Published: May 2008

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Leflunomide - Update on Serious Toxicity

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Prescriber Update 29(1): 13-14
May 2008

Ruth Savage, Senior Medical Assessor, New Zealand Pharmacovigilance Centre, Dunedin

Leflunomide is an effective disease modifying anti-rheumatic drug (DMARD).  However, it can cause serious hepatic, haematologic, respiratory, and dermatologic adverse effects.  Leflunomide is a potent immunosuppressant, reducing resistance to infection which, when it occurs, can be severe and disseminated.  Tuberculosis reactivation has also been reported.  There is evidence that leflunomide causes peripheral neuropathy, and presenting symptoms may mimic rheumatoid vasculitis.  There is emerging evidence of a greater likelihood of pancytopenia, pneumonitis, and hepatotoxicity occurring when leflunomide is prescribed with methotrexate; these reactions have also been reported in patients taking leflunomide alone.

Serious infection and tuberculosis reactivation

Reports to CARM and published case reports include opportunistic infection, pneumonia, sepsis, other serious infections, and tuberculosis reactivation attributed to leflunomide.^1,2  In many of the CARM reports, patients were also taking other DMARDs, corticosteroids, or TNF alpha inhibitors³ which, as well as severe rheumatoid arthritis itself, can also reduce resistance to infection.^1,2   It is important that infection is diagnosed and treated promptly in patients taking leflunomide as it is a potent immunosuppressant; and infection can become severe and difficult to control.^1,2

Peripheral neuropathy presents with sensory changes

In a published case series from Australia, leflunomide was the sole suspect medicine in the 24 reports of peripheral neuropathy.⁴  Onset was described as insidious, usually with sensory changes - a clinical picture that could be confused with rheumatoid vasculitis.  Six patients improved on dechallenge, three after washout with cholestyramine.  Several had not improved at the time of reporting.  It is important to be aware that peripheral sensory changes may represent a potentially reversible reaction to leflunomide.

Pancytopenia, pneumonitis and hepatotoxicity with combination therapy

Using a combination of methotrexate and leflunomide has proved to be effective in some patients with rheumatoid arthritis.⁵  Methotrexate, like leflunomide, is known to be hepatotoxic; and is a recognised cause of pancytopenia and pneumonitis.  The combination appears to increase the likelihood of these toxicities occurring.

In a study of 30 patients taking methotrexate and leflunomide in combination, five patients (17%) developed an increase in hepatic transaminases to more than 3 times the upper limit of normal - an incidence greater than that usually observed with either medicine alone.^1,2

Co-prescription of methotrexate has been noted in 9 of the 11 (82%) Australian reports⁶ and in both of the New Zealand reports of pancytopenia attributed to leflunomide.  In contrast, there was co-prescription of methotrexate in only 32% of all adverse reaction reports for leflunomide in the Australian database, and 38% in the CARM database.  Estimates of the incidence of pancytopenia were approximately 1 in 4000 for leflunomide monotherapy, and 1 in 700 for leflunomide with methotrexate.⁶

A similar pattern was seen in the New Zealand and Australian databases in 12 reports of leflunomide-associated pneumonitis, a form of interstitial lung disease that can be rapidly progressive and fatal.  Nine of these 12 patients (75%) were also taking methotrexate.⁷

Caution is advised whenever leflunomide is prescribed with other medicines known to be haemo- or hepatotoxic.^1,2

Further information

Details of the reactions described, as well as other serious leflunomide adverse reactions, monitoring advice, and cholestyramine washout procedures can be found in previous Prescriber Update issues^,8-9 and in the product data sheets for leflunomide.^1,2

Competing interests (author): none declared.

References

1. Sanofi-aventis New Zealand Limited. Arava (leflunomide) data sheet. 3 July 2007. www.medsafe.govt.nz/profs/datasheet/a/aravatab.htm
2. Savage R. Tumour necrosis factor inhibitors: recognise and treat infection promptly. Prescriber Update 2008;29(1):5-6.
3. Australian Adverse Drug Reactions Advisory Committee (ADRAC). Leflunomide and peripheral neuropathy. Aust Adverse Drug React Bull 2006;25(5):18-19. www.tga.gov.au/adr/aadrb/aadr0610.htm
4. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable dose of methotrexate: a randomized double-blind, placebo-controlled trial. Ann Intern Med 2002;137:726-733.
5. McEwen J, Purcell PM, Hill RL, et al. The incidence of pancytopenia in patients taking leflunomide alone or with methotrexate. Pharmacoepidemiology and Drug Safety 2007;16:65-73.
6. Savage RL, Highton J, Boyd IW, et al. Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports. Internal Medicine Journal 2006;36(3):162-165.
7. Medsafe Editorial Team. Leflunomide: serious multi-system adverse effects. Prescriber Update 2004;25(1):2-3.
8. Savage R. Leflunomide and pneumonitis. Prescriber Update 2006;27(1):7-8.