Leflunomide

Pharmacological properties

leflunomide is a disease-modifying antirheumatic agent with antiproliferative properties.

Mechanism of action. A771726, the active metabolite of leflunomide, inhibits the human enzyme dihydroorotate dehydrogenase (DHODH) and exhibits antiproliferative activity.

Pharmacokinetics Leflunomide is rapidly converted into the active metabolite A771726 by presystemic metabolism (ring opening) in the walls of the intestine and liver. Plasma unchanged leflunomide levels were rarely determined. The only metabolite found in blood plasma is A771726. This metabolite determines mainly all the activity of leflunomide in the body.

Suction. 82-95% of a dose of leflunomide is absorbed. Time to reach C_max A771726 in blood plasma is very different: from 1 to 24 hours after a single application. Leflunomide can be taken with food, since the absorption volume when taking the drug after meals and on an empty stomach is similar. Due to long T_½ A771726 (approximately 2 weeks) to ensure rapid achievement of a stable level of A771726, a loading dose of 100 mg was applied for 3 days. It has been established that without the use of a loading dose, it may take almost 2 months of taking the drug to achieve a stable plasma concentration. Studies in which different dosages of the drug were studied showed that the pharmacokinetic parameters of A771726 are linear when using the drug in a dose range of 5–25 mg.

In these studies, the clinical effect was closely related to the concentration of A771726 in blood plasma and to the daily dose of leflunomide. When using a dose of 20 mg / day, the average plasma concentration of A771726 in the saturation stage is about 35 μg / ml. In the saturation stage, the concentration of A771726 in blood plasma is 33–35 times higher compared to that with a single application.

Distribution. In human blood plasma, A771726 almost completely binds to a protein (albumin). The unbound fraction of A771726 is about 0.62%. The binding of A771726 is linear within therapeutic doses. Binding A771726 was found to be somewhat weaker and more variable in the blood plasma of patients with rheumatoid arthritis or chronic renal failure. Extensive binding of A771726 to a protein can lead to the displacement of other substances that are largely bound to proteins. However, the results of a study on the interaction of protein binding under in vitro conditions with the use of warfarin in clinically appropriate doses did not show any interaction. Similar studies showed that ibuprofen and diclofenac did not displace A771726, while in the presence of tolbutamide, the unbound fraction of A771726 increased 2–3 times. A771726 replaced ibuprofen, diclofenac, and tolbutamide, but the unbound fraction of these agents increased by only 10–50%. There is no evidence that these effects are of clinical significance. With significant protein binding, A771726 has a low apparent volume of distribution (about 11 L). The predominant absorption of red blood cells was not detected.

Metabolism. Leflunomide is metabolized to one major (A771726) and many minor metabolites, including TFMA (4-trifluoromethylaniline). The metabolic biotransformation of leflunomide on A771726 and the subsequent metabolism of A771726 are not controlled by one specific enzyme and, as has been shown, occurs in microsomal and cytosolic cell fractions. Interaction studies using cimetidine (a non-specific inhibitor of cytochrome P450) and rifampicin (a non-specific inducer of cytochrome P450) indicate that, in vivo, CYP enzymes are only slightly involved in the metabolism of leflunomide.

Withdrawal of A771726 is slow and is characterized by an apparent clearance of 31 ml / h. In patients T_½ is about 2 weeks.After administration of a dose of leflunomide labeled with a radionuclide, the same amount of radioactivity was observed in the feces, probably due to biliary excretion, and in the urine. A771726 continued to be detected in urine and feces 36 days after a single dose. The main metabolites excreted in the urine were leflunomide glucuronides (mainly in samples taken during the first day (0–24 hours) after taking the drug) and the oxalic acid derivative A771726. The main component that was excreted in the feces was A771726.

It has been found that in humans, oral administration of a suspension of powdered activated carbon or colestyramine leads to a rapid and significant increase in the rate of A771726 excretion and a decrease in its concentration in blood plasma (see OVERDOSAGE). It is believed that this is achieved due to the mechanism of gastrointestinal dialysis and / or suspension of the hepatic metabolic cycle.

Pharmacokinetics in renal failure. The pharmacokinetics of A771726 in patients who received long-term peritoneal dialysis (DPD) was similar to that in healthy volunteers. Faster elimination of A771726 was observed in individuals who received hemodialysis, not associated with extraction of the drug from dialysate.

