Elafra (Ehlafra)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLeflunomideLeflunomide
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    • Dosage form: & nbspfilm coated tablets
    Composition:

    One tablet contains

    Active substance: leflunomide - 10 mg or 20 mg;

    Excipients: lactose monohydrate 80.0 mg or 160.0 mg, low-substituted giprolase 5.0 mg or 10.0 mg, tartaric acid 3.0 mg or 6.0 mg, sodium lauryl sulfate 0.5 mg or 1.0 mg, magnesium stearate - 1.5 mg or 3.0 mg;

    Shell composition: polyvinyl alcohol - 1.3656 mg or 2.7312 mg, titanium dioxide - 0.9600 mg or 1.9200 mg, talc, - 0.6000 mg or 1.2000 mg, lecithin - 0.0600 mg or 0.1200 mg , gum xanthan - 0.0144 mg or 0.0288 mg.

    Description:

    The tablets covered with a film membrane of white or almost white color, biconvex, round form - for a dosage of 10 mg.

    The tablets covered with a film cover, white or, almost white color, biconcave, round form with one-sided risk - for a dosage of 20 mg.

    Pharmacotherapeutic group:Immunosuppressive remedy
    ATX: & nbsp

    L.04.A.A.13   Leflunomide

    L.04.A.A   Selective immunosuppressants

    Pharmacodynamics:

    Elafra is the basic antirheumatic drug that modifies the course of the disease, with an antiproliferative effect. The active leflunomide metabolite A771726 inhibits the enzyme dihydroorotate dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits proliferation caused by mitogens and the synthesis of T-lymphocyte DNA. 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 the metabolite A771726. Using radioisotope ligands it was shown that A771726 selectively binds to the enzyme dehydroorotate dehydrogenase, which explains its property to inhibit this enzyme and lymphocyte proliferation in the stage G1. At the same time, A771726 inhibits the expression of receptors for interleukin-2 and antigens of the nucleus Ki-67 and PCNA, associated with the cell cycle.

    The therapeutic effect of leflunomide was demonstrated in several experimental models of autoimmune diseases, including rheumatoid arthritis.
    Pharmacokinetics:

    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 the shock dose is not applied at the beginning of the treatment. Because of the long half-life (T1/2) A771726 a loading dose of 100 mg was used for 3 days. This allowed us to quickly achieve the equilibrium state of the plasma concentration of A771726. Pharmacokinetic parameters of A771726 have a linear dependence at 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 leflunomide. At a dose of 20 mg / day, the average plasma concentrations of A771726 in the steady state were 35 μg / ml. Concentration of the drug in blood plasma with repeated intake increases by 33-35 times compared with a single dose.

    In plasma, A771726 binds rapidly to albumin. The unbound fraction of A771726 is 0.62%. Binding of A771726 is more variable and somewhat reduced in patients with rheumatoid arthritis or chronic renal insufficiency.

    Leflunomide is rapidly metabolized in the intestinal wall and liver to one major (A771726) metabolite and several secondary metabolites, including 4-trifluoromethylalanine. Biotransformation of leflunomide in A771726 and 1 the subsequent metabolism of A771726 itself is controlled by several enzymes and occurs in microsomal and other cell fractions.

    In plasma, urine and feces, traces of leflunomide are determined. Excretion of A771726 is slow and characterized by clearance of 31 ml / h. T1 / 2 - about 2 weeks.
    Indications:Active form of rheumatoid arthritis.
    Contraindications:

    Hypersensitivity to the components of the drug. Hepatic insufficiency, severe immunodeficiency conditions (including AIDS), severe bone marrow function or anemia, leukopenia, neutropenia, thrombocytopenia due to other causes (except rheumatoid arthritis), severe infections, moderate or severe renal failure, severe hypoproteinemia (including nephrotic syndrome); during pregnancy (it is necessary to exclude the possibility of pregnancy before starting treatment with leflunomide) and breastfeeding; children under the age of 18 years.

    Pregnancy and lactation:

    The drug is contraindicated in pregnancy and women of childbearing age who do not use reliable contraceptives. Women need to be protected from pregnancy within 2 years afterdiscontinuation of the drug!

