nuclear ligands are shown that A771726 selectively binds to the enzyme dihydroorotatdehydrogenase, which explains its ability to inhibit this enzyme and proliferation of lymphocytes in G1 phase. Proliferation of lymphocytes is one of the key stages in the development of rheumatoid arthritis. At the same time A771726 inhibits expression of receptors for Il-2 (SV-25) and core antigens Ki-67 and PCNA associated with the cell cycle. Therapeutic effect of Leflunomide was shown in several experimental models of autoimmune diseases, including rheumatoid arthritis. Leflunomide decreases the symptoms and slows the progression of joint damage in active form rheumatoid arthritis. The therapeutic effect usually manifests after 4 to 6 weeks and can grow further for 4 to 6 months. Pharmacokinetics of Leflunomide is quickly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). In plasma, urine or feces was observed only trace amounts of unchanged Leflunomide. The only defined by the metabolite is A771726, is responsible for the basic properties of the drug in vivo. If ingestion is absorbed from 82 to 95% of the drug. Maximum plasma concentrations of A771726 are defined from 1 to 24 hours once the dose. The Leflunomide may be taken with food. Due to the very long half-life (T1/2) of A771726 (approximately 2 weeks) has been used loading dose of 100 mg per day for 3 days. Is allowed to quickly reach an equilibrium state plasma concentrations of A771726. Without a loading dose to achieve equilibrium concentrations would need 2 months of taking the drug. In studies with repeated application of the drug the pharmacokinetic parameters of A771726 was dose-dependent in the dose range of 5 to 25 mg. In these studies the clinical effect was closely related to plasma concentration of A771726 and the daily dose of Leflunomide. At the dose of 20 mg / day, average plasma concentration of A771726 at steady state had a value of 35 µg/ml In plasma is a rapid binding of A771726 to albumin. The 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. The Leflunomide is metabolized to one primary (A771726) and several minor metabolites, including 4-trifluoromethylaniline. Biotransformation of Leflunomide to A771726 and the subsequent metabolism of A771726 is controlled by several enzymes and occur in microsomal and other cellular fractions. Studies of the interaction with cimetidine (nonspecific cytochrome P450 inhibitor) and rifampicin (non-specific inducer of cytochrome P450) showed that in vivo SUR-enzymes involved in the metabolism of Leflunomide only to a small extent. A771726 elimination from the body is slow and is characterized by a clearance of 31 ml/HR. The Leflunomide is excreted in the feces (probably due to biliary excretion) and urine. (T1/2) is about 2 weeks. The pharmacokinetics of A771726 in patients on chronic ambulatory peritoneal dialysis (GAPD), similar to that in healthy volunteers. More rapid elimination of A771726 was observed in patients undergoing hemodialysis that is not due to extraction of drug in the dialysate, and with the displacement of its connection with protein. Although clearance of A771726 is increased approximately in 2 times, end (T1/2) is similar to that in healthy individuals, as simultaneously increasing distribution. Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent. Pharmacokinetic characteristics in patients younger than 18 years has not been studied. In elderly patients (65 years and older) pharmacokinetic data correspond roughly to the middle age group. 

Side effects

From the cardiovascular system. Common: mild increase in blood pressure rare: pronounced increase in blood pressure, frequency unknown: angina, migraine, palpitations, tachycardia, varicose vein, vasculitis, vasodilatation. The gastro-intestinal tract. Often: diarrhea, nausea, vomiting, diseases of the oral mucosa (e.g., aphthous stomatitis, ulceration of the lips), abdominal pain, uncommon: a violation of taste sensations, very rare: pancreatitis, frequency not known: gingivitis, candidiasis of the oral cavity, esophagitis, gastritis, gastroenteritis, dyspepsia, colitis, constipation, flatulence, and melena. From the hepato-biliary system. Frequent: increased activity of "liver" transaminases (alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), hyperbilirubinemia, rare: hepatitis, cholestasis, jaundice, cholelithiasis, very rare: severe liver damage (including liver failure, acute liver necrosis), which can be fatal. On the part of the respiratory system. Frequent: respiratory infections of the upper respiratory tract, cough rare: interstitial pulmonary process (including interstitial pneumonia and pulmonary fibrosis), which may be fatal, unknown speed: asthma, shortness of breath, nasal bleeding. Disorders of metabolism and nutrition. Frequent: increase in creatine phosphokinase (CPK), uncommon: hypokalaemia, hyperlipidemia, hypophosphatemia, is rare: increased level of lactate dehydrogenase, unknown speed: hypouricemia, diabetes mellitus, hyperthyroidism, peripheral edema. From the nervous system. Often: headache, dizziness, paraesthesia, uncommon: anxiety very rare: peripheral neuropathy, the frequency is unknown: anxiety, depression, dryness of the mucous membrane of the oral cavity, insomnia, neuralgia, neuritis, sweating. From the musculoskeletal system. Common: tenosynovitis, uncommon: tendon rupture, frequency unknown: arthralgia, synovitis, muscle spasm, arthrosis, bone necrosis, bursitis, myalgia. The skin and subcutaneous tissue. Common: increased hair loss, alopecia, eczema, rash (including maculopapular), pruritus, dry skin uncommon: urticaria very rare: toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome, the frequency is unknown: acne, contact dermatitis, fungal dermatitis, change hair color, herpes simplex, shingles, nail infections, pigmentation disorders of the skin, ulceration of the skin. From the immune system. Common: allergic reactions very rare: severe anaphylactic/anaphylactoid reactions, angioedema. Infections and invasions. Rare: severe infections (including opportunistic and sepsis), which can be fatal. Increased risk of infectious diseases, in particular of rhinitis, bronchitis and pneumonia. Hematopoietic system and lymphatic system. Common: leukopenia (leukocytes >, 2000/µl), uncommon: anaemia, mild thrombocytopenia (platelets >, 100 000/µl), rare: pancytopenia (apparently due to the antiproliferative action) eosinophilia, leukopenia (leukocyte count of < 2000/µl), very rare: agranulocytosis. Recent, concomitant or subsequent use of potentially mielotoksicnae agents can be associated with a higher risk of haematological effects. From the reproductive system. Frequency unknown: a slight decrease in sperm concentration, total sperm count and their mobility. The kidneys and urinary system. Frequency unknown: infection of urinary system, renal insufficiency, albuminuria, cystitis, dysuria, hematuria, lesions of the prostate, frequent urination, vaginal candidiasis. From the senses. Frequency unknown: blurred vision, cataract, conjunctivitis, breach of taste. Common. Common: anorexia, weight loss (usually insignificant), asthenia, Frequency unknown: fever, weakness. Other. The risk of malignancy, particularly lymphoproliferative diseases is increased by the use of some immunosuppressive drugs.

