Avandia

Avandia

This case was issued on July 23, 2007.

Health Canada has a new warning on Avandia. The FDA has given Avandia its most stringent warning, a "black box" warning.

Previously, in November of 2001, Health Canada posted an Advisory indicating:

November 30, 2001

Important safety reminder for patients taking oral diabetes drugs of the glitazone class, Avandia® and Actos®

OTTAWA - Health Canada, following a review of current safety information and medical literature, is advising Canadians of some safety concerns related to a class of oral diabetes medications known as thiazolidinediones (TZDs) or glitazones. Two TZDs, Avandia® (rosiglitazone) and Actos® (pioglitazone), are available in Canada.

Drugs of this class can cause fluid retention that can progress to congestive heart failure. These drugs should not be used in patients with acute heart failure. If you have or have had heart failure, fluid retention or active liver disease, these safety concerns may apply to you.

Patients who develop fluid retention or swelling (edema), shortness of breath, weakness, fatigue, or excessive weight gain, should inform their physician immediately and the treatment of these patients should be reevaluated. If the symptoms are due to congestive heart failure, the medication should be discontinued. This is consistent with the safety information provided when Avandia® and Actos® were launched in Canada last year.

It should be noted that people with type 2 diabetes are at an increased risk for diabetes-related complications, such as congestive heart failure, whether they take any specific type of diabetes treatment or not.

In Canada, Actos®, in addition to diet and exercise, can be used alone to control blood sugar. Avandia® can be used alone or in combination with either metformin or sulfonylureas, in patients not controlled by diet and exercise alone.

In Canada, Actos® and Avandia® are not approved for use in combination with insulin, where these safety concerns may be more frequent.

This advisory is in addition to letters issued by the manufacturers of Actos® and Avandia®, following discussions with Health Canada, to health care professionals reminding them of the above mentioned safety concerns.

Recent Developments

Health Canada Endorsed Important Safety Information on

PrAvandia®, PrAvandamet® and PrAvandarylTM

June 1, 2007

Dear Health Care Professional:

Subject: Cardiac Safety of Avandia® (rosiglitazone maleate)

An article in the New England Journal of Medicine (NEJM) on May 21, 2007, has generated significant public attention on the cardiac safety of Avandia®, Avandamet® and AvandarylTM. The Nissen & Wolski article1, based on a meta-analysis of 42 clinical studies, noted a statistically significant increased risk of myocardial infarction (OR 1.43, CI 1.03-1.98, p = 0.03) and a statistically non-significant increase in the risk of cardiovascular death (OR 1.64, CI 0.98-2.74, p = 0.06) associated with the use of rosiglitazone in comparison to the use of a placebo or other anti-diabetic therapies.

The conclusions reached require confirmation. Analysis of all currently available data is ongoing and findings will be communicated when review is complete.

Some of the studies in the NEJM article included patients using rosiglitazone in combination with other anti-diabetic therapies. Some of these combinations, specifically rosiglitazone + metformin + sulfonylurea or rosiglitazone + insulin are not approved for use in Canada.

Important Advice for Managing Your Patients

* In Canada, Avandia® is NOT approved for use:

- with insulin therapy

- with the combination of metformin AND a sulfonylurea

- in patients with pre-diabetes.

* Avandia® is contraindicated in patients with NYHA Class III and IV cardiac status.

* Avandia® should be used with caution in any patient with NYHA Class I and II cardiac status.

* All patients should be monitored for signs and symptoms of fluid retention, edema, and rapid weight gain.

* The dose of Avandia® used in combination with a sulfonylurea should not exceed 4mg daily.

When considering treatment decisions, physicians are recommended to carefully weigh the overall benefit versus the risk of Avandia®, Avandamet® or AvandarylTM for each individual patient.

In Canada, Avandia® is indicated for2:

* use as monotherapy, in patients not controlled by diet and exercise alone, to reduce insulin resistance and lower elevated blood glucose in patients with type 2 diabetes mellitus.

* use in combination with metformin or a sulfonylurea when diet and exercise plus the single agent do not result in adequate glycemic control. For patients inadequately controlled on metformin or a sulfonylurea, Avandia® should be added to, not substituted for, metformin or the sulfonylurea.

Currently, the Canadian Product Monograph also contains the following statement in the Warnings and Precautions section:

Cardiovascular and Edema

Thiazolidinediones, like Avandia®, alone or in combination with other antidiabetic agents, can cause fluid retention, which can exacerbate or lead to congestive heart failure. The fluid retention may very rarely present as rapid and excessive weight gain. All patients should be monitored for signs and symptoms of adverse reactions relating to fluid retention and heart failure. In particular, patients who are at risk for heart failure including those receiving concurrent therapy which increases insulin levels (i.e. sulfonylureas), and those patients with mild to moderate heart failure (NYHA Class I and II) should be closely monitored.

Treatment with thiazolidinediones has been associated with cases of congestive heart failure, some of which were difficult to treat unless the medication was discontinued. Avandia® should be discontinued if any deterioration in cardiac status occurs.

As a result of an ongoing regulatory review, the Product Monograph for Avandia® is currently being updated to include additional information on cardiac safety, and that the dose of Avandia® used in combination with a sulfonylurea should not exceed 4mg daily.

Avandia has recently been implicated in increasing the risk of congestive heart failure.

Avandia, or rosiglitazone, raises the risk of cardiovascular-related death by 64 percent and the risk of heart attack by 43 percent.

Health officials were aware of heart risks linked to GlaxoSmithKline Plc's widely prescribed diabetes drug Avandia for a number of years. In 2002, for example, the FDA requested reports of congestive heart failure to be included on the label of Avandia as well as Actos, made by Takeda Pharmaceutical Co. Ltd.

Avandia was approved in Canada on March 30, 2000.

If you or someone you know has suffered congestive heart failure or other cardiac effects while taking Avandia, or Actos, please contact us for more information.