What Is Leflunomide?

Leflunomide tablets, the indication is adult human rheumatoid arthritis.

Leflunomide tablets, the indication is adult human rheumatoid arthritis.

Drug Name

Leflunomide tablets

Drug type

Prescription drugs, medicines for medical workers' injuries

Use classification

Other immunosuppressants

Leflunomide tablets ingredients

The main ingredient of this product is Leflunomide.
Chemical name: N- (4-trifluoromethylphenyl) -5-methylisoxazole-4-carboxamide.
Chemical Structure:

Molecular formula: C ₁₂ H ₉ F ₃ N ₂ 0 ₂
Molecular weight: 270.2

Leflunomide tablets

This product is a film-coated tablet that appears white after removal of the coating.

Leflunomide tablets indications

Rheumatoid arthritis in adults.

Leflunomide tablets specifications

10 mg

Leflunomide tablets dosage

Take it orally before bedtime, 20 mg once daily (2 tablets).
During the treatment with this drug, non-steroidal anti-inflammatory analgesics or low-dose corticosteroids can continue to be used.

Leflunomide tablets adverse reactions

The main manifestations are: white blood cell decline, itching, decreased appetite, fatigue, dizziness, diarrhea, mild liver damage, rash, and nausea.
During the phase III clinical trial of similar foreign drugs, 1-3% of patients experienced the following adverse reactions:
Systemic: abscess, cyst, fever, neck pain, discomfort and pelvic pain;
Cardiovascular: angina, migraine, palpitations, tachycardia, varicose veins, vasculitis and vasodilation;
Digestive system: gallstones, colitis, constipation, esophagitis, flatulence, melena, pharyngitis, hypertrophy of salivary glands, gingivitis, stomatitis and malaligned teeth;
Endocrine: diabetes and hyperthyroidism;
Blood and lymphatic system: anemia (iron deficiency anemia) and purpura;
Metabolism and nutrition: increased creatine phosphokinase activity, hyperglycemia and hyperlipidemia;
Musculoskeletal system: arthritis, osteonecrosis, bone pain, bursitis and muscle spasms;
Respiratory system: lung discomfort, asthma, dyspnea and nosebleeds;
Nervous system: anxiety, depression, dry mouth, insomnia, neuralgia, neuritis, sleep disorders, sweating and dizziness;
Skin and appendages: acne, contact dermatitis, fungal dermatitis, hair discoloration, herpes simplex, shingles, maculopapular rash, nail abnormalities, skin discoloration, skin allergy, skin nodules, subcutaneous nodules and skin ulcers
Genitourinary system: proteinuria, hematuria, cystitis, dysuria, prostatitis and frequent urination, irregular menstruation, vaginal candidiasis;
Senses: Blurred vision, cataracts, eye discomfort, conjunctivitis, perverted taste.

Leflunomide tablets contraindications

The following patients are disabled:
1. Those who are allergic to leflunomide and its metabolites;
2. Pregnant women and women of childbearing age and lactating women who have not taken reliable contraceptive measures.

Leflunomide tablets precautions

1. Patients with severe immunodeficiency, bone marrow dysplasia, patients with hepatitis B or C, patients with severe or uncontrollable infection, and live vaccine immunization should not use this product.
2. Men who are planning to give birth should consider stopping treatment while taking cholestyramine or activated carbon.
3. During the use of leflunomide, rare adverse reactions occurred, such as bone marrow suppression, Stewart's syndrome, toxic epidermal necrosis, stop taking leflunomide and taking cholestyramine or activated carbon at the same time, reducing M1 in plasma Level.
4. Transient alanine aminotransferase (ALT) elevation may occur during the use of leflunomide. Therefore, ALT should be tested once a month during the initial period of administration. If ALT rises within 2 times the normal value (<80U / L), continue observation: If ALT rises within 2 to 3 times the normal value (80 ~ 120U / L), take half the dose and continue observation. If ALT continues to rise or is still maintained at 80 ~ 120U / L, treatment should be discontinued; if ALT is more than three times the normal value (> 120U / L), the drug should be discontinued and cholestyramine or activated carbon treatment should be given. After stopping the drug, ALT returned to normal, and the drug can be continued. At the same time, liver protection treatment and follow-up should be strengthened. Most patients will not have ALT elevation again.
5. During the taking of white blood cells, if the white blood cells are more than 3 × 10 ⁹ / L, continue to take observations; if the white blood cells are between 2 × 109 / L 3 × 10 ⁹ / L, halve the observation. During the continuous treatment, most patients can recover. Normally, if the re-examination of white blood cells is still lower than 3 × 109 / L, the treatment is discontinued; if the white blood cells are less than 2 × 10 ⁹ / L, the treatment is discontinued.
6. If the patient has a history of abnormal blood or patients with renal and liver dysfunction, use this product with caution and perform blood and clinical tests frequently.
7. If the dose is too large or toxic. Elimination can be given by cholestyramine or activated carbon. Specific method: Cholestyramine is taken orally 3 times a day, 8 grams each time, for 11 consecutive days, M1 plasma concentration is reduced by about 40% on one day, 49% to 65% on two days, and about 0.02ug / mL on 11 days . Alternatively, activated charcoal (suspension) was administered via a gastric tube or orally, and 50 g every 6 hours, the M1 plasma concentration decreased by about 37% on one day and about 48% on two days.

