Pharmacology Update

Leflunomide (Arava)

By William T. Elliott, MD and James Chan, PharmD, PhD

The FDA recently approved a new disease modifying agent for the treatment of rheumatoid arthritis (RA), the first new drug to be approved for this indication in more than a decade. Leflunomide (Arava-Hoechst Marion Roussel) was given a priority review by the FDA and was approved with the indication of retarding the structural damage of the disease, the first medication of it's kind to receive this indication.

Leflunomide seems to work by causing cell arrest of lymphocytes involved in the autoimmune process. The drug is a de novo uridine synthesis inhibitor. It acts by inhibiting dihydroorotate dehydrogenase and tyrosine kinases with the former action predominating.1,6 This action is postulated to arrest stimulated cells at the G1 phase, thereby not allowing the production of ribonuc leotides needed to proceed to the S phase.1 Leflunomide is metabolized to an active metabolite (A77 1726) which has a long elimination half-life of approximately 16 days.

The drug is marketed by Hoechst Marion Roussel and is manufactured in France by Usiphar.

Indications

For the treatment of active rheumatoid arthritis to reduce signs and symptoms and to retard structural damage as evidenced by X-ray erosions and joint space narrowing.2

Dosing Information

Leflunomide is supplied as 10 mg, 20 mg, and 100 mg tablets. Due to the long elimination half-life, a loading dose is needed to achieve steady-state concentration more quickly. A loading dose of one 100 mg tablet daily for three days is recommended. A daily dose of 20 mg is recommended as a maintenance dose. If there are problems with tolerance, the dose may be reduced to 10 mg2. NSAIDs and low-dose corticosteroids may be used concomitantly with leflunomide.2

Should leflunomide need to be discontinued for pregnancy or other reasons, the elimination half-life can be reduced from over 1 week to about 1 day by administering cholestyramine 8 g three times daily for 11 days.2

Potential Advantages

Leflunomide provides an alternative to disease-modifying antirheumatic drugs (DMARDs) such as methotrexate or sulfasalazine particularly when the latter agents are not tolerated. Leflunomide does not seem to be associated with (albeit rare) severe and occasionally life-threatening toxicities that are seen with methotrexate such as pulmonary toxicity and myelosuppression. In the European comparative trial two cases of agranulocytosis were reported with sulfasalazine (n = 132) and none in the leflunomide group.9 Coadministration of folate is not necessary.

Potential Disadvantages

Due to its potential teratogenic effect, leflunomide is contraindicated in women who are or may become pregnant. In addition, men wishing to father a child should consider discontinuing leflunomide.2 Elevation of liver enzymes (ALT and AST) occurs in 5-10% of patients in clinical trials. Elevations were generally mild (2 x ULN). ALT should be performed at baseline and monitored monthly for several months. If the levels are stable, further levels should be determined by the individual clinical situation.2 Leflunomide is not recommended in patients with hepatic insufficiency and should be used with caution in patients with renal insufficiency.

It is not recommended in patients with severe immunodefficiency, bone marrow dysplasia, or severe uncontrolled infections; use of live virus vaccines should be avoided during or for a period of time after stopping leflunomide.2

Common side effects include diarrhea (17-27%) and rash (10-12%).2 These side effects appear to be more common than with methotrexate.2

Rifampin increases the peak levels of leflunomide by about 40% and caution should be exercised during concomitant therapy.2 The FDA has requested that Hoechst conduct a drug-interaction study involving cytochrome P450 3A4 inhibitors such as erythromycin or ketoconazole.3

Comments

The approval of leflunomide was based on three controlled trials (2 European and 1 U S/Canada) involving 1839 patients and treatment durations of up to 52 weeks. Efficacy was assessed by improvement of signs and symptoms and by radiographic assessment of structural damage. Relief of signs and symptoms was determined by using American College of Rheumatology (ACR) 20 Responder Index. A responder is a patient who had 20% improvement in both tender and swollen joint counts and in three of the following five criteria: physician global assessment, patient global assessment, function/disability measure, visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. Progression of structural damage was assessed radiographically using the Sharp Score, a composite score of erosions and joint space narrowing in hands/wrists and forefeet.2

One trial compared leflunomide with placebo and methotrexate, another compared leflunomide with placebo and sulfasalzine, and the third compared methotrexate with leflunomide. Leflunomide was dosed at 20 mg daily following an initial loading dose of 100 mg/day for three days, methotrexate was dosed at 7.5 mg/week increasing to 15 mg/week, and sulfasalazine was dosed at 2 g/day. Results indicate that the efficiacy of leflunomide is similar to methotrexate and sulfasalazine and superior to placebo. One study, however, indicated that methotrexate showed a higher response rate than leflunomide (69% vs. 56%), although there was no significant difference in Sharp Scores.2 Treatment effect is generally evident by one month and stablized by 3-6 months.2 Additional details of one of the phase III trials, in abstract form, suggested that leflunomide-treated patients may achieve sustained response earlier and of longer duration, with greater improvement in quality of life scores compared to methotrexate.7,8

Clinical Implications

Rheumatoid arthritis affects about 1% of the general population. Initial pharmacotherapy of rheumatoid arthritis is generally nonsteroidal anti-inflammatory drugs (NSAIDs). Patients in whom disease remains active after adequate treatment with NSAIDs are candidates for DMARD therapy such as methotrexate, sulfasalazine, and hydroxchloroquine.4 Methotrexate is often selected as the initial DMARD as it is effective and generally well tolerated. Over 50% of patients taking methotrexate conti nue for three years or longer,4,5 however GI symptoms, stomatitis, alopecia, and rare, but potentially serious, myelosuppression or pulmonary toxicity have been reported. Leflunomide provides an alterative to methotrexate and other DMARDs. Pulmonary toxicity has not been reported with leflunomide, although GI symptoms such as diarrhea seem to be more frequent. The efficiacy of leflunomide in patients not responding to methotrexate or other DMARDs remains to be determined. Rheumatology consultation should be considered before initiating DMARD therapy.

Leflunomide is expensive, the average wholesale cost is $8 per day or about $3000 per year. This is more than twice the cost for methotrexate (15 mg/week, not including the cost of folate) and more than 10 times the cost for sulfasalazine (2 g/d).

References

1. Fox RI. J Rheumatol Suppl 1998;53:20-26.

2. Arava Product Information. Hoechst Marion Roussel, Inc. September 1998.

3. FDC Report, The Pink Sheet. September 14, 1998.

4. American College of Rheumatology. Arthritis Rheum 1996;713-722.

5. Kremer JM. Rheumatic Diseases Clinics of North America 1998;24:651-657.

6. Cherwinski HM, et al. J Pharmacol Exp Ther 1995;275:1043-1049.

7. Furst D, et al. Arthritis Rheum 1998;41:9(suppl) abstract 734.

8. Tugwell P, et al. Arthritis Rheum 1998;41:9(suppl) abstract 732.

9. Smolen JS, et al. Arthritis Rheum 1998;41:9(suppl) abstract 594.