LEFLUNOMIDE

What it is

Leflunomide is a tablet containing 10 mg or 20 mg of leflunomide as the active ingredient. The 10 mg tablets are white and round, while the 20 mg tablets are yellow and round with a scoreline on one side. Leflunomide is an isoxazole immunomodulatory agent that is rapidly metabolised in the body to its active form, A771726, which has immunomodulating and immunosuppressive characteristics, acts as an anti-proliferative agent and displays weak anti-inflammatory properties.

Approved indications

— Active Rheumatoid Arthritis — Active Psoriatic Arthritis

Dosing overview

Leflunomide therapy for rheumatoid arthritis and psoriatic arthritis is started with a loading dose of 100 mg once daily for three days. The recommended maintenance dose for both rheumatoid arthritis and psoriatic arthritis is 20 mg once daily. If dosing at 20 mg per day is not well tolerated, the dose may be decreased to 10 mg daily. An improvement in the patient's rheumatoid condition may begin as early as four weeks after starting therapy, however, there may be further improvement after four to six months of treatment.

Key safety warnings

Pancytopenia is a rare event reported with leflunomide, with a fatal outcome in isolated cases, occurring most frequently in cases of recent, concomitant or subsequent use of potentially myelotoxic agents such as methotrexate. A complete blood cell count must be performed in all patients before starting leflunomide and monthly for the first six months, followed by six to eight weeks thereafter; if used with concomitant methotrexate or other potential immunosuppressives, chronic monitoring should be monthly. Leflunomide treatment was associated with elevations of liver function tests, primarily ALT and AST, which were generally reversible. Most transaminase elevations were mild and usually resolved while continuing treatment, whilst clinically significant elevations were less common and generally reversible with dose reduction or discontinuation. Very rare cases of severe liver injury, with fatal outcome in isolated cases, have been reported during treatment with leflunomide, with most cases occurring within the first six months of treatment. ALT and AST must be checked before starting leflunomide and monitored at monthly or more frequent intervals for at least the first six months, then every six to eight weeks thereafter; if leflunomide and methotrexate are given concomitantly, ALT, AST and serum albumin testing must be performed monthly. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and symptoms have been reported in patients treated with leflunomide; if a patient develops any of these skin conditions, therapy should be stopped and washout procedures initiated immediately.

Contraindications

Leflunomide is contraindicated in patients with hypersensitivity to leflunomide, teriflunomide or to any of the excipients in the tablets; patients with severe immunodeficiency states such as AIDS; patients with significantly impaired bone marrow function or significant anaemia, leukopenia or thrombocytopenia due to causes other than rheumatoid arthritis or psoriatic arthritis; and patients with severe, uncontrolled infections. It is also contraindicated in patients with impairment of liver function; pregnant women; women of childbearing potential who are not using reliable contraception during treatment and for a certain period of time thereafter as long as the plasma levels of the active metabolite are above 0.02 mg/L; women who are breast-feeding; patients with severe hypoproteinaemia; and patients who have or have had Stevens-Johnson syndrome, toxic epidermal necrolysis or erythema multiforme.

Regulatory history

Leflunomide products were first listed on the Australian Register of Therapeutic Goods on 2 April 2014, with multiple formulations registered under different brand variants including LEFLUNOMIDE SZ, LEFLUNOMIDE SANDOZ, LEFLUNOMIDE CH and LEFLUNOMIDE GENERICHEALTH, in strengths of 10 mg, 20 mg and 100 mg.