Buy Leflunomide Canon film-coated tablets 20 mg No. 30 in pharmacies

Pharmacological properties of the drug Leflunomide

a basic antirheumatic drug with antiproliferative, immunosuppressive and anti-inflammatory properties. The active metabolite of leflunomide, A771726, inhibits the enzyme dehydroorotate dehydrogenase and exhibits antiproliferative activity. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T lymphocytes. The antiproliferative activity of A771726 appears to manifest itself at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the A771726 metabolite. Using radioisotope ligands, it was shown that A771726 selectively binds to dehydroorotate dehydrogenase, 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 interleukin-2 receptors and nuclear antigens Ki-67 and PCNA, which are associated with the cell cycle. The therapeutic effect usually appears after 4–6 weeks and may further increase over 4–6 months. Leflunomide quickly turns into an active metabolite - A771726 (primary metabolism occurs in the intestines and liver). Trace amounts of unchanged leflunomide are found in plasma, urine or feces. The only detectable metabolite is A771726, which is responsible for the main properties of the drug in vivo . When taken orally, absorption is 82–95%. The maximum concentration of A771726 is achieved 1–24 hours after a single dose. Eating does not affect the absorption of the drug. At a dose of 5–25 mg, the pharmacokinetic parameters of A771726 have a linear relationship. At a dose of 20 mg per day, the average plasma concentrations of A771726 at steady state were 35 μg/ml. A771726 quickly binds to albumin. Unbound fraction A771726 - 0.2%. The association with A771726 proteins is more variable and is slightly reduced in patients with rheumatoid arthritis or chronic renal failure. Leflunomide is metabolized to one major (A771726) and several minor metabolites, including 4-trifluoromethylalanine. A771726 is excreted slowly, clearance is 31 ml/h. The half-life is 2 weeks. In patients with chronic renal failure, the half-life is prolonged.

Clinical and pharmacological examination of leflunomide in rheumatoid arthritis

Despite significant advances in the development of treatment strategies for rheumatoid arthritis (RA), pharmacotherapy of this disease continues to remain one of the most difficult areas of medicine [1, 2]. Due to its high prevalence, high frequency of damage to people of working age, and a significant percentage of disability in patients with RA, it represents a serious medical and social problem. Studies of the pathogenesis of the inflammatory process in RA over the past 20 years suggest that T cells play a key role in both the development and further progression of the disease [1]. It is with the activation of T cells that the inclusion in the inflammatory process of some other types of cells (B cells, dendritic cells, fibroblast-like synoviocytes) necessary for maintaining inflammation and progression of joint destruction, stimulation of plasma cells, macrophages, fibroblasts to produce pro-inflammatory cytokines (TNF, IL) is associated -12].

This view of the pathogenesis of RA suggests that the main efforts of pharmacotherapy should be aimed at the use of regulators of the proliferation of activated T cells. The basic drug that effectively affects these cells and suppresses inflammation is leflunomide (Arava) (Sanofi-Aventis, France), unlike other drugs, specifically developed for the treatment of RA, which (including its severe forms) is the main indication for leflunomide . Leflunomide reduces the synthesis of pyrimidine nucleotides, inhibits the proliferation of activated T cells, [3] changes the T cell autoimmune response, suppresses the synthesis of proinflammatory cytokines, and reduces T-dependent synthesis of antibodies by B cells [4]. Under the influence of leflunomide, the transcription factor NF-k is inhibited. [5] (a factor necessary for the activation of genes encoding the synthesis of proinflammatory mediators). The high clinical efficacy and basic properties of leflunomide against RA were confirmed by a number of multicenter randomized controlled trials comparing leflunomide with placebo, methotrexate and sulfasalazine [6].

According to the chemical structure, leflunomide is a low molecular weight (270 D) isoxazole derivative. In the gastrointestinal tract and plasma, leflunomide is quickly converted into the active metabolite malononitrilamide, which is 99.3% bound to plasma proteins. The half-life of the drug is about two weeks. Leflunomide is excreted through the kidneys and gastrointestinal tract in almost equal proportions [7]. Comparative characteristics of the drugs are presented in table. 1.

Table 1. Comparative characteristics of basic antirheumatic drugs

Leflunomide is initially prescribed at a dose of 100 mg once a day for 3 days; then switch to maintenance therapy at a dose of 20 mg per day. Only when stable remission is achieved or side effects develop is it possible to reduce the maintenance dose to 10 mg. Numerous international studies indicate the high effectiveness of leflunomide, a persistent decrease in the severity of bone tissue destruction in RA, confirmed radiographically during the 1st and 2nd year, significantly more pronounced compared to methotrexate [7]. In addition, leflunomide can be successfully used in combination with methotrexate in patients in whom methotrexate monotherapy is insufficiently effective.

We conducted pharmacoeconomic examination of Arava using generally accepted methods of economic analysis. Cost-effectiveness and cost-utility (utility) analyzes and economic modeling (“Markov models”) were used.

The economic assessment of the effectiveness of a particular medical program or treatment method as a whole is the ratio of the costs of its implementation and its effectiveness, including direct and indirect “costs”. Direct medical costs include the cost of medications, hospital treatment, visits to doctors, the cost of correcting side effects and treating concomitant diseases [8]. It seems more difficult to take into account indirect costs, such as loss of income for the family, decreased productivity for society, deterioration in quality of life (QoL), etc. Mathematical modeling of the treatment of patients with RA was carried out, taking into account the use of various treatment methods (Fig. 1).

Rice. 1. Decision tree: direct medical costs for 1200 people

The following treatment regimens were compared:

Arava 100 mg 1-3 times a day, then 20 mg 1 time a day compared with:

• Methotrexate 7.5-25 mg/week
• Sulfasalazine 2 g/day
• Sandimmune-neoral 3 mg/kg per day
• Remicade 3 mg/kg IV, repeat injections at 2 and 6 weeks, then every 8 weeks

When conducting pharmacoeconomic analysis, the cost-effectiveness criterion (CEA) was used according to the formula CEA=C/Ef, where “CEA” shows the cost of drugs per unit of effectiveness, “C” is the average cost of treatment (cost of drugs) . “Ef” – treatment effectiveness (probability of achieving a positive result according to the selected effectiveness criterion). Prices for medicines were taken into account (March 2008). Basic costs per unit of efficiency are presented in table. 2.

Table 2. Evaluation of basic therapy for rheumatoid arthritis for 1 year according to the cost-effectiveness parameter, taking into account the number of remissions and exacerbations (per 1200 people )

Note.

* – studies US301, MN301, MN302 (Practical Management of Rheumatoid Arthritis Patients Treated with Leflunomide)

** – studies US301, MN302

*** – studies MN301, COBRA

1 – for patients sensitive to methotrexate (resistance 40%)

2 – for patients sensitive to sulfasalazine (resistance 36%)

^ – ATTRACT study

Table 3. Comparative assessment of side effects during basic therapy for rheumatoid arthritis for 1 year

Note.

* – without drug withdrawal.

** – with drug withdrawal and switching to other drugs

1 – for patients sensitive to methotrexate (resistance 40%)

2 – for patients sensitive to sulfasalazine (resistance 36%)

Lower costs for sulfasalazine monotherapy compared to leflunomide are valid only for 64% of patients, since primary resistance to this drug occurs in 36% of cases [9]. Consequently, for every hundred patients there will be at least 36 people who are initially not sensitive to the drug. To identify clinical resistance, a minimum of three months of sulfasalazine therapy is required, followed by a transition to combination therapy, which significantly increases costs and argues for the cost-effectiveness of initial leflunomide therapy. Methotrexate also demonstrates low levels of initial sensitivity, the level of induced resistance to which is at least 40% [10]. Leflunomide has only one reliably established mechanism of resistance - changes in target enzymes (increased activity or expression of dihydro-orotate dehydrogenase). Sulfasalazine already has at least two mechanisms - increasing efflux and increasing metabolism to 5-aminosalicylic acid and sulfapyridine, which are inactive in RA.

