Cart
Instruction for use: Leflunomide
I want this, give me price
Trade name of the drug – Arava, Leflaid, Leflunomide, Leflunomide Canon, Lefomide, Ralef, Ehlafra
The Latin name of the substance Leflunomide
Leflunomidum (genus. Leflunomidi)
Chemical name
5-Methyl-N- [4- (trifluoromethyl) phenyl] -4-isoxazolecarboxamide
Gross formula
C12H9F3N2O2
Pharmacological group:
Immunosuppressive drugs
The nosological classification (ICD-10)
M05 Seropositive rheumatoid arthritis: Rheumatoid seropositive arthritis
M06 Other rheumatoid arthritis
CAS code
75706-12-6
Characteristics of the substance Leflunomide
Inhibitor of pyrimidine synthesis. The molecular weight is 270.2.
Pharmacology
Mode action - Anti-inflammatory, immunosuppressive, antirheumatic, antiproliferative.
The mechanism of action is due to the inhibition of dihydroorotate dehydrogenase, an enzyme involved in the synthesis of pyrimidines.
Pharmacokinetics
After ingestion, leflunomide is metabolized to the active metabolite A77 1726 (hereinafter referred to as M1), which determines the effect of the drug in vivo.
Leflunomide in blood plasma is detected in trace amounts, therefore, in pharmacokinetic studies, concentrations of M1 were determined.
After ingestion, Cmax is reached in 6-12 hours. The half-life in the plasma is long (T1 / 2 about 2 weeks). To quickly achieve an equilibrium concentration of M1 in blood plasma, the use of a loading dose of 100 mg for 3 days was used in clinical trials. It was shown that without a preloading dose, the M1 concentration in the plasma reaches equilibrium values within 2 months. The resulting M1 concentrations in the blood plasma, determined after taking the loading and subsequent therapeutic doses of leflunomide, show that the plasma levels of M1 are dose-dependent. Determination of pharmacokinetic parameters of M1 was carried out after ingestion of leflunomide in daily doses of 5, 10 and 25 mg per day (preliminary loading doses - 50, 100 and 100 mg, respectively) in patients with rheumatoid arthritis (n = 54). At 24 hours after the loading dose, the concentrations of M1 were 4.0 ± 0.6; 8.4 ± 2.1 and 8.5 ± 2.2 μg / ml, respectively; 24 hours after the administration of therapeutic doses and in a state of equilibrium - 8.8 ± 2.9; 18 ± 9.6 and 63 ± 36 μg / ml.
The bioavailability of the leflunomide tableted form is 80%. Joint ingestion of tablets leflunomide and fatty foods does not significantly affect the level of M1 in blood plasma.
M1 has a low volume of distribution (0.13 l / kg) and a high degree of binding to plasma albumin (> 99.3%) in healthy patients. It was shown that binding to proteins is linear at therapeutic concentrations. The level of unbound M1 fraction is slightly higher in patients with rheumatoid arthritis and approximately doubles in patients with chronic renal failure. The mechanism and significance of these enhancements are unknown.
Leflunomide is metabolized to one major (M1) and several secondary metabolites. Of the secondary metabolites, only 4-trifluoromethylalanine (TFMA) is quantitatively determined in some patients at low concentrations. Related compounds are rarely detected in plasma. At present, there are no specific places for leflunomide metabolism. Based on in vivo and in vitro studies, it can be assumed that the gastrointestinal wall and liver participate in this process. Specific enzymes of leflunomide metabolism have not been isolated, however, participation of cytoplasmic and microsomal fractions of liver cells in the metabolism of the compound has been demonstrated.
The active metabolite M1 is excreted by subsequent metabolism and excretion by the kidneys, and by direct excretion with bile. In a 28-day study of the route of elimination of the compound (n = 3), using a single dose of the radiolabeled drug, it was shown that about 43% of the radioactive dose is excreted in the urine and 48% - with feces. Subsequent analysis of the samples showed that the main metabolites in the urine are leflunomide glucuronides and M1 derivatives. The main metabolite in the feces was M1. Of these two ways, excretion in the urine was more significant in the first 96 hours, after which the second way of excretion dominated. In a study with intravenous M1 injection, the clearance was 31 mL / h.
In small studies using activated charcoal (n = 1) and colostiramine (n = 3), in order to facilitate removal of the drug, the T1 / 2 M1 values from plasma in vivo decreased from more than 1 week to about 1 day. Similar decreases in T1 / 2 were observed in a group of volunteers (n = 96) who participated in studies with colistramine load. This fact suggests that reabsorption from the bile contributes to the maintenance of prolonged T1 / 2 M1 from the plasma. Studies conducted using hemodialysis and ambulatory peritoneal dialysis show that M1 is not dialyzed from plasma and peritoneal fluid.
