Diabetes Drug Risk Of Cancer And Other Side Effects. The U.S. Food and Drug Administration (FDA) approved Actos, which is manufactured by Takeda Chemical Industries, on July 15, 1999. Actos includes the active ingredient pioglitazone hydrochloride and is used for treatment of Type 2 and Type 1 diabetes; Type 1 diabetes mellitus; diabetes mellitus inadequate control; and high blood pressure. Two Actos-metformin combination drugs, Actoplusmet and Actoplusmet XR, contain both pioglitazone and metformin HCI.
Pioglitazone drugs are sold as a single-ingredient product under the brand name Actos and are also sold in combination with metformin as Actoplus Met (pioglitazone/metformin), Actoplus Met XR (pioglitazone/metformin extended-release), and DueTact (pioglitazone/glimepiride). The complete Actos portfolio of drugs includes the following:
- ActoPlus Met (active ingredient: metformin hydrochloride; pioglitazone hydrochloride)
- ActoPlus Met XR (active ingredient: metformin hydrochloride; pioglitazone hydrochloride extended release)
- Actos (active ingredient: pioglitazone hydrochloride)
- DueTact (active ingredient: glimepiride; pioglitazone hydrochloride)
- Pioglitazone (active ingredient: pioglitazone hydrochloride)
- Pioglitazone hydrochloride and metformin hydrochloride (active ingredient: metformin hydrochloride; pioglitazone hydrochloride)
Actos and other pioglitazone products are typically prescribed, along with diet and exercise, to individuals who have been diagnosed with Type 2 diabetes; the drugs are meant to stabilize the unusually high blood sugar levels associated with diabetes. Actos and other pioglitazone drugs work by increasing the body’s sensitivity to insulin, which is a natural hormone that helps to control blood sugar levels. If left untreated, Type 2 diabetes may lead to serious, long-term health problems such as blindness, nerve damage, kidney damage, and heart disease. Mounting patients and patient families, allege, in a growing number of lawsuits, that Actos led to their bladder cancer, or the death of a loved one due to Actos bladder cancer.
Bladder cancer is an aggressive cancer that often recurs, even after years of remission. Treatment, as with most cancers, involves chemotherapy and radiation therapy, as well as surgery and other medications.
The attorneys at Parker Waichman LLP are accepting cases and investigating the filing of lawsuits, including class action lawsuits, on behalf of individuals who experienced adverse health reactions, including bladder cancer, following treatment with Actos and pioglitazone-containing Actos medications that also contain the active ingredient, metformin. If you or someone you know experienced Actos bladder cancer or other adverse reactions associated with Actos use, we urge you to contact one of our Actos attorneys for a free consultation.
Since the approval of the Actos drug line, our Actos lawyers have heard from many individuals who suffered various adverse reactions after taking these medications, including bladder cancer.
Parker Waichman remains actively involved in the Actos multidistrict litigation (MDL) and Jerrold S. Parker, founding partner of the firm, has maintained a leadership role throughout the litigation by serving on the Plaintiff’s Steering Committee.
Actos May Increase Bladder Cancer Risks
In an update to an FDA Drug Safety Communication “Updated Drug Labels for Pioglitazone-Containing Medications” released on August 4, 2011, the federal regulators pointed out that, following an updated review, it found that use of Type 2 piogliazone-containing diabetes drugs may be associated with increased risks for bladder cancer. The labels of pioglitazone-containing drugs do include bladder cancer risk warnings; however, in late 2016, the agency approved label updates that discuss the additional studies confirming this risk that it reviewed.
The FDA previously alerted the public about the possible risk of Actos-related bladder cancer in September 2010 and June 2011; this, following interim reports from a 10-year epidemiologic study. The agency changed the labels of pioglitazone-containing drugs, such as Actos, in August 2011 to reflect warnings concerning the bladder cancer risk and mandated the maker of the drug to modify and continue the study.
Doctors and other health care professionals have been warned that pioglitazone products, including Actos, should not be prescribed to patients diagnosed with active bladder cancer and caution should be used when prescribing the drug to patients with a history of bladder cancer. Experts also note that other significant Actos side effects may include heart failure, heart attacks, and serious liver problems.