    It is necessary to make sure that there is no pregnancy before starting treatment. Women who take leflunomide and they want to become pregnant (or already with pregnancy), it is recommended to carry out the procedure of "laundering" the drug, which will allow to quickly reduce the level of the active metabolite, in the blood plasma (after stopping treatment with leflunomide appoint colestramine in a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon, crushed into powder, 4 times / day for 11 days). Further, it is necessary to determine the concentration of the metabolite A771726 2 times interval for 14 days. From the moment when the concentration of the drug for the first time is fixed below 20 mcg / l until the time of fertilization should pass 1.5 months. It should be borne in mind that without the procedure of "laundering" of the drug, a decrease in the concentration of the metabolite below 20 μg / l occurs after 2 years. Kolestyramine 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 withdrawal period.

    It is recommended to use alternative methods of contraception.

    Leflunomide and its metabolites penetrate into breast milk. Therefore, the administration of leflunomide during breastfeeding is contraindicated.

    Dosing and Administration:

    Inside, swallowing whole, with enough liquid. The ingestion of food has no effect on the absorption of leflunomide.

    Treatment with leflunomide should begin under the supervision of a doctor who has experience in the treatment of rheumatoid arthritis.

    Treatment with leflunomide begins with a single dose of a shock dose of 100 mg for 3 days. As a maintenance dose for rheumatoid arthritis, it is recommended to take 10-20 mg leflunomide once a day.

    The therapeutic effect usually manifests itself in 4-6 weeks and can grow further to 4-6 months.

    There are no recommendations regarding the dosage of the drug for patients with mild renal insufficiency.

    No dose adjustment is required for patients over 65 years of age.

    Side effects:

    The most common side effects (1-10%): leukopenia; allergic reactions; loss of appetite; weight loss (usually minor); fatigue (weakness), headache, dizziness; paresthesia; moderate increase blood pressure; diarrhea, nausea; vomiting; erosive and ulcerative lesions of the mucous membrane of the oral cavity; stomach ache; increased liver function; increased hair loss; eczema, dry skin, rash, itching; Tendovaginitis, an increase in some enzymes in the blood (creatine phosphokinThreat).

    Unusual side effects (0.1-1%): decrease in the number of red blood cells in the blood (anemia) and a decrease in the number of platelets (thrombocytopenia); decrease in the level of potassium in the blood; anxiety; a violation of taste sensations; hives; increased levels of fats, in the blood (cholesterol and triglycerides), decrease in phosphate levels in the blood.

    Rare side effects (0.01-0.1%): eosinophilia; leukopenia; pancytopenia; a sharp increase in blood pressure; violations of liver function in the form of hepatitis, cholestasis, jaundice; sepsis, which can become a possible fatal outcome;


    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 the tests of the functional state of the liver.

    Treatment: in case of an overdose or toxicity, it is recommended to take colestramine or Activated carbon, to accelerate the cleansing of the body. Kolestyramine, taken by three healthy volunteers orally 8 g 3 times a day for 24 hours, reduced the level of A771726 in the blood plasma by about 40% - after 24 hours and by 49-65% - after 48 h. It is shown that The administration of activated carbon (a powder converted into a suspension) orally or through a gastric tube (50 g every 6 hours for 24 hours) reduced the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and 48% at 48 hours.

    These procedures for "laundering" can be repeated according to clinical indications. Studies with hemodialysis and chronic outpatient peritoneal dialysis (HAFA) indicate that A771726, the main leflunomide metabolite, is not able to be eliminated by dialysis.

    Interaction:

    An increase in adverse reactions may occur in the case of recent or concomitant use of hepatotoxic or hematotoxic drugs, or when the administration of these drugs begins after treatment with leflunomide without the procedure for "laundering".There was no pharmacokinetic interaction between leflunomide (10-20 mg / day) and methotrexate (10-25 mg per week). There is no clinically significant interaction with the simultaneous use of leflunomide and three-phase oral contraceptives, non-steroidal anti-inflammatory drugs (NSAIDs), cimetidine, rifampicin.

