Pioglitazone

Monotherapy and Combination Therapy ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. Important Limitations of Use ACTOS exerts its antihyperglycemic effect only in the presence of endogenous insulin. ACTOS should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings. Use caution in patients with liver disease. ACTOS is a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. Important Limitations of Use: • Not for treatment of type 1 diabetes or diabetic ketoacidosis.

ACTOS is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. ACTOS decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. 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. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes.

• Initiate ACTOS at 15 mg or 30 mg once daily. Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure. • If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily. • Obtain liver tests before starting ACTOS. If abnormal, use caution when treating with ACTOS, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on ACTOS is not recommended in patients without liver disease.

• Initiation in patients with established NYHA Class III or IV heart failure. • Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOS. • Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure. • Use in patients with known hypersensitivity to pioglitazone or any other component of ACTOS.

Boxed warning (congestive heart failure •): Thiazolidinediones, including ACTOS ®, cause or exacerbate congestive heart failure in some patients. • 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). • Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. • Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded.

The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive heart failure • Edema • Fractures Most common adverse reactions (≥5%) are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.

• Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit ACTOS dose to 15 mg daily. • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. • Topiramate may decrease pioglitazone concentrations.

Storage Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F). Keep container tightly closed, and protect from light, moisture and humidity.