Pharmacokinetics for liver failure. There are no data on the treatment of patients with liver failure. The active metabolite A771726 is largely bound to proteins and excreted through hepatic metabolism and secretion with bile. These processes may be impaired due to liver dysfunction.

Pharmacokinetics in pediatric patients. In patients with body weight ≤40 kg, a less systemic effect (defined as C_ss) A771726 compared with adult rheumatoid arthritis patients.

Pharmacokinetics in the elderly. Data on the pharmacokinetics of the elderly (65 years) are limited, but are consistent with pharmacokinetics in young adults.

Indications

Treatment with disease-modifying antirheumatic agents (bmars) of the active phase of rheumatoid arthritis in adults. treatment of the active phase of psoriatic arthritis in adults. recent or simultaneous treatment with hepatotoxic or hematotoxic bars (e.g. methotrexate) may increase the risk of serious adverse reactions; therefore, the initiation of treatment with leflunomide should be carefully considered in light of the benefit / risk. in addition, the transition from leflunomide to another bmars without carrying out the withdrawal procedure (see special instructions) can also increase the risk of serious adverse reactions, even after a long period after the transition.

Application

Leflunomide is prescribed as bmars. Leflunomide treatment should be prescribed and monitored by a specialist with experience in the treatment of rheumatoid and psoriatic arthritis.

At the same time and with the same frequency, it is necessary to control the level of ALAT or glutamopyrruvate transferase (GPTF) in blood plasma, perform an extensive blood test, including differential analysis of leukocytes and platelets:

• before starting leflunomide;
• 1 time in 2 weeks for 6 months of treatment;
• 1 time in 8 weeks after treatment (see SPECIAL INSTRUCTIONS).

The tablets should be swallowed without chewing, washed down with water. The degree of absorption of leflunomide is independent of food intake.

Rheumatoid arthritis:

• the saturating dose is 100 mg once a day for the first three days;
• the maintenance dose is from 10 * to 20 mg once a day.

* If it is necessary to use a dose of 10 mg, tablets with the appropriate content of active ingredient should be taken.

Psoriatic arthritis:

• the saturating dose is 100 mg once a day for the first 3 days;
• the maintenance dose is 20 mg 1 time per day.

The therapeutic effect begins to manifest after 4-6 weeks from the start of treatment and can be enhanced within 4-6 months from the start of treatment.

Patients over the age of 65: dose adjustment not required.

Patients with moderate renal failure: dose adjustment is not required.

Contraindications

• Hypersensitivity to leflunomide (especially if there is a history of Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema polyforma), the main active metabolite of teriflunamide, or other components of the drug; impaired liver function; severe immunodeficiency conditions (including HIV infection); severe bone marrow dysfunction or severe anemia, leukopenia, neutropenia, or thrombocytopenia due to other causes (except for rheumatoid or psoriatic arthritis); severe infections; moderate or severe renal failure (due to little experience in clinical observations in this group of patients); severe hypoproteinemia (including with nephrotic syndrome); pregnancy period; lactation period; use in women of reproductive age who do not use reliable contraception during and after treatment, if the level of active metabolite in the blood plasma is more than 0.02 mg / l.

It is necessary to exclude the possibility of pregnancy before starting treatment with leflunomide!

Side effects

Infections and infestations: various infections (including rhinitis, bronchitis, pneumonia); opportunistic infections; severe infections, including sepsis (including fatal).

Benign, malignant and non-specific neoplasms (cysts and polyps): an increased risk of developing malignant neoplasms, in particular lymphoproliferative diseases, increases when used with immunosuppressive drugs.

On the part of the blood: leukopenia, anemia, thrombocytopenia, pancytopenia, eosinophilia, agranulocytosis.

Previous, concomitant or subsequent use of potentially myelotoxic drugs may be associated with a greater risk of hematological effects.

From the immune system: mild allergic reactions; severe anaphylactic / anaphylactoid reactions, vasculitis (including cutaneous necrotizing vasculitis).

On the part of the metabolism: increased levels of CPK, hypokalemia, hyperlipidemia, hypophosphatemia, increased LDH levels, decreased uric acid levels (hypuricemia).

Mental disorders: anxiety.

From the nervous system: paresthesia, headache, dizziness, peripheral neuropathies.

From the cardiovascular system: increased blood pressure.

From the respiratory system: interstitial lung disease (including interstitial pneumonitis), including fatal cases, pulmonary hypertension.

