For Health Professionals - Association between Long-Term Treatment with Actos (pioglitazone hydrochloride) Tablets for Type 2 Diabetes Mellitus and Fractures in Women

Starting date:

April 18, 2007

Posting date:

May 7, 2007

Type of communication:

Dear Healthcare Professional Letter

Subcategory:

Drugs

Source of recall:

Health Canada

Audience:

Healthcare Professionals

Identification number:

RA-170001515

This is duplicated text of a letter from Eli Lilly 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 ^PrACTOS^{Footnote ®} (pioglitazone hydrochloride)

April 18, 2007

Dear Health Care Professional:

Subject: Increased Incidence of Fractures in Female Patients Who Received Long-Term Treatment with ACTOS^{Footnote ®} (pioglitazone hydrochloride) Tablets for Type 2 Diabetes Mellitus

Eli Lilly Canada, after consultation with Health Canada, would like to bring to your attention important safety information concerning ACTOS^{Footnote ®} (pioglitazone hydrochloride) tablets, used in the treatment of type 2 diabetes mellitus and the occurrence of bone fractures in female patients.

Eli Lilly Canada has recently received an analysis of the pioglitazone clinical trial database with a special focus on fractures reported as adverse events. Nineteen randomized, controlled, double blind clinical trials, comparing patients treated with pioglitazone to a non-TZD (thiazolidinedione) comparator (placebo, or metformin, or sulfonylureas i.e. gliclazide, glyburide or glimepiride) were reviewed. The main study endpoint of 16 of these trials was glycemic control. For the other three studies, the main study endpoints were liver function, carotid intima-media thickness, and a combined cardiovascular endpoint. The study durations ranged from 16 weeks to 3.5 years. There were 8,157 patients in the pioglitazone-analysis group and 7,442 patients in the non-TZD comparator analysis groups.

• Findings from this analysis of nineteen trials showed that significantly more pioglitazone-treated female patients experienced at least one event of bone fracture than patients treated with non-TZD comparator drugs (other diabetes medicines such as metformin or sulfonylureas i.e. gliclazide, glyburide or glimepiride, or placebo) (2.6% versus 1.7%, respectively).
• There was no increased risk of fracture identified in men.
• The risk of fracture should be carefully considered in the care of female patients with type 2 diabetes mellitus who are currently being treated with pioglitazone, or when initiation of pioglitazone treatment is being considered. In these patients, as in all patients with type 2 diabetes mellitus, attention should be given to assessing and maintaining bone health according to current standards of care.

Findings from these clinical trials showed that 1.8% of pioglitazone-treated patients experienced at least one event of bone fracture versus 1.6% of patients treated with comparator drugs (other diabetes medicines or placebo). There was a higher reporting rate of fractures in women in the pioglitazone group (2.6%) than in the comparator group (1.7%). The fracture incidence calculated was 1.9 fractures per 100 patient-years in the pioglitazone treated group and 1.1 fractures per 100 patient-years in the comparator treated group. The observed excess risk of fractures for women in this dataset on pioglitazone is therefore 0.8 fractures per 100 patient-years of use. There was no increased risk of fracture identified in men (1.3% for pioglitazone-treated male patients versus 1.5% for non-TZD comparator treated male patients). The significant difference in fracture rate in women is only noted when all 19 studies are pooled.

The majority of fractures observed in female patients who received pioglitazone were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia). These fractures are in different sites from those typically associated with post-menopausal osteoporosis (e.g., fractures in the hip and spine).

The explanation for this finding is currently not known. It should be noted that none of the above described trials were designed to study the effects of pioglitazone on bones. Due to the limitations of the existing dataset, multiple known risk factors for fractures cannot be excluded as confounding variables. Eli Lilly Canada will continue to monitor fractures as an adverse event in both the clinical trial and spontaneous reporting database. However, presently there are no ongoing or planned clinical trials designed to study fractures as the primary outcome.

Eli Lilly Canada will continue to review new safety data for ACTOS^{Footnote ®}, including post-marketing adverse event reports and will be working with Health Canada to further integrate new safety information in the Canadian Product Monograph.

Managing marketed health product-related adverse reactions depends on healthcare professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious fracture or other serious or unexpected adverse reactions in patients receiving ACTOS^{Footnote ®}, should be reported to Eli Lilly Canada or Health Canada at the following addresses:

Customer Response Centre
Eli Lilly Canada Inc.
3650 Danforth Avenue
Toronto, Ontario
M1N 2E8
Tel.: 1-888-545-5972
Fax: 1-888-898-2961

Any suspected adverse reaction can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0701C
OTTAWA, Ontario, K1A 0K9
Tel: 613-957-0337 or Fax: 613-957-0335
To report an Adverse Reaction, consumers and health professionals may call toll free:
Tel: 866-234-2345
Fax: 866-678-6789
cadrmp@hc-sc.gc.ca

The AR Reporting Form and the AR Guidelines can be found on the Health Canada web site or in The Canadian Compendium of Pharmaceuticals and Specialties.

For other inquiries related to this communication, please contact Health Canada at:
Marketed Health Products Directorate (MHPD)
E-mail: mhpd_dpsc@hc-sc.gc.ca
Tel: 613-954-6522
Fax: 613-952-7738

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. A copy of this letter is also available on the Health Canada website.

Sincerely,

original signed by

Loren D. Grossman, MD, FRCPC, FACP
Vice-President, Research and Development
Eli Lilly Canada Inc