Actos

Physicians prescribe Actos along with diet and exercise to help regulate blood sugar levels in people with Type 2 diabetes. The medication has made billions for its manufacturer, Takeda Pharmaceuticals, as one of the company’s best-selling drugs. But studies have linked long-term use of the medicine to a number of serious health complications, including heart failure and bladder cancer.

Actos Pills
Actos Facts
  1. Uses Doctors prescribe pioglitazone along with diet and exercise and sometimes other diabetes medications to improve blood sugar control in adults with Type 2 diabetes.
  2. Side Effects The most common side effects are cold-like symptoms, headache, sinus infection, muscle pain and sore throat. More serious risks include congestive heart failure, bladder cancer, fractures, liver failure, swelling, low blood sugar and eye problems.
  3. Manufacturer Takeda Pharmaceuticals America Inc.

Actos is a Type 2 diabetes drug that lowers blood sugar by increasing the body’s sensitivity to insulin and reducing the amount of glucose the liver releases. This allows the body to better dispose of excess blood sugar.

Its manufacturer, Takeda Pharmaceuticals America Inc., makes two additional versions of the drug that combine the active ingredient pioglitazone with metformin: Actoplus Met and Actoplus Met XR (extended release).

The FDA approved Actos in 1999, Actoplus Met in 2005 and Actoplus Met XR in 2009.

Eli Lilly partnered with Takeda to market the drug, and it became one of the most successful diabetes medications of all time. In 2007, it ranked as the world’s best-selling diabetes drug after studies linked rival drug Avandia to a higher risk of heart attack.

Both come from the same family of drugs: thiazolidinediones, or TZDs.

Before the medication’s patent expired in 2011, it had brought in $3.58 billion in United States sales in 2010. The drug’s sales made up 27 percent of Takeda’s revenue.

However, numerous studies and a review by the U.S. Food and Drug Administration linked higher dosages and prolonged use of the drug to an increased risk of bladder cancer.

In its 2015 annual report, Takeda said it had set aside $2.7 billion to cover the costs of settling Actos lawsuits that blamed the drug for bladder cancer and other injuries.

Despite the lawsuits and FDA review, doctors can still prescribe the drug in the United States.

Meanwhile, health regulators in Germany and France ordered Takeda to pull the drug off the market in 2011 after an analysis of a company-sponsored study showed an increased risk of developing bladder cancer or heart problems. The government in India also banned the drug.

Important Information on Taking Actos

Actos is meant to be used along with diet and exercise to improve blood sugar control in adults with Type 2 diabetes. Depending on how well your body naturally controls blood sugar, your doctor may prescribe pioglitazone by itself or with other diabetes medications.

The medicine comes in a tablet, and you should take it only as directed by your doctor. Instructions in the drug’s label say take it once a day with or without food.

Typically, the dose starts at 15 mg or 30 mg, but some people may require a stronger dose. Doctors can increase the dose by 15 mg increments up to a maximum of 45 mg daily.

Actos tablet dosage 15 mg, 30 mg and 45 mg.
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15 mg, 30 mg and 45 mg Actos tablets.

Do not change your dose unless your doctor tells you to. Let your doctor know if you are in an accident, undergo surgery, or develop a fever or an infection. Experiences like these can put added stress on your body, and your doctor may need to alter your dose.

It’s important to continue to follow your diet and exercise regimen and routinely test your blood sugar. Your doctor will likely test your hemoglobin A1C to gauge whether the medication is working. He or she should also examine your eyes on a regular basis because the medicine can cause a build-up of fluid in the eyes and affect your vision.

Risks to Discuss with Your Doctor Before Starting Treatment

Before prescribing Actos, your doctor should order certain blood tests, including ones that check for liver problems. He or she may decide against prescribing the drug to patients with certain conditions, so it’s important to tell your doctor about your medical history.

Let your doctor know if you have heart failure, Type 1 diabetes or diabetic ketoacidosis. Patients with these conditions should not take Actos. And neither should children who are under 18 years old.

Checklist to ask doctor when taking Actos.
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Source: Actos Medication Guide

Also tell your doctor if you have been diagnosed with bladder cancer, liver problems or macular edema, which is a diabetic eye disease that causes swelling in the back of the eye.

Pioglitazone can increase your chance of becoming pregnant and can harm your unborn baby. The medicine also passes into breast milk and can affect a nursing baby.

Talk to your doctor about birth control options and let him or her know if you are pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed.

Other medicines, vitamins or supplements you take can interact with pioglitazone and cause problems. For example, combining Actos with insulin or other antidiabetic medications can increase your risk of developing very low blood sugar, so a doctor may reduce the dose of the other diabetes drug.

Show your doctor or pharmacist a list of everything you take before you start using a new medication, so they can determine whether to adjust your dose or prescribe a different treatment.