If any of the following signs or symptoms are seen upon treatment with Actos, patients are advised to contact their physicians or health care professionals as these symptoms may potentially indicate bladder cancer:
- Blood in the urine or red-colored urine
- New or increasing urge to urine
- Pain when urinating
The FDA also indicated that it had reviewed other published studies that reviewed the risk of bladder cancer in patients treated with Actos and other pioglitazone drugs. Given the varied results, the agency now warns that overall data suggests that Actos/pioglitazone use may be tied to increased risks of bladder cancer.
The prior agency Safety Communication, entitled, “Updated Drug Labels for Pioglitazone-Containing Medicines” issued on August 4, 2011 contained information that followed up on the June 2011 “Drug Safety Communication” that was an “Update to Ongoing Safety Review of Actos (pioglitazone) and Increased Risk of Bladder Cancer.”
The FDA also informed the public in August 2011 that it approved updating the drug labels for pioglitazone-containing medicines, such as Actos. The then-new warning had to include safety information that use of pioglitazone for more than one year may be tied to an increased risk of developing bladder cancer. This information on labeling was previously communicated in the June 2011 Drug Safety Communication.
Prior Actos Bladder Cancer Research
The September 2010 FDA Drug Safety Communication: “Ongoing Safety Review of Actos (pioglitazone) and
Potential Increased Risk of Bladder Cancer After Two Years Exposure” issued information about the risk of bladder cancer after taking Actos for two years. The release was issued after the agency reviewed data from on the ongoing, ten-year epidemiological study that was created to determine if Actos was tied to an increased risk of developing bladder cancer. At that time, findings from studies in animals and humans suggested this to be a potential safety risk that called for further study.
At the time, Actos manufacturer, Takeda Pharmaceutical, conducted a review of the research data five years into the study, submitting their results the FDA. At the time, no statistically significant association was found between Actos exposure and bladder cancer risk. Yet, further analyses reviewed for how long patients were taking Actos and the total amount of Actos they received during that time found an increased risk of bladder cancer was seen in those patients who had the longest exposure to Actos and in patients who were exposed to the highest cumulative dose of Actos.
In preclinical carcinogenicity pioglitazone research, bladder tumors were seen in male rats receiving pioglitazone in doses that produced blood pioglitazone levels that were equal to a clinical dose. Results from two three-year controlled clinical Actos studies-the PROactive study and a liver safety study-revealed an increased percentage of individuals diagnosed with bladder cancer in those taking Actos when compared to those taking a “comparator” drug.
The FDA also discussed an epidemiological study conducted in France, which suggested, among other findings, a statistically significant increase in bladder cancer associated with pioglitazone. Based on the study results, France suspended the use of pioglitazone and Germany recommended against starting pioglitazone in new patients.
Actos has been the subject of mounting lawsuits brought against Takeda and Eli Lilly & Co. The two firms originally jointly marketed Actos. According to Bloomberg News, Actos drug makers may face up to 10,000 Actos Bladder Cancer lawsuits.
The U.S. Judicial Panel on multidistrict litigation (MDL) moved that all Actos lawsuits pending in federal court be consolidated and heard in the U.S. District Court for the Western District of Louisiana. Meanwhile, in April 2016. Takeda agreed to a settlement program in which it would pay $2.37 billion if 95 percent of eligible plaintiffs agree to participate and $2.4 billion if at least 97 percent of eligible plaintiffs choose to participate in the program, Bloomberg News reported that each of the eligible plaintiffs may receive more than $296,000.
Actos Lawsuit Continues in Nevada
A jury in Las Vegas, Nevada had been hearing arguments over potential safety issues associated with Actos. The trial commenced on August 27, 2015 and was heard before Judge Jerry Wiese II. The case is in the Supreme Court of the State of Nevada, No. 68598, district court number A-13-683446-C, Department No. 30, consolidated with Case No. A-14-697468-C, filed August 12, 2015, Takeda Pharmaceuticals America, Inc.; Takeda Pharmaceuticals North America, Inc.; Takeda Pharmaceuticals Company Limited; and Dustin Hindmarch, Does I through X, and Roes 1, through X, petitioners, v. the Eighth Judicial District Court of the State of Nevada, in and for the County of Clark; and The Honorable Jerry A. Wiese II, District Judge, respondents, and George F. Decou, individually; Joann Passer as special administratrix of the estate of Maurice J. Iorio; and Mary Iorio, individually and as surviving spouse of Maurice J. Iorio, deceased, real parties in interest.