Methotrexate has the most resistance mechanisms. Among the main ones:

• insufficient transport through a reduced folate pump (change in kinetics);
• slow transport through the folate receptor (lower affinity for methotrexate than for folic acid);
• increased efflux through ATP-dependent channels;
• disruption of enzyme activity;
• accelerated destruction of methotrexate in the liver;
• local accelerated destruction of methotrexate (at the level of target cells).

Taking into account the above data, a modification of the calculations, reflecting the real pharmacoeconomic component of the use of leflunomide, methotrexate and sulfasalazine, is as follows. Situation modeling tolerances:

Scenario 1: treatment with leflunomide or methotrexate, followed in the latter case by switching to a combination with infliximab (Fig. 2).

Scenario 2: treatment with leflunomide or methotrexate, followed in the latter case by switching to a combination with cyclosporine (Fig. 3).

Scenario 3: treatment with leflunomide or sulfasalazine, followed in the latter case by switching to a combination with infliximab (Fig. 4).

Scenario 4: treatment with leflunomide or sulfasalazine, followed in the latter case by switching to a combination with cyclosporine (Fig. 5).

Based on the data obtained, the so-called dissolved CER coefficient is established, averaging the costs of carrying out different combination therapy options using methotrexate or sulfasalazine, respectively. The calculations show that leflunomide has economic advantages over monotherapy with methotrexate or sulfasalazine, mainly due to its higher efficiency (Fig. 6).

The cost-utility ratio (utility) was calculated: C UR = DC / Ef , where CUR is the cost-utility ratio (utility), DC is direct costs, Ef is the effectiveness of treatment for patients sensitive to methotrexate. It should be noted that for such patients (0.55 is considered an acceptable coefficient), methotrexate is considered effective if it helps at least 55% of patients. The change (in %) in patients’ assessment of their quality of life on the SF-36 scale was taken as a unit of “usefulness” (“utility”). The SF-36 questionnaire is generally accepted for assessing the quality of life in RA in terms of physical and psychological health. The following criteria are assessed: physical health (PH), role functioning (RF), pain (B), general health (GO), vitality (VV), social activity (SA), role emotional functioning (RE) and psychological health (PH). ).

In response to methotrexate, the quality-of-life years (QALYs) gained is 9.1 years. At the same time, in the case of methotrexate resistance, it decreases on average by 15.11 times (!) – to 0.6 [11]

The utilitarian cost results are associated in some way with QALYs. Since direct data are not available, the assumption is made that these costs cover 1 QALY in the case of methotrexate sensitivity. In the case of methotrexate resistance, the indicators change significantly. It should be emphasized that for these patients (with methotrexate resistance), Arava, as a rule, retains its effectiveness, and, therefore, its pharmacoeconomic characteristics do not change. At the same time, with methotrexate resistance, costs increase in proportion to the decrease in QALY, i.e. 15.11 times, which is reflected in the table. 4.

Table 4. Comparative C UR (rubles) for different regimens of basic therapy for rheumatoid arthritis for 1 year (per 1200 people) using the SF -36 scale [56]

An assessment of the economic parameters associated with the quality of life of treatment with basic therapy drugs for RA shows that methotrexate has advantages over leflunomide in the case of methotrexate-sensitive patients. In the case of methotrexate resistance (40% of cases), methotrexate is inferior to leflunomide in terms of cost effectiveness.

On the other hand, it is known that in some cases, when leflunomide is ineffective, it is combined with methotrexate or switched to methotrexate monotherapy. Because the utilitarian cost of methotrexate is lower than that of leflunomide, this scenario was not considered in our economic analysis.

Conclusions:

1. Leflunomide (Arava), based on the cumulative indicator of achieving remission and significant improvement in the course of RA, can be recommended for active use (taking into account indications and contraindications for use). Arava demonstrates high activity as a means of basic treatment of RA.
2. Arava meets the criteria of good tolerability and compliance; drug withdrawal due to intolerance symptoms is minimal and lower than with methotrexate or sulfasalazine.
3. The cost-effectiveness indicator of leflunomide allows us to consider the drug economically justified for the treatment of RA and use it in government reimbursement programs for preferential categories of citizens. According to the results of pharmacoeconomic modeling, which evaluates the prospects for using the drug, the cost of initial monotherapy with Arava is less than the cost of monotherapy with methotrexate or sulfasalazine in the event of switching to other anti-inflammatory drugs or combination therapy due to the ineffectiveness of these drugs.

Contraindications to the use of the drug Leflunomide

Hypersensitivity to leflunomide, liver failure, severe immunodeficiency (including AIDS), bone marrow hematopoiesis disorders (anemia, leukopenia or thrombocytopenia not associated with rheumatoid arthritis), severe infections, moderate or severe renal failure, severe hypoproteinemia (including nephrotic syndrome), pregnancy and lactation, women of reproductive age (not using contraceptives during treatment with leflunomide and while the plasma level of the active metabolite is above 0.02 mg/l), age under 18 years.

Side effects of the drug Leflunomide

From the cardiovascular system: increased blood pressure. From the gastrointestinal tract: diarrhea, nausea, vomiting, anorexia, erosive and ulcerative lesions of the oral mucosa (aphthous stomatitis, lip ulceration), abdominal pain, increased activity of liver transaminases, especially ALT, less often γ-glutamine transferase, alkaline phosphatase, hyperbilirubinemia, hepatitis, cholestastatic jaundice, liver failure, acute liver necrosis. From the musculoskeletal system: tenosynovitis; ligament rupture. From the skin: increased hair loss, eczema, dry skin. Allergic reactions: rash (including maculopapular rash), skin itching; urticaria, erythema multiforme, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome); anaphylactic/anaphylactoid reactions. From the hematopoietic organs: leukopenia, anemia, slight thrombocytopenia (platelets less than 100,000/μl), eosinophilia, pancytopenia; less than 0.01% - agranulocytosis. Laboratory indicators: slight hyperlipidemia, hypouricemia, increased activity of LDH and CPK, slight hypophosphatemia. Other: reversible decrease in sperm concentration, total sperm count and motility; less than 0.01% - development of severe infections and sepsis.