Leflunomide tablets for pregnant and lactating women

Leflunomide is reproductive and can cause embryo damage. When mice took 15 mg / kg leflunomide, the rate of sperm deformity in male rats increased significantly, the rate of female embryos absorbed and dead embryos increased, and the rate of live embryos decreased. Therefore, pregnant and lactating women are prohibited. Women of gestational age who may be pregnant are contraindicated.

Leflunomide tablets for children

The efficacy and safety of this product have not been studied in children, so patients younger than 18 years are advised not to use this product.

Leflunomide tablets for the elderly

Use with caution.

Leflunomide tablets drug interactions

1. Cholestyramine and activated charcoal Volunteers and patients taking cholestatic or activated charcoal significantly reduced blood M1 levels.
2. When the liver toxicity drug Leflunomide is combined with the liver toxicity drug, the adverse reactions are enhanced. After treatment with leflunomide, taking hepatotoxic drugs without drug elimination can also lead to increased adverse reactions. Among the 30 patients who used leflunomide and methotrexate, 5 patients had a 2- to 3-fold increase in transaminase, of which 2 continued to take the drug, and 3 patients discontinued leflunomide; the other 5 patients had a transaminase elevation greater than 3 Of the patients, 2 patients continued to take the drug in combination, and 3 patients discontinued leflunomide. The transaminase returned to normal in 10 patients at the end of the study. All patients met ACR liver biopsy criteria.
3. Non-steroidal antipyretic and analgesics in vitro tests showed that M1 can increase the concentration of free diclofenac and ibuprofen by 13-50%. However, in clinical trials, when nonsteroidal antipyretic and analgesics were combined with leflunomide, no adverse reaction enhancement occurred.
4. The in vitro test of tolbutamide has shown that M1 can increase the concentration of free tolbutamide by 13-50%, and its clinical significance is not clear.
5. Rifampicin Multiple doses of rifampicin combined with single-dose leflunomide, the free M1 in the blood is 40% higher than that of leflunomide alone. With the use of rifampicin, the concentration of M1 may continue to increase, so Use caution with leflunomide and rifampicin in combination.

Leflunomide tablets overdose

In mice and rats acute toxicity tests, the minimum toxic doses of oral leflunomide were 200-500 mg / kg and 100 mg / kg. If clinical overdose or toxic reaction occurs, it is recommended to use cholestyramine and activated carbon to accelerate drug clearance.

Leflunomide tablets pharmacology and toxicology

Pharmacological effect Leflunomide is an isoxazole immunosuppressant with anti-proliferative activity. Its mechanism of action is mainly to inhibit the activity of dihydroorotate dehydrogenase, thereby affecting the pyrimidine synthesis of activated lymphocytes. In vitro and in vivo tests have shown that this product has anti-inflammatory effects. Leflunomide's in vivo activity is mainly produced by its active metabolite A771726 (hereinafter referred to as M1).
Toxicological studies for genotoxicity:
Leflunomide Ames test, off-program DNA synthesis test, HGPRT (hypoxanthine guanine phosphoribosyl transferase) gene mutation test results were all negative. In addition, leflunomide did not cause chromosomal aberration in the mouse micronucleus test and the Chinese hamster (in vivo) bone marrow cell test, while Leflunomide's secondary metabolite 4-trifluoromethylaniline (TFMA ) This effect appeared in Ames test, HGPRT gene mutation test and Chinese hamster cell (in vitro) chromosome aberration test, but TFMA did not appear in mouse micronucleus test and Chinese hamster (in vivo) bone marrow cytogenetics test. effect.
Reproductive toxicity:
Leflunomide was administered orally at a dose of up to 4.0 mg / kg, and had no effect on fertility in male and female rats.
Clinically, pregnant women can cause fetal damage when taking leflunomide. Oral administration of 15 mg / kg leflunomide during pregnancy during the formation of pregnant rats (based on AUC, the systemic exposure of rat M1 is about 1/10 of the human exposure), which has teratogenic effects, mainly manifested as no eyes or micro Eye, obstructive hydrocephalus. At this exposure, leflunomide also caused weight loss in pregnant rats, increased death in fetal rats, and weight loss. Pregnant rabbits were given leflunomide 10 mg / kg during organogenesis (calculated by AUC, the systemic exposure of rat M1 was approximately equal to the maximum human exposure), resulting in sternum fusion and dysplasia. Rats and rabbits did not show teratogenic effects at a dose of 1 mg / kg of leflunomide. Female rats were given leflunomide 1.25 mg / kg from 14 days before mating to the end of lactation (calculated by AUC, the exposure of rat M1 is approximately equal to 1/100 of the maximum human exposure), and the survival rate of the pups was obvious. (Greater than 90%).
Carcinogenicity:
The carcinogenic effect was not observed in a test in which the maximum tolerated dose of leflunomide was 6 mg / kg (approximately 1/40 of the maximum systemic exposure of human M1 based on AUC calculations) in rats for 2 consecutive years.
However, in a study in which oral administration of a maximum dose of 15 mg / kg (about 1.7 times the systemic exposure of human M1 in terms of AUC) for 2 consecutive years, the incidence of lymphoma in male mice increased, compared with 1.5 in female mice. At a dose of mg / kg (the initial dose, calculated as AUC, approximately 1/10 of the total human M1 exposure), there was an increase in the incidence of dose-related bronchoalveolar adenomas and bronchoalveolar carcinomas. The clinical significance of the results of the above mouse studies is unknown.