Dependence of pharmacokinetics parameters on some factors
There were no significant sex and age differences in the M1 pharmacokinetics in vivo.
Population pharmacokinetic analysis in Phase III studies shows that smokers have a 38% increase in clearance compared with non-smokers; However, there is no difference in clinical efficacy (leflunomide) in smokers and non-smokers.
In patients with chronic renal insufficiency requiring hemodialysis or laboratory peritoneal dialysis (n = 6), after a single dose of drugs, no significant effect on the levels of circulating M1 was detected. The fraction of unbound M1 was almost doubled, but the mechanism of this increase is not known. In the light of the fact that the kidneys participate in the process of excretion of the drug and in the absence of adequate studies with leflunomide in patients with renal insufficiency, care should be taken when prescribing treatment with this drug.
Studies of the effect of hepatic insufficiency on the pharmacokinetics of M1 have not been conducted. Taking into account the metabolism of leflunomide in active metabolites, the role of the liver in elimination and recycling in the body of drugs, the possible risk of an increase in hepatotoxicity, the use of leflunomide in patients with hepatic insufficiency is not recommended.
Carcinogenicity, mutagenicity and effects on fertility
In two-year studies in rats, the carcinogenicity of leflunomide was not detected at oral doses, up to the maximum tolerated dose of 6 mg / kg (approximately 1/40 of the maximum systemic exposure of M1 in humans based on AUC). However, in two-year studies in male mice, there was an increase in lymphoma formation at the maximum oral dose of 15 mg / kg (1.7-fold M1 exposure in humans based on AUC). In the same studies in female mice, a combined, dose-dependent increase in the formation of bronchoalveolar adenomas and carcinomas was observed at increasing doses, starting at 1.5 mg / kg (approximately 1/10 of the M1 exposure in humans based on AUC). The significance of these data regarding the clinical use of leflunomide is not determined.
Leflunomide showed no mutagenicity in the Ames test, an unscheduled DNA synthesis test, and / or a hypoxanthine guanine phosphoribosyltransferase test of Chinese hamster ovary cells. Also, leflunomide did not exhibit clastogenic properties in the micronucleus test in mice in vivo and in the cytogenetic test on Chinese hamster bone marrow cells in vivo. However, 4-trifluoromethylaniline (TFMA), a secondary leflunomide metabolite, exhibited mutagenic properties in the Ames test and in the hypoxanthine-guanine phosphoribosyltransferase test of Chinese hamster ovary cells and showed clastogenic properties in a test of chromosomal aberrations in Chinese hamster cells in vitro. TFMA did not show clastogenic properties in a micronucleus test in mice in vivo or a cytogenetic test on Chinese hamster bone marrow cells in vivo.
Leflunomide does not affect the fertility of male and female rats at oral dosages to 4.0 mg / kg (approximately 1/30 of the M1 exposure in humans based on AUC).
Clinical trials
The efficacy of leflunomide in the treatment of rheumatoid arthritis (RA) has been demonstrated in 3 controlled trials. Symptomatic relief was assessed using the Response Criterion ACR20, which is a complex of clinical, laboratory and functional studies in RA (ACR20 Responder Index, ACR - American College of Rheumatology - American College of Rheumatology). The "ACR20 respondent" is a patient with RA who has a 20% or more improvement in assessing the number of painful / inflamed joints and in 3 of the following 5 criteria: general assessment of the condition by the doctor, general assessment of the patient's condition, disability score (on the modified health assessment questionnaire - MHAQ-Modified Health Assessment Questionnaire), a visual analogue of the pain scale and an indicator of ESR or a concentration of C-reactive protein. The "ACR20 respondent at the endpoint" is the patient who, at the end of the study, had a 20% or more improvement in the above parameters. The delay in the progression of structural damage to the joints in comparison with the control was determined using the Sharpe Scale by a general count of the marginal erosions and narrowing of the joint cracks in the wrists and wrists and the forefoot.
At the beginning of the clinical trials, all patients who received leflunomide received a loading dose of 100 mg / day for 3 days.
In US301 clinical trials, 482 patients with an active form of RA of at least 6 months were randomly assigned to the United States. Patients received leflunomide at a dosage of 20 mg / day (n = 182), or methotrexate with an increasing dosage of 7.5 to 15 mg per week (n = 182), or placebo (n = 118). All patients took folic acid 1 mg twice daily. The treatment time was 52 weeks.
