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Health professional risk communication

ACTOS (pioglitazone hydrochloride) - Potential Association with Bladder Cancer - For Health Professionals

Starting date:
April 16, 2012
Posting date:
April 19, 2012
Type of communication:
Dear Healthcare Professional Letter
Source of recall:
Health Canada
Healthcare Professionals
Identification number:

This is duplicated text of a letter from Takeda Canada, Inc.

Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on ACTOS (pioglitazone hydrochloride)

April 16, 2012

Dear Health Care Professional:

Subject: Potential association between ACTOS (pioglitazone hydrochloride) and Bladder Cancer

Takeda Canada Inc., in collaboration with Health Canada, would like to inform you of important safety information in regards to a potential risk of bladder cancer in patients treated with ACTOS (pioglitazone hydrochloride). Health Canada has recently completed a safety assessment of the available data and the Product Monograph (PM) was updated to reflect the potential risk of bladder cancer in treated patients.

ACTOS (pioglitazone hydrochloride), an oral anti-diabetic drug, is authorized in Canada as an adjunct to decrease blood glucose levels not controlled by diet and exercise alone, in patients with type 2 diabetes mellitus. ACTOS (pioglitazone hydrochloride) is also indicated in combination with a sulfonylurea or metformin when diet and exercise plus the single agent do not result in adequate glycemic control.

  • Findings from new studies reveal that there is a potential increased risk of bladder cancer in patients treated with pioglitazone-containing products.
  • ACTOS (pioglitazone hydrochloride) is now contraindicated in patients with active bladder cancer, a history of bladder cancer or uninvestigated macroscopic haematuria.
  • Any macroscopic haematuria should be investigated before starting pioglitazone therapy.
  • Risk factors for bladder cancer should be assessed before initiating treatment with pioglitazone (risks include age, smoking, family history of bladder cancer, exposure to chemicals in the workplace, certain cancer treatments and radiation therapy).

Patients prescribed pioglitazone should be advised to seek medical attention if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment, as these may be symptoms of bladder cancer.

The potential association between bladder cancer and pioglitazone-containing products is based on the data from the following studies:

In two 3-year studiesFootnote 1,Footnote 2 in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) on placebo.

A five-year interim reportFootnote 3 of an ongoing 10-year observational cohort study in patients with diabetes (KPNC study) found a non-significant increase in the risk for bladder cancer in subjects ever exposed to pioglitazone, compared to subjects never exposed to pioglitazone (HR 1.2 [95% CI 0.9 - 1.5]). Compared to never exposure, a duration of pioglitazone therapy longer than 12 months was associated with an increased risk (HR 1.4 [95% CI 0.9 - 2.1]), which reached statistical significance after more than 24 months of pioglitazone use (HR 1.4 [95% CI 1.03 - 2.0]). Interim results from this study suggested that taking pioglitazone longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 from approximately 7 in 10,000 (without pioglitazone) to approximately 10 in 10,000 (with pioglitazone).

Cases of bladder cancer were reported more frequently in a meta-analysis of controlled clinical trials with pioglitazone (19 cases from 12506 patients, 0.15%) than in control groups (7 cases from 10212 patients, 0.07%) HR=2.64 (95% CI 1.11-6.31, p=0.029). After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 7 cases (0.06%) on pioglitazone and 2 cases (0.02%) in control groups. Available epidemiological data also suggest a small increased risk of bladder cancer in diabetic patients treated with pioglitazone in particular in patients treated for the longest durations and with the highest cumulative doses. A possible risk after short term treatment cannot be excluded.

The newly revised PM for ACTOS (pioglitazone hydrochloride), which includes the above mentioned information, can be accessed on the Web Sites of Health CanadaFootnote 4 and Takeda Canada, IncFootnote 5. Takeda Canada, Inc. will continue to review new safety data for ACTOS, including post-marketing adverse event reports.

Managing marketed health product-related adverse reactions depends on healthcare professionals and consumers reporting them. Any case of unexpected adverse reactions in patients receiving ACTOS (pioglitazone hydrochloride), should be reported to Takeda Canada, Inc. or Health Canada at the following addresses:

Takeda Canada, Inc.

435 North Service Road West

Oakville, ON L6M 4X8

Telephone: 1-888-825-3321

You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways:

    Report online at MedEffectTM Canada
  • Call toll-free at 1-866-234-2345
  • Complete a Reporting Form and:
    • Fax toll-free to 1-866-678-6789, or
    • Mail to: Canada Vigilance Program

      Health Canada

      Postal Locator 0701E

      Ottawa, Ontario K1A 0K9

The Reporting Forms, postage paid labels, and Guidelines can be found on the MedEffectTM Canada Web site in the Adverse Reaction Reporting section. The Reporting Form is also in the Canadian Compendium of Pharmaceuticals and Specialties.

For other health product inquiries related to this communication, please contact Health Canada at:

Marketed Health Products Directorate


Telephone: 613-954-6522

Fax: 613-952-7738

To change your mailing address or fax number, contact the Market Authorization Holder (Industry).


original signed by

Dr. Brad Pamenter

Vice President, Medical and Scientific Affairs

Takeda Canada, Inc.

ACTOS is a trademark of Takeda Pharmaceutical Company Limited used under license by Takeda Canada, Inc.

[Text of letter ends]


Footnote 1

Dormandy JA et al. (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366(9493):1279-89.

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Footnote 2

Tolman K et al. (2009) Liver Safety in Patients with Type 2 Diabetes Treated with Pioglitazone: Results from a Three-year,Randomized Comparator-Controlled Study. Drug Safety 32(9):787-800.

Return to footnote 2 referrer

Footnote 3

Lewis JD et al. (2011) Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. Apr; 34(4):916-22.

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Footnote 4

Drug Product Database Online Query

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Footnote 5

Takeda Canada, Inc.

Return to footnote 5 referrer