Elafra film coated pills 20mg N30
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Active ingredients
Leflunomide
Release form
Pills
Composition
Leflunomid 20 mg; Excipients: lactose monohydrate - 160.0 mg, low-substituted hyprolosis - 10.0 mg, tartaric acid - 6.0 mg, sodium lauryl sulfate - 1.0 mg, magnesium stearate - 3.0 mg; Coating composition: polyvinyl alcohol - 2.7312 mg, titanium dioxide - 1.9200 mg, talc - 1.2000 mg, lecithin - 0.1200 mg, xanthan gum - 0.0288 mg.
Pharmacological effect
Elafra is a basic antirheumatic drug that modifies the course of the disease, with antiproliferative action. The active metabolite of leflunomide, A771726, inhibits the enzyme dihydroorotat dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes. 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 metabolite A771726. Using radioisotope ligands, it has been shown that A771726 binds selectively to the enzyme dihydroorotat dehydrogenase, which explains its ability to inhibit this enzyme and the proliferation of lymphocytes at the G1 stage. At the same time, A771726 inhibits the expression of receptors for interleukin-2 and Ki-67 and PCNA core antigens associated with the cell cycle. The therapeutic effect of leflunomide has been shown in several experimental models of autoimmune diseases, including rheumatoid arthritis.
Pharmacokinetics
Absorption and distribution; Absorption of the drug is 82-95% and does not depend on food intake. The period of achieving a stable concentration of the drug in the blood plasma is approximately 2 months of daily intake, provided that at the beginning of treatment the loading dose is not applied. Because of the prolonged T1 / 2 A771726, a loading dose of 100 mg was used for 3 days. This made it possible to quickly reach the equilibrium state of plasma concentration A771726.; The pharmacokinetic parameters of A771726 are linearly dependent when used in doses from 5 mg to 25 mg. In these studies, the clinical effect is closely related to the plasma concentration of A771726 and the daily dose of leflunomide. When used at a dose of 20 mg / day, the mean plasma concentrations of A771726 in the equilibrium state were 35 mcg / ml.The concentration of the drug in the blood plasma with repeated administration increases 33-35 times compared with a single dose.; In plasma A771726 quickly binds to albumin. The unbound fraction A771726 is 0.62%. Binding of A771726 is more variable and somewhat decreases in patients with rheumatoid arthritis or chronic renal failure.; Metabolism and excretion; Leflunomide is rapidly metabolized in the intestinal wall and liver to one major metabolite (A771726) and several minor metabolites, including 4-trifluoromethylalanine. The biotransformation of leflunomide in A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cellular fractions. Trace amounts of leflunomide are determined in plasma, urine and feces. Withdrawal of A771726 is slow and is characterized by a clearance of 31 ml / h. T1 / 2 - about 2 weeks.
Indications
- active form of rheumatoid arthritis.
Contraindications
- liver failure; - severe immunodeficiency states (including AIDS); - pronounced dysfunction of the bone marrow or anemia, leukopenia, neutropenia, thrombocytopenia due to other causes (except rheumatoid arthritis); - severe infections; - moderate or severe renal failure; - severe hypoproteinemia (including in nephrotic syndrome); - pregnancy (it is necessary to exclude pregnancy before starting treatment with leflunomide); - breast-feeding; - children's and teenage age up to 18 years; - hypersensitivity to the drug.
Use during pregnancy and lactation
The drug is contraindicated in pregnancy and women of childbearing age who do not use reliable contraceptives. Women should be protected from pregnancy for 2 years after discontinuing the drug. Make sure that there is no pregnancy before treatment. Women who take leflunomide and want to get pregnant (or already at the onset of pregnancy) are recommended to “wash” the drug, which will quickly reduce the level of active metabolite in the blood plasma (after stopping treatment with leflunomide, Kolestiramine is administered at a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon, powdered, 4 times / day for 11 days). Next, you need to determine the concentration of metabolite A771726 2 times with an interval of 14 days.From the moment when the concentration of the drug will be fixed for the first time below 20 mcg / l until the time of fertilization, 1.5 months should pass. It should be borne in mind that without the procedure of "washing" the drug, a decrease in the concentration of the metabolite below 20 mcg / l occurs after 2 years. Kolestiramine and activated carbon can affect the absorption of estrogen and progesterone in such a way that reliable oral contraceptives do not guarantee the necessary contraception during the drug withdrawal period. It is recommended to use alternative methods of contraception. Leflunomide and its metabolites pass into breast milk. Therefore, the use of leflunomide during breastfeeding is contraindicated.