In MN301 studies in Europe, 358 patients with active RA were randomized to receive either leflunomide 20 mg / day (n = 133) or sulfasalazine 2.0 g / day (n = 133) or placebo (n = 92). Duration of treatment - 24 weeks. Clinical trials of MN303 in Europe were an additional 6-month placebo-uncontrolled continuation of MN301 studies, which resulted in a comparison of the efficacy of leflunomide and sulfasalazine for 12 months.
In clinical trials of MN302 in Europe, 999 patients with active RA who received either leflunomide 20 mg / day (n = 501) or methotrexate at an increasing dosage of 7.5 to 15 mg per week (n = 498) were randomized. 10% of patients additionally took folic acid. The treatment time was 52 weeks.
Results of clinical trials
According to the ACR20 Response Criteria at the endpoint, the number of RA patients with improvements in the treatment with leflunomide was statistically significantly higher in comparison with the response to placebo: 41% and 18% respectively in the US301, 49% and 28% group, respectively, in the MN301 / 303 groups. For this modification, the response rate of ACR20 was stable over time and was 41% at 6 months and 49% at 12 months. There were no significant differences in the efficacy of treatment between leflunomide and methotrexate and between leflunomide and sulfasalazine.
According to the main modification of ACR20, the statistically significant effect of leflunomide treatment in the US301 group in comparison with placebo was determined only 1 month after the initiation of therapy (38 and 20%, respectively), reached a maximum and stabilized for 3-6 months (50-55 and 26-30% Respectively) and practically did not change during the next 6 months.
Table 1 presents in comparison the amounts (in% of total) of ACR20, ACR50 and ACR70 of responding patients with RA, in whom 20, 50 or 70%, respectively, an improvement in the parameters studied (Table 2).
Table 1
Comparative results of clinical studies leflunomida
| Study group | Response Criteria | ||
| ACR 20% | ACR 50% | ACR 70% | |
| Placebo-controlled trials | |||
| US301 (12 months) | |||
| Leflunomide (n = 178) | 52,21 | 34,31 | 20,21 |
| Placebo (n = 118) | 26,3 | 7,6 | 4,2 |
| Methotrexate (n = 180) | 45,6 | 22,8 | 9,4 |
| MN301 (6 months) | |||
| Leflunomide (n = 130) | 54,62 | 33,12 | 10,02 |
| Placebo (n = 91) | 28,6 | 14,3 | 2,2 |
| Sulfasalazine (n = 132) | 56,8 | 30,3 | 7,6 |
| Placebo-uncontrolled studies | |||
| MN302 (12 months) | |||
| Leflunomide (n = 495) | 51,1 | 31,1 | 9,9 |
| Methotrexate (n = 489) | 65,2 | 43,8 | 16,4 |
2 - p<0,02 (Leflunomide to placebo)Table 2
Mean changes in individual study parameters included in the ACR response Criteria
| Options | Placebo-controlled trials | Placebo-uncontrolled studies | ||||||
| US301 | MN301 | MN302 | ||||||
| Leflunomide | Methotrexate | Placebo | Leflunomide | Methotrexate | Placebo | Leflunomide | Methotrexate | |
| Number of painful joints1 | -7,7 | -6,6 | -3,0 | -9,7 | -8,1 | -4,3 | -8,3 | -9,7 |
| Number of inflamed joints1 | -5,7 | -5,4 | -2,9 | -7,2 | -6,2 | -3,4 | -6,8 | -9,0 |
| Patient evaluation | -2,1 | -1,5 | 0,1 | -2,8 | -2,6 | -0,9 | -2,3 | -3,0 |
| Assessment by a doctor | -2,8 | -2,4 | -1,0 | -2,7 | -2,5 | -0,8 | -2,3 | -3,1 |
| Invalidization | -0,29 | -0,15 | 0,07 | -0,50 | -0,29 | -0,04 | -0,37 | -0,44 |
| Intensity of pain2 | -2,2 | -1,7 | -0,5 | -2,7 | -2,0 | -0,9 | -2,1 | -2,9 |
| ESR | -6,26 | -6,48 | 2,56 | -7,48 | -16,56 | 3,44 | -10,12 | -22,18 |
| C-reactive protein | -0,62 | -0,50 | 0,47 | -2,26 | -1,19 | 0,16 | -1,86 | -2,45 |
2 - Visual analogue of the pain scale (0 - no pain, 10 - maximum)According to the data of X-ray studies of structural lesions of joints assessed on the Sharpe scale, treatment with leflunomide in comparison with placebo statistically significantly slows down the rate of RA progression. In patients of the US301 group, this parameter was 0.5 units per year at a rate of 2.2 units in the placebo case, and in the MN301 / 303 studies, the process was stabilized, while in the placebo group, the rate of radiologic progression was 5.5 units per year. There were no significant differences in the treatment with leflunomide and methotrexate or leflunomide and sulfasalazine.
