You have been prescribed this medicine if you have any of the following:
Active phase of rheumatoid arthritis in adults, active phase of psoriatic arthritis.
Recent or concomitant treatment with hepatotoxic or hematotoxic disease-modifying antirheumatic drugs (DMARDs) (e.g. methotrexate) may increase the risk of serious adverse reactions, therefore, the beginning of treatment with leflunomide should be carefully considered, taking into account the aspects of benefit/risk.
Besides, the transfer from leflunomide to another DMARD without the elimination procedure (see section “Peculiarities of use”) may also increase the risk of serious adverse effects, even after a long period since the transfer.
You should consult your doctor if you experience any of the following:
You should consult your doctor if you experience any of the following:
Classification of expected frequencies of adverse reactions: very common (> 1/10), common (> 1/100, <1/10); uncommon (> 1/1000, <1/100); rare (> 1/10000, <1/1000), very rare (<1/10000), including isolated reports.
In each group, the adverse reactions are presented according to their frequency, in order of decreasing severity:
Infections and invasions:
rare – severe infections, including sepsis (including cases with fatal outcome).
Leflunomide, as well as other immunosuppressive agents, may increase the patients; sensitivity to various infections, including opportunistic infections.
Thus, the risk of infections may increase, in particular, rhinitis, bronchitis and pneumonia.
Benign neoplasms, malignant neoplasms and non-specific ones (cysts and polyps).
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive agents.
Blood system:
common – leukopenia (leukocytes > 2 g/L); rare – anemia, thrombocytopenia; rare – pancytopenia, leucopenia (leukocytes < 2 g/L), eosinophilia; very rare – agranulocytosis.
Recent, concomitant or following administration of potentially myelotoxic agents may be associated with a higher risk of hematologic effects.
Immune system:
common – mild allergic reactions, very rare – anaphylactic/anaphylactoid reactions, vasculitis (including cutaneous necrotizing vasculitis).
Metabolism:
common – increased creatine phosphokinase, rare – increased lactate dehydrogenase; unknown (isolated reports) – decreased content of uric acid.
Mental disorders:
common – anxiety.
Nervous system:
common – paresthesia, headache, dizziness; very rare – peripheral neuropathy.
Cardiovascular system:
common – moderate increase in blood pressure; rare – significant increase in blood pressure.
Respiratory system:
rare – interstitial pneumonia (including cases with fatal outcome).
Digestive tract:
common – diarrhea, nausea, vomiting, abdominal pain, lesions of the oral mucosa (stomatitis, ulcers); rare – dysgeusia; very rare – pancreatitis.
Hepatobiliary system:
common – increased liver transaminases (particularly alanine aminotransferase (ALT)), less common – increased gamma-glutathione transferase, and alkaline phosphatase, hyperbilirubinemia; rare – hepatitis, jaundice, cholestasis; very rare – severe liver damage such as liver failure or acute liver necrosis (including cases with fatal outcome).
Skin and skin appendages:
common – increased hair loss, eczema, skin rashes (including maculopapular rash), itching, dry skin; rare – urticaria; very rare – urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal system:
common – tenosynovitis; sometimes – tendon rupture.
Urinary system:
unknown – kidney failure.
Reproductive system:
unknown (isolated reports) – reduction in the number and mobility of spermatozoa (reversible).
General disorders:
common – anorexia, weight loss (usually insignificant), asthenia.
The active metabolite of leflunomide, A771726, is characterized by long half-life, usually from 1 to 4 weeks. In case of severe adverse effects of leflunomide or necessity of rapid elimination of А771726 for some other reason, the elimination procedure, which is described in section “Peculiarities of use”, should be performed. The procedure may be performed when clinically indicated. If severe immunological/allergic reactions such as Stevens-Johnson syndrome or Lyell’s syndrome are suspected, a complete elimination procedure is necessary.
Если приближается время для принятия следующей дозы , проигнорируйте пропущенную дозу и примите следующую дозу как вам назначено.
В противном случае , примите дозу сразу , как только Вы вспомнили о ней и далее принимайте как обычно.
The adverse effects may increase in case of recent or concomitant with Lefno® usage of hepatotoxic or hematotoxic drugs, and when using these drugs after treatment with the drug without taking into account the period necessary for complete elimination. Thus, close monitoring of liver enzymes and hematological parameters is recommended at the initial phase of transfer.
