Actos is a prescription diabetes medication produced by the Japanese drug company Takeda Pharmaceuticals. Actos was approved by the FDA in July of 1999 and become the market leader after a 2007 study showed a 43 percent higher chance of heart attacks from GlaxoSmithKline Plc’s Avandia. (According to a study published last year in the American Heart Association journal, Circulation: Cardiovascular Quality and Outcomes, the heart risk from Actos is just as great as the risk posed by Avandia.)
In the last year, the medication had global sales of $4.8 billion and accounted for 27% of Takeda’s revenue. In 2008, Actos was the tenth best selling medication in the United States. From January 2010 through October 2010, there were an estimated 2.3 million prescriptions filled by diabetic patients that had a pioglitazone containing product from pharmacies in the United States.
Actos is used to treat type 2 diabetes in adults (aged 18 years or over), particularly those who are overweight. It is used in addition to diet and exercise.
Actos is used on its own in patients for whom metformin (another antidiabetes medicine) is not suitable. Actos can also be used in combination with metformin in patients who are not satisfactorily controlled on metformin alone, or with a sulphonylurea (another type of antidiabetes medicine) when metformin is not suitable (‘dual therapy’). It can be used together with both metformin and a sulphonylurea in patients who are not satisfactorily controlled despite dual therapy by mouth (‘triple therapy’). Actos can also be used together with insulin in patients who are not satisfactorily controlled with insulin alone and cannot take metformin.
Type 2 diabetes is a disease in which the pancreas does not make enough insulin to control the level of glucose in the blood or when the body is unable to use insulin effectively. The active substance in Actos, pioglitazone, makes cells (fat, muscle and liver) more sensitive to insulin, which means that the body makes better use of the insulin it produces. As a consequence, the blood glucose levels are reduced and this helps to control type 2 diabetes.
Serious adverse effects of this molecule that are most frequent include heart failure, bone fractures in women, lung effects (dyspnea, edema), eye disorders (including macular edema) and weight gain.
Association with Bladder Cancer
In preclinical carcinogenicity studies of pioglitazone performed by Takeda, bladder tumors were observed in male rats receiving doses of pioglitazone that produced blood drug levels equivalent to those resulting from a clinical dose for humans. In addition, two 3-year controlled trials of Actos (including the PROactive study) demonstrated a higher percentage of bladder cancer cases in patients receiving Actos, 16/1656 (0.44%), and those receiving a comparator, 5/3679 (0.14%).
Due to these initial results, in 2003 the U.S. Food and Drug Administration requested that the manufacturer of pioglitazone conduct a safety study to assess whether therapy with pioglitazone increases the risk of bladder cancer.
On September 17, 2010 the FDA issued an alert regarding a potential risk of bladder cancer during treatment with pioglitazone seen in the intermediate outcomes of the 5th year of the 10 year Kaiser Permanente of Northern California study. The results showed that after adjusting for age, sex, use of tobacco products, use of other categories of diabetes medications, and other risk factors, there was no significant increase in the risk for bladder cancer in patients ever exposed to pioglitazone compared to patients never exposed to pioglitazone. However, the risk of bladder cancer increased with increasing dose and duration of pioglitazone use. Compared to never being exposed to pioglitazone, a duration of pioglitazone therapy longer than 12 months was associated with a 40% increase in risk. The hazard ratio after more than 24 months of pioglitazone use was 1.4 and was of nominal statistical significance. Based on these data, FDA calculated that 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 never using pioglitazone.
On June 9, 2011 the French Agency for the Safety of Health Products (Afssaps) pulled Actos and Competact (pioglitazone in combination with metformin) from their market because of safety concerns over the association with bladder cancer. This action was the result of a clinical study conducted by the French National Health Insurance Plan (CNAMTS) using 1.5 million diabetic patients treated with pioglitazone. It was shown that there was a statistically significant increase in the risk for bladder cancer in patients using pioglitazone and that risk increased with exposure longer than one year. There was also a dose-response relationship with a significant risk for those with a cumulative dose greater than or equal to 28,000 mg. Germany soon followed. The European Medicines Agency is currently evaluating the results of the French study and will update the public on its findings in July.
- Blood or red color in urine
- Urgent need to urinate
- Pain while urinating
- Pain in back
- Pain in lower abdomen
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