Even though the type 2 diabetes drug Actos (pioglitazone) increases the risk of bladder cancer, heart failure and eye problems, U.S. drug regulators have issued only safety communications and not a drug recall.
Countries that recalled Actos
Actos Recall Background InformationActos became the world’s best-selling diabetes drug in 2007 after rival drug Avandia (rosiglitazone), made by GlaxoSmithKline, was linked to a higher risk of heart attack. The active ingredient in Actos, pioglitazone, works by increasing the body’s sensitivity to insulin, a natural hormone that helps control blood sugar. Avandia and Actos come from the same family of drugs, thiazolidinediones (TZDs). Before the FDA approved Actos in 1999, premarket studies showed bladder tumors had developed in animals. Actos manufacturer Takeda Pharmaceuticals soon launched a 10-year study to investigate the long-term bladder cancer risks. The first five years of the study showed an increased bladder cancer risk. Although the FDA has not implemented an Actos recall, drug regulators in France and Germany have ordered doctors to stop prescribing Actos because of bladder cancer risks. The drug-regulation body in Europe, the European Medicines Agency (EMA), is performing its own safety review, saying the drug is safe in certain circumstances. The French Medicines Agency conducted its own study, which found that users of the diabetes drug have a 22 percent higher bladder cancer incidence than those taking other diabetes drugs.
FDA Study Leading Some to Call for an Actos RecallIn issuing the drug-safety announcement, the FDA said it is continuing to evaluate the data from the Takeda Pharmaceuticals study. The agency also will review the results of an epidemiological study in France that monitored about 1.5 million diabetes patients. That four-year study showed a “statistically significant increase in the risk for bladder cancer in patients exposed to pioglitazone compared to patients exposed to other anti-diabetic agents.” To issue a recall, the FDA must generally conclude that there is a “reasonable probability” that the drug in question will cause “serious adverse health consequences or death.” French medical regulators recalled Actos in June 2011. While the FDA is reviewing the data, it has issued advisories for health care professionals and Actos patients. The agency also updated the Actos drug label to include safety information stating that the use of pioglitazone for more than one year could be associated with an increased risk of bladder cancer. In May 2012, however, the FDA dialed back its requirement that Actos risks be given to patients in a separate Medication Guide. The FDA recommends that patients with active bladder cancer should not use pioglitazone. The agency also said patients with a history of bladder cancer should use pioglitazone with caution.
Black Box Warning for ActosThere are other reasons why experts believe Actos should be recalled. The medication is among a class of drugs known as thiazolidinedione, which has a history of causing side effects that include heart failure, heart attacks, serious liver problems in addition to bladder cancer. Soon after Actos was released onto the market in 1999, adverse reaction reports began being filed with the FDA claiming that Actos had caused congestive heart failure and other serious cardiovascular problems. These reports sparked a number of studies that concluded that Actos does increase the risk of heart failure. Despite mounting evidence that Actos increases the risk of cardiovascular problems, it took the FDA nearly eight years to elevate the risk to a black-box warning on the drug’s label. Two incidents occurred in 2007 that put pressure on the FDA to require a boxed warning for Actos. First, the Journal of the American Medical Association (JAMA) published a study that definitively linked Actos to heart failure. Second, intense pressure was placed on the FDA by the U.S. House Oversight and Government Reform Committee, chaired by Henry Waxman, which was investigating reports of collusion between the FDA and pharmaceutical companies, and misconduct by senior FDA officials.
Warning For Heart FailureBy 2007, the FDA had plenty of evidence linking Actos to congestive heart failure. However, the agency did not mandate a specific boxed warning, but instead negotiated with Takeda Pharmaceuticals, the maker of Actos. Here is the boxed warning as it appears on the Actos packaging label:
|WARNING: Congestive Heart Failure|
|Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure. In some patients [see Warnings and Precautions.|
|After initiation of Actos, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Actos must be considered.|
|Actos is not recommended in patients with symptomatic heart failure.|
|Initiation of Actos in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions.|