Index of drugs

Treatment of active rheumatoid arthritis in adults (a DMARD medicine) and active psoriatic arthritis.

1 tabl powl. contains 10 mg, 20 mg or 100 mg of leflunomide. The preparation contains lactose.

Anti-rheumatic drug with immunomodulatory and immunosuppressive properties, antiproliferative and anti-inflammatory from the group of DMARD = disease-modifying. Absorbed in the intestine (82-95% of the dose), it is rapidly and almost completely metabolized (ring opening) in the intestinal wall and liver (first pass metabolism) to the active metabolite A771726 responsible for the therapeutic effect and many metabolites of lesser clinical significance (including TFMA = 4-trifluoromethylaniline). A771726 inhibits the activity of dihydroorotate dehydrogenase (DHODH) and has anti-proliferative properties. Biotransformation of leflunomide and further metabolism A771726 are carried out in microsomes and cell cytoplasm with the participation of many enzymes. Cytochrome P450 (CYP) enzymes only participate to a small extent in the metabolism of leflunomide. The maximum concentration in blood A771726 reaches after 1-24 h (after a single dose). Due to the long half-life of A771726 (about 2 weeks), the application of a 100 mg / day saturating dose for 3 days allows you to quickly achieve a dynamic balance (without applying the saturating dose, the state of balance is achieved after about 2 months). At constant doses of 20 mg / day, the blood balance is about 35 μg / ml; there is a close relationship between the clinical effect, the plasma metabolite concentration and the daily dose administered. Intensively combines with plasma albumin (free fraction about 0.62%) with a linear characteristic in the therapeutic dose range. In patients with RA or chronic renal impairment, protein binding may be diminished or more varied. Major metabolites excreted in equal proportions with urine and faeces: urine - glucuronide derivatives of leflunomide and oxaniline derivatives A771726; the main metabolite excreted in the faeces is A771726. In patients with renal insufficiency: those treated with hemodialysis A771726 are eliminated more quickly and have a shorter biological half-life; treated with peritoneal dialysis - pharmacokinetic parameters as in healthy people. There are no pharmacokinetic data for patients with impaired liver function (because A771726 is largely bound to plasma proteins, is metabolized in the liver and excreted in the bile one should be aware of the disruption of these processes in hepatic failure). There are no adequate data on the use of the drug in children under 18 years of age.

Hypersensitivity to leflunomide (especially patients who have experienced in the past: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to other components of the preparation. Hepatic dysfunction. Severe immunodeficiency (eg AIDS). Significant bone marrow dysfunction or significant anemia, leukopenia, neutropenia or thrombocytopenia induced by factors other than RA or psoriatic arthritis. Severe infections. Moderate to severe renal failure. Severe hypoproteinemia, e.g. in the nephrotic syndrome. Pregnant women or women of childbearing potential not using effective contraception during and after treatment until the concentration of the active metabolite (A771726) in the blood is reduced to a value not higher than 0.02 mg / l). Breastfeeding women.

The decision to initiate leflunomide therapy should be preceded by a thorough analysis of the expected benefits in relation to possible risks. Do not use in patients under 18 years of age, because the efficacy and safety of use in this age group has not been studied. Co-administration of other DMARD preparations with hepatotoxic or hematotoxic effects (eg methotrexate) is not recommended. Even after discontinuation of treatment with leflunomide, serious side effects (eg liver damage, hematopoietic toxicity or allergic reactions) may occur due to the long half-life of the active metabolite A771726 (up to 4 weeks).Patients who were anemic, leukopenia or thrombocytopenia, myelosuppression before surgery - have an increased risk of hematological disorders during treatment with leflunomide. If this type of disorder appears, the use of the elution procedure should be considered. Before and during the treatment, blood counts and transaminase levels should be monitored - when ALT levels are 2 to 3 times higher than the upper limit of normal, a dose reduction should be considered, monitoring of liver enzymes; if ALT is 2 x above normal or above 3 x norm, discontinue the drug and use the elution procedure. Caution is advised when co-administered with non-NSAID-mediated drugs metabolised by CYP2C9 (eg, phenytoin, Warfarin, phenprocoumon, tolbutamide). The conversion of leflunomide to another DMARD drug without the use of a preceding washout procedure may increase the risk of side effects even after a long time from the time the medication is changed. Occurrence of: ulcerative stomatitis, skin lesions or mucosal changes that raise the fear of becoming Stevens-Johnson syndrome or toxic epidermal necrolysis, severe untreatable infection, respiratory symptoms (cough, dyspnea), severe hematological disorders, including pancytopenia, require discontinuation of the drug and consideration of the leflunomide elution procedure. Patients with hereditary galactose intolerance, lactase deficiency (Lapp type) or glucose-galactose malabsorption should not take the medicine. Do not drink alcohol during treatment.

