France and Germany Withdraw Use of Actos Because of Risk of Bladder Cancer   (June 12, 2011)

The French equivalent of the FDA, the Agence Francaise De Securite Sanitaire Des Produits De Sante, or AFSSAPS, said this past week that it will suspend the use of a diabetes drug, Actos (pioglitazone) as well as a combination drug including both Actos and metformin from sale in France "after considering the results of the study by CNAMTS [available in French on-line] at the request of AFSSAPS, confirming a small increased risk of bladder cancer patients treated with pioglitazone. This decision will take effect July 11, 2011 to allow patients to contact their doctor who will adjust their diabetic treatment."

The following day, the German regulators (Bundesinstitut für Arzneimittel und Medizinprodukte, or BfArM) also suspended the drug. And the European Medicines Agency (EMA) said that its Committee for Medicinal Products for Human Use, which had began a review of Actos-containing medicines in March, will now also assess the results of the French study. The EMA added a comment that "While this review is ongoing the CHMP is not recommending any changes to the use of pioglitazone-containing medicines."

Two recent publications in Diabetes Care also pointed to an association between the use of Actos (pioglitazone) and an increased risk of bladder cancer:

(1) Assessing the Association of Pioglitazone Use and Bladder Cancer Through Drug Adverse Event Reporting looked at spontaneous reports of adverse events reported to the FDA between 2004 and 2009, and concluded that the data "is consistent with an association between pioglitazone and bladder cancer." To be sure, there were reports of bladder cancers with other diabetes drugs, including insulin, metformin, glimepiride, exenatide, and others.
(2) Risk of Bladder Cancer Among Diabetic Patients Treated With PioglitazoneInterim report of a longitudinal cohort study presented interim results of an ongoing study of 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age, and found that use of pioglitazone for more than 2 years was weakly associated with an increased risk of bladder cancer.

Urologic complications of diabetes, including bladder problems, are well-known, but a recent review article doesn't mention bladder cancer as a problem for people with diabetes. But it's been known for Actos, and the US label for Actos states:

• "Urinary Bladder Tumors: Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study...  In two 3-year trials in which ACTOS was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking ACTOS compared to 5/3679 (0.14%) in patients not taking ACTOS.  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 ACTOS and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality."

In September 2010, the FDA announced their concern about the potential safety risk of bladder cancer with Actos, and pointed out that the manufacturer, Takeda, is  conducting a 10-year study to assess the long-term risk of bladder cancer associated with Actos. At the five-year mark, the data showed no overall statistically significant association between Actos exposure and bladder cancer risk, but "an increased risk of bladder cancer was observed among patients with the longest exposure to Actos, as well as in those exposed to the highest cumulative dose of Actos."

As of today, I can find no information on the Internet that the FDA has yet issued a statement in response to the French and German actions; I suspect that if they do, their response will be like that of the EMA, described above.

What should patients taking Actos do? The FDA last year suggested the following advice for patients taking Actos:

* Do not stop taking your Actos unless told to do so by your healthcare professional.

* Talk to your healthcare professional if you have concerns about Actos.

* Report any side effects from the use of Actos to the FDA MedWatch program.

Sounds like a reasonable set of recommendations to me.

Update June 19:

The FDA posted an Update to ongoing safety review of Actos (pioglitazone) and increased risk of bladder cancer on June 15. They indicate that use of Actos may be associated with an increased risk of bladder cancer in patients who take the drug for more than a year. The Actos label will be updated to include this warning.