Takeda Pharmaceutical Co.' s thiazolidinedione Actos (pioglitazone) is set to get stronger labeling language warning of a risk for bladder cancer after use of the diabetes drug for more than one year.

The Warning and Precautions section of the label will be updated to mention the risk of long-term treatment, FDA said in a drug safety communication on June 15.

In a same-day press statement, Takeda responded by saying it is "working with FDA to make appropriate changes to prescribing information."

Takeda also confirmed, however, that the information on potential for bladder cancer risk will not be included in the drug's existing boxed warning. This has the potential to blunt the commercial fallout; Actos is an enormous revenue generator for Takeda, delivering ¥387.9 billion ($4.79 billion) in fiscal year 2010.

FDA's move followed the drug's suspension in France and withdrawal of use in new patients in Germany (Also see "First France, Now Germany Pulls Takeda's Actos For New Patients On Bladder Cancer Risk" - Pink Sheet, 10 June, 2011.). The European developments had been sparked by a retrospective cohort study using data from the French National Health Insurance plan.

Even a boxed warning for cancer is far from a deal breaker in the warning-laden diabetes space, as the success of Novo Nordisk's GLP-1 Victoza (liraglutide) attests.

On June 13, however, FDA notified endocrinologists and family practitioners that as part of its risk evaluation and mitigation strategy, Novo is reaching out to professionals after a "recent assessment of healthcare providers" suggested "some primary care providers are not aware of the serious risks associated with use of Victoza," notably dose-dependent and treatment duration dependent thyroid c-cell tumors in rats and mice (Also see "FDA Clears Victoza, But Warnings And More Studies Pose Hurdles" - Pink Sheet, 1 February, 2010.).

Bladder Cancer Currently Has Low Profile On Actos Label

In Actos' current prescribing information, the first mention of potential for urinary bladder tumors doesn't appear until page 18, noting tumors in male rats. Also, the label notes, in two to three- year trials against the treatment glyburide, 16 out of 3656 (.44%) patients on Actos developed bladder cancer, versus 5 out of 3679 not on Actos (.14%). Not counting patients on the drug for more than one year, these rates declined to 6 (.16%) for Actos and 2 (.05%) for non-Actos.

This section on bladder cancer has a low profile though, under weight gain and edema. "There are too few events of bladder cancer to establish causality," the section concludes.

In its communication on June 15 however, FDA said it is advising doctors not to use pioglitazone in patients with active bladder cancer and suggests cautious use in those with a prior history of bladder cancer.

FDA has been examining the possible link between duration of use of Actos and bladder cancer for some time. Interim five-year data from a 10-year epidemiological study of about 193,000 diabetes patients didn't show an increased risk overall, but there was a suggestion of risk for patients taking the highest cumulative dose for the longest periods (Also see "Actos' Bladder Cancer Signal May Hinge On Dose, Duration Of Use" - Pink Sheet, 17 September, 2010.). Results from the interim analysis were published in the journal Diabetes Care this spring and the study will wrap up at the end of 2012.

Based on these data, FDA said it "calculated that the duration of therapy longer than 12 months was associated with 27.5 excess cases of bladder cancer per 100,000 person-years follow-up" compared to no use of pioglitazone.

FDA also said its action was taken with awareness of the French study finding an increased risk. The European Medicines Assocication Committee for Medicinal Products for Human Use is set to meet June 20 to 23 to review the risk for bladder cancer.

Meanwhile, Takeda said in its statement that it remains committed to ongoing research to understand safety concerns, notably through its support of the 10-year epidemiology study.

Commercial Impact In U.S. As Yet Unclear

Just how doctors and patients will respond to updated labeling for Actos remains to be seen.

Doctors will need to review the available data on Actos and educate their patients about the risks, but they won't necessarily switch patients off the drug until further analysis is done, commented Karen Earle, head of endocrinology at California Pacific Medical Center in San Francisco.

"This certainly is not the first cancer scare," said Earle.

In particular, Earle cited the studies suggesting a risk for Sanofi Aventis SA's insulin blockbuster long-acting insulin product Lantus, but the consensus now is that evidence is lacking (Also see "FDA Notes Lack Of Proof For Cancer Risk, But Lantus Isn't Out Of The Woods Yet" - Pink Sheet, 15 January, 2011.).

Actos had been put forward as a better option than GlaxoSmithKline's beleaguered same-class Avandia (rosiglitazone), which was allowed to stay on the market despite a controversy over cardiovascular risks but with a strict risk evaluation and mitigation strategy.

According to the REMS and Avandia drug label, health professionals are obliged to mention the availability of Actos and inform them that Actos has not been linked to problems with cardiovascular safety (Also see "Avandia REMS Requires Doctors To Tell Patients About Actos’ CV Safety" - Pink Sheet, 23 May, 2011.).

Many Risks To Communicate

In light of the CV risks, patients have been switching in recent years from Avandia to Actos, but they have also in the process been questioning the class as a whole, Earle commented. The latest development with bladder cancer has the potential to push them away from the class altogether, based on the overall picture rather than just the stronger warning on bladder cancer, Earle said.

Earle added that in her practice it is standard to inform patients about the risk for thyroid cancer associated with Victoza, because the risk is included in the label's boxed warning, though the fact that it has only been seen in rodents is "reassuring."

In contrast, if risks are "buried in the prescribing information," there is more potential to be missed due to the many other potential side effects listed, she said.

Still, the black box for Victoza does not seem to be getting enough attention.

In its recent communication about Victoza, FDA reminded professionals that in preclinical studies, the drug had been associated with thyroid C-cell tumors. "It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma," in humans as human relevance could not be ruled out by clinical or non-clinical studies, the letter states.

Patients who have thyroid nodules discovered on physical examination or in neck imaging done for other reasons should be further evaluated by an endocrinologist, FDA advised.

The FDA communication also reminded professionals about the risk for acute pancreatitis, noting that patients should be observed for signs and symptoms.

-Emily Hayes (e.hayes@elsevier.com)

Actos Gets Stronger Bladder Cancer Warning, But Escapes Black Box

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