Indications and Usage

ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

ACTOplus met and ACTOplus met XR are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with pioglitazone and metformin or who have inadequate glycemic control on pioglitazone alone or metformin alone.

duetact is a thiazolidinedione and sulfonylurea combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus who are already treated with a thiazolidinedione and a sulfonylurea or who have inadequate glycemic control on a thiazolidinedione alone or a sulfonylurea alone.

ACTOS, ACTOplus met, ACTOplus met XR, and duetact are not for treatment of type 1 diabetes or diabetic ketoacidosis (DKA).

Important Safety Information

Contraindications

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

• Do not initiate in patients with NYHA Class III or IV heart failure.
• Do not use in patients with a history of serious hypersensitivity reaction to any of the ingredients of these products.

ACTOplus met and ACTOplus met XR:

• Do not use in patients with renal disease or dysfunction (as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia.
• Do not use in patients with acute or chronic metabolic acidosis, including DKA, with or without coma.
• Temporarily discontinue in patients administered intravascular iodinated contrast materials, because such materials may acutely alter renal function.

Warnings and Precautions

ACTOS, ACTOplus met, ACTOplus met XR, and duetact:

• Congestive Heart Failure: May cause fluid retention which 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.
• Edema: Dose-related edema may occur. Use with caution in patients with edema.
• Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal, have been received. Causality cannot be excluded. Obtain liver tests before starting treatment. Use caution in patients with liver disease. If liver injury is detected, promptly interrupt treatment and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart treatment if liver injury is confirmed and no alternate etiology can be found.
• Fractures: An increased incidence of bone fracture has been noted in female patients.
• Bladder cancer: Data suggest an increased risk of bladder cancer in ACTOS users. Data also suggest that the risk increases with duration of use. Do not use ACTOS, ACTOplus met, ACTOplus met XR, or duetact 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 used with insulin or insulin secretagogues, hypoglycemia may occur and a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk.
• Macular edema: Macular edema has been reported in some patients. Recommend regular eye exams. Instruct patients to report any visual changes promptly.
• Ovulation: Ovulation in premenopausal anovulatory women may occur.
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with these, or any other anti-diabetic drugs.
• Use with CYP2C8 inducers or strong inhibitors may require dose adjustment.

Additional Warnings and Precautions

ACTOplus met and ACTOplus met XR:

• Lactic acidosis due to metformin accumulation during therapy is rare. However, when it occurs, it is fatal in approximately 50% of cases. The risk increases in patients with renal dysfunction, congestive heart failure requiring drug treatment, and with increasing age.
  • Risk may be significantly decreased by regular monitoring of renal function, and by using the minimum effective dose. Monitor renal function, particularly in the elderly. Do not initiate in patients ≥80 years of age, unless creatinine clearance is normal.
  • Tell patients that subtle and nonspecific symptoms, such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress, may be important and should be reported immediately. Caution against excessive alcohol intake.
• Avoid in patients with evidence of hepatic disease, hypoxemia, dehydration, or sepsis, and temporarily discontinue use prior to any surgical procedure.
• A reversible decrease in vitamin B₁₂ level, without clinical effects, is possible. Measure hematologic parameters annually.

duetact:

• Cardiac Mortality: The University Group Diabetes Program (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.
• Severe hypoglycemia may occur with sulfonylurea use. Dosing should be conservative for elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency.
• Sulfonylurea treatment can lead to hemolytic anemia in patients with, or without, known glucose-6-phosphate dehydrogenase (G6PD) deficiency. Use caution in patients with G6PD deficiency.

Adverse Reactions

The most common adverse events (≥5% and greater than placebo) seen with ACTOS in monotherapy include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. Use of ACTOS may be associated with weight gain.

The most common adverse events (≥5%) seen with ACTOS in combination with metformin include upper respiratory tract infection, diarrhea, nausea, headache, urinary tract infection, sinusitis, dizziness, lower limb edema, and increased weight.

The most common adverse events (≥5%) seen with ACTOS in combination with a sulfonylurea include hypoglycemia, upper respiratory tract infection, weight increase, lower limb edema, headache, urinary tract infection, diarrhea, nausea, and pain in limb.

Please see ACTOS Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.

Please see ACTOplus met Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see ACTOplus met XR Complete Prescribing Information, including boxed warnings about congestive heart failure and lactic acidosis, and Medication Guide.

Please see duetact Complete Prescribing Information, including boxed warning about congestive heart failure, and Medication Guide.