Application of the substance Leflunomide
According to the Physician Desk Reference (2005), leflunomide is shown in adults for the treatment of active RA, reduction of objective symptoms and improvement of the subjective state of patients, delay in formation of marginal joint erosions and narrowing of joint slots detected by fluoroscopy. Treatment with acetylsalicylic acid, NSAIDs and / or low doses of corticosteroids can be continued with leflunomide therapy. Combined use of leflunomide with antimalarial drugs, gold preparations for intramuscular or oral administration, penicillamine, azathioprine and methotrexate has not been sufficiently investigated.
Contraindications
Hypersensitivity, pregnancy.
Restrictions
The possibility of immunosuppression
Leflunomide is not recommended for patients with severe immunodeficiency, bone marrow dysplasia, severe, uncontrolled infections.
In a few reports, it was indicated that pancytopenia was detected with leflunomide. In most of these cases, patients received co-therapy with methotrexate or other immunosuppressive drugs, or therapy with these compounds was canceled before the study; In some cases, patients had a history of significant hematologic abnormalities. When treating such patients with leflunomide therapy should be conducted with caution and under constant clinical and hematological control. The use of leflunomide in combination therapy with methotrexate in controlled trials has not been adequately studied.
If bone marrow depression is detected in a leflunomide patient, treatment with this drug should be discontinued, and to rapidly reduce the concentration of the active metabolite leflunomide in blood plasma, it is necessary to use colestyramine or activated charcoal (see "Pharmacology, Pharmacokinetics", "Precautions. Excretion of the drug ").
In the case where a decision is made to replace leflunomide with another anti-rheumatic drug with known hematodepressant properties, it is reasonable to continue to control hematotoxicity due to possible overlapping of the systemic effect of both drugs. Withdrawal of leflunomide with colestyramine or activated charcoal may reduce this risk, but may worsen the patient's susceptibility to leflunomide treatment.
Skin Reactions
There are reports of isolated cases of Stevens-Johnson syndrome and toxic epidermal necrosis in patients taking leflunomide. If the patient receiving leflunomide develops one of these conditions, leflunomide therapy should be discontinued and the recommended drug removal procedure should be carried out (see Pharmacology, Pharmacokinetics, Precautions: Necessity for Drug Derivation).
Hepatotoxicity
In clinical trials, treatment with leflunomide in a certain number of patients was associated with an increase in hepatic enzyme activity, primarily ALT and AST; These effects were reversible in most cases. Most of the increases in transaminase activity were moderate (≤2 times the upper limit of normal, IGN) and usually decreased with continued treatment. Significant increases (> 3-fold HHV) were rare and were reversible with a decrease in dosage or interruption of treatment. Table 3 presents data on the increase in activity of hepatic enzymes, determined during clinical trials on a monthly basis. It should be noted that the lack of folic acid in clinical trials of MN302 is associated with a greater frequency of increased hepatic enzyme activity in the treatment of methotrexate.
Table 3
Activity of hepatic transaminases in clinical trials
| Options | US301 | MN301 | MN302* | |||||
| Leflunomide | Placebo | Methotrexate | Leflunomide | Placebo | Sulfasalazine | Leflunomide | Methotrexate | |
| ALT> 3 VGN (n,%) Return to ≤2 VGN: | 8 (4,4) 8 | 3 (2,5) 3 | 5 (2,7) 5 | 2 (1,5) 2 | 1 (1,1) 1 | 2 (1,5) 2 | 13 (2,6) 12 | 83 (16,7) 82 |
| Lift time 0-3 months 4-6 months 7-9 month 10-12 months | 6 1 1 - | 1 1 1 - | 1 3 1 - | 2 - - - | 1 - - - | 2 - - - | 7 1 - 5 | 27 34 16 6 |
| AST> 3 VGN (n,%) Return to ≤2 VGN: | 4 (2,2) 4 | 2 (1,7) 2 | 1 (0,6) 1 | 2 (1,5) 2 | 0 - | 5 (3,8) 4 | 7 (1,4) 5 | 29 (5,8) 29 |
| Lift time 0-3 months 4-6 months 7-9 month 10-12 months | 2 1 1 - | 1 1 - - | - 1 - - | 2 - - - | - - - - | 4 1 - - | 3 1 - 3 | 10 11 8 - |
Individual cases of increased activity of alkaline phosphatase and bilirubin concentration in serum were observed.