Dosage and administration
Tablets are swallowed, swallowed whole and washed down with a sufficient amount of liquid. Eating does not affect the absorption of leflunomide. Leflunomide treatment should begin under the supervision of a physician experienced in the treatment of rheumatoid arthritis. Treatment with leflunomide begins with a loading dose of 100 mg for 3 days.; The maintenance dose for rheumatoid arthritis is 10–20 mg 1 time / day; The therapeutic effect usually occurs after 4–6 weeks and can increase further to 4–6 months. ; There are no recommendations regarding dosing of the drug in patients with mild renal failure.; Dose adjustment is not required in patients over 65 years of age.
Side effects
The most frequent side effects (1-10%): leukopenia; allergic reactions; loss of appetite, weight loss (usually minor); fatigue (weakness), headache, dizziness, paresthesia; moderate increase in blood pressure; diarrhea, nausea, vomiting, erosive-ulcerative lesions of the oral mucosa, abdominal pain, increased liver function tests; increased hair loss, eczema, dry skin, rash, itching; tendovaginitis, increased activity of certain enzymes in the blood (creatine phosphokinase); Atypical side effects (0.1-1%): a decrease in the number of red blood cells in the blood, thrombocytopenia; decrease in the level of potassium in the blood; anxiety; violation of taste sensations; hives; elevated blood lipids (cholesterol and triglycerides), reduced phosphate levels in the blood.; Rare side effects (0.01-0.1%): eosinophilia, leukopenia,pancytopenia; a sharp increase in blood pressure; abnormal liver function in the form of hepatitis, cholestasis, jaundice; sepsis (possibly fatal); Very rare side effects (0.001% or less): agranulocytosis, severe allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, vasculitis, peripheral neuropathy, pancreatitis.
Overdose
Symptoms: diarrhea, abdominal pain, leukopenia, anemia and an increase in liver function tests. Treatment: In case of overdose or toxicity, it is recommended to take Kolestiramine or activated charcoal to speed up the cleansing of the body. Kolestiramine, taken orally by three healthy volunteers, 8 g 3 times / day for 24 hours, reduced plasma plasma levels of A771726 by about 40% after 24 hours and by 49-65% after 48 hours. It was shown that administration of activated Coal (powder, turned into a suspension) orally or through a stomach tube (50 g every 6 hours during the day) reduced the plasma concentration of the active metabolite A771726 by 37% - after 24 hours and by 48% - after 48 hours; laundering "can be repeated for clinical reasons. Studies with hemodialysis and chronic ambulatory peritoneal dialysis (HAPD) indicate that A771726, the main metabolite of leflunomide, is not eliminated by dialysis.
Interaction with other drugs
Increased adverse reactions may occur in the case of recent or concomitant use of hepatotoxic or hematotoxic drugs, or when these drugs are started after treatment with leflunomide without laundering. No pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10 -25 mg per week); There is no established clinically significant interaction with simultaneous use of leflunomide and three-phase oral contraceptives, NSAIDs, cimetidine, rifampicin; In vitro studies Zali that metabolite of leflunomide A771726 inhibits the activity of CYP2C9. Leflunomide should be prescribed with drugs that are metabolized by this enzyme system (phenytoin, warfarin, tolbutamide); Kolestiramine or activated carbon is not recommended for patients receiving leflunomide treatment, since this results in a rapid and significant decrease in the concentration of A771726 (active metabolite leflomidida) in blood plasma.This is believed to be due to impaired recycling of A771726 in the liver and small intestine and / or impaired gastrointestinal dialysis. After the concomitant administration of a single dose of leflunomide, patients who received multiple doses of rifampicin (a non-specific cytochrome P450 inducer), Cmax A771726 increased by about 40% while the AUC has not changed significantly. The mechanism of this effect is not clear. In a study in which leflunomide was administered to healthy female volunteers with three-phase oral contraceptive preparations containing 30 μg of ethinyl estradiol, no decrease in the contraceptive effect of the pills was found, and the A771726 pharmacokinetics was fully within the prescribed range. There is no information regarding the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxy Orin), gold preparations (V / m or orally), D-penicillamine, azathioprine, and other immunosuppressive agents (except methotrexate). Unknown risk associated with the conduct of complex therapy, especially with long-term treatment. Since this kind of therapy can lead to the development of additional or even synergistic toxicity (for example, hepato-or hematoxia), combinations of Elafra with other basic drugs (for example, methotrexate) are undesirable. The recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects. Immunosuppressants increase the risk of developing infections, as well as malignant, especially lymphoproliferative diseases. There is no clinical data on the efficacy and safety of vaccination in conditions of treatment with leflunomide. However, vaccination with live vaccines is not recommended. Long-term T1 / 2 leflunomide should be considered when planning vaccination with a live vaccine after discontinuation of the drug Elafra.