Administration of cholestyramine and activated carbon brings on rapid and significant decrease in plasma concentration of leflunomide active metabolite. This is believed to be due to violated recirculation of А771726 in the liver and small intestine and/or violation of its gastrointestinal dialysis.
In co-administration of leflunomide (10 to 20 mg per day day) and methotrexate (10 to 25 mg per week) a 2-3-fold increase in liver enzymes activity has been observed.
It is not recommended that the patients receiving leflunomide are treated with cholestyramine or powdered activated carbon, as this brings on rapid and significant decrease in plasma concentration of A771726 (leflunomide active metabolite). The mechanism of this phenomenon is believed to be due to interruption of enterohepatic metabolic cycles and/or gastrointestinal dialysis of A771726
Patients treated with nonsteroidal anti-inflammatory drugs and/or corticosteroids before starting treatment with Lefno®, may continue these drugs concomitantly with Lefno®.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known.
In co-administration of leflunomide and methotrexate increased liver enzymes are marked.
Increased prothrombin time when co-administration of leflunomide and warfarin has been reported.
Co-administration of leflunomide and antimalarial drugs that are used to treat rheumatism (chloroquinolones, hydroxychloroquinolones), preparations of gold (oral or intramuscular), D-penicillamine, azathioprine and other immunosuppressive drugs (cyclosporine, methotrexate) is still not studied enough.
There are no data on incompatibility of leflunomide with other drugs.
In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. no safety problems were observed when leflunomide and NSAIDs metabolized by CYP2C9 were co-administered. Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolized by CYP2C9 such as phenytoin, tolbutamide, warfarin and phenprocoumon. Vaccination.
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment. The long half-life of leflunomide should be determined when administration of a live vaccine after stopping leflunomide.
Symptoms:
abdominal pain, nausea, vomiting, diarrhea, increased biochemical parameters of liver function, anemia, leukopenia, itching and rash.
Treatment:
oral administration of cholestyramine or activated carbon is recommended to accelerate elimination of the drug. The duration of therapy is determined individually depending on the clinical picture.
The elimination procedure may be repeated when clinically indicated.
There is no need for hemodialysis or chronic peritoneal dialysis, as the studies indicate that primary metabolite of leflunomide А771726 is not dialyzable.
Tell your doctor immediately if you become pregnant while taking this medication.
For safety of any drug during pregnancy or breastfeeding – please consult your doctor.
Store in a dry, protected from light place at a temperature not more than 25° C.
Keep it out of reach of children.
COMPOSITION:
active substance:
leflunomide;
1 tablet contains leflunomide 20 mg;
Starlac*, Povidone, Croscarmellose sodium, Sodium lauryl sulfate, Colloidal anhydrous silica, Talc, Kollicoat IR White II.
*Starlac contains:
lactose monohydrate, corn starch.
INDICATIONS:
Active phase of rheumatoid arthritis in adults, active phase of psoriatic arthritis.
Recent or concomitant treatment with hepatotoxic or hematotoxic disease-modifying antirheumatic drugs (DMARDs) (e.g. methotrexate) may increase the risk of serious adverse reactions, therefore, the beginning of treatment with leflunomide should be carefully considered, taking into account the aspects of benefit/risk.
Besides, the transfer from leflunomide to another DMARD without the elimination procedure (see section “Peculiarities of use”) may also increase the risk of serious adverse effects, even after a long period since the transfer.
DOSAGE:
Leflunomide is administered as a disease-modifying antirheumatic drug (DMARD). Treatment with leflunomide should be prescribed and controlled by a specialist with the experience in treatment of rheumatoid and psoriatic arthritis.
The levels of alanine aminotransferase (ALT) and serum glutamic pyruvic transaminase (SGPT) should be controlled, and complete blood count, including differential analysis of leukocytes and platelets, should be performed simultaneously and at the same intervals:
– prior to administration of leflunomide;
– once in 2 weeks for 6 months of treatment;
– once in 8 weeks after the treatment (see “Peculiarities of use”).
Treatment with leflunomide starts with a saturating dose, which is 100 mg once per day for 3 days. Further, a maintenance dose of 20 mg once per day is recommended in rheumatoid arthritis. If the maintenance dose of 20 mg is poorly tolerated by the patient, it can be reduced to 10 mg once per day.
If the use of 10 mg dose is necessary, tablets with the appropriate content of active substance should be taken.
The recommended maintenance dose in patients with psoriatic arthritis in active phase is 20 mg once per day.