Indications for use

As a basic tool for the treatment of adult patients with active form of rheumatoid arthritis to reduce disease symptoms and delay the development of structural joint damage, the Active form of psoriatic arthritis. 

Contraindications

Leflunomide or hypersensitivity to any component of the drug, liver dysfunction, severe immunodeficiency (including acquired immunodeficiency syndrome), significant disorders of bone marrow hematopoiesis or severe anemia, leukopenia or thrombocytopenia resulting from other causes (except rheumatoid arthritis), severe, uncontrolled infections, moderate or severe renal insufficiency (creatinine clearance less than 60 ml/min, due to the lack of experience of clinical observations), severe hypoproteinemia (e.g. in nephrotic syndrome), pregnant women or women of childbearing age not using reliable methods of contraception during treatment with Leflunomide and for as long as the plasma levels of the active metabolite remains above 0.02 mg/l. Pregnancy should be excluded before treatment with Leflunomide, in the period of breast-feeding (see section "Use during pregnancy and breastfeeding"), children's age (under 18) in the absence of data on efficacy and safety. Men receiving treatment with Leflunomide should be warned about the possible fetotoksicheskoe the effect of the drug (related to its possible effect on the sperm of the father) and the need to use reliable contraception.

Method of application and dosage

Treatment with Leflunomide should begin under the supervision of a physician experienced in the treatment of rheumatoid arthritis and psoriatic arthritis. The pills should be taken with or without food, swallowed whole, squeezed enough liquid. Treatment with Leflunomide starts with the ingestion of a loading dose of 100 mg once a day for 3 days. As a maintenance dose in rheumatoid arthritis, we recommend taking from 10 mg to 20 mg of Leflunomide once daily, with psoriatic arthritis is 20 mg 1 time per day. The therapeutic effect usually manifests after 4 to 6 weeks and could increase further to 4 - 6 months. 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 five times the recommended daily dose and reports of acute overdose in adults and children. In most cases of overdose have not been reported on the development of adverse reactions. Emergent adverse reactions were comparable with the safety profile of Leflunomide. The most commonly observed adverse reactions were diarrhoea, abdominal pain, leukopenia, anemia and increase the performance tests of the functional state of the liver. Treatment. In case of overdose or toxicity, it is recommended to take cholestyramine or activated charcoal to accelerate cleansing of the body. Cholestyramine, taken orally, 8 g 3 times per day during the day, reduces the concentration in plasma A771726 by approximately 40 % after 24 hours, and 49-65 % in 48 hours. Introduction activated carbon (in the form of a suspension) orally or via gastric tube (50 g every 6 hours during the day) reduces the concentration of the active metabolite A771726 in plasma at 37 % after 24 hours and by 48% in 48 hours. These procedures can be repeated as clinically indicated. Studies with hemodialysis and GAPD indicate that A771726, the primary metabolite of Leflunomide, is not able to excreted through dialysis.

