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Important Drug Safety Information - ACTOS (pioglitazone hydrochloride) - Lilly

Date: 2001-11-06

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Eli Lilly Canada Inc.
3650 Danforth Avenue
Toronto, ON
M1N 2E8
Canada

IMPORTANT DRUG SAFETY INFORMATION

November 6, 2001

IMPORTANT SAFETY INFORMATION REGARDING ACTOS®

Dear Health Care Professional:

This letter is being sent out following discussions with Health Canada. It is intended to remind health care professionals that thiazolidinediones (including Actos) can cause fluid retention which can exacerbate or lead to congestive heart failure (CHF). Patients at risk for heart failure should be monitored for signs and symptoms of heart failure. Actos should be discontinued if patients develop clinical heart failure. Actos is not indicated in patients with New York Heart Association (NYHA) Class II, III and IV cardiac status. In addition, we would like to update you on the post-marketing cardiac adverse events reported with Actos in Canada.

Actos (pioglitazone hydrochloride) is indicated as monotherapy in patients not controlled by diet and exercise alone to decrease insulin resistance and blood glucose levels in patients with type 2 diabetes mellitus (non-insulin dependent diabetes mellitus, NIDDM). It is recommended that patients be treated for an adequate period of time to evaluate change in HbA1c unless glycemic control deteriorates. Actos is not indicated for combination therapy with other anti-diabetic agents. Actos is not currently indicated for use in combination with insulin.

However, in clinical trials evaluating the combination use of another thiazolidinedione with insulin, an increased incidence of cardiac failure and other cardiovascular adverse events was seen in patients receiving the thiazolidinedione and insulin compared to insulin alone. Patients who experienced heart failure in these trials were on average older, had a longer duration of diabetes and were mostly on higher doses. In the insulin combination studies, adverse events of edema were reported. Patients with ongoing edema are more likely to have adverse events associated with edema if started on combination therapy with insulin and thiazolidinediones.

Management of type 2 diabetes should also include nutritional counseling weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy.

While the mechanism of weight gain is unclear, weight gain with thiazolidinediones can result from increases in subcutaneous adipose tissue and/or from fluid retention. Treatment should be re-evaluated in patients with excessive weight gain.

As the safety and effectiveness of pioglitazone have not been established in patients younger than 18 years of age, Actos is not indicated for use in this population. Thiazolidinediones promote the maturation of preadipocytes and have been associated with weight gain. Obesity is a major problem in adolescents with type 2 diabetes.

Post-Marketing Spontaneous Adverse Reaction Reports

In world wide postmarketing experience with Actos, adverse events potentially related to volume expansion (e.g. congestive heart failure and pulmonary edema) have been reported. We estimate that about 17,000 patients (representing approximately 8,000 patient-years) have been treated with Actos in Canada since its launch in August 2000 to August 2001. The Canadian Adverse Drug Reaction Monitoring Programme (CADRMP) has received a total of 9 reports of serious adverse reactions associated with the use of Actos, as of August 3, 2001. These included one case of CHF and one case of pulmonary edema; both of these cases resulted in hospitalization. Subsequently, both patients recovered after the drug was discontinued and appropriate medical therapy was initiated. In addition, Eli Lilly Canada has received reports of non-serious adverse events potentially relating to volume expansion: edema, breathing difficulty, weight gain, and anemia. Cause and effect relationships have not been established nor, have in the vast majority of reports submitted, been speculated upon.

Congestive heart failure is a relatively common condition in patients with type 2 diabetes. Since thiazolidinediones can cause fluid retention, they may, in patients with reduced cardiac reserve, lead to an increased risk of exacerbation of CHF.

It is important to remember that adverse event rates determined on the basis of spontaneous reported post-marketing adverse event reports are generally presumed to underestimate the risks associated with drug treatments.

Canadian Prescribing Information

The attached revised Prescribing Information from the Product Monograph with the updated information is provided for your information. However, to ensure physicians are prescribing Actos optimally, please note the following important safety information regarding the potential association between thiazolidinediones and CHF.

1. CONTRAINDICATIONS
   
   - Actos (pioglitazone hydrochloride) is contraindicated in patients with:
   
   - known hypersensitivity to this product or any of its components · serious hepatic impairment (see PRECAUTIONS, Hepatic Insufficiency) · acute heart failure (see WARNINGS, Heart Disease)
   
   
2. WARNINGS - Heart Disease
   
   Treatment with thiazolidinediones has been associated with cases of heart failure which were difficult to treat unless the medication was discontinued. Thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure. Patients at risk for heart failure, particularly any patient also taking insulin, should be monitored for the signs and symptoms of heart failure. (Clinical evidence for the safety of ACTOS in combination with other anti-diabetic drugs is the subject of on-going clinical trials).
   
   ACTOS is not indicated in patients with NYHA Class II, III or IV cardiac status. ACTOS should be discontinued if patients develop clinical heart failure.
   
   
3. INFORMATION TO PATIENTS - (Re Heart Disease)

Since thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure, patients should be monitored for the signs and symptoms of heart failure. All patients should be told to inform their physician immediately if they develop edema, shortness of breath, weakness, fatigue, or excessive weight gain.

Reporting of Adverse Events

Eli Lilly routinely assesses safety information as it becomes available and updates Product Monographs accordingly. The identification, characterization, and management of drug-related adverse events are dependent on the active participation of health care professionals in adverse drug reaction reporting programmes. Any occurrences of cardiac adverse events or other serious and/or unexpected adverse events in patients receiving Actos should be reported to Eli Lilly Canada, Inc., or the Bureau of Licensed Product Assessment, at the following addresses:

Customer Response Centre
Eli Lilly Canada, Inc.
3650 Danforth Avenue
Toronto, Ontario M1N 2E8

Toll Free Number : 1-888-545-5972
Fax : 1-888-898-2961

Your professional commitment in this regard has an important role in protecting the well-being of your patients by contributing to early signal detection and informed drug use.    

original signed by

Joerg Rustige, MD
Vice President, Research and Development
Eli Lilly
Canada Inc.