The therapeutic effect is seen after 4-6 weeks since the start of treatment and may increase within 4-6 months. As a rule, the drug should be taken for a long time.
The tablets should be swallowed without chewing, followed by a sufficient amount of water.
The degree of absorption of leflunomide does not depend of food intake.
ADVERSE REACTIONS:
Classification of expected frequencies of adverse reactions: very common (> 1/10), common (> 1/100, <1/10); uncommon (> 1/1000, <1/100); rare (> 1/10000, <1/1000), very rare (<1/10000), including isolated reports. In each group, the adverse reactions are presented according to their frequency, in order of decreasing severity:
Infections and invasions:
rare – severe infections, including sepsis (including cases with fatal outcome).
Leflunomide, as well as other immunosuppressive agents, may increase the patients; sensitivity to various infections, including opportunistic infections.
Thus, the risk of infections may increase, in particular, rhinitis, bronchitis and pneumonia.
Benign neoplasms, malignant neoplasms and non-specific ones (cysts and polyps).
The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive agents.
Blood system:
common – leukopenia (leukocytes > 2 g/L); rare – anemia, thrombocytopenia; rare – pancytopenia, leucopenia (leukocytes < 2 g/L), eosinophilia; very rare – agranulocytosis.
Recent, concomitant or following administration of potentially myelotoxic agents may be associated with a higher risk of hematologic effects.
Immune system:
common – mild allergic reactions, very rare – anaphylactic/anaphylactoid reactions, vasculitis (including cutaneous necrotizing vasculitis).
Metabolism:
common – increased creatine phosphokinase, rare – increased lactate dehydrogenase; unknown (isolated reports) – decreased content of uric acid.
Mental disorders:
common – anxiety.
Nervous system:
common – paresthesia, headache, dizziness; very rare – peripheral neuropathy.
Cardiovascular system:
common – moderate increase in blood pressure; rare – significant increase in blood pressure.
Respiratory system:
rare – interstitial pneumonia (including cases with fatal outcome).
Digestive tract:
common – diarrhea, nausea, vomiting, abdominal pain, lesions of the oral mucosa (stomatitis, ulcers); rare – dysgeusia; very rare – pancreatitis.
Hepatobiliary system:
common – increased liver transaminases (particularly alanine aminotransferase (ALT)), less common – increased gamma-glutathione transferase, and alkaline phosphatase, hyperbilirubinemia; rare – hepatitis, jaundice, cholestasis; very rare – severe liver damage such as liver failure or acute liver necrosis (including cases with fatal outcome).
Skin and skin appendages:
common – increased hair loss, eczema, skin rashes (including maculopapular rash), itching, dry skin; rare – urticaria; very rare – urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal system:
common – tenosynovitis; sometimes – tendon rupture.
Urinary system: unknown – kidney failure.
Reproductive system:
unknown (isolated reports) – reduction in the number and mobility of spermatozoa (reversible).
General disorders:
common – anorexia, weight loss (usually insignificant), asthenia.
The active metabolite of leflunomide, A771726, is characterized by long half-life, usually from 1 to 4 weeks. In case of severe adverse effects of leflunomide or necessity of rapid elimination of А771726 for some other reason, the elimination procedure, which is described in section “Peculiarities of use”, should be performed. The procedure may be performed when clinically indicated. If severe immunological/allergic reactions such as Stevens-Johnson syndrome or Lyell’s syndrome are suspected, a complete elimination procedure is necessary.
Drug interactions:
The adverse effects may increase in case of recent or concomitant with Lefno® usage of hepatotoxic or hematotoxic drugs, and when using these drugs after treatment with the drug without taking into account the period necessary for complete elimination. Thus, close monitoring of liver enzymes and hematological parameters is recommended at the initial phase of transfer.
Administration of cholestyramine and activated carbon brings on rapid and significant decrease in plasma concentration of leflunomide active metabolite. This is believed to be due to violated recirculation of А771726 in the liver and small intestine and/or violation of its gastrointestinal dialysis.
In co-administration of leflunomide (10 to 20 mg per day day) and methotrexate (10 to 25 mg per week) a 2-3-fold increase in liver enzymes activity has been observed.
It is not recommended that the patients receiving leflunomide are treated with cholestyramine or powdered activated carbon, as this brings on rapid and significant decrease in plasma concentration of A771726 (leflunomide active metabolite). The mechanism of this phenomenon is believed to be due to interruption of enterohepatic metabolic cycles and/or gastrointestinal dialysis of A771726
Patients treated with nonsteroidal anti-inflammatory drugs and/or corticosteroids before starting treatment with Lefno®, may continue these drugs concomitantly with Lefno®.
