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Health professional risk communication

ARAVA (Leflunomide) and Interstitial Lung Disease – For Health Professionals

Starting date:
June 21, 2004
Posting date:
June 24, 2004
Type of communication:
Dear Healthcare Professional Letter
Source of recall:
Health Canada
Important Safety Information
Healthcare Professionals
Identification number:

This is duplicated text of a letter from Aventis Pharma Inc.
Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

[Text of letter begins]

Health Canada Endorsed Important Safety Information on ARAVA (leflunomide)

June 21, 2004

Subject: Arava® (leflunomide) and interstitial lung disease

Dear Health Care Professional,

Aventis Pharma Inc. in consultation with Health Canada is updating you on leflunomide and spontaneous reports of interstitial lung disease (ILD). In Canada, leflunomide is indicated for the treatment of adult patients with active rheumatoid arthritis.

Rare spontaneous reports of ILD occurring during treatment with leflunomide have been received worldwide. Several of these cases had a fatal outcome. ILD has been reported in 0.19 per 1000 person-years of exposure to leflunomide.

In a Japanese postmarketing surveillance program of 3658 patients with rheumatoid arthritis (RA) initiated in September 2003, which included all patients treated with Arava® in Japan, ILD was reported in 0.8% of patients, including cases with confounding factors. Twenty-nine (29) cases of interstitial pneumonitis were reported, 11 with a fatal outcome. The causality assessment between leflunomide use and the reported ILD was frequently confounded by pre-existing pulmonary disease (e.g. interstitial pneumonitis), and/or previous or concomitant use of other Disease-Modifying Antirheumatic Drugs (DMARDs) known to induce ILD, including methotrexate.

The underlying natural history of RA presents a major challenge to understanding the relationship between treatment and ILD because approximately 40-50% of RA patients develop ILD, regardless of treatment received.

ILD is a potentially fatal disorder, which may occur at any time during therapy and sometimes acutely, with variable etiology and clinical presentation. Evidence from epidemiologic studies and spontaneous report data suggest that ILD does not occur more frequently in patients treated with leflunomide than in patients treated with other DMARDs. New onset and worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and further investigation, as appropriate.

These events are being further evaluated as part of ongoing risk management efforts by Aventis, which include analysis of all spontaneous report data and performance of observational studies.

Reporting rates determined on the basis of spontaneously reported post-marketing adverse events are generally presumed to underestimate the risks associated with drug treatments.

Based on the above-mentioned considerations, the Product Monograph for Arava® has been updated as follows:



Rare (<0.1%) 11 3658 spontaneous reports of interstitial lung disease (ILD) occurring during treatment with leflunomide have been received worldwide (see ADVERSE REACTIONS). Several these cases had a fatal outcome. In Japanese postmarketing surveillance program patients rheumatoid arthritis, the rate ILD was estimated at 0.8%, regardless causality. Twenty-nine (29) pneumonitis were reported, Assessment causality between use and reported is frequently confounded by pre-existing pulmonary (e.g. pneumonitis), or previous concomitant other DMARDs known to induce (including methotrexate).< p>

In patients with a current or previous history of pulmonary disease or who have been recently treated with drugs known to induce ILD, it is recommended that pulmonary status be evaluated prior to initiation of ARAVA® therapy and that patients be closely monitored during treatment.

Interstitial lung disease is a potentially fatal disorder, which may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation, as appropriate. If discontinuation of the drug is needed, the long half-life of leflunomide's active metabolite may necessitate the initiation of wash-out procedures (see PRECAUTIONS, Washout Procedures).

Patients should be informed about the early warning signs of ILD and asked to contact their physician as soon as possible if these symptoms appear or worsen during therapy.

Adverse reactions

Respiratory System (1% to <3%): asthma, dyspnea, epistaxis, lung disorder: (Less than 0.1%): Interstitial disease (including interstitial pneumonitis and pulmonary fibrosis), sometimes fatal;< p>

Information for the consumer

Cases of lung inflammation causing difficulty breathing have occurred rarely in patients receiving Arava®. Tell your doctor without delay if you experience new or worsening of shortness of breath and/or cough, with or without associated fever, at any time while you are taking Arava®.

The identification, characterization, and management of marketed health product-adverse reactions are dependent on the active participation of health care professionals in adverse reaction reporting programmes. Any occurrences of ILD or other serious and/or unexpected adverse reactions in patients receiving Arava® should be reported to Aventis Pharma Inc. or Health Canada at the following addresses:

Aventis Pharma Inc.
2150 St. Elzear Blvd. West,
LAVAL, Quebec, H7L 4A8
Tel : 1-800-265-7927

Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: (613) 957-0337 or Fax: (613) 957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 1 866 234-2345
Fax: 1 866 678-6789

For other inquiries: please refer to contact information.

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.


original signed by

Franca Mancino, M.Sc.
Director, Regulatory Affairs
Aventis Pharma Inc.

® Registered trade-mark of Aventis Group. Used under licence by Aventis Pharma Inc., Laval, Quebec H7L 4A8

[Text of letter ends]