Arava film coated pills 20mg N30
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Pharmacokinetics Absorption and distribution When ingestion is absorbed from 82% to 95% of the drug. Leflunomide can be taken with food. Leflunomide quickly turns into its active metabolite A771726 (primary metabolism in the intestinal wall and metabolism during the "first pass" through the liver). Only traces of unchanged leflunomide were observed in plasma, urine or feces. The only detectable metabolite is A771726, which is responsible for the basic properties of the drug in vivo. After a once taken dose, Cmax A771726 is determined in 1-24 hours. Due to the very long T1 / 2 A771726 (about 2 weeks), a loading dose of 100 mg per day was used for 3 days. This allowed us to quickly reach the equilibrium state of the plasma concentration A771726. Without a loading dose, a 2-month dose would be required to achieve Css. In studies with repeated administration of the drug, the pharmacokinetic parameters of A771726 were dose-dependent in the dose range from 5 to 25 mg. In these studies, the clinical effect was closely related to the plasma concentration of A771726 and the daily dose of leflunomide. With a daily dose of 20 mg, the mean plasma concentrations of A771726 in the equilibrium state were 35 mcg / ml. In plasma, A771726 is rapidly bound to albumin. The unbound fraction A771726 is approximately 0.62%. The binding of A771726 is more variable and somewhat decreases in patients with rheumatoid arthritis or chronic renal failure. Metabolism Leflunomide is metabolized to one major (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. Studies on the interaction with cimetidine (a non-specific inhibitor of cytochrome P450) and rifampicin (a non-specific inducer of cytochrome P450) have shown that in vivo CYP enzymes are only slightly involved in the metabolism of leflunomide. Withdrawal Withdrawal of A771726 from the body is slow and is characterized by a clearance of 31 ml / h. Leflunomide is excreted in the feces (probably due to biliary excretion) and in the urine. T1 / 2 is about 2 weeks. Pharmacokinetics in special clinical situations The pharmacokinetics of A771726 in patients undergoing chronic outpatient peritoneal dialysis are similar to those in healthy volunteers.Faster elimination of A771726 is observed in patients on hemodialysis, which is connected not with the extraction of the drug into dialysate, but with its displacement from the connection with the protein. Although the clearance of A771726 increases approximately 2 times, the final T1 / 2 is similar to that in healthy individuals, since simultaneously increases Vd. Data on the pharmacokinetics of the drug in patients with hepatic insufficiency are absent. Pharmacokinetics in persons younger than 18 years have not been studied. In elderly patients (65 years and older), the pharmacokinetic data roughly correspond to the middle age group. Pharmacological action Basic antirheumatic drug. It has antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory effects. The active metabolite of leflunomide A771726 inhibits the enzyme dehydroorotat dehydrogenase and has an antiproliferative effect. 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 dehydrogenative dehydrogenase dehydrogenase enzyme, which explains its ability to inhibit this enzyme and the proliferation of lymphocytes at the G1 stage. Lymphocyte proliferation is one of the key stages in the development of rheumatoid arthritis. At the same time, A771726 inhibits the expression of receptors for interleukin-2 (CB-25) 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. Leflunomide reduces symptoms and slows the progression of joint damage in the active form of rheumatoid arthritis and psoriatic arthritis. The therapeutic effect usually appears after 4-6 weeks and may increase further over 4-6 months. Indications for use as a basic drug for the treatment of adult patients with the active form of rheumatoid arthritis in order to reduce the symptoms of the disease and delay the development of structural damage to the joints. active form of psoriatic arthritis.