The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known.
In co-administration of leflunomide and methotrexate increased liver enzymes are marked.
Increased prothrombin time when co-administration of leflunomide and warfarin has been reported.
Co-administration of leflunomide and antimalarial drugs that are used to treat rheumatism (chloroquinolones, hydroxychloroquinolones), preparations of gold (oral or intramuscular), D-penicillamine, azathioprine and other immunosuppressive drugs (cyclosporine, methotrexate) is still not studied enough.
There are no data on incompatibility of leflunomide with other drugs.
In vitro studies indicate that A771726 inhibits cytochrome P4502C9 (CYP2C9) activity. no safety problems were observed when leflunomide and NSAIDs metabolized by CYP2C9 were co-administered. Caution is advised when leflunomide is given together with drugs, other than NSAIDs, metabolized by CYP2C9 such as phenytoin, tolbutamide, warfarin and phenprocoumon.
Vaccination.
No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment. The long half-life of leflunomide should be determined when administration of a live vaccine after stopping leflunomide.
Pregnancy and lactation:
Pregnancy
The active metabolite of leflunomide, A771726, is suspected to cause severe developmental defects of the fetus when using the drug during pregnancy.
The drug is contraindicated during pregnancy!
It is not administered in women of reproductive age using no effective contraception during and after the treatment on condition that the level of active metabolite is 0.02 mg/L.
Women of reproductive age should use effective means contraception during 2 years since the drug therapy (see “waiting period” in section “Peculiarities of use”) or up to 11 days after the end of treatment see short “elimination period” in section “Peculiarities of use”).
The possibility of pregnancy should be excluded before starting treatment with leflunomide!
The patient should be warned that in case of delayed menstruation or other signs indicating the onset of pregnancy, she should immediately report to the physician to diagnose pregnancy. If the test is positive, the physician should weigh the risks which may be faced by the pregnant woman, taking the drug, and inform the patient. During the first month of delay, the risk to the fetus caused by taking leflunomide may be decreased by leflunomide elimination procedure.
Women taking leflunomide and planning to conceive are recommended one of the procedures of elimination (see “Peculiarities of use”) of leflunomide to minimize the potential toxic effect of А771726 on the fetus (the concentration of А771726 less than 0.02 mg/L is considered to be associated with minimum risk to the fetus).
Lactation
Leflunomide and its metabolites may be excreted into the breast milk. Therefore, leflunomide is contraindicated in lactating women.
Children:
The drug is not used in children (efficacy and safety in juvenile rheumatoid arthritis (JRA) have not been established).
PRECAUTIONS:
Concomitant administration of hepatotoxic or hematotoxic DMARDs (e.g. methotrexate) is not recommended.
The active metabolite of leflunomide, A771726, has a long half-life period, which usually is 1 to 4 weeks. Serious adverse effects may occur (such as hepatotoxic effect, hematotoxic effect or allergic reactions, see below) even if leflunomide therapy has been stopped. Thus, in case of such toxic effects or for any other reason, elimination procedure should be performed. This procedure may be repeated depending on clinical needs.
The procedures of elimination and other recommended procedures in case of desired or unintended pregnancy are given in section “Pregnancy”.
Hepatic reactions
Rare cases of severe liver disease, including cases with fatal outcome that occurred during treatment with leflunomide have been reported. Most of these cases occurred within the first 6 months of treatment. Often, there has been simultaneous treatment with other hepatotoxic drugs. It is considered appropriate to monitor strict compliance with the recommendations.
ALT (SGPT) levels should be checked before starting leflunomide, and at the same intervals as performing complete blood count (once in 2 weeks), during the first 6 months of treatment and every 8 weeks after its termination.
In case of a 2-3-fold increase over the upper limit of normal in ALT (SGPT) levels, a possibility of decreasing the dose from 20 mg to 10 mg should be considered, and a weekly monitoring should be performed. If the 2-fold increase over the upper limit of normal in ALT (SGPT) levels persists, or if ALT levels increase more than 3-fold over the upper limit of normal, leflunomide should be withdrawn and elimination procedure should be started. It is recommended to continue the monitoring of liver enzymes after termination of leflunomide therapy, until liver enzymes returned to normal.
