Takeda Announces Completion of the Pioglitazone Post-Marketing Commitment and Submission of Results to the EMA, the FDA and the PMDA

OSAKA, Japan, July 30, 2015 /PRNewswire/ -- Takeda Pharmaceutical Company Limited ("Takeda") today announced the completion of the study to fulfill the post-marketing commitment and submissions of data to regulatory authorities from the Pan European Multi-Database Bladder Cancer Risk Characterization Study, a large (n= 112,674), multi-database retrospective matched cohort study, conducted in four European countries, for pioglitazone containing medicines, including ACTOS (pioglitazone HCI) with up to 10 years of follow-up. Findings demonstrate that there is no association between the use of pioglitazone and the risk of bladder cancer, (hazard ratio [HR] 0.99 [95% CI: 0.75, 1.30]). These results are consistent with those of a 10-year, prospective cohort study, conducted by the University of Pennsylvania (U. of Penn.) and Division of Research at Kaiser Permanente Northern California (KPNC), which demonstrated no increased risk of bladder cancer among patients ever exposed to pioglitazone ([HR] 1.06 [95% CI 0.89-1.26]). Additionally, both studies found no association between the risk of bladder cancer and cumulative dose of pioglitazone, or duration of pioglitazone exposure.

"ACTOS is an important treatment option for patients with Type 2 diabetes. These data further reinforce the positive benefit/risk profile for ACTOS," said Alfonso Perez, MD, vice president, clinical research, Takeda. "These long-term studies underscore Takeda's commitment to ensuring physicians have the best available information to make treatment decisions."

The data from the Pan European Multi-Database Bladder Cancer Risk Characterization Study also shows a mortality decrease with ever use of pioglitazone (adjusted HR 0.67 [95% CI: 0.64, 0.70]). This study was completed as part of the post-marketing request from the Committee for Medicinal Products for Human Use (CHMP). In addition to the European Medicines Agency (EMA), the results from the Pan European study were also submitted to the U.S. Food and Drug Administration (FDA) and the Japanese Ministry of Health, Labour and Welfare (MHLW)/Pharmaceuticals and Medical Devices Agency (PMDA). The data will be shared with additional regulatory authorities in accordance with local requirements around the world.

"Patient safety remains a top priority for Takeda," said Perez. "Throughout a product's lifecycle we continue to monitor and conduct additional research to further our knowledge. This milestone is an important example of Takeda's commitment to conducting further research and sharing the outcomes with regulatory agencies, physicians, and others."

About the Study
The retrospective cohort study of the European Union (EU) medical record databases was conducted using six medical records databases across four countries, including Finland, The Netherlands, Sweden, and the United Kingdom. Type 2 diabetes patients treated with pioglitazone were matched equally with patients with similar characteristics who were not treated with pioglitazone. Patients were matched based on diabetes duration, diabetes complications, cardiovascular complications, and previous antidiabetic drug use. This study design was developed to minimize treatment allocation bias, an issue seen in some previous epidemiological studies of pioglitazone.

About Pioglitazone
Pioglitazone is a thiazolidinedione for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise.

Unlike many oral antidiabetic drugs, pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. Therefore, pioglitazone is a medication that depends on the presence of insulin for its mechanism of action, and it decreases insulin resistance in muscle and the liver, resulting in increased insulin-dependent glucose disposal as well as decreased hepatic glucose output.

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with Type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with sulfonylurea, metformin, or insulin.

Important Safety Information
Contraindications
Initiation of ACTOS is contraindicated in patients with NYHA Class III or IV heart failure. ACTOS is contraindicated in patients with known hypersensitivity to pioglitazone or any of its excipients so as to avoid inducing a potentially serious hypersensitivity reaction.

Warnings and Precautions
Fluid retention and cardiac failure: Thiazolidinediones, including ACTOS, can cause dose-dependent fluid retention, which may exacerbate or precipitate heart failure. After initiation of ACTOS, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, discontinuation of ACTOS must be considered. ACTOS should be used with caution in patients with cardiac dysfunction whose physical activity is markedly limited. Combination use with insulin may increase risk.

Hepatic effects: Post-marketing reports of hepatitis and hepatic dysfunction have been received. Very rarely these reports have involved hepatic failure, with and without a fatal outcome, although causality has not been established. Obtain liver tests before starting ACTOS and periodically thereafter. Pioglitazone therapy should not be initiated in patients with increased liver enzyme levels (ALT> 2.5x upper limit of normal) or with any other evidence of liver disease. Existing pioglitazone therapy should be discontinued if ALT levels are persistently higher than 3x the upper limit of normal, and symptoms suggesting hepatic dysfunction should cause the liver enzymes to be checked. Pending the results of laboratory investigations, the decision as to whether pioglitazone therapy should continue must be based on clinical judgment; in the presence of jaundice, drug therapy should be discontinued.

Weight gain: Weight gain was observed in clinical trials and has been seen in post-marketing experience with pioglitazone, so patient weight should be closely monitored.

Fractures: An increased incidence of bone fracture has been noted in female patients.

Bladder cancer: Some data suggest there may be an increased risk of bladder cancer in ACTOS users and also that the risk increases with duration of use. Do not use ACTOS in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.

Hypoglycemia: When ACTOS is used with insulin, a sulfonylurea or other oral hypoglycemic agents, hypoglycemia may occur.

Ovulation: Ovulation in premenopausal anovulatory women or women with polycystic ovarian syndrome may occur with ACTOS.

Macular edema: Post-marketing reports of new-onset or worsening diabetic macular edema with decreased visual acuity have been reported with thiazolidinediones, including pioglitazone. Physicians should consider the possibility of macular edema if a patient reports decreased visual activity.

Drug interactions: Use of ACTOS with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Please refer to the Summary of Product Characteristics (SmPC) for ACTOS before prescribing.

ACTOS should be used according to the indication, posology and method of administration described in the SmPC.

Please consult with your local regulatory agency for approved labeling in your country.

About Takeda's Diabetes Business
Takeda's heritage in diabetes globally includes significant contributions towards scientific discovery and exchange, starting with the discovery of the thiazolidinedione (TZD) pioglitazone. Takeda launched alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in Japan in 2010. Since that time alogliptin has been launched in a variety of markets across the globe including the U.S., Italy, the United Kingdom, China, Mexico and South Korea. Diabetes prevalence continues to grow worldwide, with more than 382 million people impacted by Type 2 diabetes. As the disease becomes increasingly prevalent, Takeda remains focused on expanding access of alogliptin, especially in emerging markets like Brazil, Russia, and the Middle East. In 2015, Takeda launched Zafatek, a DPP-4 inhibitor for the treatment of Type 2 diabetes, in Japan. The company's diverse diabetes portfolio of medications represent Takeda's ongoing commitment to advancing patient care and helping to meet the individual needs of this growing patient population.

About Takeda Pharmaceutical Company Limited
Located in Osaka, Japan, Takeda (TYO: 4502) is a research-based global company with its main focus on pharmaceuticals. As the largest pharmaceutical company in Japan and one of the global leaders of the industry, Takeda is committed to strive towards better health for people worldwide through leading innovation in medicine.

Additional information about Takeda is available through its corporate website, www.takeda.com.

SOURCE Takeda Pharmaceutical Company Limited