Archived - Important Safety Information Severe and Serious Hepatic Reactions ARAVA - Aventis Pharma Inc.

Important Drug Safety Information

Aventis Pharma Inc.

May 4, 2001

Dear Healthcare Professional(s):

The purpose of this communication is to inform you of important post-marketing safety information for leflunomide (ARAVA) which the European Medicines Evaluation Agency's (EMEA) scientific committee has released. In Canada, leflunomide is indicated for the treatment of adult patients with active rheumatoid arthritis. Leflunomide inhibits the enzyme dihydroorotate dehydrogenase (an enzyme involved in the de novo pyrimidine synthesis) and has anti-proliferative activity.

The European Medicines Evaluation Agency's scientific committee has recently been made aware of a total of 296 cases of hepatic reactions among patients exposed to leflunomide for an estimated 104,000 patient years (77,200 US, 17,200 European Union, 300 Canada, 9,600 rest of world). By Regulatory definition, 129 of these events were considered as serious and included 2 cases of liver cirrhosis and 15 cases of liver failure, 9 with fatal outcome. Hepatic reactions tended to occur within, but not limited to, the first 6 months of therapy. Although, confounding factors were present in many cases (e.g. concomitant potentially hepatotoxic medications and/or disease states), a causal relationship to leflunomide cannot be excluded. These include concomitant use of hepatotoxic medications, history of liver diseases as well as the background prevalence of similar serious adverse events in this patient population. Of the serious reports, 101 patients (78%) were treated concomitantly with hepatotoxic medications. In patients with elevated liver function tests, 58% were also being treated with methotrexate and/or NSAIDs (including the selective Cox-2 inhibitor celecoxib). In 33 of the serious cases (27%), other risk factors were reported including a history of alcohol abuse, liver function disturbance, acute heart failure, severe pulmonary disease or pancreatic carcinoma. Some post-marketing safety data concerning the prescribing profile of leflunomide suggest that monitoring of liver function and washout procedures might not have been fully adhered to. All of the cases with fatal outcome had evidence that monitoring recommendations for dose reductions, discontinuation of therapy, or washout procedures had not been followed. Therefore, it is mandatory to reinforce labeling recommendations to ensure monitoring compliance.

Based on the above-mentioned consideration, the specific guidelines for monitoring liver enzyme levels contained in the current Product Monograph for ARAVA, were reinforced (recent changes are presented below in bold). We want to emphasize the need to institute the following monitoring procedures, as documented in the Product Monograph:

• Leflunomide is contraindicated in patients with pre-existing impairment of liver function.
• AST (SGOT) and ALT (SGPT) must be checked before initiation of treatment and at monthly or more frequent intervals during the first 6 months of treatment and every 8 weeks thereafter.
  
  
  
  For ALT (SGPT) elevations between 2 and 3 times the upper limit of normal, the dose of leflunomide may be reduced from 20 mg to 10 mg/day and monitoring should be performed weekly. If ALT (SGPT) elevations of more than 2 times the upper limit of normal persist or if ALT increases to more than 3 times the upper limit of normal, leflunomide must be discontinued and washout procedures initiated (see Monitoring Recommendations, Precaution section - Product Monograph).
• If a severe undesirable effect of leflunomide occurs, or if for any reason the active metabolite needs to be cleared rapidly from the body (persistent ALT elevations, hematologic toxicity, allergic reaction, pregnancy, switching to methotrexate), the following washout procedures should be initiated:

Washout Procedure

Cholestyramine, 8 grams, is administered 3 times a day for 11 days.

Alternatively, 50 grams of activated charcoal is administered 4 times a day for 11 days.

The duration of washout may be modified depending on clinical or laboratory variables. (See Precautions section - Product Monograph)

As reported by the European Agency for the Evaluation of Medicinal Products, concomitant administration of leflunomide with methotrexate and/or other hepatotoxic medications is associated with an increased risk of serious hepatic reactions. Combined use of leflunomide and methotrexate has not been approved by Health Canada and should not be prescribed unless it is in the professional judgement of the physician that the clinical benefits significantly outweigh the documented (serious) risks for hepatotoxicity. If use of the combination is contemplated, the physician must fully discuss the toxicities with the patient prior to the initiation of therapy. Monitoring of liver function tests must be fully adhered to.

As with all medications, the numbers of officially reported adverse reactions may represent only a small fraction of actual events, therefore caution should be exercised in estimating the incidence of such events.

Additionally, we draw your attention to the existing Canadian Product Monograph in regard to Contraindications, Warnings and Special Precautions for the Use, Interactions and Undesirable Effects of leflunomide. Please note that the current Product Monograph and Patient Package Insert for ARAVA will be available on the Aventis website: www.aventispharma.ca

Aventis Pharma Inc. is currently updating the ARAVA Product Monograph to reflect the most recent safety information. Healthcare Professionals should check for revisions on a regular basis.

You can also assist in monitoring the safety of ARAVA by reporting all adverse events to Aventis Pharma Pharmacovigilance by telephone at 1-800-265-7927 or by fax at 1-514-333-2956. You may also report adverse events to the Canadian Adverse Reaction Monitoring Program (CADRMP) Bureau of Licensed Product Assessment, Therapeutic Product Directorate, HEALTH CANADA (please see phone numbers and address below).

Sincerely, Aventis Pharma Inc.

original signed by

Franca Mancino, M.Sc.

Director, Regulatory Affairs and Pharmacovigilance

Questions regarding this message can be directed to the Bureau of Pharmaceutical Assessment, Therapeutic Products Directorate at :

(613) 941-3171

Any suspected adverse drug reactions can also be reported to:



Canadian Adverse Reaction Monitoring Program (CADRMP)

Bureau of Licensed Product Assessment

Therapeutic Products Directorate

HEALTH CANADA

Address Locator: 0201C2

OTTAWA, Ontario, K1A 1B9

Tel: (613) 957-0337 or Fax: (613) 957-0335

cadrmp@hc-sc.gc.ca



The ADR Reporting Form can be found in The Canadian Compendium of Pharmaceutical and Specialties, or on the TPD website, along with the ADR Guidelines.