Preclinical stage of liver disease
In connection with the fact of the likely risk of increased toxic effect on the liver, the role of the liver in activation, excretion and recycling of drugs, the use of leflunomide is not recommended in patients with a significant impairment of liver function or infected with hepatitis B or C viruses.
Malignization
The risk of malignancy, especially of lymphoproliferative diseases, increases with the use of some drugs with immunosuppressive action. Leflunomide possesses the ability of immunosuppressive action. In clinical trials with leflunomide, there was no increase in the frequency of malignancy or the appearance of lymphoproliferative diseases, but more extensive and longer-term studies are needed to determine the possible risk of these processes.
Methods for excretion of the drug
It is recommended that the following drug elimination procedure be used to achieve its undetectable plasma level (less than 0.02 mg / L or 0.02 mkg / ml) after treatment with leflunomide is discontinued:
1) reception of colestyramine 8 g 3 times a day for 11 days (it is not necessary to take colestyramine for 11 consecutive days, if there is no need to rapidly reduce the M1 level in plasma);
2) Monitor less than 0.2 mg / L (0.2 mkg / ml) M1 plasma levels with 2 independent tests for at least 14 days. If the plasma levels are higher than 0.02 mg / l, an additional method of colestyramine is needed.
Without the elimination technique, the plasma level of M1 may not reach values less than 0.02 mg / L for 2 years, depending on individual variations in clearance.
Pregnancy and breast-feeding
Leflunomide can harm the fetus when taken by pregnant women. Leflunomide was teratogenous when administered orally to rats during organogenesis at a dose of 15 mg / kg (mainly anophthalmia or microphthalmia and internal hydrocephalus). Systemic exposure in rats at this dose was approximately 1/10 of the exposure level based on AUC in humans. Under these conditions, leflunomide also caused a decrease in the body weight of females and an increase in embryo-lethality and a decrease in the weight of the fetuses of surviving newborns. In rabbits, the oral administration of leflunomide at a dose of 10 mg / kg during organogenesis led to the formation of fused dysplastic segments of the sternum. The exposure level at this dose was almost equal to the maximum exposure level based on AUC in humans. At a dose of 1 mg / kg leflunomide did not show teratogenicity in rats and rabbits.
When the leflunomide is exposed to leflunomide at a dose of 1.25 mg / kg, starting 14 days before the crossing and ending with lactation, the survival of the offspring is reduced by more than 90%. The level of systemic exposure at a dose of 1.25 mg / kg was about 1/100 of the exposure level in a person based on AUC.
Use in women of childbearing age. Adequate and strictly controlled studies to evaluate the effect of leflunomide in pregnant women were not conducted. However, based on animal studies, leflunomide can increase the risk of fetal death during admission during pregnancy. Women of childbearing age should not be treated with leflunomide before pregnancy is excluded and (or) evidence of the use of reliable contraception. Before beginning treatment with leflunomide, the patients should be fully consulted about the potential serious hazard to the fetus.
Patients should be warned that with any delay in menstruating or other reasons suggesting pregnancy, they should immediately notify the doctor for a pregnancy test, and if the result is positive, the doctor and patient should discuss the risk for pregnancy. It is likely that a rapid decrease in the level of active metabolite in the blood with the use of the drug elimination technique, with the first delay in menstruation, can reduce the risk of leflunomide for the fetus.
All women of childbearing age after stopping treatment with leflunomide are recommended to undergo the procedure of excretion of the drug. Women undergoing treatment with leflunomide and wishing to become pregnant should stop taking the drug and undergo a procedure for its removal, including confirmation of a decrease in the level of metabolite M1 in the plasma below 0.02 mg / l (0.02 μg / ml). It is believed, based on animal studies, that the concentration of the active metabolite M1 in human plasma is less than 0.02 mg / L (0.02 μg / ml), the risk is minimized.
The action category for fetus by FDA is X.
Lactation. Leflunomide cannot be used when breastfeeding. It is not known whether leflunomide is excreted in breast milk. Since many drugs penetrate the milk of lactating women, there is a possibility of occurrence under the influence of leflunomide of serious adverse reactions in children who are breastfed. However, the decision to initiate treatment with leflunomide or continue breastfeeding should be made taking into account the importance of the drug for the mother.