special instructions
Elafra can be prescribed to patients only after a thorough medical examination.; Before starting treatment with Elafra, one should be aware of a possible increase in the number of side effects in patientspreviously treated with other basic agents for the treatment of rheumatoid arthritis, which have hepatotoxic and hematotoxic effects. The active metabolite of leflunomide, А771726, is characterized by prolonged T1 / 2, usually 1-4 weeks, as a result of which serious undesirable effects (eg, hepatotoxicity, hematoxicity, or allergic reactions). In this case, the “laundering” procedure should be carried out (after stopping the treatment with leflunomide, Kolestiramine is administered at a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon, powdered, 4 times / day for 11 days). The procedure can be repeated according to clinical indications. If you suspect severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome, a full laundering procedure is required. If such cases occur or if you switch to a different basic drug (for example, methotrexate ) after treatment with leflunomide, it is necessary to carry out the "laundering" procedure. Since the active metabolite of leflunomide, A771726, binds to proteins and is excreted through the hepatic metabolite ma and secretion of bile, it is assumed that the level of A771726 plasma levels may be increased in patients with hypoproteinaemia,. it has been reported rare cases of severe liver injury, in some cases with fatal outcome, in the treatment with leflunomide. Most of these cases were observed during the first 6 months of treatment. Although the causal relationship of these adverse events with leflunomide has not been established, and in most cases there were several additional suspicious factors, accurate follow-up of treatment control recommendations is considered mandatory. , with the subsequent check 1 time in 6-8 weeks.; There are the following recommendations for correction of the dosage regimen or discontinuation of the drug, depending on the severity and sustainability and increased ALT. With confirmed 2-3-fold excess of VGN dose reduction from 20 mg / day to 10 mg / day may allow to continue taking leflunomide, subject to careful monitoring of this indicator.If a 2-3-fold excess of VGN ALT persists or if there is a confirmed increase in ALT level exceeding VGN more than 3 times, taking leflunomide should be stopped and the procedure of "laundering" should be started.; Because of possible additional hepatotoxic effects, it is recommended to refrain from taking alcohol ; treatment with leflunomide.; A complete clinical blood test, including the determination of leukocyte formula and platelet count, should be carried out before the start of treatment with leflunomide, as well as every 2 weeks during the first 6 months of treatment and so every 6-8 weeks. For 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 hematological disorders. If such a phenomenon occurs, you should use the laundering procedure to reduce plasma A771726.; In the event of serious hematological reactions, including pancytopenia, you should stop taking Elafra and any other concomitant bone marrow hematopoietic drug, and start the laundering procedure ".; Since leflunomide remains in the body for a long time, switching to a different basic drug (e.g., methotrexate) can be taken without proper washing procedure. I "can increase the possibility of additional risk even after a long time after the transition (for example, kinetic interaction, organotoxicity). Similarly, recent treatment with hepatotoxic or hematotoxic drugs (for example, methotrexate) can lead to an increase in the number of side effects, so when starting treatment with leflunomide, you should carefully consider all the positive and negative aspects associated with taking this drug.; In the case of ulcerative stomatitis, you should stop taking leflunomide.; Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving x leflunomide. In the event of skin reactions and / or reactions from the mucous membranes, it is necessary to stop taking Elafra and any other drug associated with it and immediately start the “laundering” procedure. It is necessary to achieve complete elimination of the drug from the body.In such cases, repeated administration of the drug is contraindicated. It is known that drugs like leflunomide and which have immunosuppressive properties increase the susceptibility of the patient to various infections, including opportunistic infections (arising only in conditions of reduced immunity). Infectious diseases are, as a rule, difficult and require early and intensive treatment. In the event of a serious infectious disease, it may be necessary to interrupt treatment with leflunomide and begin the procedure of "laundering."; Patients with a positive reaction to tuberculin should be carefully monitored because of the risk of reactivation of tuberculosis. Rare cases of interstitial pulmonary process have been noted during therapy with leflunomide. Symptoms such as cough and dyspnea can cause discontinuation of leflunomide. Before starting treatment with leflunomide and periodically after it begins, blood pressure should be monitored. No data are available on the risk of fetotoxicity (associated with the toxic effect of the drug on the father's spermatozoa) when men are using leflunomide . To maximize the possible risk to men when planning a baby, you must stop taking leflunomide and use the "laundering" procedure. During the period of use of the drug, men need to take measures to prevent their partner from becoming pregnant.; Influencing the ability to drive vehicles and control mechanisms; Use caution when driving and performing work that require high concentration of attention and speed of psychomotor reactions.