Special instructions for the use of Leflunomide

The drug should be prescribed after a thorough medical examination by specialists who have the necessary experience in the treatment of rheumatoid arthritis. The dosage regimen for mild chronic renal failure has not been determined. Before starting treatment, it is necessary to remember about the possible increase in the number of side effects in patients who have previously received basic drugs for the treatment of rheumatoid arthritis that have hepato- and hematotoxic effects. The active metabolite of leflunomide, A771726, is characterized by a long half-life of 1–4 weeks. Serious adverse effects (eg, hepatotoxicity, hematotoxicity, or allergic reactions) may occur even if leflunomide treatment is discontinued. Therefore, if such cases of toxicity occur or when switching to taking another basic drug (for example, methotrexate) after treatment with leflunomide, it is necessary to carry out a “washing” procedure: cholestyramine - 8 g 3 times a day for 11 days; alternatively, 50 g of activated carbon, crushed into powder, 4 times a day for 11 days. Rare cases of severe liver damage, in some cases fatal, have been reported during treatment with leflunomide, most of which were observed in the first 6 months of treatment. Although the causal relationship of these adverse events to leflunomide has not been established, and in most cases there were multiple risk factors, recommendations for monitoring patients during treatment must be carefully followed. It is necessary to monitor ALT activity before starting therapy, and then every month during the first 6 months of treatment, followed by monitoring once every 2–3 months. Recommendations for adjusting the dosage regimen or discontinuing the drug depending on the severity and persistence of the increase in ALT levels: if the upper limit of the ALT level is confirmed to be exceeded by 2–3 times, reduce the dose from 20 to 10 mg/day (it is possible to continue taking leflunomide subject to careful monitoring this indicator); If a 2- or 3-fold increase in the upper limit of normal for ALT persists, or if there is a rise in the level of ALT that exceeds the upper limit of normal by more than 3 times, leflunomide should be discontinued and a washout procedure initiated. During the treatment period, it is recommended to refrain from taking ethanol (increased risk of hepatotoxicity). A complete clinical blood test, including determination of the leukocyte formula and platelet count, must be performed before starting treatment, as well as every 2 weeks during the first 6 months of treatment and every 8 weeks after completion of treatment. In patients with pre-existing anemia, leukopenia and/or thrombocytopenia, as well as in patients with impaired bone marrow function or at risk of developing such disorders, the risk of hematological disorders increases. If this type of phenomenon occurs, a “washing” procedure should be used to reduce the level of A771726 in the blood plasma. If severe hematotoxicity develops, it is necessary to stop taking leflunomide and any other concomitant drug that inhibits bone marrow hematopoiesis and begin a washout procedure. If ulcerative stomatitis develops, leflunomide should be discontinued. Very rare cases of Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in patients receiving leflunomide. In case of skin and/or mucous reactions, it is necessary to stop taking leflunomide and any other drug associated with it and immediately begin the “washing out” procedure (in such cases it is essential); re-prescription is contraindicated. Drugs like leflunomide, which have immunosuppressive properties, increase the risk of developing various infections. Infectious diseases that arise are usually severe and require early and intensive treatment. If a severe infectious disease occurs, it is necessary to interrupt treatment with leflunomide and begin a washout procedure. It is necessary to carefully monitor patients with severe tuberculin reactivity due to the risk of reactivation of tuberculosis. Blood pressure levels should be monitored before starting treatment with leflunomide and periodically after starting it. There are no experimental data on the risk of fetotoxicity when using leflunomide in men. To minimize the possible risk, men planning offspring should stop taking leflunomide and use cholestyramine 8 g 3 times a day for 11 days or 50 g of powdered activated carbon 4 times a day for 11 days. Men receiving treatment with leflunomide should be warned about the possible fetotoxic effects of the drug and the need to use adequate contraception. It is necessary to ensure that there is no pregnancy before starting treatment with leflunomide. If you suspect pregnancy, you must immediately inform your doctor. The doctor should discuss with the patient the possible risks to which this pregnancy is exposed. A rapid decrease in the level of the active metabolite in the blood using a drug “washout” procedure if pregnancy is suspected will help reduce the risk to the fetus. If a woman taking leflunomide wishes to become pregnant, it is recommended that one of the following procedures be followed to ensure that the fetus is not exposed to toxic concentrations of A771726 (control concentration below 0.02 mg/L). Waiting period: It is accepted that the plasma concentration of A771726 may be above 0.02 mg/l for an extended period. It is expected that concentrations may fall below 0.02 mg/L 2 years after discontinuation of leflunomide treatment. After this, it is necessary to measure the concentration of A771726 in the blood plasma after at least 14 days. If both measurements are below 0.02 mg/l, there is no risk of teratogenicity. Next comes the “laundering” procedure. Regardless of the laundering procedure chosen, it must be verified by two separate tests at least 14 days apart. Fertilization is possible 1.5 months after the concentration of the active metabolite is below 0.02 mg/l. It is necessary to refrain from conceiving for 2 years after stopping treatment with leflunomide. If a waiting period of approximately 2 years with reliable contraception seems unreasonable, a “washing out” procedure can be performed for preventive purposes. The contraceptive activity of oral contraceptives may be reduced as a result of the “washing” procedure with cholestyramine or activated carbon. It is recommended to use alternative methods of contraception. The experiment showed that leflunomide and its metabolites pass into breast milk.