Side effects of Leflunomide
Adverse reactions associated with the use of leflunomide in the treatment of RA include: diarrhea, increased activity of liver enzymes (ALT and AST), alopecia and rash. Below are the side reactions identified in controlled trials (regardless of causality) and observed with a frequency of ≥3% in at least one of the groups studied (Table 4).
Table 4
Side effects of Leflunomide
| Body systems | Frequency of adverse reactions,% | ||||||
| All researches | Placebo-controlled trials | Placebo-uncontrolled studies | |||||
| MN301 è US301 | MN 302 | ||||||
| Leflunomide, n=13391 | Leflunomide, n=315 | Placebo, n=210 | Sulfasalazine, n=133 | Methotrexate, n=182 | Leflunomide, n=501 | Methotrexate, n=498 | |
| Organism as a whole | |||||||
| Allergic reactions | 2 | 5 | 2 | 0 | 6 | 1 | 2 |
| Asthenia | 3 | 6 | 4 | 5 | 6 | 3 | 3 |
| Influenza syndrome | 2 | 4 | 2 | 0 | 7 | 0 | 0 |
| Infections | 4 | 0 | 0 | 0 | 0 | 0 | 0 |
| Accidental injury | 5 | 7 | 5 | 3 | 11 | 6 | 7 |
| Pain | 2 | 4 | 2 | 2 | 5 | 1 | <1 |
| Abdominal pain | 6 | 5 | 4 | 4 | 8 | 6 | 4 |
| Backache | 5 | 6 | 3 | 4 | 9 | 8 | 7 |
| Cardiovascular | |||||||
| Hypertension2 | 10 | 9 | 4 | 4 | 3 | 10 | 4 |
| Chest pain | 2 | 4 | 2 | 2 | 4 | 1 | 2 |
| Gastrointestinal | |||||||
| Anorexia | 3 | 3 | 2 | 5 | 2 | 3 | 3 |
| Diarrhea | 17 | 27 | 12 | 10 | 20 | 22 | 10 |
| Dyspepsia | 5 | 10 | 10 | 9 | 13 | 6 | 7 |
| Gastroenteritis | 3 | 1 | 1 | 0 | 6 | 3 | 3 |
| Enlargement of the liver | 5 | 10 | 2 | 4 | 10 | 6 | 17 |
| Nausea | 9 | 13 | 11 | 19 | 18 | 13 | 18 |
| Gastrointestinal / abdominal pain | 5 | 6 | 4 | 7 | 8 | 8 | 8 |
| Ulcers in the mouth | 3 | 5 | 4 | 3 | 10 | 3 | 6 |
| Vomiting | 3 | 5 | 4 | 4 | 3 | 3 | 3 |
| Metabolism | |||||||
| Hypokalemia | 1 | 3 | 1 | 1 | 1 | 1 | <1 |
| Weight loss | 4 | 2 | 1 | 2 | 0 | 2 | 2 |
| Musculoskeletal | |||||||
| Arthralgia | 1 | 4 | 3 | 0 | 9 | <1 | 1 |
| Leg cramps | 1 | 4 | 2 | 2 | 6 | 0 | 0 |
| Diseases of the joints | 4 | 2 | 2 | 2 | 2 | 8 | 6 |
| Synovitis | 2 | <1 | 1 | 0 | 2 | 4 | 2 |
| Tendosinovit | 3 | 2 | 0 | 1 | 2 | 5 | 1 |
| Nervous | |||||||
| Dizziness | 4 | 5 | 3 | 6 | 5 | 7 | 6 |
| Headache | 7 | 13 | 11 | 12 | 21 | 10 | 8 |
| Paresthesia | 2 | 3 | 1 | 1 | 2 | 4 | 3 |
| Respiratory | |||||||
| Bronchitis | 7 | 5 | 2 | 4 | 7 | 8 | 7 |
| Coughing up | 3 | 4 | 5 | 3 | 6 | 5 | 7 |
| Respiratory infections | 15 | 21 | 21 | 20 | 32 | 27 | 25 |
| Pharyngitis | 3 | 2 | 1 | 2 | 1 | 3 | 3 |
| Pneumonia | 2 | 3 | 0 | 0 | 1 | 2 | 2 |
| Rhinitis | 2 | 5 | 2 | 4 | 3 | 2 | 2 |
| Sinusitis | 2 | 5 | 5 | 0 | 10 | 1 | 1 |
| Skin and appendages (skin) | |||||||
| Baldness | 10 | 9 | 1 | 6 | 6 | 17 | 10 |
| Eczema | 2 | 1 | 1 | 1 | 1 | 3 | 2 |
| Itching | 4 | 5 | 2 | 3 | 2 | 6 | 2 |
| Rash | 10 | 12 | 7 | 11 | 9 | 11 | 10 |
| Dryness of the skin | 2 | 3 | 2 | 2 | 0 | 3 | 1 |
| Urogenital | |||||||
| Urinary tract infections | 5 | 5 | 7 | 4 | 2 | 5 | 6 |
All patients in group US301 took folic acid; In the MN301 group, folic acid was not taken; Only 10% of patients in the MN302 group took folic acid.