Due to the possibility of additional hepatotoxic effects, it is recommended to abstain from alcohol during treatment with leflunomide.
Hematological reactions
Along with ALT levels control, before starting treatment with leflunomide, as well as once in 2 weeks during the first 6 months of treatment and once in 8 after its termination, complete blood count including differential analysis of leukocytes and platelets should be performed.
In patients with pre-existing anemia, leukopenia and/or thrombocytopenia, as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression there is an increased risk of hematological disorders. In case of such effects, a possibility of performing elimination to reduce plasma levels of A771726 should be considered.
In case of severe hematological effects, including pancytopenia, the drug and any co-administered myelosuppressive treatment should be stopped, and leflunomide elimination procedure should be started.
Transfer to other ways of treatment
As leflunomide stays in the body for a long time, transfer to another DMARD (e.g. methotrexate) without performing the elimination procedure may increase the possibility of additional risks, even after a long period since the transfer (i.e. kinetic interaction, toxic effect on organs).
Also, a recent treatment with hepatotoxic or hematotoxic agents (e.g. methotrexate) may increase the adverse effects, therefore, the beginning of treatment with leflunomide should be carefully considered, taking into account the aspects of benefit/risk, close monitoring is recommended at the initial phase of transfer.
Skin reactions
In the case of ulcerative stomatitis, leflunomide should be stopped.
Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis in patients treated with leflunomide have been reported. As soon as skin or mucous membrane reactions occur, giving rise to suspicions of such severe reactions, the drug Lefno® and any other agents that are likely to be associated with such reactions, should be stopped, and leflunomide elimination procedure should be started. In such cases, complete elimination is very important, and repeated administration of leflunomide is contraindicated (see “Contraindications”).
Infections
Immunosuppressive agents such as leflunomide are known to increase susceptibility to infections, including opportunistic infections. The infections may be more severe, and thus may require early and intensive treatment. In case of severe uncontrolled infections, discontinuation of leflunomide and elimination procedure may be required.
Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving leflunomide with other immunosuppressive agents.
Patients with tuberculin reactivity must be closely monitored because of the risk of reactivation of tuberculosis.
Respiratory system
Interstitial lung disease has been reported during treatment with leflunomide (see “Adverse effects”). Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Such symptoms as cough and labored respiration may be the reason for stopping the therapy and further examination, depending on situation.
Arterial blood pressure
Arterial blood pressure should be checked before the start of treatment with leflunomide, and regularly thereafter.
Waiting period
Plasma concentration of А771726 may be expected to be over 0.02 mg/L for a long period. Its concentration is believed to reduce to less than 0.02 mg/L years after stopping treatment with leflunomide.
For the first time plasma concentration of А771726 is measured after a two-year waiting period.
Plasma concentration of А771726 is measured again at least after 14 days. If the value of both measurements is below 0.02 mg/L, no teratogenic risk is expected.
Elimination procedure
After stopping treatment with leflunomide the following is prescribed:
– as alternative, oral activated carbon, powdered, 50 g 4 times per day for 11 days.
The duration of procedure may vary depending on clinical or laboratory parameters.
Regardless of the chosen way of elimination, by the moment of fertilization, plasma concentration of А771726 should be checked twice at an interval not less than 14 days, then fertilization should be postponed for 45 days since the value of plasma concentration of А771726 is below 0.02 mg/L registered for the first time. Women of reproductive age should be informed that before conceiving they should wait for 2 years since stopping the drug. If the waiting period of about 2 years on condition of using effective contraception is believed unacceptable, elimination procedure should be recommended.
Both cholestyramine and activated carbon may affect the absorption of estrogens and progestogens, and therefore reliable oral contraceptives do not give a 100% guarantee during the elimination. It is recommended to use alternative methods of contraception.
Reproduction (recommendations for men)
Male patients should realize the possibility of toxic effects on the fetus from their side. Also, during treatment with leflunomide, effective contraception should be used.
There are no reliable data on risk of toxic effect on the fetus from the side of man, however, to minimize any possible risk, men wishing to father a child should consider the possibility of withdrawal of leflunomide and administration of cholestyramine, 8 g 3 times per day for 11 days or oral activated carbon, powdered, 50 g 4 times per day for 11 days. In any case, first of all plasma concentration of A771726 is measured. Then plasma concentration of А771726 should be measured again at least after 14 days. If the value of both measurements is below 0.02 mg/L, and after a waiting period of at least 3 months, risk of toxic effect on fetus is very low.