    Research in vitro showed that the leflunomide metabolite A771726 inhibits the activity of cytochrome P450 2C9. Caution should be given leflunomide with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide).

    Patients receiving leflunomide, it is recommended not to give colestramine or Activated carbon, as this leads to a rapid and significant decrease in the concentration of A771726 (the active metabolite leflunomide) in blood plasma. It is believed that this is due to a violation of recirculation of A771726 in the liver and small intestine and / or disruption of its gastrointestinal dialysis.

    After the concomitant administration of a single dose of leflunomide to patients receiving multiple doses of rifampicin (a nonspecific inducer of cytochrome P450), the peak levels of A771726 increased by about 40%, then as the area under the concentration-time curve did not change significantly. MeThe mechanism of this effect is not clear.

    With extreme caution should be given leflunomide together with other drugs that are not NSAIDs metabolized by CYP2C9, such as phenytoin, warfarin and tolbutamide.

    In the study, in which leflunomide were given to healthy female volunteers together with three-phase oral contraceptives; containing 30 μg of ethinyl estradiol, there was no reduction in the contraceptive effect of the tablets, and the pharmacokinetics of the A771726 were completely within the prescribed range.

    At present, there is no information on the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychlorine), preparations Au (w / m or orally), Dpenicillamine, azathioprine, and other immunosuppressive drugs (with the exception of methotrexate). The risk associated with complex therapy is unknown, especially with long-term treatment. Because this type of therapy can lead to the development of additional or even synergistic toxicity (eg, hepatotoxicity or hematoxicity), combinations of this drug with other basic drugs (eg methotrexate) are undesirable.The recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects. Immunosuppressants increase the risk of infections, as well as malignant, especially lymphoproliferative diseases.

    There are no clinical data on the efficacy and safety of vaccination in the treatment of leflunomide. However, vaccination with live vaccines is not recommended. Consider the long T1 / 2 drug Elafra when planning vaccination with live vaccine after it is discontinued.
    Special instructions:

    Elafra can only be administered to patients after a thorough medical examination.

    Before starting treatment with Elafra, you should remember about the possible increase in the number of side effects in patients who previously received other basic drugs for the treatment of rheumatoid arthritis; which have hepatoma and hematotoxic effects.

    The active leflunomide metabolite A771726 is characterized by a long T1 / 2, usually ranging from 1-4 weeks. Due to the long T1 / 2 active metabolite leflunomide - A771726,even with the cessation of treatment with leflunomide, serious adverse effects (eg, hepatotoxicity, hematoxicity or allergic reactions - see below) may or may not occur. In this case, the procedure of "laundering" should be followed (after the cessation of treatment with leflunomide is prescribed colestramine in a dose of 8 g 3 times / day for 11 days or 50 g of activated carbon powdered into powder, 4 times / day for 11 days).

    The procedure can be repeated according to clinical indications. If suspected of severe immunological / allergic reactions such as Stevens-Johnson syndrome or Lyell's syndrome, a full procedure for "laundering" is mandatory.

    Therefore, when such cases of toxicity occur or when switching to another basic drug (eg methotrexate) after treatment with leflunomide, it is necessary to carry out the "laundering" procedure.

    Since the active metabolite leflunomide, A771726, is bound to proteins and is excreted by hepatic metabolism and bile secretion, it is suggested that the level of A771726 in the blood plasma may increase in patients with hypoproteinemia.

    There have been reports of rare cases of severe liver damage, in some cases fatal, with leflunomide treatment.

    Most of these cases were observed during the first six months of treatment. Although there is no causal relationship between these undesirable events and leflunomide, and in most cases there were several additional suspicious factors, the precise implementation of the treatment control recommendations is considered mandatory.

    The alanine aminotransferase (ALT) level should be checked before starting leflunomide therapy, and then every 2 weeks for the first 6 months of treatment, with the subsequent check once every 6-8 weeks.

    There are the following recommendations for correcting the dosing regimen or discontinuation of the drug depending on severity and persistence increase in ALT levels.

    With a confirmed 2-3-fold excess of the upper limit of normal ALT, a decrease in the dose from 20 to 10 mg / day may allow the continued use of leflunomide provided that the indicator is closely monitored.