Buy Leflunomide Canon film-coated tablets 20 mg No. 30 in pharmacies

Instructions for use

Leflunomide tab p.o 20 mg No. 30

Dosage forms tablets 10 mg tablets 20 mg Synonyms Arava Leflide Leflunomide Elafra Group Anti-inflammatory drugs of different groups International nonproprietary name Leflunomide Composition Active substance: leflunomide 10 mg. Manufacturers Canonpharma Production (Russia) Pharmacological action Pharmacodynamics Leflunomide belongs to the class of basic antirheumatic drugs and has antiproliferative, immunomodulatory, immunosuppressive and anti-inflammatory properties. The active metabolite of leflunomide A771726 inhibits the enzyme dehydroorotate dehydrogenase and has antiproliferative activity. A771726 in vitro inhibits mitogen-induced proliferation and deoxyribonucleic acid (DNA) synthesis of T lymphocytes. The antiproliferative activity of A771726 appears to manifest itself at the level of pyrimidine biosynthesis, since the addition of uridine to the cell culture eliminates the inhibitory effect of the A771726 metabolite. Using radioisotope ligands, it was shown that A771726 selectively binds to the enzyme dehydroorotate dehydrogenase, 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 nuclear antigens Ki-67 and PCNA, associated with the cell cycle. The therapeutic effects of leflunomide have been demonstrated in several experimental models of autoimmune diseases, including rheumatoid arthritis. Leflunomide reduces symptoms and slows the progression of joint damage in active rheumatoid arthritis. The therapeutic effect usually appears after 4 - 6 weeks and can further increase over 4 - 6 months. Pharmacokinetics Leflunomide is rapidly converted to its active metabolite A771726 (primary metabolism in the intestinal wall and liver). Only trace amounts of unchanged leflunomide were observed in plasma, urine or feces. The only detectable metabolite is A771726, which is responsible for the main properties of the drug in vivo. When taken orally, 82 to 95% of the drug is absorbed. Maximum plasma concentrations of A771726 are determined from 1 to 24 hours after a single dose. Leflunomide may be taken with food. Due to the very long half-life (T1/2) of A771726 (about 2 weeks), a loading dose of 100 mg per day was used for 3 days. This made it possible to quickly achieve an equilibrium state of the plasma concentration of A771726. Without a loading dose, 2 months of drug administration would be required to achieve steady-state concentrations. In multiple dose studies, the pharmacokinetic parameters of A771726 were dose dependent over the dose range of 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. At a dose of 20 mg per day, the average plasma concentrations of A771726 at steady state were 35 μg/ml. In plasma, A771726 rapidly binds to albumin. The unbound fraction of A771726 is approximately 0.62%. Binding of A771726 is more variable and is slightly reduced in patients with rheumatoid arthritis or chronic renal failure. Leflunomide is metabolized to one major (A771726) and several minor metabolites, including 4-trifluoromethylalanine. The biotransformation of leflunomide to A771726 and the subsequent metabolism of A771726 itself is controlled by several enzymes and occurs in microsomal and other cellular fractions. Interaction studies with cimetidine (a non-specific cytochrome P450 inhibitor) and rifampicin (a non-specific cytochrome P450 inducer) showed that in vivo CYP enzymes are involved in the metabolism of leflunomide only to a small extent. The elimination of A771726 from the body is slow and is characterized by a clearance of 31 ml/hour. Leflunomide is excreted in feces (probably due to biliary excretion) and urine. (T1/2) is about 2 weeks. The pharmacokinetics of A771726 in patients on chronic ambulatory peritoneal dialysis (CAPD) are similar to those in healthy volunteers. A more rapid elimination of A771726 is observed in patients on hemodialysis, which is not due to the extraction of the drug into the dialysate, but to its displacement from the protein. Although the clearance of A771726 increases approximately 2-fold, the final clearance (T1/2) is similar to that in healthy individuals, since the volume of distribution simultaneously increases. There are no data on the pharmacokinetics of the drug in patients with liver failure. Pharmacokinetic characteristics have not been studied in patients under 18 years of age. In elderly patients (65 years and older), pharmacokinetic data approximately correspond to the average age group. effects From the cardiovascular system. Often: moderate increase in blood pressure; rarely: marked increase in blood pressure; frequency unknown: angina pectoris, migraine, palpitations, tachycardia, varicose veins, vasculitis, vasodilation. From the gastrointestinal tract. Common: diarrhea, nausea, vomiting, diseases of the oral mucosa (for example, aphthous stomatitis, lip ulceration), abdominal pain; uncommon: disturbance of taste; very rarely: pancreatitis; frequency unknown: gingivitis, oral candidiasis, esophagitis, gastritis, gastroenteritis, dyspepsia, colitis, constipation, flatulence, melena. From the hepato-biliary system. Often: increased activity of “liver” transaminases (alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), hyperbilirubinemia; rarely: hepatitis, cholestasis, jaundice, cholelithiasis; very rarely: severe liver damage (including liver failure, acute liver necrosis), which can be fatal. On the respiratory system. Common: upper respiratory tract respiratory infections, cough; rare: interstitial pulmonary process (including interstitial pneumonia and pulmonary fibrosis) with possible death; frequency unknown: asthma, shortness of breath, nosebleeds Metabolic and nutritional disorders Common: increased creatine phosphokinase (CPK) Uncommon: hypokalemia, hyperlipidemia, hypophosphatemia Rare: increased lactate dehydrogenase levels Frequency unknown: hypouricemia, diabetes mellitus, hyperthyroidism, peripheral edema Nervous system disorders Common : headache, dizziness, paresthesia; uncommon: anxiety; very rare: peripheral neuropathy; frequency unknown: anxiety, depression, dry oral mucosa, sleep disturbances, neuralgia, neuritis, increased sweating. From the musculoskeletal system. Common: tenosynovitis; uncommon: tendon rupture; frequency unknown: arthralgia, synovitis, muscle spasms, arthrosis, bone necrosis, bursitis, myalgia. From the skin and subcutaneous tissue. Common: increased hair loss, alopecia, eczema, skin rash (including maculopapular), itching, dry skin; uncommon: urticaria; very rare: toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, Stevens-Johnson syndrome; frequency unknown: acne, contact dermatitis, fungal dermatitis, hair color change, herpes simplex, herpes zoster, nail lesions, skin pigmentation disorders, skin ulceration. From the immune system. Often: allergic reactions; very rare: serious anaphylactic/anaphylactoid reactions, angioedema. Infections and infestations. Rare: severe infections (including opportunistic infections and sepsis), which can be fatal. The risk of infectious diseases, in particular rhinitis, bronchitis and pneumonia, is increased. Hematopoietic system and lymphatic system. Common: leukopenia (leukocytes > 2000/µl); uncommon: anemia, mild thrombocytopenia (platelets > 100,000/µl); rarely: pancytopenia (apparently due to antiproliferative effects), eosinophilia, leukopenia (leukocytes <2000/μl); very rare: agranulocytosis. Recent, concomitant, or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects. From the reproductive system. Not known: slight decrease in sperm concentration, total sperm count and motility. From the kidneys and urinary system. Frequency unknown: urinary tract infections, renal failure, albuminuria, cystitis, dysuria, hematuria, prostate damage, frequent urination, vaginal candidiasis. From the senses. Frequency unknown: blurred vision, cataracts, conjunctivitis, taste disturbances. Are common. Common: anorexia, weight loss (usually minor), asthenia; Frequency unknown: fever, weakness. Other. The risk of malignant diseases, especially lymphoproliferative diseases, increases with the use of certain immunosuppressive drugs. Indications for use As a basic treatment for adult patients with active rheumatoid arthritis in order to reduce symptoms of the disease and delay the development of structural damage to the joints; Active form of psoriatic arthritis. Contraindications Hypersensitivity to leflunomide or any other component of the drug; liver dysfunction; severe immunodeficiency (including acquired immunodeficiency syndrome); significant disorders of bone marrow hematopoiesis or severe anemia, leukopenia or thrombocytopenia due to causes other than rheumatoid arthritis; severe, uncontrolled infections; moderate or severe renal failure (creatinine clearance less than 60 ml/min, due to little experience with clinical observation); severe hypoproteinemia (for example, with nephrotic syndrome); in pregnant women or women of childbearing potential who are not using reliable contraception, during treatment with leflunomide and as long as the plasma level of the active metabolite remains above 0.02 mg/l. Pregnancy should be excluded before starting treatment with leflunomide; during breastfeeding (see section “Use during pregnancy and breastfeeding”); children's age (under 18 years), due to the lack of data on effectiveness and safety. Men receiving treatment with leflunomide should be warned about the possible fetotoxic effect of the drug (associated with its possible effect on the father's sperm) and the need to use reliable contraception. Route of administration and dosage Treatment with leflunomide should be initiated under the supervision of a physician experienced in the treatment of rheumatoid arthritis and psoriatic arthritis. The tablets must be taken regardless of food intake, swallowed whole with a sufficient amount of liquid. Treatment with leflunomide begins with an oral loading dose of 100 mg once daily for 3 days. As a maintenance dose for rheumatoid arthritis, it is recommended to take 10 mg to 20 mg of leflunomide once a day, for psoriatic arthritis - 20 mg 1 time a day. The therapeutic effect usually appears after 4 - 6 weeks and can further increase up to 4 - 6 months. No dose adjustment is required for patients over 65 years of age. Overdose Symptoms. There have been reports of chronic overdose in patients receiving leflunomide at doses up to five times the recommended daily dose, as well as reports of acute overdose in adults and children. In most cases of overdose, no adverse reactions were reported. The adverse reactions that occurred were comparable to the safety profile of leflunomide. The most commonly observed adverse reactions were diarrhea, abdominal pain, leukopenia, anemia and increased liver function tests. Treatment. In case of overdose or toxicity, it is recommended to take cholestyramine or activated carbon to speed up the cleansing of the body. Cholestyramine, taken orally 8 g 3 times a day for 24 hours, reduces plasma A771726 levels by approximately 40% after 24 hours, and by 49-65% after 48 hours. Administration of activated carbon (in the form of a suspension) orally or through a gastric tube (50 g every 6 hours during the day) reduces the concentration of the active metabolite A771726 in plasma by 37% after 24 hours, and by 48% after 48 hours. These procedures can be repeated according to clinical indications. Studies with hemodialysis and CAPD indicate that A771726, the major metabolite of leflunomide, is not excreted by dialysis. Interaction Increased side effects may occur in the case of recent or concomitant use of hepatotoxic (including alcohol) or hematotoxic and immunosuppressive drugs, or when these drugs are started after treatment with leflunomide without a washout procedure. In patients with rheumatoid arthritis, no pharmacokinetic interaction was found between leflunomide (10 - 20 mg per day) and methotrexate (10 - 25 mg per week). In patients taking leflunomide, concomitant administration of cholestyramine or activated charcoal is not recommended as this will result in a rapid and significant decrease in plasma concentrations of A771726. This is believed to be due to impaired recycling of A771726 in the liver and small intestine and/or impaired gastrointestinal dialysis. If the patient is already taking non-steroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, they can be continued after starting treatment with leflunomide. The enzymes involved in the metabolism of leflunomide and its metabolites are not precisely known. An in vivo study of its interaction with cimetidine (a non-specific cytochrome P450 inhibitor) showed no significant interaction. Following concomitant administration of a single dose of leflunomide to subjects receiving multiple doses of rifampicin (a nonspecific cytochrome P450 inducer), peak levels of A771726 increased by approximately 40%, whereas the area under the concentration-time curve did not change significantly. The mechanism of this effect is not clear. In vitro studies have shown that A771726 inhibits the activity of cytochrome P4502C9 (CYP2C9). In clinical studies, no problems were observed with the concomitant use of leflunomide and NSAIDs metabolized by CYP2C9. Leflunomide should be used with extreme caution with other non-NSAID drugs metabolized by CYP2C9, such as phenytoin, warfarin and tolbutamide. An increase in prothrombin time has been reported with the simultaneous use of leflunomide and warfarin. In a study in which leflunomide was given to healthy female volunteers concomitantly with triphasic oral contraceptives containing 30 mcg ethinyl estradiol, no decrease in the contraceptive effect of the contraceptives was observed, and the pharmacokinetics of A771726 were well within the prescribed range. There is currently no information regarding the concomitant use of leflunomide with antimalarials used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (intramuscular or oral), D-penicillamine, azathioprine and other immunosuppressive drugs (except methotrexate). The risk associated with combination therapy is unknown, especially during long-term treatment. Since this type of therapy can lead to the development of additive or even synergistic toxicity (for example, hepato- or hematotoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are undesirable. Recent concomitant or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects. Immunosuppressants increase the risk of developing infections, as well as malignancies, especially lymphoproliferative diseases. Vaccination. There are no clinical data regarding the effectiveness and safety of vaccination in the setting of leflunomide treatment. However, vaccination with live vaccines is not recommended. When planning vaccination with a live vaccine, the long T1/2 of leflunomide after discontinuation of the drug should be taken into account. Special instructions Use during pregnancy and breastfeeding. Leflunomide should not be used by pregnant women or women of childbearing potential who are not using reliable contraception during treatment with leflunomide and for a certain period after this treatment. Before starting treatment with the drug, you must ensure that there is no pregnancy. Patients should be informed that as soon as a missed period occurs or if there is any other reason to suspect pregnancy, they should immediately inform the doctor about this in order to take a pregnancy test. In the case of a positive pregnancy test, the doctor should discuss with the patient the possible risks to which the pregnancy is exposed. It is possible that rapid reduction of the active metabolite in the blood using the drug elimination procedure described below will help reduce the risk to the fetus from leflunomide during the first missed period. Women who are taking leflunomide and wish to become pregnant are advised to follow one of the following procedures to ensure that the fetus is not exposed to toxic concentrations of A771726 (reference concentration below 0.02 mg/L). Waiting period. It can be expected that the plasma concentration of A771726 may be higher than 0.02 mg/L for a long period. It is believed that its concentration may become less than 0.02 mg/l 2 years after stopping treatment with leflunomide. The first time the concentration of A771726 in blood plasma is measured after a two-year waiting period. After that, it is necessary to measure the concentration of A771726 in blood plasma, at least after 14 days. If the value of both measurements is below 0.02 mg/l, no teratogenic risk is expected. The procedure of "laundering". Colorumin 8 g is introduced 3 times a day for 11 days; As an alternative to 50 g of activated coal chopped into powder, is introduced 4 times a day for 11 days. Regardless of the selected “laundering” procedure, it is necessary to check with two separate tests with the interval of at least 14 days and wait a month and a half from the moment when the concentration of the drug in the plasma will be recorded for the first time below 0.02 mg/l, until fertilization. It is necessary to inform women of the childbearing period that 2 years should pass after the cessation of treatment with leflunomide before they may try to get pregnant. If the 2-year waiting period with reliable contraception seems unreasonable, it is possible to advise the procedure for “laundering” for preventive purposes. Both colestyramine and activated carbon can affect the absorption of estrogens and progestogen, therefore reliable oral contraceptives do not give one hundred percent guarantees during the period of “washing” with a coal or activated coal. It is recommended to use alternative contraceptive methods. Animal studies have shown that leflunomide or its metabolites pass into breast milk, so women who breastfeed should not take the drug. Leflunomide can be used in patients only after a thorough medical examination. The procedure of "laundering". The “laundering” procedure is carried out according to the following scheme: -Kolestiramin 8 g is introduced 3 times a day for 11 days; -in the quality of alternatives -50 g of activated coal chopped into powder, is introduced 4 times a day for 11 days. Impact on the ability to drive vehicles and machinery. Taking the drug may be accompanied by headache, dizziness. In this regard, patients taking leflunomide should be cautioned when managing dangerous mechanical agents, including a car. Storage conditions Store in a dry place, protected from light, out of reach of children at a temperature not exceeding 25 C.

