Leflunomide Canon (Tablets) Instructions for Use

ATC Code

L04AK01 (Leflunomide)

Active Substance

Leflunomide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Basic antirheumatic drug

Pharmacotherapeutic Group

Immunosuppressants; dihydroorotate dehydrogenase inhibitors

Pharmacological Action

An agent with antiproliferative, immunomodulatory (immunosuppressive) and anti-inflammatory action. The active metabolite of leflunomide, A771726, inhibits the enzyme dihydroorotate dehydrogenase and exerts an antiproliferative effect. A771726 in vitro inhibits mitogen-induced proliferation and DNA synthesis of T-lymphocytes.

The therapeutic effect of leflunomide has been demonstrated in several experimental models of autoimmune diseases, including rheumatoid arthritis.

Pharmacokinetics

After oral administration, absorption is 82-95%. Food intake does not affect the absorption of leflunomide.

Leflunomide is rapidly metabolized in the intestinal wall and liver to one main (A771726) metabolite and several minor metabolites, including 4-trifluoromethylalanine. The C_max of the A771726 metabolite is determined within 1-24 hours after a single dose. In plasma, A771726 rapidly binds to albumin. The unbound fraction of A771726 is 0.62%.

The biotransformation of leflunomide into A771726 and the subsequent metabolism of A771726 itself are controlled by several enzymes and occur in microsomal and other cellular fractions.

Trace amounts of leflunomide are detected in plasma, urine, and feces. The elimination of A771726 is slow and characterized by a clearance of 31 ml/h. T_1/2 is about 2 weeks.

In patients on hemodialysis, elimination occurs faster and T_1/2 decreases.

Indications

Basic therapy of rheumatoid arthritis to reduce the symptoms of the disease and delay the development of structural joint damage.

Active form of psoriatic arthritis.

ICD codes

Dosage Regimen

Initiate treatment with a loading dose of 100 mg once daily for 3 consecutive days to rapidly achieve therapeutic plasma concentrations.

Follow the loading dose with a maintenance dose of 10 mg to 20 mg once daily; the specific dose within this range is determined by the physician based on individual patient response and tolerability.

Administer tablets orally at any time of day, irrespective of meals, as food intake does not significantly alter absorption.

Do not exceed the maximum recommended daily maintenance dose of 20 mg.

Anticipate the onset of therapeutic effect typically after 4 to 6 weeks of continuous therapy; the full clinical response may continue to improve over a period of 4 to 6 months.

Omit the loading dose in patients at increased risk of hematological toxicity, hepatotoxicity, or when transitioning from another disease-modifying antirheumatic drug (DMARD); in such cases, initiate therapy directly with the maintenance dose.

Perform baseline and regular monitoring of ALT (SGPT) levels and complete blood count (CBC) before and during treatment to detect potential hepatotoxicity or myelosuppression; adjust dosage or discontinue therapy based on laboratory results and clinical status.

Consider dose reduction to 10 mg daily if the higher maintenance dose is not well tolerated.

Discontinue leflunomide and initiate an accelerated elimination procedure ( washout with cholestyramine or activated charcoal) in cases of significant toxicity, when switching to another DMARD, or prior to conception.

Adverse Reactions

From the cardiovascular system common – increased blood pressure.

From the digestive system common – diarrhea, nausea, vomiting, anorexia, lesions of the oral mucosa (aphthous stomatitis, lip ulceration), abdominal pain, increased levels of liver enzymes (especially ALT, less often – GGT, ALP, bilirubin); rare – hepatitis, jaundice, cholestasis; in some cases – liver failure, acute liver necrosis.

From the musculoskeletal system common – tenosynovitis; possible – ligament rupture.

Dermatological reactions common – hair loss, eczema, dry skin; possible – Stevens-Johnson syndrome, Lyell’s syndrome, erythema multiforme.

From the hematopoietic system common – leukopenia (leukocytes more than 2000/µl); possible – anemia, thrombocytopenia (platelets less than 100,000/µl); rare – eosinophilia, leukopenia (leukocytes less than 2000/µl), pancytopenia; in some cases – agranulocytosis. The risk of developing hematological disorders increases with recent, concomitant and subsequent use of myelotoxic drugs.

Allergic reactions common – rash (including maculopapular), itching; atypical – urticaria; in some cases – anaphylactic reactions.

From metabolic processes mild hyperlipidemia, hypophosphatemia, decreased uric acid level. Laboratory data (not clinically confirmed) indicate a slight increase in LDH, CPK.

Other in some cases – development of severe infections and sepsis; possible development of rhinitis, bronchitis and pneumonia. When using immunosuppressive drugs, the risk of developing malignant and some lymphoproliferative processes increases. The possibility of a reversible decrease in sperm concentration, total sperm count and their motility cannot be ruled out.

Contraindications

Impaired liver function, severe immunodeficiency conditions (including AIDS); severe bone marrow hematopoiesis disorders or anemia, leukopenia, thrombocytopenia due to other causes (except rheumatoid arthritis), severe infections, moderate or severe renal failure (due to limited clinical experience), severe hypoproteinemia (including in nephrotic syndrome), pregnancy, lactation, children and adolescents under 18 years of age, hypersensitivity to leflunomide.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Contraindicated in women of childbearing potential who are not using adequate contraception.

Men receiving leflunomide treatment should be warned about the possible fetotoxic effect and the need to use adequate contraception.

Use in Hepatic Impairment

Contraindicated in impaired liver function.

Use in Renal Impairment

Contraindicated in moderate or severe renal failure.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Special Precautions

Use is possible only after a thorough medical examination of the patient.

Before starting treatment, the possibility of an increase in the number of side effects in patients who have previously received other basic agents for the treatment of rheumatoid arthritis that have hepatotoxic and hematotoxic effects should be considered.

The active metabolite of leflunomide, A771726, is characterized by a long T_1/2. Therefore, side effects may occur even after discontinuation of leflunomide treatment. In case of such toxicity or when switching to another basic drug after leflunomide treatment, a “washout” procedure should be performed (after discontinuation of leflunomide, cholestyramine is prescribed at a dose of 8 g 3 times/day for 11 days or 50 g of activated charcoal, crushed into powder, 4 times/day for 11 days).

It should be taken into account that if severe dermatological adverse reactions or severe infections develop, leflunomide should be discontinued and the “washout” procedure should be started immediately.

Patients with tuberculin reactivity should be monitored due to the risk of tuberculosis activation.

Given the long T_1/2 of leflunomide, vaccination with live vaccines is not recommended during treatment.

Drug Interactions

An increase in adverse reactions may occur in case of recent or concomitant use of hepatotoxic or hematotoxic drugs or when these drugs are started after leflunomide treatment without a “washout” procedure.

In vitro studies have shown that the leflunomide metabolite A771726 inhibits the activity of the CYP2C9 isoenzyme. When used concomitantly with drugs metabolized by this enzyme system (phenytoin, warfarin, tolbutamide), the development of undesirable drug interaction effects cannot be excluded.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.