Boxed Warning: Congestive Heart Failure
• Thiazolidinediones (TZDs), including pioglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS, ACTOplus met, or duetact, 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 the TZD must be considered.[1-3]
• ACTOS, ACTOplus met, and duetact are not recommended in patients with symptomatic heart failure. Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated.[1-3]
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.[2] • 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.[2] • 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] • 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]
Additional 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.[2]
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.[2]
Additional contraindication for duetact
Diabetic ketoacidosis (DKA), with or without coma. DKA should be treated with insulin.[3]
Cardiac considerations
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 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.[3]
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. 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 pioglitazone.[1-3]
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. 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. 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]
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.[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, headache, diarrhea, edema, urinary tract infection, pain in limb, and nausea.[3]
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.[1] • 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.[2] • Duetact is indicated as an adjunct to 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.[3] • 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.[1-3]
• The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output.[4] Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.[5] Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.[6]
References:
1. ACTOS package insert, Takeda Pharmaceuticals America, Inc. 2. ACTOplus met package insert, Takeda Pharmaceuticals America, Inc.
3. Duetact package insert, Takeda Pharmaceuticals America, Inc. 4. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674-682. 5. American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S68-S71. 6. American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care. 2008;31(suppl 1):S12-S54.