Index of drugs

Treatment of adult patients with: active rheumatoid arthritis, as a disease-modifying anti-rheumatic drug (DMARD), active psoriatic arthritis. Recent or simultaneous treatment with DMARDs with hepatotoxic or hematotoxic effects (eg methotrexate) may increase the risk of serious adverse reactions, therefore the decision to initiate leflunomide therapy should be preceded by a thorough analysis of the benefit / risk ratio. In addition, switching from leflunomide to another DMARD preparation without an elution procedure may also increase the risk of side effects, even long after the change.

1 tabl powl. contains 20 mg of leflunomide. The drug contains lactose and soya lecithin.

An anti-rheumatic drug with immunomodulatory and immunosuppressive properties, with antiproliferative and anti-inflammatory properties from the DMARD group (modifying the course of the disease). 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 rheumatoid arthritis (RA) or chronic renal impairment, protein binding may be diminished or more variable. 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).

Hypersensitivity to leflunomide (especially if you previously had Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme), peanut or soy, or any of the excipients. Hepatic dysfunction. Severe immunodeficiency, e.g. AIDS. Severe bone marrow abnormalities or significant anemia, leukopenia, neutropenia or thrombocytopenia caused by factors other than rheumatoid arthritis or psoriatic arthritis. Severe infections. Moderate to severe renal failure due to inadequate clinical experience in this group of patients. Severe hypoproteinemia, e.g. in the nephrotic syndrome. Pregnancy, breastfeeding period. Women of childbearing potential who do not use effective contraception during treatment with leflunomide and for as long as it is completed, until the concentration of the active metabolite in the plasma is greater than 0.02 mg / l.

The decision to initiate leflunomide therapy should be preceded by a thorough analysis of the expected benefits in relation to possible risks. It is not recommended for 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. Severe side effects (eg liver damage, hematopoietic toxicity or allergic reactions) can occur even after discontinuation of leflunomide therapy. Therefore, if such effects occur or if for any reason it is necessary to quickly remove the active metabolite of leflunomide (A771726) from the body, an elution procedure must be used (this procedure can be repeated if clinically necessary).Elution procedure - 8 g cholestyramine is given 3 times a day for 11 days or alternatively 50 g activated charcoal powder 4 times a day for 11 days. Patients who experienced anemia, leukopenia or thrombocytopenia, bone marrow dysfunction - have an increased risk of hematological disorders during treatment with leflunomide; if this type of disorder appears, the use of the drug elution procedure should be considered. Before starting treatment and during treatment - every 2 weeks for the first 6 months, and then every 8 weeks, the blood count (including white blood cell count and platelet count determination) and transaminase activity should be monitored - when ALT is 2 up to 3 times higher than the upper limit of normal (ULN), a dose reduction should be considered, monitoring of liver enzymes at weekly intervals; if ALT activity is maintained at 2 × ULN or more than 3x ULN - discontinue the drug and use the elution procedure. It is recommended to continue monitoring liver enzymes after discontinuation of leflunomide therapy until normalization of results. In addition, blood pressure should be monitored before and during treatment. 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 mucous membrane changes that raise the fear of becoming Stevens-Johnson syndrome or toxic epidermal necrolysis, severe untowable infection, respiratory symptoms (cough, shortness of breath), severe disorder hematologic in this pancytopenia, peripheral neuropathy - require discontinuation of the drug and consideration of the leflunomide elution procedure. Patients with a positive tuberculin reaction should be carefully observed because of the risk of tuberculosis activation. Avoid drinking alcohol during treatment due to the possibility of additional liver damage. The drug contains lactose - patients with hereditary galactose intolerance, lactase deficiency (Lapp type) or glucose-galactose malabsorption should not take the drug.

The use of the drug in pregnancy is contraindicated. There is a suspicion that the active metabolite of leflunomide (A771726) may cause serious birth defects. Animal studies indicate that leflunomide or its metabolites are excreted in human milk, therefore leflunomide should not be used during breastfeeding. Women of childbearing potential must use effective contraception during and up to 2 years after the treatment period or up to 11 days after the treatment period if an elution procedure is used. For the 2-year waiting period, the A771726 plasma concentration should be measured after 2 years and the measurement should be repeated after at least 14 days - if the concentration results of both measurements are less than 0.02 mg / l there is no teratogenic effect of the drug. After the elution procedure (see Precautions), 2 measurements of the active metabolite in the 14-day interval are recommended, as well as a grace period of 1.5 months from when the plasma metabolite concentration was no more than 0.02 mg / l. The cholestyramine and powdered Activated carbon used in the washing procedure can affect the absorption of estrogens and progestagens, hence the use of hormonal contraception at this time may be unreliable - it is recommended to use alternative methods of contraception.Men should be warned that they can mediate the toxic effects of leflunomide on the fetus, so they should use effective contraception during treatment.

Common: leukopenia (leukocyte count> 2 G / l); slight allergic reactions; increase in creatine kinase (CK); paresthesia, headache, dizziness, peripheral neuropathy; a mild increase in blood pressure; diarrhea, nausea, vomiting, disorders of the oral mucosa (eg aphthous stomatitis, ulceration of the oral mucosa), abdominal pain; increased values ​​of liver function (transaminase levels, especially ALT, rarely gamma-GT, alkaline phosphatase and bilirubin); increased hair loss, eczema, rash (including papular-macular rash), pruritus, dry skin; tenosynovitis; anorexia, weight loss (usually insignificant), weakness. Uncommon: anemia, slight thrombocytopenia (platelet count <100 G / l), hypokalaemia, hyperlipidemia, hypophosphatemia, anxiety; taste disorders, urticaria, tendon rupture. Rare: severe infections, including sepsis which may result in death, pancytopenia (probably due to an antiproliferative mechanism), leukopenia (leukocyte count <2 G / l), eosinophilia, increased lactate dehydrogenase (LDH), severe increase in blood pressure, interstitial lung disease (including interstitial pneumonia) that may end with death, hepatitis, jaundice / cholestasis. Very rare: agranulocytosis, severe anaphylactic / anaphylactoid reactions, vasculitis including vasculitis with pertussis, pancreatitis, severe liver damage such as liver failure and acute hepatic necrosis, which can lead to death, toxic necrotic epithelial separation, Stevens-Johnson, erythema multiforme. Not known: hypoglycaemia, cutaneous lupus erythematosus, pustular psoriasis or worsening of psoriasis, drug eradication with eosinophilia and systemic symptoms (DRESS), renal failure, minimal (reversible) reduction in sperm concentration, total sperm count and motility. As with other immunosuppressants, leflunomide may increase the sensitivity of patients to infections, including opportunistic infections. Therefore, the incidence of infections (especially rhinitis, bronchitis and pneumonia) may increase. The use of certain immunosuppressive drugs increases the risk of malignant tumors, especially lymphoproliferative disorders. Pre-existing, concomitant or subsequent administration of leflunomide with possible myelotoxic effects may be associated with a higher risk of adverse haematological effects.

Orally. Adults. Treatment starts with a 100 mg loading dose given once daily for 3 days.Rheumatoid arthritis: the recommended maintenance dose is 10-20 mg once a day, treatment can start with a dose of 10 mg or 20 mg depending on the severity of the disease (skipping the loading dose may reduce the risk of side effects).Psoriasis arthropathy: the recommended maintenance dose is 20 mg once a day. Therapeutic effects usually start after 4 to 6 weeks, and the patient's condition may continue to improve for 4 to 6 months.Way of giving. Table. should be swallowed whole, regardless of the meal.