INFORMATION FOR HEALTH PROFESSIONALS
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Web site: March 2006
Prescriber Update 2006;27(1):7-8.
Ruth Savage, Medical Assessor, CARM,
New Zealand Pharmacovigilance Centre, Dunedin
There is increasing evidence that leflunomide alone or in conjunction with methotrexate can cause pneumonitis, an acute respiratory illness characterised by dyspnoea, hypoxia and lung infiltrates. Prompt recognition is important as pneumonitis may be fatal or cause persisting disability. Early symptoms usually include dyspnoea but may be non-specific. Evaluation of baseline pulmonary status prior to treatment should be considered. Inform all patients of initial warning symptoms so that these can be investigated immediately and the suspect medicines discontinued.
Pneumonitis with leflunomide can have serious
consequences
Seven NZ reports of pneumonitis with leflunomide
Pre-existing pulmonary disease and use of other DMARDs may
increase the risk
Inform all patients of early warning symptoms and consider
baseline assessment
References
Pneumonitis with leflunomide can have serious
consequences
Leflunomide (Arava®) is a
disease-modifying anti-rheumatic agent (DMARD) with anti-inflammatory and
immunomodulating properties. It is indicated for the treatment of
rheumatoid arthritis.1 Clinical trials and
post-marketing surveillance indicate that leflunomide can cause pneumonitis
either as monotherapy or in conjunction with methotrexate, which is also known
to cause this disorder.1,2
Pneumonitis due to drug toxicity is an acute respiratory illness characterised by dyspnoea, hypoxia, and lung infiltrates. It is distinguishable from similar illnesses caused by infective organisms (e.g. Pneumocystis carinii) by an absence of organisms in blood, initial (induced) sputum cultures or bronchial wash/brush microscopy or cultures. Pneumonitis can be life-threatening, fatal or cause persisting respiratory compromise.3
Seven NZ reports of pneumonitis with leflunomide
The Centre for Adverse Reactions Monitoring (CARM) has received seven
reports of pneumonitis occurring in patients taking leflunomide. All seven
were taking methotrexate concurrently. There were four female and three
male patients, aged 43 to 83 years. Initial symptoms were various combinations
of dyspnoea, cough, fever, lethargy, weight loss and influenza-like symptoms
followed by rapid progression to acute respiratory compromise. All
patients had chest x-ray or computerised tomography (CT) evidence of lung
infiltrates. Two patients required ventilatory support in intensive care.
Management consisted of discontinuation of leflunomide and methotrexate,
treatment with oxygen or ventilatory support, and high-dose corticosteroids.
Because leflunomide has a long half-life of one to four weeks,1
cholestyramine was used to remove leflunomide in three patients with good
effect. Five patients recovered, one died, and the other improved but had
some persisting respiratory impairment.
Methotrexate itself can cause pneumonitis, usually within the first year of use.3 In the seven patients reported to CARM, the duration of leflunomide use prior to the onset of symptoms was 12 to 36 weeks. The duration of methotrexate use was usually longer and in four patients was greater than one year, thus supporting a causal role for leflunomide in the development of pneumonitis. These observations, together with similar reports from Australia, have been published.2
Pre-existing pulmonary disease and use of other DMARDs
may increase the risk
By 2004, it was estimated that 400,000 people had received leflunomide
worldwide, and the reported incidence of pneumonitis was 1 in 5000.4
However, in a post-marketing surveillance programme in Japan, 29 of the 3658
patients developed pneumonitis and 11 patients died.5
While not all cases may have been attributable to leflunomide, these
observations suggest that the incidence of pneumonitis may be greater in
clinical practice than in clinical trials. As with the New Zealand
patients, the Japanese patients frequently had past or present exposure to other
DMARDs and some had pre-existing pulmonary disorders. It is possible that
pre-existing pulmonary disease and other DMARDs, particularly methotrexate, may
increase the likelihood of pneumonitis occurring with leflunomide.
However, it should be borne in mind that many patients benefit from combination
therapy where single agents have failed.
Inform all patients of early warning symptoms and
consider baseline assessment
Clinical trials and the case reports to CARM indicate that leflunomide as
monotherapy, or perhaps more commonly with methotrexate, can cause pneumonitis.
Since patients with rheumatoid disease may have respiratory involvement or other
lung disorders, a pre-treatment chest x-ray and evaluation of pulmonary status
is useful in establishing a baseline should respiratory symptoms occur.
Patients should be informed of the early symptoms of pneumonitis and advised to seek medical attention promptly. New or worsening pulmonary symptoms need to be investigated without delay and leflunomide stopped, if appropriate.1,6 Methotrexate should also be discontinued if it is being taken concomitantly. Prescribers are reminded that monitoring for hepatic dysfunction and blood dyscrasias is also imperative in patients taking leflunomide.1,7 Additionally, please continue reporting leflunomide-associated adverse reactions to CARM.
Competing interests (author): none declared