Plaintiffs involved in the Las Vegas Actos trial claimed that Takeda knew of Actos’ alleged risks but did not appropriately advise patients and those in the healthcare community; plaintiffs are expected to seek $2 billion in damages on behalf of George Decou and the estate of Maurice J. Iorio. Mr. Decou was diagnosed with bladder cancer, which he alleges is the result of his having taken Actos. Mr. Iorio, also diagnosed with bladder cancer, succumbed to the disease November 25, 2013; his widow is demanding Takeda take responsibility for the death of her husband.
Judge Wiese advised the jury at the beginning of the trial that Takeda intentionally destroyed documents related to Actos cases. Judge Wiese also noted that the jury could presume that the destroyed documents would have contributed to the two plaintiffs’ case. Similar instructions were also given to a 2014 jury who heard a different Actos bladder cancer trial. In this case, plaintiffs’ counsel noted that the evidence was intentionally destroyed and that the hard drives of eight of Takeda’s executives were compromised even after the firm was advised to preserve this specific evidence. According to opening statements for the plaintiffs, the following was read: “Takeda Pharmaceuticals already acknowledged they have no ability to rebut the presumption that the evidence they destroyed, on a massive scale, was damning. To put it into perspective, they could have filled a football stadium with the amount of evidence they destroyed if it were printed on paper.”
Meanwhile, in 2014, a Louisiana jury found Takeda liable for $9 billion after agreeing with the plaintiff that the Takeda intentionally concealed the health risks associated with Actos. A judge later ruled for a 99.6 percent reduction in the award; Takeda was found liable for $36.8 million. In all, at that time, Court dockets reveal that there are over 3,500 Actos lawsuits consolidated before U.S. District Judge Rebecca Doherty in Lafayette, Louisiana for pretrial discovery and, an additional 4,500 cases have been filed in state courts in Illinois, West Virginia, California, and Pennsylvania.
Results of the First Actos Bladder Cancer Bellwether Trial
The couple who brought the first Actos bellwether case alleged that the husband was prescribed and took Actos to treat his Type 2 diabetes from 2004 to 2011; in 2011, he was diagnosed with bladder cancer. He alleged that it was his taking Actos that caused him to develop bladder cancer and that Takeda Pharmaceutical Co. hid the drug’s potential risks from the public.
This couple’s claim’s are similar to the claims that have been made in the 2,700 other lawsuits that are pending in the Actos multidistrict litigation (MDL). Actos patients who have brought lawsuits all generally allege that Takeda ignored or minimized Actos’ association with increased cancer risks prior to the drug being released in the United States in 1999. Litigation also includes arguments that Takeda misled U.S. regulators about these risks. This bellwether is expected help determine how the remaining cases will proceed.
The case was heard prior to thousands of other lawsuits brought over Actos due to the man’s grave condition. Court documents indicate that, in April 2013, a verdict was issued against Takeda over allegations that Takeda failed to adequately inform about the link between Actos and bladder cancer. The jury awarded the plaintiffs $6.5 million-$5 million to the man and $1.5 million to his wife pertaining to her loss of consortium.
In this case, a $6.5 million verdict was tossed five days after it was issued, with a trial judge finding that an expert’s testimony was speculative. Since, that decision was reversed and the verdict reinstated when a California appeals court found that the lower court erred and exceeded the boundaries of its function when it required the expert to rule out all other potential causes of bladder cancer, despite a lack of evidence for other causes. The case is Nancy Cooper et al. v. Takeda Pharmaceuticals America Inc. et al., case number B250163, in the Court of Appeal of the State of California, Second Appellate District, Division Three. The original case, Cooper v. Takeda Pharmaceuticals America Inc., Case Number CGC-12-518535, Superior Court of the State of California, County of Los Angeles, was filed on behalf of a couple who alleged that Actos was to blame for the man’s terminal bladder cancer.
|Quick Facts: Actos|
|Generic Name||Pioglitazone hydrochloride|
|Other Types||Actosplus Met
Actosplus Met XR
Pioglitazone Hydrochloride Chloride & Metformin Hydrochloride
|Date Approved||July 15, 1999|
|Status||On the market|
|Serious Side Effects||Bladder Cancer
Swelling of the feet
Congestive heart failure
Studies, Data Regarding Actos-Bladder Cancer Link
The website eHealthMe conducted a study on May 24, 2013 to analyze Actos and the risk of bladder cancer. In total 29,989 Actos users participated in the study, which was also based on reports from the FDA and is updated regularly.