From the digestive tract: diarrhea, nausea, vomiting, abdominal pain, damage to the mucous membrane of the oral cavity (stomatitis, ulcers), taste disturbance, pancreatitis, colitis (including microscopic colitis, lymphocytic colitis and collagenous colitis).

From the hepatobiliary system: increased levels of liver enzymes (AlAT, gamma-glutathione transferase and alkaline phosphatase), hyperbilirubinemia, hepatitis, jaundice, cholestasis, severe liver damage (liver failure or acute liver necrosis, including fatal).

On the part of the skin and subcutaneous tissue: increased hair loss, eczema, skin rashes (including maculopapular rash), itching, dry skin, urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, lupus erythematosus, pustular psoriasis or exacerbation psoriasis, hypersensitivity syndrome with eosinophilia and systemic symptoms (DRESS syndrome).

From the musculoskeletal system: tendosynovitis, tendon rupture.

From the urinary system: renal failure.

From the reproductive system: a decrease in sperm concentration (reversible), a decrease in the total number and motility of sperm.

General disorders: anorexia, weight loss (usually minor), asthenia.

special instructions

The simultaneous use of hepatotoxic or hematotoxic bmars (e.g. methotrexate) is not recommended.

The active metabolite of leflunomide, A771 726, has a prolonged T_½, which, as a rule, is 1–4 weeks. Serious adverse effects can occur (e.g., hepatotoxic, hematotoxic or allergic reactions, see below) even if treatment with leflunomide is suspended. Thus, in the event of such toxic phenomena or for any other reason, an elimination procedure should be carried out. This procedure can be repeated depending on clinical need.

Excretion procedures and other recommended actions in the event of a desired or unplanned pregnancy are given in the Pregnancy section.

Reactions from the liver. Rare cases of severe liver damage have been reported, including those with fatal outcome, which were recorded during treatment with leflunomide. Most of these cases occurred during the first 6 months of treatment. Often noted simultaneous treatment with other hepatotoxic drugs. It is considered advisable to monitor strict compliance with the recommendations.

The level of AlAT (GPTF) should be checked before starting the use of leflunomide, and also with the same regularity as conducting an extensive blood test (1 time in 2 weeks), during the first 6 months of treatment and every 8 weeks after its completion.

With an increase in the level of AlAT (GPTF) 2–3 times higher than the upper limit of the norm, one should consider the possibility of reducing the dose from 20 mg to 10 mg and monitor weekly. If the increase in the level of AlAT (GPTF) is more than 2 times higher than the upper limit of the norm, or if there is an increase in the level of AlAT more than 3 times higher than the upper limit of the norm, then the administration of leflunomide should be stopped and the withdrawal procedure should begin. It is recommended that monitoring of hepatic enzymes be continued after discontinuation of leflunomide treatment until the level of hepatic enzymes normalizes.

In connection with the possible occurrence of additional hepatotoxic effects, it is recommended to avoid drinking alcohol during treatment with leflunomide.

Hematologic reactions. Together with the control of the level of AlAT, before starting treatment with leflunomide, as well as 1 time in 2 weeks during the first 6 months of therapy and 1 time in 8 weeks after its completion, it is recommended to conduct a detailed blood test, including differential analysis of leukocytes and platelets.

In patients with pre-existing anemia, leukopenia and / or thrombocytopenia, as well as in patients with impaired bone marrow function or in patients at risk of developing inhibition of bone marrow function, there is an increased risk of hematological disorders. If such effects occur, the possibility of elimination should be considered in order to reduce the level of A771 726 in blood plasma.

In case of severe hematological effects, including pancytopenia, taking the drug and any simultaneous myelosuppressive treatment, it is necessary to stop and begin the procedure for eliminating leflunomide.

Transition to other treatment methods. Since leflunomide remains in the body for a long time, switching to another BMARS (for example, methotrexate) without carrying out the elimination procedure can increase the likelihood of additional risks even after a long period after the transition (i.e. kinetic interaction, toxic effects on organs).

Also, recent treatment with hepatotoxic or hematotoxic drugs (eg methotrexate) can lead to increased side effects; Thus, the start of treatment with leflunomide must be carefully weighed taking into account the benefit / risk aspect, and careful monitoring is recommended at the initial stage after the transition.

On the part of the skin. In case of ulcerative stomatitis, the administration of leflunomide should be discontinued.

Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients treated with leflunomide. As soon as reactions occur on the part of the skin and / or mucous membrane, which give rise to a suspicion of the development of such severe reactions, taking Lefno and any other drugs that are suspected to be associated with the occurrence of these reactions, discontinue and immediately begin the procedure for excretion of leflunomide . In such cases, complete elimination is important, and repeated use of leflunomide is contraindicated (see CONTRAINDICATIONS).

Infectious diseases. It is known that drugs with immunosuppressive properties, such as leflunomide, can cause patients a greater tendency to infectious diseases, including opportunistic infectious diseases. Infectious diseases can be more serious and thus require early and intensive treatment. In the case of severe uncontrolled infectious diseases, it may be necessary to suspend treatment with leflunomide and conduct an excretion procedure.

Rare cases of progressive multifocal leukocerebral dystrophy have been reported in patients receiving leflunomide along with other immunosuppressive agents.

Patients with tuberculin reactivity should be closely monitored because of the risk of reactivation of tuberculosis.

From the respiratory system. An interstitial pulmonary process has been reported in the treatment of leflunomide (see ADVERSE EFFECTS). Interstitial pulmonary process is a potentially fatal disorder that can occur in acute form during therapy. Symptoms from the lungs, such as coughing and shortness of breath, can cause the cessation of therapy and, depending on the situation, further examination.

HELL. Blood pressure should be monitored before treatment with leflunomide and periodically after it.

The period of "waiting." It can be expected that the concentration of A771 726 in blood plasma will be 0.02 mg / l for a long period. It is believed that its concentration decreases to the level of 0.02 mg / l 2 years after discontinuation of leflunomide treatment.

For the first time, the concentration of A771 726 in plasma is measured after a 2-year waiting period.

Re-concentration of A771 726 in blood plasma is determined after at least 14 days. If both values ​​are 0.02 mg / L, no teratogenic risk is expected.

The elimination procedure (excretion). After treatment with leflunomide is discontinued:

• colestyramine 8 g orally 3 times a day for 11 days;
• as an alternative - orally, 50 g of activated carbon, powdered, taken 4 times a day for 11 days.

The duration of the procedure may vary depending on clinical or laboratory parameters.

Regardless of the chosen method of drug elimination, at the time of fertilization, it is necessary to determine the concentration of A771 726 in blood plasma twice, with an interval of at least 14 days, and then wait with fertilization for 45 days from the moment when the concentration of A771 726 0.02 was first recorded in the analysis mg / l Women of reproductive age should be informed that before pregnancy, it is necessary to wait 2 years after discontinuation of the drug.If a waiting period of approximately 2 years, subject to reliable contraception, is deemed unacceptable, an elimination procedure should be recommended.

Both colestyramine and activated carbon can affect the absorption of estrogens and progestogens, so reliable oral contraceptives do not give a 100% guarantee during the elimination period. Alternative contraceptive methods are recommended.

Reproduction (recommendations for men). Male patients should be aware of the possibility of toxic effects on the fetus on their part. Also during treatment with leflunomide, reliable contraception should be provided.

There are no specific data on the risk of toxic effects on the fetus from a man, however, to minimize any possible risk, men who want to become a father should consider stopping the use of leflunomide and colestyramine at a dose of 8 g 3 times a day for 11 days or 50 g of activated powder coal 4 times a day for 11 days.

In any case, first determine the concentration of A771 726 in blood plasma. After this, the concentration of A771 726 in blood plasma should be re-measured at least 14 days later. If both plasma concentrations are 0.02 mg / l, and also after a waiting period of at least 3 months, the risk of toxic effects on the fetus is very low.

Elderly patients. For patients over the age of 65, there is no need for dose adjustment.

Lactose. The composition of the drug includes lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose should not take this drug.

Corn starch. The composition of the drug includes corn starch, so it should not be prescribed to patients with celiac disease (celiac enteropathy).

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. If a side effect such as dizziness occurs, the patient’s ability to concentrate and respond appropriately may be impaired. In such cases, the patient should refrain from driving and working with machinery.

Use during pregnancy and lactation. Pregnancy. There is a suspicion that the active metabolite of leflunomide, A771 726, causes severe defects in the development of the fetus when using the drug during pregnancy.

The drug is contraindicated during pregnancy!

Women of reproductive age who do not use reliable contraception during treatment or after it are not prescribed, provided that the level of active metabolite is 0.02 mg / ml.

