FDA Joins France and Germany With Actos Bladder Cancer Warning But Stops Short of Recall

Actos (pioglitazone) is a blockbuster diabetes medication produced by the Japanese drug company Takeda Pharmaceuticals.  Actos belongs to the thiazolidinedione (TZD) drug class and works by decreasing insulin resistance in type 2 diabetic patients.  In the last year, the medication had global sales of $4.8 billion and accounted for 27% of Takeda’s revenue.  In 2008, Actos was the tenth best selling medication in the United States.  From January 2010 through October 2010, there were an estimated 2.3 million prescriptions filled by diabetic patients that had a pioglitazone containing product from pharmacies in the United States.  In preclinical in vivo studies, bladder cancer was observed in male rats receiving clinical equivalent doses of pioglitazone.  In addition, two clinical studies of Actos (the PROactive study and a liver safety study) showed a high percentage of bladder cancer cases in patients taking Actos.  As a result, the Food and Drug Administration (FDA) has included these findings in the precautions section of the Actos drug label.  To address the concerns regarding the possible association with bladder cancer, Takeda is conducting a ten-year observational cohort study and a nested case control study in diabetic patients from the Kaiser Permanente Northern California (KPNC) health plan.  Preliminary data from this epidemiological study suggests a possible link between pioglitazone and bladder cancer, and the FDA ordered a safety review in September of 2010.  Recently, on June 9, 2011 the French Agency for the Safety of Health Products pulled the product from their market because of safety concerns over the association with bladder cancer.   This action was the result of a clinical study conducted by the French National Health Insurance Plan using 1.5 million diabetic patients treated with pioglitazone.  It was show that there was a statistically significant increase in the risk for bladder cancer in patients using pioglitazone, and that risk increased with exposure longer than one year. Shortly thereafter, on June 10, 2011 the German Federal Institute for Drugs and Medical Devices advised physicians not to prescribe the medication to their diabetic patients based upon the French data.  There have been no other countries that have withdrawn the medication from their markets.  At a five-year interim analysis of the KPNC study, the FDA found that there was no significant increase in the risk for bladder cancer in patients taking pioglitazone.  However, it was found that the risk for bladder cancer did increase with increasing dose and use longer than one year.  Pioglitazone treatment for over 12 months carried a 40% increased risk of bladder cancer.  Today, June 15, 2011 the FDA has released a drug safety communication to inform the public of these results.  The FDA will include this information on the warnings and precautions section of the drug label.  The FDA is recommending that physicians not prescribe pioglitazone to patients with active bladder cancer, and to use caution in patients with a prior history of bladder cancer.  The drug was not pulled from the market in the United States.  There will be continued analysis of the KPNC data as well as the data from the French study.  There will be future updates as additional results are obtained.

Tagged as: Actos, bladder cancer, French Agency for the Safety of Health Products, German Federal Institute for Drugs and Medical Devices, Kaiser Permanente Northern California health plan, pioglitazone, Takeda Pharmaceuticals, the PROactive study, type 2 diabetes