Potential alternatives to Actos include Amaryl (glimepiride), Glucotrol (glipizide) and DiaBeta (glyburide). Prandin (repaglinide), Precose (acarbose) or Symlin (pramlintide) may also be substitutes for pioglitazone. As with Actos, these drugs can either be used alone or with another medication.

Common Side Effects

The most common side effects reported during Actos clinical trials were upper respiratory tract infection, headache, sinus infection, muscle pain and sore throat.

Other reported side effects included swelling, weight gain, back pain, dizziness, gas and diarrhea. The drug’s label says to call your doctor if you experience these side effects and they get worse or don’t go away.

Actoplus Met and Actoplus Met XR can cause the same side effects as Actos, but they can also cause side effects of metformin such as lactic acidosis, a life-threatening condition that occurs when too much lactic acid builds up in the body.

As of September 2018, the FDA Adverse Events Reporting System (FAERS) Public Dashboard showed 18,524 reports of complications possibly related to the drug since 1999. Of these, 15,029 were flagged as serious, including 2,618 deaths. The FDA points out that the medication may not have been the direct cause of the complications or deaths.

Congestive Heart Failure Black Box Warning

Actos has a black box warning for congestive heart failure. A black box warning is the most serious type of warning the FDA requires on a drug label.

Actos blackbox warning
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Source: Actos blackbox warning.

The boxed warning says Actos and other thiazolidinediones can cause fluid retention when used alone or with other antidiabetic drugs, particularly insulin. This can lead to congestive heart failure or make the condition worse in some patients.

It instructs doctors to carefully monitor patients for signs of heart failure such as rapid weight gain, labored breathing or swelling. This is especially the case after a patient first starts treatment or after dose increases.

Combining the drug with insulin may also increase the risk. And so can using the drug if you have New York Heart Association (NYHA) Class III or IV heart failure.

Because of the risk, the drug is not recommended for patients with symptomatic heart failure or NYHA Class III or IV heart failure.

The FDA based this warning on clinical trials Takeda had conducted before it released the drug. In one study called the PROactive trial, 5,238 patients with Type 2 diabetes and preexisting cardiovascular disease were treated with Actos or a placebo. According to the results, more pioglitazone patients experienced a serious heart failure event than those who had taken the placebo.

In addition, congestive heart failure caused more people to drop out of the trial than any other serious adverse event. About 1.3 percent of pioglitazone patients withdrew from the trial because of the side effect compared to 0.6 percent of patients who had taken a placebo.

FDA Bladder Cancer Review

The FDA alerted the public about a possible risk of bladder cancer in September 2010 and in June 2011 based on results from the first five years of a 10-year study that was designed to evaluate whether Actos is associated with an increased risk of bladder cancer.

In August 2011, the agency updated the labels of all drugs that contain pioglitazone to warn that using the drugs for more than a year may be associated with a possible increased risk of bladder cancer.

The updated drug labels recommended doctors not prescribe the drugs to patients with active bladder cancer and use caution when prescribing the drugs to patients with a prior history of bladder cancer.

The FDA also required Takeda to modify and continue its 10-year study.

Then in 2016, the agency again updated the drugs’ labels to describe additional studies it had reviewed. While Takeda’s 10-year study ultimately did not find an increased risk, the PROactive clinical trial and a study using data from the United Kingdom did. The agency also noted early animal studies had shown bladder tumors in rats.

“Overall, we conclude that pioglitazone may be associated with an increased risk in urinary bladder cancer, and we have updated the drug labels to include information about these additional studies.”

Source: FDA Safety Communication, Dec. 12, 2016

“Overall, we conclude that pioglitazone may be associated with an increased risk in urinary bladder cancer, and we have updated the drug labels to include information about these additional studies,” the FDA said.

According to the most recent data from the FDA, bladder cancer is the most frequently reported reaction to Actos. With more than 8,500 reports, it accounts for 46 percent of all adverse events reported to the FAERS database involving the drug.

Recent Bladder Cancer Studies
  • 2018
    A review and meta-analysis published in Cancer Medicine found a “slightly but significantly increased risk of bladder cancer.” The authors also found increased risk was tied to higher doses and prolonged use.
  • 2017
    A study published in Diabetes, Obesity and Metabolism analyzed Medicare data from nearly a quarter-million beneficiaries. Researchers found a “small absolute increase in risk of bladder cancer” among Actos users compared to people taking other diabetes drugs. They reported the increased risk appeared within the first two years of drug use and continued to increase the longer people took pioglitazone.
  • 2016
    A population-based cohort study published in the British Medical Journal found pioglitazone was associated with an increased bladder cancer risk. The researchers looked at medical records of 145,000 people treated with different diabetes drugs in the same class. They found an increased risk and said it was specific to pioglitazone.

