What is the use of Leflunomide?

From the Guidelines

Leflunomide should be considered as an alternative to methotrexate in patients with contraindications or early intolerance, with a recommended dose of 20 mg/day without a loading dose. Leflunomide is an immunosuppressive disease-modifying antirheumatic drug (DMARD) primarily used to treat rheumatoid arthritis, psoriatic arthritis, and occasionally other autoimmune conditions. The standard dosing regimen typically begins with a loading dose of 100 mg daily for 3 days, followed by a maintenance dose of 10-20 mg once daily. The 20 mg dose is more effective but may have more side effects, while the 10 mg dose is often better tolerated. Leflunomide works by inhibiting pyrimidine synthesis through blocking the enzyme dihydroorotate dehydrogenase, which reduces proliferation of activated lymphocytes involved in autoimmune inflammation. Common side effects include diarrhea, hair loss, elevated liver enzymes, and increased risk of infections. Regular monitoring of liver function tests, complete blood counts, and blood pressure is necessary during treatment. Leflunomide has a very long half-life (approximately 2 weeks), so if rapid elimination is needed (such as for serious side effects or planned pregnancy), cholestyramine washout (8g three times daily for 11 days) is recommended. The medication is contraindicated in pregnancy (category X) and requires effective contraception during and for up to 2 years after discontinuation unless a drug elimination procedure is performed. According to the most recent guidelines, leflunomide is considered a suitable alternative to methotrexate in patients with contraindications or early intolerance, as stated in the 2020 EULAR recommendations 1.

Some key points to consider when using leflunomide include:

• The medication should be used with caution in patients with liver or kidney disease, as it may exacerbate these conditions.
• Leflunomide has a similar clinical efficacy to methotrexate in established and recent rheumatoid arthritis, as shown in previous studies 1.
• The combination of leflunomide with other DMARDs or biologic agents may be considered in patients who do not respond to monotherapy, as suggested in the 2014 EULAR recommendations 1.
• Regular monitoring of patients on leflunomide is necessary to minimize the risk of adverse effects and optimize treatment outcomes.

Overall, leflunomide is a valuable treatment option for patients with rheumatoid arthritis and other autoimmune conditions, and its use should be guided by the most recent clinical guidelines and evidence-based recommendations 1.

From the FDA Drug Label

Leflunomide is indicated in adults for the treatment of active rheumatoid arthritis (RA): to reduce signs and symptoms to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing to improve physical function The combined use of leflunomide with antimalarials, intramuscular or oral gold, D penicillamine, azathioprine, or methotrexate has not been adequately studied Guidelines for dose adjustment or discontinuation based on the severity and persistence of ALT elevation are recommended as follows: For confirmed ALT elevations between 2- and 3-fold ULN, dose reduction to 10 mg/day may allow continued administration of leflunomide under close monitoring Pre-existing Hepatic Disease Given the possible risk of increased hepatotoxicity, and the role of the liver in drug activation, elimination and recycling, the use of leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses. The main uses of Leflunomide are:

• To reduce signs and symptoms of active rheumatoid arthritis (RA)
• To inhibit structural damage as evidenced by X-ray erosions and joint space narrowing
• To improve physical function Key warnings include:
• The combined use of leflunomide with certain other medications has not been adequately studied
• Leflunomide may cause liver enzyme elevations, and dose adjustment or discontinuation may be necessary
• Leflunomide is not recommended in patients with significant hepatic impairment or evidence of infection with hepatitis B or C viruses 2 2

From the Research

Leflunomide Overview

• Leflunomide is a disease-modifying antirheumatic drug (DMARD) used to treat active rheumatoid arthritis (RA) 3, 4, 5, 6, 7.
• It works by inhibiting the enzyme dihydroorotate dehydrogenase, which is involved in the production of uridine monophosphate, thereby arresting the growth of activated lymphocytes 3.

Efficacy of Leflunomide

• Leflunomide has been shown to be effective in improving the signs and symptoms of RA, with significant improvements in tender and swollen joint counts, physician and patient global assessments, and pain intensity index 3, 4, 6, 7.
• It has also been shown to delay the progression of disease, with significant reductions in radiological progression of disease compared to placebo 3, 4.
• Leflunomide has been compared to other DMARDs, such as methotrexate and sulfasalazine, and has been shown to be equally effective in terms of symptom outcomes 3, 4, 7.

Safety and Tolerability of Leflunomide

• The most common adverse events associated with leflunomide include diarrhea, respiratory infections, nausea, headache, rash, and elevated liver enzymes 4, 5, 6, 7.
• Leflunomide has been shown to be well-tolerated, with a similar safety profile to other DMARDs such as methotrexate and sulfasalazine 4, 7.
• Monitoring of liver enzymes is recommended in patients receiving leflunomide, and the drug is not recommended in female patients who are or may become pregnant 3, 4.

Dosage and Administration of Leflunomide

• Leflunomide is typically administered at a dose of 20 mg per day, with a loading dose of 100 mg per day for 3 days 3, 4, 6, 7.
• The active metabolite of leflunomide, A77 1726, has a long half-life of approximately 2 weeks, allowing for once-daily dosing 4.