Lefomid^® (Tablets) Instructions for Use

Marketing Authorization Holder

Aristo Pharma, LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

Or

Sintez PJSC (Russia)

ATC Code

L04AK01 (Leflunomide)

Active Substance

Leflunomide (Rec.INN WHO registered)

Dosage Forms

	Lefomid®	Film-coated tablets, 10 mg: 30 or 100 pcs.
		Film-coated tablets, 20 mg: 30 or 100 pcs.
		Film-coated tablets, 100 mg: 3 or 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex; a cross-section shows one layer of white or almost white color.

Excipients: lactose monohydrate (milk sugar) – 38 mg, croscarmellose sodium (primellose) – 5 mg, povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700, plasdone-K 17) – 3.6 mg, talc – 3 mg, calcium stearate – 1 mg, corn starch – 39.4 mg.

Coating composition hypromellose (hydroxypropyl methylcellulose, methocel) – 1.9 mg, macrogol-4000 (polyethylene oxide 4000, polyethylene glycol 4000) – 0.8 mg, titanium dioxide – 0.3 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
20 pcs. – contour cell packaging (5) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex; a cross-section shows one layer of white or almost white color.

Excipients: lactose monohydrate (milk sugar) – 55 mg, croscarmellose sodium (primellose) – 7.5 mg, povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700, plasdone-K 17) – 5.4 mg, talc – 4.5 mg, calcium stearate – 1.5 mg, corn starch – 56.1 mg.

Coating composition hypromellose (hydroxypropyl methylcellulose, methocel) – 3.1 mg, macrogol-4000 (polyethylene oxide 4000, polyethylene glycol 4000) – 1.3 mg, titanium dioxide – 0.6 mg.

10 pcs. – contour cell packaging (3) – cardboard packs.
20 pcs. – contour cell packaging (5) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.

Film-coated tablets white or almost white, round, biconvex; a cross-section shows one layer of white or almost white color.

Excipients: lactose monohydrate (milk sugar) – 70 mg, croscarmellose sodium (primellose) – 13.5 mg, povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700, plasdone-K 17) – 14.5 mg, talc – 8.1 mg, calcium stearate – 2.7 mg, corn starch – 61.2 mg.

Coating composition hypromellose (hydroxypropyl methylcellulose, methocel) – 5 mg, macrogol-4000 (polyethylene oxide 4000, polyethylene glycol 4000) – 2 mg, titanium dioxide – 1 mg.

3 pcs. – contour cell packaging (1) – cardboard packs.
3 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Basic antirheumatic drug

Pharmacotherapeutic Group

Immunosuppressive agent

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. 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 disease symptoms 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.

Follow with a maintenance dose of 10 mg to 20 mg once daily.

Adjust the maintenance dose based on clinical response and tolerability.

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

Take tablets orally, with or without food.

Swallow tablets whole with water; do not crush or chew.

Anticipate a therapeutic effect after 4 to 6 weeks of continuous therapy.

Maximum clinical benefit may develop over 4 to 6 months of treatment.

Monitor liver enzymes (ALT) and complete blood count (CBC) before and during therapy.

Discontinue treatment and initiate a drug elimination procedure if severe toxicity occurs.

Use the 100 mg tablet exclusively for the initial 3-day loading regimen.

Use the 10 mg or 20 mg tablets for long-term maintenance therapy.

Adverse Reactions

From the cardiovascular system frequently – increased blood pressure.

From the digestive system frequently – 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); rarely – hepatitis, jaundice, cholestasis; in some cases – liver failure, acute liver necrosis.

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

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

From the hematopoietic system frequently – leukopenia (leukocytes more than 2000/µl); possible – anemia, thrombocytopenia (platelets less than 100,000/µl); rarely – 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 frequently – 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 excluded.

Contraindications

Liver dysfunction, severe immunodeficiency states (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 liver dysfunction.

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 increased number of side effects in patients who 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 the event of such cases of 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 considered 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 the 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.