    If 2-3 a multiple excess of the upper limit of the ALT norm is maintained, or if there is a confirmed elevation in ALT levels that exceeds the upper limit of the norm by more than 3 times, leflunomide should be discontinued and the "laundering" procedure should begin.

    Because of the possible additional hepatotoxic effects, it is recommended to refrain from taking alcohol while treating leflunomide.

    Complete clinical analysis of blood, including the definition of leukocyte the formula and the number of platelets should be performed prior to the initiation of leflunomide treatment, and every 2 weeks for the first 6 months of treatment and then every 6-8 weeks.

    In patients with previous anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or the risk of developing such disorders, the risk of hematological disorders increases. If such a phenomenon occurs, you should use the "laundering" procedure to reduce the level of A771726 in blood plasma.

    In case of serious hematologic reactions; including pancytopenia, it is necessary to stop taking Elafra and any other concomitant drug that suppresses bone marrow hematopoiesis and begin the procedure of "laundering".

    Because the leflunomide long remains in the body, switching to another basic drug (for example methotrexate) without an appropriate procedure for "laundering" can increase the possibility of additional risk even after a long time after the transition (eg, kinetic interaction, organotoxicity).

    Similarly, recent treatment with hepatotoxic or hematotoxic drugs (eg methotrexate) may lead to an increase in the number of side effects, so starting leflunomide treatment, it is necessary to carefully consider all the positive and negative aspects, associated with the use of this drug.

    If ulcerative stomatitis develops, Leflunomide should be discontinued.

    Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrosis have been reported in patients who received leflunomide. In case of skin reactions and / or reactions with the sides of the mucous membranes, it is necessary to cancel the use of Elafra and any other drug associated with it and immediately begin the procedure "laundering". It is necessary to achieve complete removal of the drug from the body.In such cases, the repeated administration of the drug is contraindicated. Infections. It is known that drugs like leflunomide and possessing immunosuppressive properties make patients more susceptible to various kinds of infections, including opportunistic infections (infections caused by fungi and microorganisms that can cause infections only in conditions of decreased immunity). Emerging infectious diseases occur, as a rule, hard and require early and intensive treatment. If a serious infectious disease occurs, it may be necessary to interrupt treatment with leflunomide and begin the procedure of "laundering".

    It is necessary to carefully monitor patients with a positive reaction to tuberculin because of the risk of reactivation of tuberculosis.

    In the treatment with leflunomide, rare cases of interstitial pulmonary process were noted. Symptoms such as cough and dyspnea may be the reason for stopping leflunomide.

    Before the start of leflunomide treatment and periodically after its beginning, it is necessary to monitor the blood pressure level.

    Recommendations for men. There is no data on the risk of fetotoxicity (associated with the toxic effect of the drug on spermatozoa father) when using leflunomide by men. To minimize the possible risk to men, when planning the appearance of a child, it is necessary to stop taking leflunomide and use the "laundering" procedure. During the period of application of the drug, men need to take measures to protect their partner from pregnancy.

    Effect on the ability to drive transp. cf. and fur:

    Care should be taken when driving vehicles and performing work that requires a high concentration of attention to the speed of psychomotor reactions.

    Form release / dosage:

    Tablets film-coated 10 mg and 20 mg.

    Packaging:

    For 10, 15, 20, 28, 30, 42, 50, 56, 60, 90, 98 or 100 tablets in polymer bottles. One bottle together with the instruction for use is placed in a cardboard box.

    Storage conditions:

    In a dry, the dark place at a temperature of no higher than 25 ° C.

    Inaccessible to children!

    Shelf life:

    3 years.

    Do not use after the expiration date stated on the package!
    Terms of leave from pharmacies:On prescription
    Registration number:LP-000804
    Date of registration:03.10.2011
    The owner of the registration certificate:K.O. Ромфарм Компани С.Р.Л.K.O. Ромфарм Компани С.Р.Л. Romania
    Manufacturer: & nbsp
    Representation: & nbspРомфарма ОООРомфарма ООО
    Information update date: & nbsp13.11.2015
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