Drug interactions Leflunomide

There is currently no information regarding the combined use of leflunomide with antimalarial drugs used in rheumatology (for example, chloroquine and hydroxychloroquine), gold preparations (IM or orally), D-penicillamine, azathioprine and other immunosuppressive drugs (except methotrexate). The risk associated with the prescription of complex therapy, especially with long-term treatment, is unknown. Since this type of therapy can lead to the development of additive or even synergistic toxicity (for example, hepato- or hematotoxicity), combinations of this drug with other basic drugs (for example, methotrexate) are undesirable. Recent, concomitant, or subsequent use of potentially myelotoxic agents may be associated with a greater risk of hematologic effects. Immunosuppressants increase the risk of developing infections, as well as malignancies, especially lymphoproliferative diseases. Caution should be exercised when prescribing drugs metabolized by CYP 2C9 (phenytoin, warfarin, tolbutamide), with the exception of NSAIDs. Increased severity of adverse events may occur when recent or concomitant use of hepatotoxic or hematotoxic drugs is used or when these drugs are started after treatment with leflunomide without a washout period. In patients with rheumatoid arthritis, no pharmacokinetic interaction was found between leflunomide (10–20 mg/day) and methotrexate (10–25 mg/week). Cholestyramine or activated carbon quickly and significantly reduce the concentration of A771726 in the blood plasma. Possible combined use with NSAIDs and GCS. The enzymes involved in the metabolism of leflunomide and its metabolites are not precisely known. There is no clinically significant interaction with cimetidine (a nonspecific inhibitor of cytochrome P450). Following concomitant administration of a single dose of leflunomide with multiple doses of rifampicin (a nonspecific cytochrome P450 inducer), maximum concentrations of A771726 increased by approximately 40%, whereas AUC did not change significantly. The mechanism of this effect is not clear. There is no decrease in the contraceptive effect when used together with triphasic oral contraceptives containing 30 mcg ethinyl estradiol, while the pharmacokinetics of A771726 did not change. There is no data regarding the effectiveness and safety of vaccination during treatment with leflunomide (vaccination with live vaccines is not recommended). The long half-life of the drug should be taken into account when planning vaccination with a live vaccine after its discontinuation.