Leflunomide tablets pharmacokinetics

The following information is reported in the literature:
Animal experiments show that after a single oral leflunomide in rats and Beagle dogs, the blood concentration-time curves of their active metabolites A771726 (M1) are measured in accordance with the two-compartment model: t1 / 2 is 12.Ooh-14.70h ; Tmax is 1.93h-5.3h. After oral administration of leflunomide, the mice quickly absorbed and converted into the active metabolite A771726 (M1), which was distributed in all tissues of the body, with the highest blood content, and the rest were liver, stomach, intestine, kidney, lung, heart, Spleen, testes, muscles and brain. Leflunomide is converted into metabolite A771726 (M1) in rats, which is mainly excreted by feces, and a small amount is excreted by urine and bile.
According to reports in the literature: Leflunomide is quickly absorbed into the body and becomes the active metabolite A771726 (M1) to exert its pharmacological effects. Occasionally, low levels of leflunomide can be detected in plasma. Kinetic studies are performed by detecting changes in M1 concentration.
Absorption: After oral leflunomide, M1 peaks between 6-12 hours. M1 has a long half-life. If the initial dose in clinical practice is 100 mg for 3 consecutive days, it will help M1 to reach steady state concentration quickly, otherwise M1 will take 2 months to reach steady state. Different Leflunomide initial / maintenance dose tests showed that M1 levels in plasma were dose-dependent. Leflunomide tablets have a bioavailability of 80% and a high-fat diet has no significant effect on M1 plasma concentrations.
Distribution: M1 is mainly distributed in liver, kidney and skin tissues, but less in brain tissues. The volume of M1 distribution in healthy volunteers was low (0.13 liters / mg), and more than 99.3% of M1 bound to albumin, and the protein binding amount was linearly correlated with the therapeutic concentration. The amount of free M1 in patients with rheumatoid arthritis increases, and the amount of free M1 in patients with chronic renal failure nearly doubles. The mechanism is not clear.
Metabolism: Leflunomide quickly metabolizes into M1 after entering the blood, and the prototype drug is difficult to detect. In addition, leflunomide has many secondary metabolites, but only trifluoromethylaniline (TFMA) is present at low levels in some patients' blood and can be quantified. The exact organs of leflunomide metabolism are unknown, and in vitro and in vivo tests have suggested that the gastrointestinal wall and liver may play a role in this process. Leflunomide-specific metabolic enzymes have not been discovered, only metabolic processes have been determined to occur in the liver cytoplasm and microsomes.
Elimination: The active metabolite M1 is excreted by the kidneys after further metabolism, and M1 can also be excreted directly through the bile. After a single dose of radiolabeled leflunomide was injected for 28 consecutive days, nearly 43% of the total radioactivity was cleared through urine, and 48% of the total radioactivity was cleared through feces. Further analysis showed that glucuronide and aniline carboxylic acid derivatives of M1 were mainly in urine, and M1 was mainly in stool; the kidney was the main clearance route within the first 96 hours, and then stool became the main clearance route. With intravenous injection of M1, the clearance rate is estimated at 31 ml / hour. Oral activated carbon or cholestyramine can promote drug elimination and reduce the M1 half-life from more than one week to less than one day, which indicates that enterohepatic circulation is the main factor for the longer half-life of M1. Hemodialysis and continuous active peritoneal dialysis tests have shown that M1 cannot be dialyzed.

Leflunomide tablets storage

Shaded, sealed and stored in a cool place.

Leflunomide tablets packaging

Packing material: Double aluminum Packaging specifications: 10 pieces / box, 20 pieces / box, 30 pieces / box.

Leflunomide tablets expiration date

Tentative 24 months.

Leflunomide tablets

"Chinese Pharmacopoeia" 2010 edition two ^[1]