Lymphovenous Canada: Health Watch

COUMARIN UPDATES

The February 1999 issue of the New England Journal of Medicine has published a study which concludes that Coumarin is not effective therapy for women who have lymphedema of the arm after treatment of breast cancer. The article, entitled: Lack of Effect of Coumarin in Women with Lymphedema after Treatment for Breast Cancer reported the findings of a study carried out by the Mayo Clinic on 140 women with chronic lymphedema in the arm after treatment for cancer.

The study found virtually no difference in volume between when the women took the drug for six months or when they took a placebo. During the 12-month trial 6 per cent of the women experienced liver toxicity. Their levels of toxicity returned to normal when the drug was discontinued. The Mayo Clinic undertook the study to confirm previous reports of the drug's effectiveness.

THE CANADIAN SITUTION

The November 5, 1996 issue of The Medical Post, reported the cancellation of a large clinical trial on the effectiveness of the drug Lodema, at Princess Margaret Hospital in Toronto, on the treatment of lymphedema, as a result of deaths and liver damage associated with use of the drug.

In the absence of an official warning from Ottawa, Dr. Charles Godfrey, professor emeritus at the University of Toronto involved in the trial, voiced his own safety concerns to individuals who may be obtaining Lodema themselves through mail order and self-medicating.

Dr. Godfrey wrote to the New England Journal of Medicine requesting that the publication print an addendum to an article it published in 1993 on the results of a study which suggested that the drug was effective and safe for use in the treament of lymphedema. He asked the publication to point out the current status of the drug (its removal from the market in Australia) and its potential dangers. He also expressed concerned that information on the internet about postmastectomy use of the drug Lodema did not carry any cautionary information.

Editor's note: the Special Access Program of the Health Protection Branch, Health Canada no longer allows patients to receive Coumarin as an emergency drug. Lodema is not available for sale in Canada.

Australia cancels registration of Lodema brand of Coumarin (5,6-benzo-[alpha]-pyrone) tablets.

CANCELLATION OF REGISTRATION

(from the Australian Department of Health and Family Services, August 1996)

LODEMA BRAND OF COUMARIN TABLETS 200mg

The Secretary of the Department of Health and Family Services has cancelled the registration in Australia of Lodema brand of coumarin tablets 200 mg.

Lodema brand of coumarin tablets 200 mg were marketed in Australia before the current Therapeutic Goods Act took effect in 1991. For this reason, they were automatically registered ("grandfathered") on to the Australian Register of Therapeutic Goods. The sponsor of the product is The Lymphoedema Association of Australia Inc.

In May 1996, the sponsor was given notice of the intention to cancel the registration and also given an opportunity to make submissions. The notice of the intention to cancel the registration was given following advice from the Australian Drug Evaluation Committee. The Committee had recommended cancellation of registration following the receipt of two reports of deaths of Australian women who developed hepatotoxicity associated with the use of Lodema. Other drugs had also been taken. There had also been a number of other Australian reports of patients who developed abnormalities of liver function test results or more serious signs of hepatoxicity associated with the use of Lodema. In addition, the Committee had some concerns about the adequacy of available information about the pharmaceutical aspects of Lodema 200mg tablets.

Following consideration of the sponsor's submission, the Secretary of the Department of Health and Family Services cancelled the registration in Australia of Lodema brand of coumarin tablets 200 mg. with effect on 15 August 1996, on the grounds that the safety of this product is unacceptable and the quality of the product is unacceptable.

It should be noted that under the provisions of the Therapeutic Goods Act 1989, the sponsor may request a reconsideration of the cancellation by the Minister for Health and Family Services and, subsequently, a review by the Administrative Appeals Tribunal.

Contact Officer:
Dr. John McEwen
Acting Head
Drug Safety and Evaluation Branch
Therapeutic Goods Administration
P.O. Box 100
WODEN ACT 2606
Telephone: (08) 289-7970
Facsimile: (08) 289-7464

From the minutes of the 178th (1995/4) Meeting of the Australian Drug Evaluation Committee (ADEC):

7.4.12 The Committee therefore resolved to advise the Minister and the Secretary that:

RESOLUTION NO 5816

The ADEC has reviewed the data submitted by the Lymphoedema Association of Australia Inc. in response to a request from the TGA [Therapeutic Goods Administration] for evidence of efficacy of Lodema tablets for the "grandfathered" indications, and has determined that coumarin tablets appear to have a positive risk to benefit ratio in the treatment of post-surgical lymphoedema and lymphoedema associated with filariasis, at the recommended dose of 200 mg twice daily. However, the risk to benefit ratio for oedema due to sports injuries, infection and chronic venous insufficiency would preclude approval of coumarin tablets for these indications, there are insufficient data to support the efficacy of topical coumarin preparations (powder or ointment) in the treatment of lymphoedema due to any cause.

Further to ADEC resolution 5713 from the 1995/3 (June) meeting, the committee would expect the inclusion of a prominent warning statement in the product information on the potential for coumarin to cause severe hepatic toxicity, which may be fatal, in accordance with the reports in the ADRAC database. The ADRAC will continue to maintain a watching brief in relation to hepatic adverse effects in association with coumarin. On the basis of efficacy and safety, the ADEC would not be opposed to the continued registration of Lodema tablets for the limited indications. However, the Committee would wish to be reassured with regard to the quality of this product. The sponsor should be requested to submit adequate pharmaceutical chemistry and quality control data to the TGA to demonstrate that Lodema tablets are of acceptable and consistent pharmaceutical quality. The ADEC and the PSC would wish to review this data.