Important Safety Information for ACTOS^® (pioglitazone HCl), ACTOplus met^® (pioglitazone HCl and metformin HCl), and duetact^™ (pioglitazone HCl and glimepiride)

Contraindications for ACTOplus met
1. Renal disease or renal dysfunction (serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females]). 2. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.^[9]

ACTOplus met should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function.^[9]

Contraindication for duetact
Diabetic ketoacidosis (DKA), with or without coma. DKA should be treated with insulin.^[10]

Boxed Warning for ACTOplus met: Lactic Acidosis
Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during therapy with ACTOplus met.^[9]
The reported incidence of lactic acidosis in patients receiving metformin HCl is very low (approximately 0.03 cases/1000 patient-years), but may be fatal in approximately half these instances. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking ACTOplus met and by use of the minimum effective dose of ACTOplus met. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. ACTOplus met should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, ACTOplus met should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.^[9]
Patients should be cautioned against excessive alcohol intake when taking ACTOplus met. In addition, ACTOplus met should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.^[9]
The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Patients should be made aware of the possible importance of such symptoms and instructed to notify their health professional immediately if they occur.^[9]

Cardiac considerations
Like other thiazolidinediones (TZDs), pioglitazone can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure.^[11] In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop congestive heart failure (CHF) when treated with pioglitazone in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.^[11] Patients with NYHA Class III and IV cardiac status were not studied in pioglitazone clinical trials; therefore, ACTOS, ACTOplus met, and duetact are not indicated in these patients.^[11] Patients with systolic heart failure (NYHA Class II) naïve to pioglitazone therapy should be initiated at the lowest approved dose. Patients should be monitored for signs and symptoms of CHF exacerbation.^[11]

Cardiac considerations for duetact
The UGDP trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.^[10]

Hepatic safety
Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established.^[11] Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, ACTOplus met, or duetact, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS, ACTOplus met, or duetact.^[9-11]

Other considerations
ACTOS, ACTOplus met, and duetact may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women.^[9-11] Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams, and be instructed to immediately report any visual changes to their healthcare provider.

Other considerations for duetact
As with all sulfonylureas, severe hypoglycemia may occur. Elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency may be more sensitive to the glucose-lowering effect of sulfonylureas and should be started on the lowest dose of duetact.^[10]

Well-tolerated therapy
In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (≥5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.^[11]

In clinical trials using pioglitazone in combination with metformin, the most common adverse events (≥5%) were upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.^[9]

In clinical trials using pioglitazone in combination with a sulfonylurea, the most common adverse events (≥5%) were hypoglycemia, upper respiratory tract infection, weight increase, headache, diarrhea, edema, urinary tract infection, pain in limb, and nausea.^[10]

Indications and usage
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.^[11]

ACTOplus met is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and metformin, or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.^[9]

Duetact is indicated with diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.^[10]

ACTOS, ACTOplus met, and duetact should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.^[9-11]

Please view full Prescribing Information for ACTOS.
Please view full Prescribing Information for ACTOplus met.
Please view full Prescribing Information for duetact.

References
1. Del Prato S, Marchetti P. Targeting insulin resistance and β-cell dysfunction: the role of thiazolidinediones. Diabetes Technol Ther. 2004;6:719-731. 2. Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA. Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med. 2001;134:61-71. 3. Kendall DM. Thiazolidinediones: the case for early use. Diabetes Care. 2006;29:154-157. 4. Haffner SM, D'Agostino R Jr, Mykkänen L, et al. Insulin sensitivity in subjects with type 2 diabetes: relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study. Diabetes Care. 1999;22:562-568. 5. Lebovitz HE. Insulin secretagogues: old and new. Diabetes Rev. 1999;7:139-153. 6. UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16: overview of 6 years' therapy of type II diabetes: a progressive disease. Diabetes. 1995;44:1249-1258. 7. American Diabetes Association. Standards of medical care in diabetes-2006. Diabetes Care. 2006;29(suppl 1):S4-S42. 8. Davidson JA, Blonde L, Jellinger PS, Lebovitz HE, Parkin CG. Road map for the prevention and treatment of type 2 diabetes. American Association of Clinical Endocrinologists website. Available at: http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf. Accessed May 18, 2006. 9. ACTOplus met package insert, Takeda Pharmaceuticals America, Inc. 10. Duetact package insert, Takeda Pharmaceuticals America, Inc. 11. ACTOS package insert, Takeda Pharmaceuticals America, Inc.