FDA Issues Sterner Warnings to Manufacturers of Diabetic Drug Actos

Although the FDA issued recommendations regarding labeling cautions for the drug Actos to manufacturer Takeda Pharmaceuticals in 2006, following further safety reviews of the drug they have recently issued more stringent instructions to the Japanese company. Actos, also known as pioglitazone is used in the treatment of Type 2 diabetes to help control the levels of sugar in the blood.

Drugs Included, Safety Updates Required
In a letter to Takeda Pharmaceuticals the FDA states that supplemental new drug applications for Actos, Actoplus Met, Actoplus Met XR and Duetact were duly received and processed, and noted receipt of certain amendments and risk evaluation assessments relating to Actos. Takeda was notified of new safety information which the FDA deemed to be a necessary inclusion of any future labeling of Actos. Further, the FDA stated the safety updates must specifically address the potential risk in increase of bladder cancer in those taking higher dosages or taking the drug for extended periods of time.

Specific Changes to Labeling of Actos
The FDA asked that Takeda include under the warnings and precautions area of the Actos label a statement that preclinical and clinical trials had shown pioglitazone users experienced an increase in incidence of bladder cancer. The Actos labels must state that those who have bladder cancer or a prior history of bladder cancer should be extremely cautious when using the drug. The label must additionally state that statistical significance in bladder cancer risk is reached in those patients taking Actos for longer than two years. More specifically, the wording that taking Actos longer than twelve months increases the risk of developing bladder cancer to a 40% statistical probability is to be included.

Patient Counseling Information
The FDA’s advice to patients taking the drug includes immediately reporting any signs or symptoms of urinary urgency, dysuria or macroscopic hematuria to their treating physician, as these can be signs of bladder cancer. Blood or red color in the urine or pain while urinating are all serious side effects and should be relayed immediately to the patient’s doctor. Actoplus Met, Actoplus Met XR and Duetact must all be labeled in the same manner as Actos according to FDA findings.

FDA Postmarketing Requirements
In the same letter to Takeda, the FDA offered specific postmarketing requirements which included directing Takeda Pharmaceuticals to continue and modify their ten-year study which assessed the related risk of bladder cancer in those taking Actos. The Final Protocol Amendment Submission must be submitted to the FDA by December 16, 2011, the 4th Interim Report Submission by June 30, 2012, the Study Completion by December 31, 2012, and the Final Report Submission by December 31, 2013. Takeda is asked to report periodically on studies and trials conducted on Actos however the Risk Evaluation and Mitigation Strategy Requirements submitted were approved with no further changes required.

Postapproval Clinical Trial
The FDA directs Takeda to include the status of any postapproval clinical trials, including when the enrollment began, how many patients were enrolled, the date of expected completion, and any difficulties encountered in the trial. Generic products for the drug Actos must have a REMS, supporting documents and appended documents prior to marketing the product.

As a final admonishment to Takeda, the FDA warns that all promotional materials and package inserts for the drug Actos as well as other drugs containing pioglitazone be submitted at the time of publication, and that all promotional materials must be revised to be consistent with mandated label changes.