1 - Including all controlled and non-controlled trials with leflunomide.
2 - Hypertension, as a condition that arose before the start of the trial, was present in all groups for the study of leflunomide in the phase III trials. Analysis of cases of newly emerging hypertension shows no differences among the study groups.
In addition, adverse reactions observed in patients with RA treated with leflunomide in controlled clinical trials were reported at rates ranging from 1% to <3%.
The body as a whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain.
Cardiovascular system: stenocardia, migraine, palpitations, tachycardia, varicose veins, vasculitis, vasodilation.
Gastrointestinal system: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, candidiasis of the oral mucosa, pharyngitis, salivary gland enlargement, stomatitis (or aphthous stomatitis), dental diseases.
Endocrine system: diabetes mellitus, hyperthyroidism.
Hematopoietic and lymphatic systems: anemia (including iron deficiency anemia), ecchymosis.
Metabolism: increased activity of creatinine phosphokinase, hyperglycemia, hyperlipidemia, peripheral edema.
Musculoskeletal system: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture.
Nervous system: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorders, excessive sweating, dizziness.
Respiratory system: asthma, shortness of breath, nosebleeds, lung diseases.
Skin and appendages of the skin: acne, contact dermatitis, fungal dermatitis, discoloration of hair and skin color, hematoma, herpes simplex, herpes zoster, papular rash, nail diseases, skin diseases, cutaneous nodules, subcutaneous nodules, skin ulcers.
Sense organs: blurred vision, cataracts, conjunctivitis, eye diseases, perversion of taste.
Urogenital system: albuminuria, cystitis, dysuria, hematuria, menstrual disorders, prostate diseases, frequency of urination, vaginal candidiasis.
Even more rare adverse reactions observed in clinical trials included the following: 1 case of an anaphylactic reaction that occurred during Phase II studies during the re-initiation of the trial after discontinuation of treatment due to rash; hives; Eosinophilia; Transient thrombocytopenia (rarely); Leukopenia <2000 cells / mm3 (rarely). In postmarketing studies, there have been isolated cases of pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, and multiform erythema.
Interaction
In addition, adverse reactions observed in patients with RA treated with leflunomide in controlled clinical trials were reported at rates ranging from 1% to <3%.
The body as a whole: abscess, cyst, fever, hernia, malaise, pain, neck pain, pelvic pain.
Cardiovascular system: stenocardia, migraine, palpitations, tachycardia, varicose veins, vasculitis, vasodilation.
Gastrointestinal system: cholelithiasis, colitis, constipation, esophagitis, flatulence, gastritis, gingivitis, melena, candidiasis of the oral mucosa, pharyngitis, salivary gland enlargement, stomatitis (or aphthous stomatitis), dental diseases.
Endocrine system: diabetes mellitus, hyperthyroidism.
Hematopoietic and lymphatic systems: anemia (including iron deficiency anemia), ecchymosis.
Metabolism: increased activity of creatinine phosphokinase, hyperglycemia, hyperlipidemia, peripheral edema.
Musculoskeletal system: arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon rupture.
Nervous system: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorders, excessive sweating, dizziness.
Respiratory system: asthma, shortness of breath, nosebleeds, lung diseases.
Skin and appendages of the skin: acne, contact dermatitis, fungal dermatitis, discoloration of hair and skin color, hematoma, herpes simplex, herpes zoster, papular rash, nail diseases, skin diseases, cutaneous nodules, subcutaneous nodules, skin ulcers.
Sense organs: blurred vision, cataracts, conjunctivitis, eye diseases, perversion of taste.
Urogenital system: albuminuria, cystitis, dysuria, hematuria, menstrual disorders, prostate diseases, frequency of urination, vaginal candidiasis.