Dosage and administration
The use of the drug should begin under the supervision of a physician with experience in treating rheumatoid arthritis and psoriatic arthritis. In rheumatoid arthritis at the beginning of treatment, the drug is prescribed in a loading dose of 100 mg (in the form of pills 100 mg) 1 time / day for 3 days. However, the exclusion of the loading dose may reduce the risk of adverse reactions (especially from the gastrointestinal tract and the effect on the activity of liver enzymes in the blood). The recommended maintenance dose is 20 mg 1 time / day. When receiving a maintenance dose of 20 mg 1 time / day immediately after the start of treatment (that is, without taking a loading dose), the effectiveness of the drug in rheumatoid arthritis did not decrease. In case of poor tolerability of a dose of 20 mg, a dose may be reduced to 10 mg 1 time / day (in the form of pills 10 mg or 20 mg). In psoriatic arthritis at the beginning of treatment, the drug is prescribed in a loading dose of 100 mg 1 time / day for 3 days. Maintenance dose is 20 mg 1 time / day. With both indications, the therapeutic effect usually appears after 4 weeks and may increase further to 4-6 months. Therapy is usually carried out for a long time. No dose adjustment is required for patients over 65 years of age. The current experience is not enough to give specific recommendations on the dosing regimen in patients with impaired renal function. It should be noted that the active metabolite of leflunomide A771726 has a high affinity for proteins. Patients with impaired liver function: recommendations for dose adjustment or discontinuation of the drug, depending on the severity or persistence of increased ALT activity in patients receiving the drug, are given in the section "Special Instructions". Contraindications - abnormal liver function. - severe immunodeficiency states (including AIDS). - pronounced disorders of bone marrow hematopoiesis or severe anemia, leukopenia, thrombocytopenia as a result of other causes (except rheumatoid arthritis and psoriatic arthritis). - severe, uncontrolled infections. - moderate to severe renal failure (due to the limited experience of clinical use). - severe hypoproteinemia (including nephrotic syndrome). - pregnancy. - lactation period (breastfeeding period). - childbearing age in women,not collected or unable to use reliable methods of contraception during treatment with leflunomide, and then until the plasma level of the active metabolite remains above 0.02 mg / l. - men who are about to conceive a child (they should be warned about the possible adverse effect of leflunomide on the sperm of the future father) (During treatment with leflunomide, you must use reliable methods of contraception). - age of patients less than 18 years (lack of data on the effectiveness and safety in this group of patients). - hypersensitivity to the drug. With care: - patients with interstitial lung diseases (increased risk of interstitial lung damage). - patients with anemia, leukopenia, thrombocytopenia, and a history of bone marrow hematopoiesis. patients who have recently received or are receiving concomitantly with leflunomide drugs with immunosuppressive or hematotoxic effects. patients with significant non-rheumatoid arthritis abnormalities in hematological parameters before starting treatment with leflunomide (frequent hematological monitoring is required). - age over 60 years, the simultaneous use of other neurotoxic drugs and diabetes mellitus (increased risk of developing peripheral neuropathy). - mild renal failure (CC less than 80 ml / min, but more than 50 ml / min) (limited clinical experience). Precautions Use for abnormal liver function Contraindicated for abnormal liver function. Application for violations of renal function Contraindicated use for moderate or severe renal failure (due to the insignificant experience of clinical observations). Dose adjustment is not required in patients with mild renal insufficiency. Use in children It is not recommended to use the drug in children and adolescents under the age of 18 years, because There are no data on efficacy and safety in this group of patients. Use in elderly patients Dose adjustment for patients over 65 is not required. Side Effects Determination of the frequency of adverse reactions: very often (> 1/10), often (> 1/100, but <1/10), infrequently (> 1/1000, but <1/100), rarely (> 1/10 000, but <1/1000), very rarely (<1/10 000), the frequency is unknown (based on the available data it is not possible to estimate the frequency). Since the cardiovascular system: often - increased blood pressure.On the part of the digestive system: often - diarrhea, nausea, vomiting, anorexia, damage to the oral mucosa (for example, aphthous stomatitis, ulceration of the oral mucosa), abdominal pain, increased activity of hepatic transaminases (especially ALT, less often - GGT and AAR. ), hyperbilirubinemia. infrequently - violations of taste sensations. rarely - hepatitis, jaundice / cholestasis. very rarely - pancreatitis, severe liver damage, such as liver failure, acute liver necrosis, which can be fatal. On the part of the respiratory system: rarely - interstitial lung disease (including interstitial pneumonitis), with a possible fatal outcome. On the part of the metabolism: often - a weak increase in CPK, weight loss. infrequently - hypokalemia, weak hyperlipidemia, slight hypophosphatemia. frequency is unknown - a slight increase in LDH, hypouricemia due to the uricosuric effect. Of the nervous system: often - headache, dizziness, paresthesia. infrequently - anxiety. very rarely, peripheral neuropathy. On the part of the musculoskeletal system: the frequency is unknown - tendinovinit and tendon rupture (a causal relationship with treatment with leflunomide has not been established). On the part of the skin and subcutaneous tissues: often - increased hair loss, eczema, itching, dry skin. very rarely, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome (at present, no causal relationship has been established with leflunomide treatment, but it cannot be excluded). frequency is unknown - cutaneous lupus erythematosus, pustular psoriasis or exacerbation of psoriasis. Allergic reactions: often - mild maculopapular rash and other types of rash. infrequently - urticaria. very rarely - serious anaphylactic / anaphylactoid reactions, vasculitis, including cutaneous necrotizing vasculitis (due to the underlying disease, a causal relationship with the treatment of leflunomide cannot be established). On the part of the hematopoietic system: often - leukopenia (leukocytes> 2000 / mcl). infrequently - anemia, small thrombocytopenia (platelets <100 000 / μl). rarely, pancytopenia (probably due to antiproliferative action), leukopenia (leukocytes <2000 / μl), eosinophilia. very rarely - agranulocytosis.The recent concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects. On the part of the reproductive system: the frequency is unknown - a slight decrease in the concentration of sperm, the total number of sperm and their motility. Infectious and parasitic diseases: rarely - the development of severe infections and sepsis, which can be fatal. Immunosuppressive drugs can make the patient more susceptible to infections, including opportunistic infections. The incidence of rhinitis, bronchitis and pneumonia may slightly increase. Benign, malignant and unspecified neoplasms: it is known that the use of certain immunosuppressive drugs increases the risk of malignancy, especially the risk of developing lymphoproliferative diseases. General reactions: often - asthenia. Specific guidance The drug Arava & # 174. can be prescribed only after a thorough medical examination. Before starting treatment with Arava & # 174. it is necessary to remember about the possible increase in the number of side effects in patients who have previously received other basic drugs for the treatment of rheumatoid arthritis, which have a hepato-and hematotoxic effect. The active metabolite of leflunomide A771726 is characterized by prolonged T1 / 2 (from 1 to 4 weeks), so even if treatment is stopped with leflunomide, serious adverse effects may occur or persist (for example, hepatotoxicity, hematotoxicity, or severe immunological / allergic reactions). If a serious adverse reaction develops, or if rapid elimination from the body of A771726 is required for any other reason, Kolestiramine or activated charcoal should be administered as described in the section “Pregnancy and Lactation”, and if it is clinically necessary, continue or repeat the administration of one of them. If severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell syndrome are suspected, a more prolonged use of Kolestiramine or activated charcoal may be required to achieve a quick and effective purification of the body from this metabolite.Due to the prolonged T1 / 2 of the active metabolite of leflunomide A771726, when going on to receive another basic preparation (for example, methotrexate) after treatment with leflunomide, it is necessary to carry out the "laundering" procedure. Reactions to the liver Since the active metabolite of leflunomide A771726 has a high affinity for proteins, it is metabolized in the liver and excreted in the bile, and leflunomide may also have a hepatotoxic effect in patients with impaired liver function is contraindicated. In patients with liver disease, leflunomide is not recommended. Rare cases of severe liver damage have been reported, in some cases fatal, with treatment with leflunomide. Most of these cases were observed during the first 6 months of therapy. Although the causal relationship of these adverse events with leflunomide has not been established, and in most cases there have been several additional suspicious factors, the exact implementation of treatment control recommendations is considered mandatory. It is necessary to determine the activity of ALT in the blood before the start of therapy with Arava & # 174., Then at least 1-2 times a month during the first 6 months of treatment and subsequently every 6-8 weeks. Recommendations for the correction of the dosing regimen or discontinuation of the drug, depending on the severity and persistence of increased ALT activity With a confirmed 2–3-fold increase in VGN of the ALT activity, reducing the dose from 20 mg to 10 mg a day may allow you to continue taking leflunomide subject to careful monitoring of this indicator. If at the same time the increase in ALT activity is 2-3 times higher than VGN is preserved or if there is an unconfirmed increase in ALT activity exceeding VGN by more than 3 times, taking leflunomide should be stopped. For a more rapid decrease in the concentration of