Chronic immune inflammation developing in patients with rheumatoid arthritis (RA) is a dynamic process, the features of which change over time. It is possible that such a transformation may be largely associated with changes in the properties of the morphological substrate of the disease. The progression of chronic arthritis is accompanied by pronounced proliferation of the synovial membrane of inflamed joints due to the accumulation of inflammatory cells in it, forming massive infiltrates, and the development of the vascular bed. As a result of this transformation, the synovium actually turns into a special organ that has a certain autonomy and produces biologically active products that support the chronic course of inflammation and mediate the destruction of the joint. The presence of such tissue structures can contribute to the occurrence of irreversible changes in the joints and the formation of resistance to drug therapy.

Recent studies have shown that the effectiveness of basic antirheumatic drugs directly depends on the duration of RA. Active treatment prescribed at the earliest stages of the disease can dramatically slow down its progression and significantly improve the prognosis. During this period, the disease is most susceptible to drug effects. It is likely that the higher sensitivity to therapy may be due to the lack of significant proliferation of the synovium of the joints in the early stages of arthritis. Therefore, this period of the disease now attracts the closest attention of clinicians.

Currently, the concept of early stage RA is interpreted ambiguously. Various authors define it as periods of time from several months to several years. Some experts identify the first 3 months of the disease as a very early stage. Scientific research carried out within the framework of the problem of early arthritis is primarily devoted to solving two closely related issues. Firstly, the possibilities of establishing a reliable diagnosis are being studied, and secondly, approaches to prescribing the optimal treatment option for a given period of illness are being developed.

Criteria for early diagnosis of RA

To date, there is no test or sign that would clearly confirm or exclude the diagnosis of RA. Diagnosis of this disease is based on identifying the totality of the most typical manifestations. Today it is believed that a reliable diagnosis can be established only in cases where the disease picture meets the criteria proposed in 1987 by the American College of Rheumatology (ACR). According to these recommendations, to verify the diagnosis of RA, the presence of a sufficient number of clearly defined signs is required, and some of them must persist for at least 6 weeks. Meanwhile, it has been shown that the opportunity to significantly improve the long-term prognosis of RA may be missed if adequate treatment is not prescribed in the first 12 weeks from the onset of the disease [1]. Probably, for clinical practice, it would be of particular interest to distinguish this particular stage of RA as an early one. In the advanced phase, the clinical picture is usually quite characteristic: when examining the patient, a sufficient number of specific changes can be detected, and the diagnosis does not raise any doubts. At an early stage, the symptoms are often not so expressive and in a number of cases the required number of diagnostic criteria cannot be found.

In such patients, the diagnosis can only be made tentatively. However, the possibility of error cannot be ruled out. In some of these patients, joint changes could theoretically be associated with diseases that do not require the use of basic drugs recommended for the treatment of RA. Of course, their use in such cases seems undesirable, since they can cause quite serious adverse reactions. However, the adverse consequences associated with delayed initiation of therapy may be much greater than the potential risk of drug complications. Therefore, prescribing a basic drug at an early stage may be quite justified even in cases where the diagnosis cannot be confirmed according to the ACR criteria.

At the same time, it should be emphasized that such a decision should be made by a qualified rheumatologist with experience in managing such patients. Such a specialist is able to much more reliably assess the characteristics of disorders of the musculoskeletal system that each individual patient has. It can quite reliably determine the real threat of developing progressive destructive arthritis in the future. Therefore, the choice he made can be considered optimal for this clinical situation. Recently, criteria have been proposed that help clinicians with limited experience in this field recognize patients at high risk of developing RA in order to refer them for consultation with a rheumatologist [1].

By themselves, these criteria do not automatically make a diagnosis of RA, but taking into account the characteristics of such symptoms, an experienced specialist can, in each specific case, assess how likely this diagnosis is in a given patient and decide on prescribing basic therapy. The patient should be referred to a rheumatologist if there are three or more swollen joints, damage to the metacarpophalangeal or metatarsophalangeal joints (detected using the “transverse compression” test), morning stiffness that lasts at least 30 minutes. It must be remembered that the use of powerful anti-inflammatory drugs can completely suppress the symptoms of RA in a very short time, especially at an early stage. Therefore, the patient should not be prescribed glucocorticoids until the diagnosis of RA has been confirmed by a specialist.

At the early stage of arthritis, a very striking effect can be achieved by prescribing non-steroidal anti-inflammatory drugs. Therefore, in doubtful situations, they can be temporarily canceled in order to obtain more reliable information about the picture of the disease. The mere absence at an early stage of such characteristic signs of RA as the presence of rheumatoid factor in the blood serum and bone erosions on radiographs, in no case allows us to exclude the diagnosis of this disease. The presence of these changes at the onset of the disease is an unfavorable prognostic sign and requires more active therapy.

Basic medications are an essential component in the treatment of RA

To date, there is no medicine that can completely cure RA. Therapy is carried out continuously throughout the patient's life. The inflammatory process in this disease is resistant to drug effects. For such resistance, the patient must be prescribed several drugs simultaneously, and basic drugs are an obligatory component of this complex. Medicines of this class are usually divided into traditional and biological. All of them are effective only in some patients and, in addition, can cause adverse reactions.

According to clinical trials, each of the basic drugs, both traditional and biological, allows for tangible improvement in approximately 60% of patients, but it is impossible to predict the result in advance - it can only be assessed during the treatment process. The choice of drug for basic therapy is carried out taking into account the effectiveness of these drugs, the risk of adverse events and the cost of treatment. Since the prescription of biological agents is associated with the risk of serious infectious complications and requires very high costs, it is believed that their use can usually be justified only if traditional basic drugs are insufficiently effective [2]. Currently, methotrexate (MTX) is most widely used as the first basic drug in the early stages of RA.

A large number of publications devoted to MT that appeared in the 1980–1990s ensured his wide popularity. During this period, standard quantitative methods were developed and began to be regularly used in practice, making it possible to reliably assess the dynamics of inflammatory changes and the rate of progression of joint destruction during therapy. The use of such methods in clinical studies made it possible to clearly demonstrate the high clinical effectiveness of MT and its reliable anti-destructive potential. These reports attracted the attention of specialists, and the drug was tested on a very large clinical material, demonstrating, along with good efficacy, completely satisfactory tolerability. The accumulated experience in the practical use of MT has made it possible to develop standard methods for monitoring adverse reactions, which are now well known to all rheumatologists and, as a rule, allow one to avoid serious complications. The high efficiency and quite satisfactory tolerability of MT, combined with a relatively low cost, allowed it to become the drug of choice for the treatment of RA and occupy a leading position among medications in its class. Currently, MT is considered the gold standard of basic therapy for RA [3].

Clinical and pharmacological characteristics of leflunomide

Leflunomide (LF; Arava) appeared in clinical practice in 1998, when MT already firmly occupied a leading position among basic drugs. The clinical use of LF is still hampered by its relatively high cost, although in terms of its parameters it can be a completely reasonable alternative to MT, especially in the early stages of RA.

Pharmacodynamics

According to the mechanism of action, both MT and LF are antienzyme drugs. MT achieves its effect by inhibiting enzymes involved in folic acid metabolism. The therapeutic effect of LF is associated with the suppression of the activity of dihydroorotate dehydrogenase, which ensures the production of pyrimidine nucleotides [4]. Their deficiency leads to disruption of DNA and RNA synthesis in lymphocytes, a decrease in the proliferation of these cells and a decrease in the production of antibodies. As a result, the activity of autoimmune reactions that support the chronic course of inflammatory and destructive processes developing in the affected joints of patients with RA decreases. In addition to the distinct immunosuppressive effect, LF also has anti-inflammatory activity. It is independent of its effect on the immune system and is mediated by inhibition of cyclooxygenase-2 in combination with a decrease in histamine release. The presence of such a combined effect attracted attention already at the very early stages of studying LF, so it was initially developed as a drug for the treatment of RA. Conducting clinical trials with the participation of rheumatology centers in many countries made it possible to accumulate extensive clinical material in a short period of time and develop an optimal treatment regimen that is very convenient for practical use.