Pregnancy must be ruled out before starting treatment. It is presumed that the active metabolite A771726 may cause severe birth defects in the fetus. It is contraindicated in pregnant and fertile women who do not use effective contraception during or after treatment (until the blood A771726 is below 0.02 mg / l). Women of childbearing potential should be informed about the 2-year period that must elapse from the end of treatment to the planned pregnancy. After the waiting period, the concentration of A771726 in the blood should be measured 2 times with an interval of 14 days. The results of two measurements below 0.02 mg / l indicate that the drug is not teratogenic. If the 2-year waiting period is not accepted by a woman, it should be appliedthe elution procedure: after stopping treatment for 11 days 8 g cholestyramine is given 3 times a day or 50 g activated charcoal 4 times a day. Drugs used during this procedure may affect the absorption of estrogens or progestagens, reducing the effectiveness of oral contraception - it is recommended to use alternative methods of contraception at this time. In addition to accelerating the elimination of the drug from the body, it is recommended to perform 2 measurements of the active metabolite concentration in the plasma 14 days apart, and a grace period of 1.5 months from the first time the concentration of the metabolite in the plasma was not more than 0.02 mg / li then you can plan to get pregnant. At the time of taking the drug, if there is any indication of pregnancy, a pregnancy test should be performed and if pregnancy is confirmed - discontinue the medicine, implement a rinsing procedure and discuss fetal risk issues with the patient. Leflunomide and its metabolites are excreted in breast milk - nursing women can not use leflunomide.
Recommendations for men: lack of accurate data on the risk of fetal toxicity transmitted by the male reproductive system. Men should use effective contraception during treatment. Men planning fatherhood should stop taking the medicine and perform the washing out procedure. In all cases, the concentration of A771726 in the blood should be measured 2 times with an interval of 14 days: if the concentration of A771726 in the blood is below 0.02 mg / l and does not increase after 3 months - the risk of fetal toxicity is very low.

Common: leukopenia (leukocytes> 2 G / l), mild allergic reactions, increased creatine kinase, paresthesia, headache, dizziness, peripheral neuropathy, mild increase in blood pressure, diarrhea, nausea, vomiting, anorexia, oral mucositis (eg.aphthous stomatitis, mouth ulcers), abdominal pain, increased liver enzymes (aminotransferases, especially ALT, rarely γ-glutamyltransferases, alkaline phosphatase and bilirubin), worsening of hair loss, eczema, rash (including papule eruption), pruritus, dry skin, tenosynovitis, anorexia, weight loss, weakness. Uncommon: anemia, benign thrombocytopenia (platelets <100 G / l), hypokalaemia, hyperlipidemia, hypophosphatemia, dysgeusia, urticaria, tendon rupture. Rare: severe infections, including sepsis, which may lead to death, aplastic anemia (probably due to antiproliferative mechanism), increased lactate dehydrogenase (LDH), severe increase in blood pressure, interstitial lung disease (including interstitial pneumonitis) that may lead to death, hepatitis, jaundice / cholestasis. Very rare: agranulocytosis, severe anaphylactic / anaphylactoid reactions, vasculitis, including vasculitis with necrosis, pancreatitis, severe liver damage such as liver failure and acute hepatic necrosis, which can lead to death, toxic epidermal necrolysis, Stevens-Johnson, erythema multiforme. Not known: hypouricemia, renal failure, minimal (reversible) reduction in sperm concentration, total sperm count and motility, cutaneous form of lupus erythematosus, pustular psoriasis or worsening of psoriasis, drug erosion with eosinophilia and general symptoms. During the use of the drug may increase: the incidence of infections, including opportunistic (especially rhinitis, bronchitis or lung), the occurrence of neoplastic diseases, especially the lymphatic system. In case of severe immunological, allergic or adverse reactions, the drug should be discontinued and the drug / metabolite elution procedure should be used.

The preparation should be prescribed by specialists experienced in the treatment of rheumatoid diseases and used only under strict medical supervision. Adults: initially 100 mg once daily for 3 days, followed by a maintenance dose - for the treatment of rheumatoid arthritis: 10-20 mg once a day; for the treatment of psoriatic arthritis: 20 mg once daily. Therapeutic effects usually occur after 4-6 weeks and the patient's condition may improve for 4-6 months. Patients with mild renal impairment and those over 65 years of age do not require dose adjustment.
The preparation can be taken regardless of the meal, the tablets should be swallowed whole with a sufficient amount of liquid.