Even more rare adverse reactions observed in clinical trials included the following: 1 case of an anaphylactic reaction that occurred during Phase II studies during the re-initiation of the trial after discontinuation of treatment due to rash; hives; Eosinophilia; Transient thrombocytopenia (rarely); Leukopenia <2000 cells / mm3 (rarely). In postmarketing studies, there have been isolated cases of pancytopenia, Stevens-Johnson syndrome, toxic epidermal necrolysis, and multiform erythema.
Overdose
Data regarding the overdose of leflunomide when applied to humans are not available. In acute toxicological experiments in mice and rats, the minimum toxic doses for oral leflunomide use were 200-500 mg / kg and 100 mg / kg, respectively (approximately more than 350 times the maximum recommended human dose). In case of a significant overdose or toxicity, to accelerate the excretion of the drug, it is recommended to take colestyramine or activated charcoal (see "Precautions: Necessity for Drug Disinfection").
Routes of administration
Inside.
Precautionary measures
Necessity in deducing a preparation. The active metabolite leflunomide is slowly removed from the plasma. In cases of high leflunomide toxicity and / or hypersensitivity, it is necessary to use the drug elimination technique to reduce the plasma concentration in the plasma more quickly after ceasing leflunomide therapy. Prolonged reception of colestyramine or activated charcoal is necessary to achieve rapid and sufficient excretion, the duration of admission may vary depending on the clinical status of the patient. Kolestiramin, taken internally at a dosage of 8 g 3 times a day for 24 hours by three healthy volunteers, reduced the plasma levels of M1 for 24 hours by approximately 40%, and for 48 hours by 49-65%. It was shown that the reception of activated carbon (powder in the form of a suspension) inside or through the stomach probe (50 g every 6 hours for 24 hours) leads to a decrease in plasma concentrations of the active metabolite M1 by 37% in 24 hours and by 48% in 48 H. These drug removal procedures can be repeated in case of clinical necessity.
Renal insufficiency. In studies with a single administration of leflunomide, it was shown that in patients who underwent hemodialysis, the concentration of free M1 in plasma doubled. However, there is no clinical evidence for the use of leflunomide in patients with renal impairment. Therefore, it is necessary to use the drug with caution in this group of patients.
Vaccination. Clinical data on the efficacy and safety of vaccination during treatment with leflunomide are absent. However, vaccination with live vaccines is not recommended. It is necessary to take into account the duration of half-life of leflunomide with the intention of administering a live vaccine after stopping leflunomide therapy.
Laboratory research. The level of ALT activity is the main diagnostic indicator of hepatotoxicity and should be monitored monthly, and then, with stabilization, determined according to the individual clinical situation.
Patients with an increased risk of hematotoxicity should be guaranteed more thorough monitoring, including hematologic (see "Limitations to use, the possibility of immunosuppression").
In connection with the specific effect on the calcified border of the renal proximal tubules, leflunomide causes acceleration of excretion of uric acid (uricosuric effect). In some patients hypophosphaturia is observed separately. These effects are not jointly observed and are not alternative to each other.
Use in men. The available information does not give grounds for supposing that the use of leflunomide increases the risk of male-dependent fetal toxicity. No animal experiments were conducted to assess this specific risk. To minimize any possible risk, men who wish to become fathers should interrupt treatment with leflunomide and take colestyramine inside 8 g 3 times daily for 11 days.
Use in pediatrics. The safety and effectiveness of leflunomide in children is not investigated. Use of leflunomide by patients younger than 18 years is not recommended.
Geriatrics. Patients over 65 years of age are not required to adjust the dosage of leflunomide.
The possibility of abuse and dependence on leflunomide is not revealed.
Special instructions
Information for patients. It is necessary to discuss with patients - women of childbearing age - the likelihood of an increased risk of congenital defects in the fetus. Women when visiting a doctor should be explained that they will be at an increased risk of having a child with congenital defects if they start taking leflunomide during pregnancy, get pregnant during the course of treatment, or until the treatment is discontinued and the drug is withdrawn. Men who want to become fathers must interrupt treatment with leflunomide.
Patients should be warned about the possibility of rare but serious skin reactions, the need for immediate contact with a doctor in the event of skin rash or lesions of the mucous membranes.
Patients should be notified of possible hepatotoxic effects of leflunomide and the need to monitor the activity of liver enzymes.
Patients who receive immunosuppressive therapy together with leflunomide therapy, or have completed this therapy before leflunomide treatment, or have a significant hematologic pathology in the anamnesis, should be notified of the possible development of pancytopenia and the need for frequent hematological control. They should be instructed about the immediate notification of the doctor in case of detection of symptoms of pancytopenia (easy formation of subcutaneous hematomas, predisposition to infections, pallor and fatigue).
