Takeda Announces Completion of the Post-Marketing Commitment to Submit Data to the FDA, the EMA and the PMDA for Pioglitazone Containing Medicines Including ACTOS

Osaka, Japan, August 29, 2014 – Takeda Pharmaceutical Company Limited (“Takeda”) today announced the completion of the post-marketing commitment and submissions of data from a 10-year epidemiology study to regulatory authorities including the United States (U.S.) Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Japanese Ministry of Health, Labour and Welfare (MHLW) / Pharmaceuticals and Medical Devices Agency (PMDA) for pioglitazone containing medicines, including ACTOS (pioglitazone HCl).^1,2 This study was a 10-year epidemiology study, conducted by the University of Pennsylvania and Division of Research at Kaiser Permanente Northern California (KPNC), and was designed to investigate whether patients exposed to pioglitazone were at an increased risk of bladder cancer.¹ Findings demonstrate that there is no statistically significant increased risk of bladder cancer among patients ever exposed to pioglitazone. ²

The primary analysis found no association between the use of pioglitazone and the risk of bladder cancer.² Additionally, no association was found between the risk of bladder cancer and the duration of pioglitazone use, increased cumulative dose of pioglitazone or the time since initiating pioglitazone.

In the five-year interim analysis published in Diabetes Care, a statistically significant increased risk among patients who used pioglitazone for two or more years was observed.¹ However, the 10-year final analysis did not show any statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone.² The data will be shared with additional regulatory authorities in accordance with local requirements around the world, and final results will be submitted for publication in 2014.

“The completion of this long-term study is a milestone in the history of pioglitazone,” said Tom Harris, head, global regulatory affairs, Takeda. “The results of the study provide reassurance with regard to the use of pioglitazone and the risk of bladder cancer and further support the positive benefit risk profile of the product.”

About Pioglitazone
Pioglitazone is approved as an agent to treat patients with Type 2 diabetes mellitus in more than 100 countries world-wide. More than 27,000 subjects have been included in clinical trials, and globally the total patient-years of exposure since first launch (1999) is estimated to be in excess of more than 29 million. Pioglitazone as a treatment of Type 2 diabetes mellitus at the recommended doses provides a valuable treatment option, and has a well established safety profile. The benefits of good glycaemic control associated with Type 2 diabetes mellitus outweigh the risks associated with therapy which are appropriately communicated and managed by the current product labelling.

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 hematuria or other symptoms such as dysuria or urinary urgency 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 Type 2 diabetes
• In 2013, 382 million people worldwide were living with Type 2 diabetes. By 2035 this number is expected to rise to 592 million.³
• In 2013, the number of people with diabetes in Europe was estimated to be 56 million.⁴ 
• The number of Type 2 diabetes patients is increasing in every country.³
• In 2013, one in 10 deaths in adults in Europe was attributed to diabetes, representing over 600,000 people.³
• Estimates indicate that more than EUR 108 billion* was spent on healthcare due to diabetes in the European region in 2013, accounting for over one-quarter of global healthcare expenditures due to diabetes.³
• Because of the increasingly complex nature of this disease, all patients require treatment to be individualized to their needs.⁵ Each patient responds differently to medications, and healthcare providers often must combine multiple treatment options to help patients manage their disease.

*Based on conversion of USD 147 billion,³ where 1 EUR = 1.36035 USD as of 21 July 2014.

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, and developments of other fixed-dose combinations. The company’s strong, diverse diabetes portfolio and available medications mark important milestones in 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 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.

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References

¹ Lewis, JD., Ferrara, A., Peng, T., et al. The Risk of Bladder Cancer Among Diabetic Patients Treated with Pioglitazone: Interim Report of a Longitudinal Cohort Study. Diabetes Care 24, April 2011, 34:4, 923-929.
² Takeda Data on File. 2014.
³ International Diabetes Federation. IDF Atlas, sixth edition. Last accessed July 10, 2014. Available at: http://www.idf.org/diabetesatlas.
⁴ International Diabetes Federation. Diabetes: Facts and figures. Last accessed July 10, 2014. Available at: http://www.idf.org/worlddiabetesday/toolkit/gp/facts-figures.
⁵ Inzucchi SE, Bergenstal RM et al. Management of Hyperglycaemia in Type 2 Diabetes: A Patient-Centred Approach. Diabetes Care. 2012:35: (6):1364-1379.