Leflunomide dosing

Male mice had an increased incidence of lymphoma at an oral leflunomide dose of 15 mg/kg, and female mice had a dose-related increased incidence of bronchoalveolar adenomas and carcinomas beginning at 1.5 mg/kg (87). 

A 68-year-old woman who had been taking leflunomide 10 mg daily for about 4 months was started on itraconazole 300 mg daily for a fungal infection. About one month later her leflunomide dose was increased to 20 mg daily, and liver function tests were normal. The following month, she developed abdominal pain, vomiting, and weakness. Despite symptomatic treatment and washout with colestyramine, fatal fulminant hepatic failure occurred. The authors of the report attribute the reaction to additive hepatotoxicity between the leflunomide and itraconazole. This interaction serves to highlight the cautions about the use of other hepatotoxic drugs, see (a) and (h). 

Low-dose methotrexate is used for treatment of rheumatoid arthritis despite side effects such as disorders of the gastrointestinal tract and the liver. Leflunomide is also approved for this indication, however, hepatoxicity limits its use as first option. 

Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis rather than purine synthesis. It is orally active, and the active metabolite has a long half-life of several weeks. Thus, the drug should be started with a loading dose, but it can be taken once daily after reaching steady state. It is approved only for rheumatoid arthritis at present, though studies are under way combining... 

Pharmacokinetics Leflunomide is well absorbed after oral administration. It is extensively bound to albumin (>90 percent), and has a half-life of 14 to 18 days. [Note Because of its long half-life, loading doses are necessary (see p. 19).] Leflunomide is rapidly converted to the active metabolite. The metabolites are excreted in the urine and the feces. The active metabolite undergoes biliary recycling. 

In animals, leflunomide had excellent antiviral activity against cytomegalovirus (CMV). It is currently indicated as second-line therapy for CMV disease after solid organ transplantation and in recipients intolerant of ganciclovir (38). Leflunomide also reduces HIV replication by about 75% at concentrations that can be obtained with conventional dosing (39). 

In 3325 patients who took leflunomide, the rate of drug withdrawal was 42% within 33 months after approval by the US Food and Drugs Administration, and was more likely in patients who received a loading dose. The most common causes of discontinuation were inefficacy (30%), gastrointestinal symptoms (29%), non-adherence to therapy or loss to follow-up (14%), and raised liver enzymes (5%) (50). 

Leflunomide is taken orally. In most regimens it is begun with a loading dose of 100 mg/day over 3 days followed by a maintenance dosage of 10-20 mg/day. Leflunomide 100 mg/week had similar effectiveness and less toxicity in open trials compared with daily dosing (21,93). 

Multiple doses of rifampicin increase leflunomide concentrations (96). 

A 49-year-old man with resistant rheumatoid arthritis took leflunomide 100 mg/day for 3 days. His international normalized ratio (INR) had been stable for 1 year while he was taking warfarin, and 2 days before starting treatment with leflunomide it was 3.4. After he took the second dose of leflunomide, he developed gross hematuria. His INR had risen to 11, and warfarin was withdrawn. The hematuria resolved spontaneously several hours later, but his INR remained raised for the next 2 days, even though he had stopped taking warfarin. He was given intravenous vitamin K 1 mg on the third day, and 12 hours later the INR fell to 1.9. 

Kremer JM, Genovese MC, Cannon GW, Caldwell JR, Cush JJ, Furst DE, Luggen ME, Keystone E, Weisman MH, Bensen WM, Kaine JL, Ruderman EM, Coleman P, Curtis DL, Kopp EJ, Kantor SM, Waltuck J, Lindsley HB, Markenson JA, Strand V, Crawford B, Fernando I, Simpson K, Bathon JM. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002 137(9) 726-33. 

Leflunomide (Arava) is an anti-inflammatory medication used to treat the symptoms of RA. Leflunomide suppresses HA release from the synovial cells that line the joint capsule in a dose-dependent marmer [130]. Leflunomide specifically suppresses induction of HASl. HAS2 and HAS3, which are constitutively expressed in synovial cells, are not affected. Leflunomide is a specific NF-kB inhibitor, but does not affect HASl in this manner. Rather, leflunomide functions here by suppressing t5o-osine kinases. 

Studies of leflunomide in kidney and liver transplant recipients utilized a loading dose of 200 mg daily for 7 days, followed by a maintenance dose of 40 to 60 mg daily. The target concentration appears to be 50 to 80 mcg/mL, which also allows for lower doses of steroids and CIs. A small open-label pilot study reported potential benefit with leflunomide in reversing chronic renal allograft dysfunction. ... 

Leflunomide is administered orally as a single daily dose without regard to meals. Therapy may be initiated with a loading dosage given for 3 days, followed by the usual maintenance dose. It undergoes primarily enterohepatic circulation, extending its duration of action. Cholestyramine can be used to enhance its elimination in cases of toxicity. 

When a single dose of leflunomide was given to subjects after taking multiple dose rifampicin, the peak levels of the active metabolite of leflunomide (A771726) were increased by 40% but the AUC was unchanged. - The reasons are not understood. There would seem to be no reason for avoiding concurrent use, but the manufacturers advise caution as A771721... 

The factors associated with a poor prognosis in leflunomide-induced lung injury have been studied in 22 patients with rheumatoid arthritis, of whom 9 died and 13 recovered [39 ]. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs. 6/13). The loading and maintenance doses, the serum concentration of the leflunomide metabolite A771726, and the duration of treatment did not differ between the groups. The patients who died had more frequent hypoxemia and mechanical ventilation, had a high serum CRP concentration (190 vs. 100 mg/1), and had a low albumin concentration (27 versus 33 g/1). The lymphocyte count was persistently low in those who died, but recovered in those who survived. 

Systemic corticosteroids are required for cases of anterior uveits that are refractory to eyedrops and for cases of intermediate and posterior uveitis because eyedrops cannot adequately penetrate deep into the eye. The initial corticosteroid dose is 40 mg/day of prednisone equivalent, which is adjusted according to the response to therapy. Corticosteroid-sparing alternatives are often considered for sarcoid uveitis because of the toxicity of systemic corticosteroids. Methotrexate (21), azathioprine (22), leflunomide (23), and infliximab (24) have been used for this purpose. 

Elevated liver enzymes were also most frequently reported adverse events in a multicenter, double-blind randomised clinical trial which included adults with rheumatoid arthritis diagnosed within 6 months. Patients were randomised to receive either a 100 mg loading dose or a 20 mg fixed dose of leflunomide for 3 days followed by a 3-month open-label maintenance period of 20 mg leflxmomide daily. Hepatic enzyme elevation occurred in 9.3% of patients randomised to the lOOmg leflunomide loading dose group, whereas only in 1.5% in the 20 mg fixed dose group [73 ]. 

A retrospective study reports the efficacy and safety of leflunomide for treatment of BK virus-associated hemorrhagic cystitis in allogeneic haematopoietic stem cell transplantation recipients (n=14). Three days of oral lOOmg/day leflunomide as loading doses followed by maintenance doses of 20mg/day resulted in complete remission in seven patients, six patients achieved partial remission and two patients had a reduction in urinary BKV-DNA load after leflunomide treatment (>l-log BKV-DNA load reduction). One patient discontinued leflunomide therapy because of GI symptoms and 2 case developed neutropenia. Al ough the role... 

Cutolo M, Bolosiu H, Perdriset G. Efficacy and safety of leflunomide in DMARD-naive patients with early rheumatoid arthritis comparison of a loading and a fixed-dose regimen. Rheumatology (Oxford) June 2013 52(6) 1132-A0. 

---