Interaction

Increased side effects may occur in case of recent or concomitant use of hepatotoxic (including alcohol) or gepatotoksicnah and immunosuppressive drugs or when the drugs begin after treatment with Leflunomide without procedure "laundering". In patients with rheumatoid arthritis not been found no pharmacokinetic interaction between the Leflunomide (10 to 20 mg per day) and methotrexate (10 to 25 mg per week). Patients taking Leflunomide, it is not recommended simultaneous reception of cholestyramine or activated charcoal because this leads to fast and considerable decrease the concentration of A771726 in plasma. It is believed that this is due to the violation of the recirculation A771726 in the liver and small intestine and/or the violation of his gastrointestinal dialysis. If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, they can continue to take after the start of treatment with Leflunomide. The enzymes involved in the metabolism of Leflunomide and its metabolites are not precisely known. In vivo study of its interaction with cimetidine (a nonspecific inhibitor of cytochrome P450) showed no significant interaction. After concomitant administration of a single dose of Leflunomide to subjects receiving multiple doses of rifampicin (non-specific cytochrome P450 inducer), peak levels of A771726 was increased by approximately 40 %, whereas the area under the curve "concentration-time" has not changed significantly. The mechanism of this effect is not clear. In vitro studies showed that A771726 inhibits the activity of cytochrome ?4502?9 (CYP2C9). Clinical studies have not observed any problems with the joint use of Leflunomide and NSAIDs, metabolized CYP2C9. With extreme caution should be used Leflunomide with other drugs that are not NSAIDs, metabolized via CYP2C9, such as phenytoin, warfarin and tolbutamide. There is a reported increase in prothrombin time during concomitant use 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 of ethinyl estradiol, no reduction in contraceptive effect of contraceptives was found, and the pharmacokinetics of A771726 is fully consistent with the intended range. Currently there is no information regarding the joint use of Leflunomide with antimalarials used in rheumatology (e.g. chloroquine and hydroxychloroquine), gold preparations (intramuscular or oral), D-penicillamine, azathioprine and other immunosuppressive drugs (with the exception of methotrexate). Unknown risk associated with combination therapy, especially with prolonged treatment. Since this sort of therapy can lead to the development of additional or even synergistic toxicity (e.g. hepato - or hematoxicity), combinations of this drug with other DMARDs (e.g., methotrexate) are undesirable. Recent, concomitant or subsequent use of potentially mielotoksicnae agents may be associated with a higher risk of haematological effects. Immunosuppressants increase the risk of developing infections and malignancies, especially lymphoproliferative disorders. Vaccination. There is no clinical data regarding the effectiveness and safety of vaccination in terms of treatment with Leflunomide. However, it is not recommended to administer live vaccines. When planning a vaccination with a live vaccine should account for the long T1/2 of Leflunomide after discontinuation of the drug.

Special instructions

Use during pregnancy and the breastfeeding period. The Leflunomide can not be applied to pregnant women or women of childbearing age who are not using reliable contraception during treatment with Leflunomide and for a certain time after this treatment. Before treatment it is necessary to verify the absence of pregnancy. Patients should be informed that as soon as the delay period or if there is other reason to suspect pregnancy, they must immediately inform the doctor to do a pregnancy test. In the case of a positive pregnancy test physician should discuss with the patient the possible risk to the pregnancy. It is possible that a rapid decrease in levels of active metabolite in the blood using the following procedure, remove the drug will help during the first delay period to reduce the risk to the fetus from Leflunomide. Women who are taking Leflunomide and want to get pregnant, it is recommended to follow one of the following procedures to ensure that the fetus will not be exposed to toxic concentrations of A771726 (the test concentration below 0.02 mg/l). Waiting period. It can be expected that the concentration of A771726 in plasma may be higher than 0.02 mg/l for an extended period. It is believed that its concentration can become less than 0.02 mg/l 2 years after stopping treatment with Leflunomide. The first time the concentration of A771726 in plasma is measured after the two year waiting period. After this it is necessary to measure the concentration of A771726 in plasma at least 14 days. If the value of both measurements is below 0.02 mg/l are anticipated no teratogenic risk. The procedure "laundering". Cholestyramine 8 g injected 3 times a day for 11 days, alternatively, 50 g of activated charcoal, crushed into powder, is injected 4 times daily for 11 days. Regardless of the procedure "laundering" should be tested in two separate tests at an interval of at least 14 days and wait a month and a half since, when the concentration of the drug in plasma for the first time will be recorded below 0.02 mg/l prior to fertilization. You must inform women of child-bearing period that must pass 2 years after stopping treatment with Leflunomide, before they can trying to get pregnant. If a 2-year waiting period under reliable contraception seems unreasonable, it may be advisable to carry out the procedure "laundering" as a preventive measure. And cholestyramine and activated charcoal may influence the absorption of estrogens and Progestogens, so reliable oral contraceptives do not give an absolute guarantee in the period of "laundering" with colestyramine or activated carbon. It is recommended to use alternative methods of contraception. Animal studies showed that Leflunomide or its metabolites pass into breast milk, so women who are breastfeeding, should not take the drug. The Leflunomide can be used in patients only after a thorough medical examination. The procedure "laundering". The procedure "laundering" is carried out according to the following scheme: -cholestyramine 8 g injected 3 times a day for 11 days, alternatively, 50 g of activated charcoal, crushed into powder, is injected 4 times daily for 11 days. Effects on ability to drive vehicles and mechanisms. The drug may be accompanied by headache, dizziness. In this regard, patients taking Leflunomide should exercise caution in the management of hazardous mechanical means, including by car.

Storage conditions

Store in a dry, dark, inaccessible to children place at temperature not above 25 C.