FDA Issues Sterner Warnings to Manufacturers of Diabetic Drug Actos

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.

Takeda Pharmaceuticals Received FDA Instructions for Diabetic Drug Actos

Takeda Pharmaceuticals Received FDA Instructions for Diabetic Drug Actos

The drug Actos, also known as pioglitazone, has recently come under fire due to studies showing a slight increased risk of bladder cancer in those taking high doses of the drug or those who have taken Actos for longer than two years. Manufactured by Takeda Pharmaceuticals of Japan, the drug has shown huge gains in popularity in the past few years as it quickly replaced the drug Avandia which suffered under claims of increased risk of heart attack and death. Actos is Takeda’s tenth best-selling drug, making over $3.4 billion dollars in the past year alone. While the recent safety reviews have alarmed many who are currently taking the drug, in fact there have been safety concerns regarding Actos for several years.

Warnings are Not New
As far back as 2006, the FDA issued instructions to Takeda regarding Actos and ActoPlus Met, advising the company to make specific label changes to the drug’s precautionary statements. These label changes were to specifically include information regarding reports of bladder cancer in those taking Actos. Takeda’s supplemental drug applications regarding Actos were approved conditionally, so long as the agreed-upon text was included in the drug’s labeling.

The FDA stipulated that the final printed label be identical to the proposed labeling changes, and required Takeda to submit an electronic version of the proposed label as well as 20 paper copies and fifteen copies mounted on heavy-weight paper, however final approval was not mandated prior to using the labels. Although these FDA instructions took place nearly five years ago, it was only recently that more stringent warnings regarding Actos were issued.

European Medicines Agency Scientific Studies on Pioglitazone

European Medicines Agency Scientific Studies on Pioglitazone
The European Medicines Agency released a scientific study on the benefits and risks of the drug pioglitazone, also known as Actos, in January of 2007. This drug is currently used as a single treatment for Type 2 diabetes or in a dual combination form with metformin or sulphonylurea. When used alone, pioglitazone is typically used as therapy for the overweight patient whose Type 2 diabetes is not being controlled through diet and exercise and for whom the drug metformin is inappropriate. The combination drug is most often used in those patients who have insufficient glycemic control despite taking metformin alone or for those patients who have shown a level of intolerance to metformin. The results of the study showed that when pioglitazone was prescribed in conjunction with other anti-diabetic therapies such as insulin, the risk of macrovascular disease was greatly reduced. Macrovascular disease is common in those with long-term diabetes and refers to a disease of the large blood vessels in the body.

Clinical Support for Pioglitazone Application
Evidence was submitted which supported the application of pioglitazone, including four clinical trial reports which studied the safety of the drug when used in conjunction with insulin therapy. The studies were conducted according to prevailing ethical standards, and were random, double-blind, placebo controlled.

First Pioglitazone Study—PNFP-014
Pioglitazone was administered both in 15 mg dosages as well as 30 mg dosages in combination with insulin then compared with using insulin therapy alone. Participants in the studies were between the ages of 30 and 75, and had been on a fixed dose of insulin for at least a month prior to beginning the study. The mean baseline age was 57 years, with an average BMI of 33.6. Nearly 3/4ths of the participants in the study were Caucasian, with slightly more than half being female. Although the baseline systolic blood pressure was minimally higher in the group receiving pioglitazone plus insulin as opposed to the group receiving insulin alone, there were no other baseline variables involved. The patients who received both pioglitazone and insulin showed statistical decreases in the HbA1c levels which measure the average amount of sugar in the blood over a period of three months, and is different from glucose measurements. The HbA1c levels essentially give the physician an indication of how well the diabetes is being controlled.