In this analysis, 29,989 people reported experiencing side effects while taking Actos. Among them, 1,631 people (or 5.44 percent) developed bladder cancer. The largest concentration (about 39.48 percent) were using Actos between two and five years before developing bladder cancer, with the next-largest concentration (about 32.17 percent) using Actos between five and 10 years.
In June 2011, medical regulators in France and Germany suspended sales of the Type 2 diabetes drug Actos because of a possible link to bladder cancer. The French and German decisions to ban the drug followed a study commissioned by the French Medicines Agency that found that people taking Actos were more likely to develop bladder cancer, an aggressive form of cancer. The study examined cancer rates in some 155,000 people taking Actos in France from 2006 to 2009, and 1.3 million other diabetics who were not receiving the drug. The study found that the risk of bladder cancer was about 22 percent higher among those taking the drug compared with diabetics taking other drugs. The bladder cancer risk was highest in those receiving a cumulative dosage of 28,000 mg or more during the study period.
Also in June 2011, the U.S. Food & Drug Administration (FDA) announced it was reviewing Actos for possible bladder cancer risk based on a September 2010 safety review. At the time the agency indicated that early data from a 10-year study submitted by Takeda, the maker of Actos, had not indicated a statistically significant association between exposure to Actos and bladder cancer risk. However, there was some evidence that patients taking Actos for at least two years or at the highest cumulative doses (>28,000 mg) did face a greater risk of developing bladder cancer.
In May 2011, another study, this one looking at adverse event reports sent to the FDA between 2004 and 2009, suggested that Actos patients faced a “disproportionate risk” of developing bladder cancer. The study looked at a half-million side effect reports associated with various diabetes medications and found that one-fifth of those involving bladder cancer occurred in patients using Actos.
New Research May Indicate Actos Also Linked to Greater Risk of Cardiovascular, Heart Disease Side
Effects and Risks
Prior research was added to the growing body of evidence linking Avandia and Actos to increased adverse health risks. Avandia had long been the center of a debate concerning cardiovascular risks, while Actos has been considered a safer alternative; this has helped sales of Actos skyrocket above Avandia.
Both Actos and Avandia fall into the drug class known as thizolidinedione. Thizolidinediones reduce insulin resistance in body tissue as well as adjust cholesterol levels; the drug class is considered to include the strongest medications for treatment of Type 2 diabetes, according to a prior the Los Angeles Times report.
The Los Angeles Times reported on a 2007 study in which more than 200,000 Medicare patients participated. The study noted that Avandia (rosiglitazone) users experienced an increased risk of heart attack, cardiovascular disease, stroke, and death by 30-40 percent compared with older diabetes medications, according to the Los Angeles Times. The study indicated that this particular risk was not seen with Actos.
The study prompted strong FDA label warnings, with even stronger warnings following more reports of increased risks with Avandia, according to the Los Angeles Times. An FDA panel found that Avandia’s benefits outweighed its risks and that it should remain on the market; the panel also indicated that no more patients were to be enrolled in prospective studies comparing the two drugs.
The panel, led by Debra Wertz, outcomes research manager at HealthCore Inc., a Wellpoint Inc. research subsidiary, analyzed the records of 28,938 patients who took either medication from 2001 to 2005, obtaining company data, according to the Los Angeles Times. Death information was derived from the National Death Index, which is managed by the National Center for Health Statistics. The research appeared in the journal Circulation: Cardiovascular Quality and Outcomes.
Accounting for age, gender, and prior heart disease, about 4 percent of each group either suffered a heart attack or heart failure or died, according to the Los Angeles Times. The figures break down to 96 Avandia patients and 121 Actos patients suffering heart attacks, and 265 Avandia patients and 243 Actos patients suffering from heart failure, wrote the Los Angeles Times; 217 patients in each group died.