Women of reproductive age should use effective contraceptives within 2 years after the end of treatment (see SPECIAL INSTRUCTIONS) or up to 11 days after the end of treatment.

It is necessary to exclude pregnancy before starting treatment with leflunomide!

The patient should be warned that in case of delayed menstruation or in the presence of other signs indicating the onset of pregnancy, she should immediately inform the doctor about it to establish pregnancy. If the test is positive, the doctor should weigh the risk that the pregnant woman may be taking while taking the drug and inform the patient about it. At the first delay of menstruation, it is possible to reduce the risk to the fetus in connection with the administration of leflunomide by prescribing the elimination of leflunomide from the body.

Women who take leflunomide and wish to become pregnant are recommended to perform one of the elimination procedures (see SPECIAL INSTRUCTIONS) for leflunomide in order to minimize the possible toxic effects of A771 726 on the fetus (A771 726 concentration of 0.02 mg / l is considered to be associated with minimal risk to the fetus )

The period of breastfeeding. Leflunomide and its metabolites may pass into breast milk.In this regard, women who are breastfeeding are contraindicated in taking leflunomide.

Children. The drug is not prescribed for children (the effectiveness and safety of use in juvenile rheumatoid arthritis have not been established).

Interactions

Strengthening of side effects is possible in cases of the recent previous, as well as simultaneous use of hepatotoxic or hematotoxic drugs, as well as when taking these drugs after treatment without taking into account the period necessary for the complete elimination of the drug from the body. Thus, at the initial stage after the transition, more careful monitoring of the level of liver enzymes and hematological parameters is recommended.

The use of colestyramine or activated carbon leads to a rapid and significant decrease in the concentration of the active metabolite of leflunomide. It is believed that this is due to a violation of A771 726 recirculation in the liver and small intestine and / or a violation of its gastrointestinal dialysis.

With the simultaneous use of leflunomide (at a dose of 10–20 mg / day) with methotrexate (at a dose of 10–25 mg / week), an increase in the level of liver enzymes by 2–3 times was noted.

It is recommended that patients who take leflunomide do not receive treatment with colestiramine or powdered activated charcoal, since this leads to a rapid and significant decrease in plasma concentration of A771 726 (active metabolite of leflunomide). It is believed that the mechanism of this phenomenon is due to the suspension of the hepatic metabolic cycle and / or gastrointestinal dialysis A771 726.

Patients who received treatment with NSAIDs and / or glucocorticosteroids before starting treatment with Lefno can continue taking them simultaneously with Lefno.

The enzymes involved in the metabolism of leflunomide and its metabolites are not exactly known.

With the simultaneous use of leflunomide and methotrexate, an increase in the level of liver enzymes is noted.

There are reports of an increase in prothrombin time when using leflunomide in combination with warfarin.

The administration of leflunomide simultaneously with antimalarial drugs that are used to treat rheumatism (chloroquinolones, hydroxychloroquinolones), gold preparations (oral or intramuscularly), D-penicillamine, azathioprine and other immunosuppressive drugs (cyclosporine, methotrexate) is still insufficiently studied.

There are no data on the incompatibility of leflunomide with other drugs.

In vitro studies indicate that A771 726 inhibits the activity of cytochrome P450 2C9 (CYP 2C9). With the simultaneous use of leflunomide and NSAIDs, which are metabolized by CYP 2C9, no effect on safety has been recorded. Safety measures are recommended when leflunomide is taken with drugs (other than NSAIDs) that are metabolized by CYP 2C9, such as phenytoin, tolbutamide, warfarin and fenprocoumone.

Vaccination. There is no clinical data on the efficacy and safety of vaccination during the administration of leflunomide, but vaccination with live vaccines is not recommended. Long T_½ the drug requires determining the timing when the use of a live vaccine may be allowed after discontinuation of leflunomide treatment.

Overdose

Symptoms: abdominal pain, vomiting, nausea, diarrhea, increased biochemical parameters of liver function, anemia, leukopenia, itching and rash.

Treatment: it is recommended to take orally colestyramine or activated charcoal to speed up the elimination (elimination) of the drug from the body. The duration of therapy is determined individually depending on the clinical picture.

The elimination procedure can be repeated if there are clinical indications.

There is no need for hemodialysis or chronic peritoneal dialysis, since studies have shown that the primary metabolite of leflunomide A771 726 is not dialyzed.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° c.