Elderly patients
For patients older than 65 the dosage adjustment is not required.
Lactose
The drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
Corn starch
The drug contains starch; therefore, it should not be used in patients with celiac disease (gluten enteropathy).
Overdose:
Symptoms:
abdominal pain, nausea, vomiting, diarrhea, increased biochemical parameters of liver function, anemia, leukopenia, itching and rash.
Treatment:
oral administration of cholestyramine or activated carbon is recommended to accelerate elimination of the drug. The duration of therapy is determined individually depending on the clinical picture.
The elimination procedure may be repeated when clinically indicated.
There is no need for hemodialysis or chronic peritoneal dialysis, as the studies indicate that primary metabolite of leflunomide А771726 is not dialyzable.
Ability to influence reaction velocity while driving or operating any other mechanisms.
In case of such adverse effect as dizziness, patient’s ability to focus and show the necessary reaction may be affected. n such cases, the patient should refrain from driving and operating machinery.
CONTRAINDICATIONS:
Hypersensitivity to leflunomide (especially with the history of Stevens-Johnson syndrome toxic epidermal necrolysis, erythema multiforme) or other components of the drug.
Abnormal liver function.
Severe immunodeficiency conditions (including AIDS).
Severe disturbances of bone marrow hematopoiesis or severe anemia, leukopenia, neutropenia or thrombocytopenia due to other causes not related to rheumatoid or psoriatic arthritis.
Severe infections.
Moderate or severe renal failure (due to the short experience of clinical observations in this group of patients).
Severe hypoproteinemia (including nephrotic syndrome).
PHARMACOLOGICAL PROPERTIES:
Immunosuppressive agents. Code АТС L04A A13.
Pharmacodynamics. Leflunomide is an isoxazole-based immunomodulator. It blocks pyrimidine synthesis by inverse inhibition of dihydroorotate dehydrogenase enzyme, and thus it has an antiproliferative effect on active lymphocytes which play an important role in rheumatic diseases pathogenesis, such as rheumatoid arthritis, psoriatic arthritis and in skin manifestations of psoriasis, which is an autoimmune T-cell-mediated disease.
Pharmacokinetics. Drug absorption does not depend on food intake and is 82 – 95%.
The period of achieving stable plasma concentration of the drug is about 2 months of daily use (on condition that loading dose is used at the beginning of treatment). By first-pass metabolism in gut wall and liver leflunomide is rapidly converted to the active metabolite, A771726, to which nearly all the activity of leflunomide is related, and which is the only labeled metabolite detected in plasma, urine and feces.
Unchanged leflunomide is present in blood in very low concentrations.
The clinical effect of the drug is linearly related to plasma concentration of A771726 and the daily dose of leflunomide. When used in a dose of 20 mg per day, average concentration of A771726 in plasma was 35 μg/mL. Plasma concentration of drug during a multiple dose is 33-35-fold higher than that for a single dose.
In plasma A771 726 actively binds to protein (albumin). Unbounded fraction of A771 726 is approximately 0.62%.
Metabolic transformation of Leflunomide into A771 726 and further A771 726 metabolism are not controlled by any single enzyme and occur in microsomal and cytosolic cell fractions.
А771 726 is eliminated slowly (clearance is about 31 mL/h). The half-life is about 2 weeks. It is excreted equally with urine (as glucuronide leflunomide derivatives and oxanilic acid, A771 726 derivative) and with feaces in unaltered form.
Oral administration of activated carbon suspension or cholestyramine accelerates and increases A771 726 elimination. Such effect is considered to be due to the mechanism of gastrointestinal dialysis and/or interruption of gastrointestinal recirculation.
According to study results, oral cholestyramine used at a dose 8 g 3 times per day for 11 days decreased plasma levels of A771726 approximately by 40% within 4 hours and by 49-65% within 48 hours.
It has been shown that the use of powdered activated carbon (suspension) orally or through nasogastric tube (50 g every 6 hours for 24 hours) decreases plasma concentration of active metabolite A771726 by 37% within 24 hours, and by 48% within 48 hours.
PHARMACEUTICAL CHARACTERISTICS:
General physic-chemical properties:
oval biconvex white coated tablets.
Shelf-life:
Shelf-life is 2 years.
Storage:
Store at the temperature not more than 25°c in the original package.
Keep out of reach of children.
Package:
10 tablets are in a blister, 3 blisters are in a carton.
Conditions of supply:
On prescription.