Fracture and Liver Failure Risks

The PROactive clinical trial also found an increase in the number of women who took pioglitazone and suffered bone fractures. Fractures were most likely to happen in the hands, forearms, feet, ankles and legs, according to information on the drug’s label.

The trial followed participants for nearly three years, and researchers started noticing the difference in female patients after the first year. The trial did not see the same increased risk for men who took the drug.

BONE FRACTURES
5.1 percent of women who took Actos during the PROactive trial suffered bone fractures compared to 2.5 percent of women who took a placebo.

A more recent study published in The Journal of Clinical Endocrinology & Metabolism in 2017 also found an increased risk of fractures among people who had taken the drug. The clinical trial followed 3,876 stroke patients for roughly five years.

Researchers found 8.8 percent of those who had taken a placebo had fractures during that time. But those taking pioglitazone had increased relative risks ranging from 47 percent to 60 percent, depending on the type of fracture.

After Actos became available in the United States, the FDA and Takeda received reports of some fatal and nonfatal cases of liver failure. The drug’s label says there is no way to definitively prove that pioglitazone does not cause liver issues.

It advises doctors to “use caution in patients with liver disease.” It also tells them to test each patient’s liver prior to prescribing the drug and to monitor each patient for signs of liver damage, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

Please seek the advice of a medical professional before making health care decisions.

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Terry Turner
Written By Terry Turner Writer

Terry Turner has been writing articles and producing news broadcasts for more than 25 years. He covers FDA policy, proton pump inhibitors, and medical devices such as hernia mesh, IVC filters, and hip and knee implants. An Emmy-winning journalist, he has reported on health and medical policy issues before Congress, the FDA and other federal agencies. Some of his qualifications include:

  • American Medical Writers Association (AMWA) and The Alliance of Professional Health Advocates member
  • Centers for Disease Control and Prevention Health Literacy certificates
  • Original works published or cited in Washington Examiner, MedPage Today and The New York Times
  • Appeared as an expert panelist on hernia mesh lawsuits on the BBC
Edited By

12 Cited Research Articles

  1. Alazraki, M. (2011, February 27). The 10 biggest-selling drugs that are about to lose their patent. Daily Finance. Retrieved from http://www.dailyfinance.com/2011/02/27/top-selling-drugs-are-about-to-lose-patent-protection-ready/
  2. National Library of Health (2013). Actos (pioglitazone). Daily Med. Retrieved from http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=d2ddc491-88a9-4063-9150-443b4fa4330c#nlm34066-1
  3. Feeley, J. (2013, March 6). Takeda put Actos sales ahead of user safety, witness says. Bloomberg. Retrieved from https://www.bloomberg.com/news/articles/2013-03-05/takeda-put-actos-sales-ahead-of-user-safety-witness-says
  4. Reinberg, S. (2012, May 31). Diabetes drug may increase bladder cancer odds. U.S. News and World Report. Retrieved from http://health.usnews.com/health-news/news/articles/2012/06/01/diabetes-drug-actos-may-increase-bladder-cancer-odds
  5. Feeley, J. & Matsuyama, K. (2014, April 8). Takeda, Lilly jury awards $9 billion over Actos risks. Bloomberg. Retrieved from https://www.bloomberg.com/news/articles/2014-04-07/takeda-actos-jury-awards-6-billion-in-punitive-damages
  6. Takeda Pharmaceutical Company Limited. (2015) Annual Report 2015. Retrieved from https://www.takeda.com/siteassets/system/investors/report/annual-reports/ar2015_en.pdf
  7. U.S. Food and Drug Administration (2011, July). ACTOS (pioglitazone hydrochloride) tablets for oral use. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf
  8. Takeda Pharmaceutical Company Limited. (2016, December). ACTOPLUS MET (pioglitazone and metformin hydrochloride) tablets for oral use. Retrieved from http://general.takedapharm.com/content/file.aspx?filetypecode=actoplusmetpi&cacheRandomizer=a69bda0f-c0d5-4f68-bdb0-5a7a18a36580
  9. Takeda Pharmaceutical Company Limited. (2017, January). ACTOPLUS MET XR (pioglitazone and metformin hydrochloride extended-release) tablets for oral use. Retrieved from http://general.takedapharm.com/content/file.aspx?filetypecode=ACTOPLUSMETXRPI&cacheRandomizer=732aa167-27e8-4a8f-8538-a188a7efda2e
  10. U.S. Food and Drug Administration (2016, December 12). Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer. Retrieved from https://www.fda.gov/downloads/Drugs/DrugSafety/UCM532691.pdf
  11. NIDDK, NIH. (2017, July 18). What is Diabetes? Retrieved from: https://www.niddk.nih.gov/health-information/diabetes/overview/what-is-diabetes
  12. MedlinePlus, NIH. (2015, July 24). Type 2 diabetes. Retrieved from: https://medlineplus.gov/ency/article/000313.htm
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