Pharmacokinetics

The unique pharmacokinetic parameters of the drug, on the one hand, ensure its rapid accumulation and stable maintenance of therapeutic concentration in the body, and on the other hand, allow the drug to be quickly removed if necessary. Initially, LF does not have significant therapeutic activity, but in the intestinal wall and in the liver it is converted into an active metabolite - teriflunomide (A771726). The concentration of A771726 reaches its maximum 6–12 hours after oral administration of LF [5]. Relative bioavailability is 82% for 100 mg tablets and 94% for 10 mg tablets. Individual variability of this parameter is 13.7%. Taking LF with food reduces the rate of its absorption, but does not affect bioavailability. When used as a maintenance dose of 20 mg/day, the average plasma concentration of A771726 stabilizes at approximately 35 mg/L. Steady-state plasma concentrations are achieved after approximately 7 weeks. The long half-life of A771726 allows for faster achievement of stable concentrations when used in the first 3 days of treatment at a loading dose of 100 mg/day.

A771726 is slowly excreted in feces and urine. During the first 96 hours, the renal route of excretion predominates, then the intestinal route. By day 28, 43% of the dose taken is excreted in the urine and 48% in feces. The low rate of elimination of the drug is explained primarily by the fact that the main part of the metabolite A771726, coming from the circulation into the intestinal lumen, is absorbed back into the bloodstream. The administration of activated carbon or cholestyramine accelerates the elimination of A771726 from plasma by binding it in the intestine and impairing recirculation. Taking cholestyramine 8 g 3 times a day or activated carbon 50 g 4 times a day reduces the concentration of A771726 by 40 and 37% in 24 hours and by 49–65 and 48% in 48 hours, respectively. Its half-life is reduced to 1–2 days.

Dosage regimens

The clinical application method developed for LF is much more convenient than the generally accepted treatment regimen using MT. A significant disadvantage of MT is the need for empirical selection of an effective therapeutic dosage. Treatment begins with a small dose (7.5–10 mg per week). After 2-3 months of regular therapy, the doctor assesses the degree of improvement achieved and, if necessary, increases the dose of the drug. There are no clear regulatory guidelines for assessing treatment effectiveness yet. Each specialist evaluates the effect completely arbitrarily, based mainly on his personal experience. As a result, the time spent on selecting an adequate dose increases significantly. Often, the necessary dose adjustment is not carried out at all or is carried out very late, and the opportunity to radically improve the long-term prognosis of the disease may be missed.

The treatment regimen for LF is standardized as much as possible and makes it possible to suppress RA activity in the shortest possible time. Typically, in the first 3 days, LF is prescribed at a dose of 100 mg/day, after which the patient continues to take it at 20 mg/day. If well tolerated, no further dose adjustment is required. You should not reduce the dose or interrupt treatment after the disease activity has decreased and the patient feels better, as this will inevitably lead to an exacerbation of the disease. If adverse reactions occur, the dose of LF can be halved (up to 10 mg/day). Arava is available in the form of tablets of 10, 20 and 100 mg. The 100 mg tablets are packaged in threes, and the patient takes one per day for the first 3 days of treatment. Tablets of 20 mg are packaged in 30 pieces and are prescribed one per day continuously as maintenance therapy. 10 mg tablets are intended for those patients who do not tolerate the drug well. They are also prescribed one per day continuously. If there is a need to reduce the dose, and 10 mg tablets are not currently commercially available, the patient can take Arava 20 mg/day every other day. Since LF remains in the body for a long time, this dosage regimen allows you to maintain the same concentration of the active metabolite as prescribing the drug at 10 mg/day.

Recently, when prescribing Arava, doctors often deviate from the classical regimen and begin therapy with a dose of 20 mg/day. This increases the time required to obtain the optimal concentration and may somewhat delay the onset of clinical improvement, but to a certain extent reduces the risk of adverse reactions. In a number of cases, such tactics may be completely justified. For many patients, reducing the rate of accumulation of the drug facilitates the process of adaptation to it and allows them to avoid undesirable effects that may be associated with an accelerated restructuring of metabolic processes. This is especially true for elderly and weakened patients, as well as in the presence of concomitant pathology.

However, at the early stage of RA, the rate of accumulation of the active metabolite of LF is likely to be of particular importance for obtaining the desired result and improving the prognosis of the disease in general. Therefore, the classical treatment regimen using high doses of LF in the first 3 days seems preferable. Often, due to a number of reasons (the patient’s late request for medical help, an insufficiently typical picture of the disease, late referral of the patient for consultation with a specialist, etc.), the decision on the issue of prescribing adequate therapy at the early stage of RA is delayed. In such situations, a dosage form that can provide an effect in the shortest possible time may prove irreplaceable. The use of a high saturating dose in the first 3 days of treatment allows you to dramatically accelerate the effect of the drug and obtain the effect much earlier than when using other traditional basic drugs, including MTX. At the same time, patients often note a clear improvement in their well-being already in the 1st week of treatment. It is possible that LF is capable of changing the prognosis of the disease not only in the first 3 months from its onset, but also at a slightly later date.

Side effects

In terms of the frequency and severity of adverse reactions, LF does not differ significantly from MT. In general, patients tolerate it quite satisfactorily. The most common side effects of LF include diarrhea, increased transaminase activity, alopecia, skin rashes, and nausea. Other adverse events are quite rare. These changes can significantly decrease or disappear when the dose of LF is reduced to 10 mg/day. However, in a number of patients (14–19%), treatment with the drug must be stopped.

Since LF, like MT, can cause an increase in the activity of liver enzymes, similar laboratory monitoring is required during treatment. Transaminase activity (AST and ALT) should be determined monthly. An increase in ALT is more often observed - a more sensitive indicator of the undesirable effect of LF on the liver. ALT activity should be assessed before prescribing the drug and then monitored monthly. If the ALT level increases 2–3 times compared to the upper limit of normal, the study should be repeated and, if the result is confirmed, the dose of LF should be reduced to 10 mg/day. If, despite a dose reduction, a 2-3-fold increase in ALT activity persists or it increases more than 3 times compared to the norm, treatment should be stopped and a “washing” procedure should be performed. Activated carbon or cholestyramine are prescribed, which ensure accelerated excretion of LF from the body and a decrease in its concentration in plasma below the level accessible for determination (<0.02 mg/l).

In rare cases, LF can cause cytopenias. The likelihood of their development increases somewhat when it is used in combination with MT. Therefore, patients who receive LF need regular monitoring of the levels of leukocytes and platelets in the blood. In the first 6 months of treatment, such monitoring is recommended to be carried out monthly, and then once every 6–8 weeks.

Clinical studies and experience with leflunomide

The largest controlled double-blind trial, which compared the effectiveness and tolerability of basic therapy using MT and LF, was conducted in 999 patients observed in 117 medical centers in Europe and South Africa [6]. In this study, 501 patients took LF and 498 took MTX. It should be emphasized that only 10% of patients receiving MTX were also taking folic acid. After the 1st year of treatment, a 20% response according to the ACR criteria was significantly more often recorded in patients receiving MT, but after the 2nd year of treatment these differences disappeared. Based on the results of a two-year follow-up, the dynamics of the main clinical indicators of activity during treatment with MT and LF did not differ significantly. The progression of radiographic changes was also similar in both groups. However, the time during which significant improvement according to ACR criteria was achieved during treatment with LF was significantly shorter than when using MT (74 ± 80 and 101 ± 92.5 days, respectively).

