FDA alters Actos label, while France and Germany pull it off shelves

Research originating from France has shown an increased incidence of bladder cancer when diabetic patients were administered pioglitazone (Actos, Takeda Pharmaceuticals). As a direct response to these results, the French Medicines Agency (Afssaps) said it would pull the drug from the market, and now Germany has followed suit. The FDA also warned the public about the increased risk and has decided to revise the medication's label.

The French analysis took place between 2006 and 2009 and included approximately 1.49 million patients with diabetes who were between the ages of 40 and 79. Researchers found that the use of pioglitazone was significantly associated with a higher incidence of bladder cancer and that risk was even higher for patients administered the drug at higher doses and longer durations.

Takeda responded to this decision by France and Germany by stating its “[confidence] in the therapeutic benefits of Actos and its importance as a treatment for type 2 diabetes.” The company said that it remains committed to “Actos and Actos-containing medications.”

Deerfield, Ill.-based Takeda added that it is working with the appropriate regulatory agencies and said that it supports a 10-year epidemiological study performed by the University of Pennsylvania in Philadelphia and Kaiser Permanente Diabetes Registry in California that is investigating questions raised about Actos and bladder cancer.

An interim analysis of the epidemiologic study was published in Diabetes Care in April. These data showed that treatment with pioglitazone was not associated with an increased incidence of bladder cancer, according to Takeda. “Takeda is committed to supporting this study through its conclusion at the end of 2012 and will report on the final results upon completion,” the company wrote.

But is the news all bad? A recent study published in the New England Journal of Medicine in March showed that pioglitazone prevented diabetes in 72 percent of pre-diabetics. Tripathy et al found that treating 18 patients for one year with the drug prevented one case of diabetes and treating eight patients for two years prevented one case of diabetes.

The European Medicines Agency (EMA) also chimed in on the matter. The agency said that it was informed of Afssaps' decision to revoke the drug from the French market and said EMA is waiting to see the outcomes of a European review of the drug. Similar to the FDA, EMA in March began an investigation into the possible association of bladder cancer with pioglitazone.

The EMA said the Committee for Medicinal Products for Human Use (CHMP) is currently combing through data from pharmacoepidemiological studies and other published data to assess the benefits and risks of pioglitazone and its possible association with bladder cancer. The committee will add the French study to its till and said that the issue will be discussed at its June 20-23 meeting.

The EMA said that while the review is ongoing the agency will not recommend any changes to the use of pioglitazone-containing medicines.

FDA warns of increased risk, changes label
The FDA also added fuel to the fire when it warned the public yesterday that pioglitazone (Actos, Takeda Pharmaceuticals) when used for more than one year, may increase a patient's risk of bladder cancer. The FDA said that these increased warnings will be added to the drug’s label, and that it will also make these revisions to the Medication Guide.

The decision is based on a five-year analysis by the agency that examined a 10-year epidemiological study conducted by the drug's manufacturer.

The FDA found that patients who were exposed to pioglitazone for longer than 12 months had a 40 percent increased risk for bladder cancer compared to patients who had never been exposed to the drug. Continuing on pioglitazone therapy for longer than 12 months was associated with 27.5 excess cases of bladder cancer per 100,000 person-years follow-up.

The FDA has recommended that healthcare professionals:

• Discontinue pioglitazone use in patients with active bladder cancer; and
• Use pioglitazone with caution in patients with a history of bladder cancer. The benefits of blood sugar control with pioglitazone should be weighed against the unknown risks for cancer recurrence.

While the agency has not decided to pull the drug from the market, the FDA said that it will continue to evaluate the slew of data surrounding the drug, including the results of the recent French study.

Actos—a thiazolidinedione—is of the same drug class as GlaxoSmithKline’s rosiglitazone (Avandia), which has also undergone increased scrutiny after it was found that it may have the potential to increase the risk of MI.

Pioglitazone is indicated to improve glucose control in type 2 diabetes and should be used in conjunction with diet and exercise. The drug is not indicated for patients with type 1 diabetes or diabetic ketoacidosis.