Published: April 2004
ADR update


Leflunomide: Serious Multi-System Adverse Effects

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Prescriber Update 25(1): 2–3
April 2004

Medsafe Editorial Team

Leflunomide is an effective disease-modifying agent for rheumatoid arthritis.  Its use has been associated with significant and serious adverse reactions involving haematological, hepatic, immune, dermatological and respiratory systems.  The long half-life of leflunomide may delay resolution of some of these reactions.  However, regular monitoring and patient education of early warning signs can reduce morbidity.

Leflunomide indicated for rheumatoid arthritis

Disease-modifying anti-rheumatic drugs (DMARDs) are being increasingly used early in the course of active rheumatoid disease.1  Leflunomide (Arava®) is a relatively new immunomodulatory DMARD indicated for the treatment of rheumatoid arthritis (RA).  It is a pro-drug activated by metabolism in the gut wall and liver, and excreted by the renal and biliary systems.2  The active metabolite has a long half-life (1-4 weeks2), which may contribute to adverse effects that persist, worsen or even appear after leflunomide has been stopped.3,4

International adverse reaction reports include serious events

Global exposure to leflunomide is estimated to be 662,302 patient-years, to date.5  While leflunomide has demonstrated efficacy in some groups of patients with active RA, international post-marketing experience includes reports of serious adverse reactions in patients treated with leflunomide.  Although confounding factors such as concomitant use of known hepatotoxic or haematotoxic medicines (e.g. methotrexate) are present in many of the reported cases, a causal relationship with leflunomide cannot be excluded.3,4,6-8  International adverse reaction reports associated with leflunomide include the following:

  • Hepatic adverse reactions including 15 cases of liver failure (nine with fatal outcome).
  • Haematological adverse reactions ranging from neutropenia, thrombocytopenia and thrombocytosis, through to severe pancytopenia.
  • Dermatological adverse reactions including Stevens-Johnson syndrome, bullous eruptions and skin necrosis.
  • Respiratory adverse reactions such as interstitial pneumonitis and pulmonary infiltration.
  • Immune response impairments including reports of severe infections such as sepsis.

New Zealand experience with leflunomide is comparable

It is thought that between 500 and 1500 patients in New Zealand have been prescribed leflunomide, up to the end of 2003.5  The adverse reactions reported in New Zealand for this medicine are similar to those seen internationally.  Examples of the more serious local cases include:

  • Elevated hepatic enzymes, along with neutropenia, thrombocytopenia and diarrhoea.
  • Sepsis leading to multi-organ failure and death; concomitant medicines were methotrexate, ketoprofen and triamcinolone.
  • Hypersensitivity pneumonitis, resulting in life-threatening respiratory compromise.  The patient was taking leflunomide and methotrexate but did not relapse when methotrexate was re-introduced.
  • Multiple bullous eruptions occurring within three weeks of starting leflunomide, and resolving upon discontinuation.

Awareness and monitoring reduces the impact of adverse effects

Post-marketing experience with leflunomide estimates the frequency of severe hepatic, dermatological, respiratory, haematological and infection reactions as being less than 1 in 10,000 (i.e. very rare).  However, some blood dyscrasias have been reported to occur at a frequency of between 1 in 1000 and 1 in 10,000 (i.e. rare).2  Despite the serious adverse reaction profile of leflunomide, it is an effective DMARD.  As with all medicines use of leflunomide requires an assessment of its risk and benefits on an individual patient basis.  Prescribers should be aware that the concomitant use of other immunomodulating agents may have an additive effect, not only on improving symptoms of acute RA but also on the frequency and severity of adverse reactions.

To minimise the risk of serious blood and liver adverse reactions, all patients taking leflunomide should have their haematological and liver function monitored.  Once a pre-treatment baseline is established, monitor monthly for the first six months, then every 6-8 weeks thereafter.  Ongoing monthly monitoring is recommended if methotrexate is used concurrently.2 Prescribers are advised to refer to the recently updated Arava data sheet2 for comprehensive monitoring recommendations.

Patients should be informed of early warning signs of possible adverse reactions and asked to contact their general practitioner as soon as possible if they experience any of the following: easy bruising, tiredness, pallor, skin lesions or rashes, shortness of breath, or increased frequency/susceptibility to infection.  If serious reactions occur, the long half-life of leflunomide's active metabolite may necessitate wash-out with an agent such as cholestyramine.2

Leflunomide has recently been added to the list of Adverse Reactions of Current Concern..  This means that prescribers are requested to report all leflunomide-associated adverse reactions to the Centre for Adverse Reactions Monitoring (CARM) in Dunedin.

Competing interests (authors): none declared.

  1. Lee A, Pile K. Disease modifying drugs in adult rheumatoid arthritis. Aust Prescr 2003;26:36-40.
  2. Aventis Pharmaceuticals. Arava tablets data sheet. 21 September 2003.
  3. Loorand-Stiver L, Murty M. Leflunomide (Arava): hematologic, hepatic and respiratory reactions. Can ADR Newsletter 2002;12:2-3.
  4. Australian Adverse Drug Reactions Advisory Committee (ADRAC). Leflunomide - serious hepatic, blood, skin and respiratory reactions. Aust Adverse Drug React Bull 2001;20(2):7.
  5. Based on data supplied by Aventis Pharma Pty Limited (sponsor of Arava®), Australia in April 2004.
  6. Aventis Pharmaceuticals. USA Dear Healthcare Professional letter October 2003.
  7. European Agency for the Evaluation of Medicinal Products. EMEA Public Statement on Leflunomide (Arava) - pancytopenia and skin reactions. London (UK): 25 October 1999.
  8. European Agency for the Evaluation of Medicinal Products. EMEA Public Statement on Leflunomide (Arava) - severe and serious hepatic reactions. London (UK): 12 March 2001.


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