The faster action of LF is also confirmed by the results of magnetic resonance imaging. Reece RJ et al. performed tomography of inflamed knee joints in 39 patients with RA, 18 of whom received LF and 21 received MT. The study was performed before and 4 months after the administration of therapy. At the same time, LF provided a significantly more significant reduction in the severity of inflammatory changes in the synovium than MT [7].

In recent years, the practice of using folic acid to prevent adverse events associated with the prescription of MT has become increasingly widespread. This combination therapy is proposed to be used as a standard method of using MT [8]. Meanwhile, according to a study conducted in 42 centers in the USA and Canada, MTX prescribed in combination with folic acid was noticeably inferior to LF in effectiveness [9]. In this study, 182 patients received LF, 180 received MTX, and 118 received placebo. All patients took folic acid. During treatment with LF, MT and placebo, a 20% response according to ACR criteria was registered in 52, 46 and 26% of cases, respectively, and a 50% response was observed in 34, 23 and 8% of patients, respectively. There were no significant differences between the groups receiving LF and MT in these parameters. At the same time, both drugs significantly improved joint function and quality of life in RA patients compared to placebo. LF was significantly superior to MT in terms of its effect on the disability index, labor productivity, as well as on a number of indicators characterizing joint function. At the same time, the dynamics of functional indicators correlated with the response according to the ACR criteria.

After 2 years of treatment, LF ensured the maintenance of a 20% response according to ACR criteria in 79%, and when using MT – in 67% of cases (p = 0.049); The 50% response was maintained in 56 and 43% of cases (p = 0.053), and the 70% response in 26 and 20%, respectively [10]. In patients receiving LF, destructive changes in joints in the first year of treatment developed more slowly than when using MT (p = 0.0499). The progression of destructive changes in joints during treatment with LF and MT during the 2nd year did not differ significantly.

Despite the fact that LF and MT have unidirectional side effects, the combination of these drugs can be successfully used for combination basic therapy if one of them is insufficiently effective. Kremer JR et al., who studied the effectiveness of this combination, prescribed LF to patients who took MTX at a dose of 10–20 mg per week without significant clinical improvement [11]. During combination therapy, the dose of MT remained the same. Treatment with LF began with a loading dose of 100 mg/day for the first 2 days, after which patients took it at a dose of 10 mg/day. If the effectiveness was insufficient, the dose of LF was increased to 20 mg/day, and if adverse reactions occurred, it was allowed to be reduced to 10 mg every other day. In general, patients tolerated the drugs well and in most cases took LF 20 mg/day. This treatment provided a significant increase in effectiveness compared to MTX monotherapy. Later, the authors abandoned the use of a loading dose and began treatment with LF at 10 mg/day, increasing this dose as needed [12].

Therapy carried out according to this regimen was generally no less effective, but less often caused an increase in transaminase activity (laboratory monitoring when using a combination of LF and MT is carried out in the same way as with monotherapy with these drugs). Favorable results can also be obtained by adding MTX to patients who take LF without significant improvement. The authors who conducted this study recommended that patients continue treatment with LF at the same dose (20 mg/day) and added MTX at a rate of 5–7.5 mg per week [13].

Research in recent years has shown that LF can successfully compete with MT as a basis for creating combinations of basic agents. Thus, an analysis of the results of combination basic therapy with LF at a dose of 20 mg/day and cyclosporine at 2.5–5 mg/kg/day showed that this combination gave significantly more favorable results than monotherapy with these drugs, without a significant increase in the frequency of adverse reactions [ 14]. Probably, one of the most promising may be a combination of dosage forms with biological drugs. Quite a lot of experience has already been accumulated in its use in combination with infliximab [15]. The addition of infliximab to the treatment of patients who took LF without significant improvement provided a significant increase in the effectiveness of the therapy, and the tolerability of this combination was quite satisfactory.

The experience accumulated to date in the practical use of LF clearly indicates that it may be of serious interest for use as a drug of choice at the early stage of RA. Of course, these data do not allow us to draw a definite conclusion about the clear advantage of LF or MT. However, they convincingly indicate the need to conduct large-scale studies in real clinical practice. Only such work can provide the necessary material for the development of well-founded recommendations on the tactics of basic therapy, primarily on the choice of the optimal drug at the early stage of RA, when timely adequate therapy can seriously change the long-term prognosis of the disease.

Controlled trials of the drug, which make it possible to justify its introduction into clinical practice, do not allow solving all the problems associated with its use, since they are carried out on limited populations of artificially selected patients according to a strictly defined scheme. For a number of issues, the results obtained in double-blind trials are more likely to help frame the problem and outline ways for its further study. The data necessary to solve this problem can only be obtained through the combined efforts of many medical centers as part of large national programs.

An example of such fruitful cooperation is a Russian study to study the effectiveness and tolerability of LF [16]. This work involved 68 rheumatologists from different regions of Russia, who observed a total of 414 patients with RA. The materials obtained during the study made it possible to summarize the first significant experience in the use of LF in Russian medical institutions. The drug was prescribed at a dose of 100 mg/day for the first 3 days and then 20 mg/day. The DAS 28 index was used as the main indicator of disease activity and the effectiveness of therapy. Already a month from the start of therapy, there was a significant positive dynamics of clinical signs of RA activity, which increased significantly over the course of 6 months of treatment.

In the group as a whole, favorable results were obtained in 300 of 414 patients (73%) who started taking the drug. In 83 (20%) of them, the effect according to DAS 28 was assessed as good and in 217 (53%) as satisfactory. At the same time, the positive dynamics of clinical indicators of inflammatory activity was accompanied by a significant increase in the quality of life of patients. In 62 (15%) patients, significant improvement could not be achieved. As a rule, patients tolerated the therapy well. Side effects were recorded in 152 (37%) patients. The most common changes were in the gastrointestinal tract (nausea, diarrhea, abdominal pain), increased transaminase activity and skin reactions (itching, rash, hair loss).

LF was discontinued due to adverse reactions in 52 (12%) patients. The most common reason for discontinuation - in 19 patients - was skin changes. In 11 cases, the drug was discontinued due to dyspeptic symptoms (diarrhea, nausea, abdominal pain). In six patients, treatment was discontinued due to increased transaminase activity. Other adverse reactions led to the need to discontinue LF only in isolated cases. After discontinuation of the drug, all side effects disappeared completely. In 100 patients, LF discontinuation was not required and treatment was continued, but in 13 of them the dose was reduced to 10 mg/day.

Thus, the currently available results of domestic and foreign studies allow us to consider LF one of the most promising basic drugs. In terms of its clinical and pharmacoeconomic indicators, it seems to be practically the only real alternative to MT in the treatment of patients with early stage RA in Russian medical institutions.

Leflunomide overdose, symptoms and treatment

There are no data regarding overdose of leflunomide or intoxication caused by it in humans. The use of cholestyramine or activated carbon is indicated. Cholestyramine, taken orally 8 g 3 times a day for 24 hours, reduces the content of A771726 in the blood plasma by approximately 40% after 24 hours and by 49–65% after 48 hours. Administration of activated carbon (in the form of a suspension) orally or through the gastric the probe (50 g every 6 hours during the day) reduces the concentration of the active metabolite A771726 in plasma by 37% after 24 hours and by 48% after 48 hours.

List of pharmacies where you can buy Leflunomide:

• Moscow
• Saint Petersburg