Longer-term use of pioglitazone associated with an increased risk of bladder cancer

June 23, 2011

FDA published an online safety communication on June 15, informing prescribers and patients that pioglitazone (Actos, Takeda Pharmaceuticals America Inc., Deerfield, Illinois) use may be associated with a 20% to 40% increased hazard of new bladder cancer.

FDA published an online safety communication on June 15, informing prescribers and patients that pioglitazone (Actos, Takeda Pharmaceuticals America Inc., Deerfield, Illinois) use may be associated with a 20% to 40% increased hazard of new bladder cancer.

This new safety communication was based upon the agency’s review of a 5-year interim analysis of a 10-year observational study being conducted by Takeda to evaluate the risk of new bladder cancer with pioglitazone. The study is evaluating 193,099 patients with diabetes ≥40 years of age from a Kaiser Permanente Northern California health plan database.

At this time, analysis suggests that there is no significant increase in the risk for bladder cancer among patients ever exposed to pioglitazone compared to those never exposed to pioglitazone (HR=1.2; 95% CI, 0.9-1.5).

However, while any duration use was not associated with a significant increased risk, use of pioglitazone for longer than 12 and 24 months was associated with a 40% increase in bladder cancer risk (HR=1.4; 95% CI, 0.9-2.1 and HR=1.4; 95% CI, 1.03-2.0, respectively). This corresponds to nearly 28 additional cases per 100,000 person-years in patients with longer-term pioglitazone exposure.

“FDA is also aware of a recent epidemiological study conducted in France, which suggests an increased risk of bladder cancer with pioglitazone,” according to FDA officials in a statement. “Based on the results of this study, France has suspended the use of pioglitazone and Germany has recommended not to start pioglitazone in new patients.”

The French study evaluated about 1.5 million patients with diabetes followed for as many as 4 years. This nearly 10-fold larger study was sufficiently powered to show a statistically significant association between pioglitazone use and the risk for bladder cancer in patients exposed to pioglitazone compared to patients exposed to other antidiabetic agents (HR=1.22; 95% CI, 1.03-1.43). Moreover, the results showed a similar duration-response effect (HR=1.34; 95% CI, 1.02-1.75 for exposure longer than 1 year) to the Takeda-sponsored study, as well as a dose-response effect (HR=1.75; 95% CI, 1.22-2.50 for cumulative doses >28,000 mg).

Based upon these new data, the ‘Warnings and Precautions’ section of pioglitazone-containing medications’ (Actos; Actoplus Met, Actoplus Met XR when administered with metformin; Duetact with glimepiride) prescribing information and Medication Guide will now describe an increased risk of bladder cancer when pioglitazone is used for more than 1 year.

During the first three quarters of 2010, retail pharmacies filled pioglitazone-containing medication prescriptions for about 2.3 million Americans. Takeda’s sales for pioglitazone over the last fiscal year were $4.8 billion-27% of the company’s revenue.