A771726, Kolestiramine or activated carbon should be administered according to the "laundering" scheme (as described in the section "Pregnancy and Lactation"). Against the background of the use of the drug Arava & # 174. patients are advised to abstain from alcohol because of possible additional hepatotoxic action. Reactions from the hemopoietic system In patients with previously existing anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or at risk of suppressing bone marrow function, the risk of hematological disorders increases.A complete clinical blood test (including the definition of leukocyte formula and platelet count) should be carried out before starting treatment with leflunomide, and 1-2 times a month for the first 6 months of treatment and then every 6-8 weeks. Frequent monitoring of hematological parameters (complete blood count, including leukocyte formula and platelet count) should be carried out in the following cases: - in patients with recently or simultaneously taking immunosuppressive or hematotoxic drugs, as well as when taking these drugs after treatment with leflunomide without washing. . - in patients with a history of relevant abnormalities in the blood. - in patients with relevant changes in blood tests before treatment, not associated with inflammatory diseases of the joints. In case of serious hematological reactions, including pancytopenia, it is necessary to stop taking the drug Arava & # 174. and any other concomitant drug that suppresses bone marrow hematopoiesis, and begin the "laundering" procedure. Despite the lack of clinical data, due to the potential for immunosuppression, leflunomide is not recommended for patients with the following diseases: - severe immunodeficiency (for example, AIDS). - pronounced dysfunction of the bone marrow. - severe infections. Combined use with other types of treatment At present, there is still no information regarding the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), administered in v / m or orally administered gold preparations, D-penicillium, azathioprine and other immunosuppressive drugs (except for methotrexate). Unknown risk associated with the appointment of complex therapy, especially with long-term treatment. Since this type of therapy may lead to the development of additional or even synergistic toxicity (for example, hepatotoxic or hematotoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are not desirable. Switching to other types of treatment. Since leflunomide remains in the body for a long time, switching to a different basic therapy drug (for example, methotrexate) without proper washing procedure may increase the possibility of additional risk even after a long time after the transition (for example, kinetic interaction, organotoxicity ).Similarly, recent treatment with hepatitis or hematotoxic drugs (for example, methotrexate) can lead to an increase in the number of side effects, therefore, when starting treatment with leflunomide, it is necessary to carefully consider all the positive and negative aspects associated with taking this drug. Dermatological reactions With the development of ulcerative stomatitis, the drug should be discontinued. Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. In the case of skin reactions and / or reactions from the mucous membranes, you should stop taking the drug Arava & # 174. and immediately start the laundering procedure. It is necessary to achieve complete elimination of the drug from the body. In such cases, re-appointment of the drug is contraindicated. Infectious complications It is known that drugs like leflunomide and which have immunosuppressive properties make patients more susceptible to various infections (including opportunistic fungal infections). Emerging infectious diseases are usually difficult and require early and intensive treatment. With the development of a severe infectious process, it may be necessary to remove the drug and conduct a "laundering" procedure. Patients with tuberculin reactivity should be monitored due to the risk of activating tuberculosis. Reactions from the respiratory system During treatment with leflunomide, rare cases of interstitial pulmonary process were noted. The risk of occurrence increases in patients with a history of interstitial lung disease. Interstitial lung diseases are potentially fatal diseases that can be acute in patients receiving treatment. Symptoms such as coughing and dyspnea can cause discontinuation of therapy. Peripheral neuropathy There were reports of peripheral neuropathy in patients treated with Arava & # 174., Which in most patients was resolved after discontinuation of the drug, but in some patients the symptoms persisted. Over 60 years of age, concomitant use of neurotoxic drugs and diabetes mellitus may increase the risk of peripheral neuropathy.With the development of peripheral neuropathy in a patient receiving the drug Arava & # 174., Consideration should be given to discontinuing treatment with this drug and carrying out the procedure for removing the drug described in the section "Pregnancy and lactation". Blood pressure Before starting therapy and periodically during treatment, blood pressure should be monitored, because during treatment with leflunomide may increase it. Interaction Caution must be taken when prescribing drugs that are metabolized under the participation of