Indications and Usage
ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.[1]
ACTOplus met is a thiazolidinedione and biguanide 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 metformin or who have inadequate glycemic control on a thiazolidinedione alone or metformin alone.[2]
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.[3]
ACTOS, ACTOplus met, and duetact should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.[1-3]
ACTOS has been studied in monotherapy and in combination with a sulfonylurea, metformin, or insulin.[1]
Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.
Important Safety Information
Boxed Warning: Congestive Heart Failure
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Thiazolidinediones (TZDs), including pioglitazone, which is a component of ACTOplus met and duetact, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of pioglitazone and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of pioglitazone must be considered.[1-3] |
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Pioglitazone is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.[1-3] |
Boxed Warning for ACTOplus met: Lactic Acidosis
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Lactic acidosis is a rare but serious metabolic complication that can occur due to metformin accumulation during therapy with ACTOplus met.[2] |
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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.[2] |
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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.[2] |
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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.[2] |
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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.[2] |
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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.[2] |
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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.[2] |
Contraindication
Initiation of pioglitazone in patients with established NYHA Class III or IV heart failure is contraindicated (see Boxed Warning).[1-3]
Additional Contraindications for ACTOplus met
ACTOplus met is contraindicated in patients with:[2]
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.
ACTOplus met should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials because such use may result in acute alteration of renal function.[2]
Additional Contraindication for duetact
Diabetic ketoacidosis (DKA), with or without coma. DKA should be treated with insulin.[3]
Warnings and Precautions
Cardiac Effects
Like other TZDs, ACTOS, ACTOplus met, and duetact can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. Pioglitazone should be used with caution in patients at risk for heart failure. Patients should be monitored for symptoms of heart failure or other adverse events related to fluid retention. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop 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.[1-3]
Additional Cardiac Consideration for duetact
Cardiac Mortality
Glimepiride
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.[3]
Hepatic Effects
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. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, ACTOplus met, and duetact and periodically thereafter per the clinical judgment of the healthcare professional. If ALT is >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with pioglitazone. If jaundice is observed, pioglitazone should be discontinued.[1-3]
Other Precautions
• ACTOS, ACTOplus met, and duetact may also be associated with hypoglycemia, anemia, and/or weight gain.[1-3]
• ACTOS, ACTOplus met, and duetact should be used with caution in patients with edema. Reports of initiation or worsening of edema have been received in postmarketing experience with pioglitazone.[1-3]
• ACTOS, ACTOplus met, and duetact may be associated with ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women.[1-3]
• ACTOS, ACTOplus met, and duetact may cause decreases in hemoglobin and hematocrit. [1-3]
• 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.[1-3]
• An increased incidence of bone fracture was noted in female patients taking pioglitazone. The risk of fracture should be considered in the care of patients treated with TZDs, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.[1-3]
Additional Precaution for ACTOplus met
• In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, has been observed. Such decrease is rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on ACTOplus met.[2]
Additional Precautions 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 a conservative dose of duetact.[3]
• Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.
Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ACTOS, ACTOplus met, duetact, or any other antidiabetic drug.[1-3]
Tolerability
In clinical trials using pioglitazone in monotherapy, the most common adverse events (≥5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.[1]
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.[2]
In clinical trials using pioglitazone in combination with a sulfonylurea, the most common adverse events (≥5%) were hypoglycemia, upper respiratory tract infection, weight increase, lower limb edema, headache, urinary tract infection, diarrhea, nausea, and pain in limb.[3]
Pediatric Use
ACTOS, ACTOplus met, and duetact are not recommended, as safety and effectiveness in pediatric patients have not been established.[1-3]
Please see ACTOS Complete Prescribing Information, including boxed warning and Medication Guide.
Please see ACTOplus met Complete Prescribing Information, including boxed warnings and Medication Guide.
Please see duetact Complete Prescribing Information, including boxed warning and Medication Guide.