“What distinguishes this latest study from other claims-based analyses is its analysis of death records, which include out-of-hospital deaths,” Wertz said in a statement quoted by the Los Angeles Times. Also, the study followed younger patients longer than did previous studies. Earlier studies also did not include stroke data, which could affect outcomes.
Study Found Actos May Increase Risk of Fractures
Another study linked Avandia and Actos to an increased risk of fractures. The research, which appeared in the Journal of Clinical Endocrinology & Metabolism, found that the drugs increased the risk of fractures in post-menopausal women diagnosed with Type 2 diabetes, as well as in men prescribed either drug with a loop diuretic.
Women over 50 who had broken bones were 71 percent likelier to have been prescribed a thiazolidinedione. In men, this risk more than tripled and was seen among those taking both a thiazolidinedione and a loop diuretic, like Lasix, but not in just one or the other. The researchers pointed out that loop diuretics have been linked to bone density decreases. In both genders, the fracture risk increased the longer a person was on the medication. According to the researchers, the fractures seen in the study were not just the spine and hip fractures most often seen in people with osteoporosis. Many of the people in the study suffered lower-limb arm and leg fractures.
FDA Requires Actos to Include a Black Box Warning
Actoplusmet, a pioglitazone-metformin drug combination in the Actos line of medications that is prescribed to treat Tupe 2 diabetes, is now included in a list of pioglitazone-containing medications that have been associated with an increased risk of bladder cancer.
Patients who took Actos; the Actos-metformin combinations, and other Actos drugs, and who were diagnosed with bladder cancer may have legal recourse. In fact, an FDA Safety Announcement involving the links between bladder cancer and Actos, including Actoplusmet with metformin, for more than one year, may experience an increased risk for developing the deadly cancer.
Some lawsuits brought over the Actos-bladder cancer association allege that Takeda Pharmaceuticals withheld critical information about the risk of developing bladder cancer when taking Actos and did not include sufficient warnings on its various diabetes drugs, including Actos and Actos with metformin.
After an intense debate over the safety of the Type 2 diabetes drug Actos, the FDA stated that a black box warning must be added to the heart risk warnings on Actos, due to the serious risk of adverse cardiovascular events, including heart attack, heart failure, and cardiovascular-related deaths. The black box warning is the strongest FDA-requested label change that can be added to a drug.
The first approved drug in the class, Rezulin, was taken off the market in 2000 after it was linked to dozens of cases of fatal liver disease.
The American Heart Association and the American Diabetes Association both issued recommendations to guide Actos use, a glucose-lowering drug, and other drugs classified as thiazolidinediones (TZDs). Diabetics with mild heart disease or any kidney problems may be at an increased risk of developing congestive heart failure if they take certain diabetes medications, according to a study.
The study, published in the September 9, 2003 issue of the Mayo Clinic Proceedings, reported on six cases of congestive heart failure in people taking pioglitazone drugs such as Actos or rosiglitazone drugs, such as Avandia to help control their diabetes. The researchers studied the records of six men between the ages of 66 and 78 diagnosed with Type 2 diabetes who had been treated at the Dallas Veterans Affairs Medical Center emergency room.
All six patients complained of shortness of breath, swelling of their feet, and weight gain, which are symptoms of congestive heart failure and pulmonary edema (fluid buildup in the lungs). Congestive heart failure occurs when the heart can no longer pump enough blood to maintain adequate circulation. Because the heart does not pump properly, fluid often builds up in the lungs.
Four of the six people in this study were diagnosed with chronic renal insufficiency, which means that their kidneys were not functioning normally. Only two had any previous signs of heart disease. Four of the six were diagnosed with high blood pressure. The men had been on diabetes medications for between one and 16 months. Three people developed symptoms within one to three months, when their diabetes drug dosage had been increased.
In 2002, Takeda was criticized over some promotional material designed to promote Actos. The company received a letter from the Department of Health & Human Services’ (HHS) Division of Drug Marketing, Advertising and Communications (DDMAC). The agency indicated that, after reviewing promotional materials designed to support Actos, it had determined that the material, which was distributed at an industry trade show in 2002, violated the Federal Food, Drug and Cosmetic Act. Specifically, the material was misleading in that it omitted important safety information and also highlighted results that have not been demonstrated, the regulator indicated.
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