the isoenzyme CYP2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs. Recommendations for men There are no data on the risk of fetotoxicity (associated with the toxic effect of the drug on the father's spermatozoa), if men take leflunomide. Experimental studies on animals in this direction have not been conducted. To minimize the possible risk to men when planning a baby, you must stop taking leflunomide and go through the "laundering" procedure described in the section "Pregnancy and lactation". Impact on the ability to drive vehicles and control mechanisms No relevant information. However, if adverse reactions from the nervous system, such as dizziness, occur, patients should refrain from driving and other potentially hazardous activities. Use during pregnancy and lactation No clinical studies have been conducted to evaluate leflunomide in pregnant women. However, A771726 has a teratogenic effect in animals (rats, rabbits) and can have a harmful effect on the fetus in humans. Leflunomide is contraindicated for pregnant women or women of childbearing age who do not use reliable contraception during treatment with leflunomide and for some time after this treatment (waiting period or shortened laundering period. See below). You must ensure that there is no pregnancy before starting treatment with leflunomide. Patients should be informed that as soon as the menstruation delay occurs or if there is another reason to assume the onset of pregnancy, they should immediately inform the physician about it in order to make a pregnancy test. in the case of a positive pregnancy test, the doctor should discuss with the patient the possible risk to which this pregnancy is exposed.It is possible that a rapid decrease in the content of the active metabolite in the blood using the procedure for removing the drug described below will help with the first delay of menstruation to reduce the risk that the fetus is exposed to from leflunomide. When negligently taking leflunomide in the first trimester of pregnancy in patients with rheumatoid arthritis with further discontinuation of the drug and carrying out the procedure of "washing" with Kolestiramine (see below), significant developmental defects were found in 5.4% of newborns compared to 4.2% of those in the group of women with rheumatoid arthritis who did not take leflunomide and 4.2% of those in the group of healthy pregnant women who did not take leflunomide. Women who take leflunomide and want to get pregnant are advised to follow one of the following procedures to ensure that the fetus will not be exposed to toxic concentrations of A771726 (control concentration below 0.02 mg / l), because According to the available data, the concentration of the active metabolite in the plasma is less than 0.02 mg / l (0.02 μg / ml) implies minimal teratogenic risk. Waiting period It can be expected that plasma A771726 concentration may be higher than 0.02 mg / l for a long period. It is believed that its concentration may be less than 0.02 mg / l 2 years after discontinuation of treatment with leflunomide. The first time plasma concentration of A771726 is measured after a two-year waiting period. After that, it is necessary to measure the concentration of A771726 in the blood plasma, at least 14 days later. The procedure of "laundering" After discontinuation of treatment with leflunomide: - Kolestiramine 8 g is prescribed 3 times / day for 11 days. - as an alternative, 50 g of activated carbon, powdered, is prescribed 4 times / day for 11 days. Regardless of the selected "laundering" procedure, it is necessary to check with two separate tests with an interval of at least 14 days and wait one and a half months from the moment when the concentration of the drug in plasma is first fixed below 0.02 mg / l until fertilization. It is necessary to inform women of childbearing age that it should be 2 years after discontinuation of treatment with leflunomide before they can try to become pregnant. If a 2-year waiting period with reliable contraception seems to be unreasonable, it may be advisable to carry out a “laundering” procedure for preventive purposes.Both colestyramine and activated carbon can affect the absorption of estrogens and progestogens, therefore reliable oral contraceptives do not provide an absolute guarantee during the laundering period with colestiramine or activated carbon. It is recommended to use alternative methods of contraception. Experimental studies on animals have shown that leflunomide or its metabolites are excreted in breast milk. Therefore, women during breastfeeding should not be prescribed leflunomide. Depending on the importance of treatment for the mother, it should be decided whether breastfeeding will be carried out or treatment with leflunomide will be initiated, and breastfeeding should be abandoned. Type: Medicinal product Shelf life: 36 months Scope of application: Rheumatology Active ingredient: Leflunomide (Leflunomide) Route of administration: Oral Vacation order: Prescription Release form: Prescription Storage conditions: Keep out of the reach of children Maximum storage temperature, ° С: 25 Pharmacological Group: L04AA13 Leflunomide Nosological classification (ICD-10): M07 Psoriatic and enteropathic arthropathies, M05 Seropositive rheumatoid arthritisActive ingredients
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