Boxed Warning: Congestive Heart Failure
• Thiazolidinediones (TZDs), including ACTOS, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS 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 ACTOS must be considered.[1]
• ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated.[1]
Cardiac considerations
Like other TZDs, ACTOS can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. ACTOS 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 ACTOS in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.[1]
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, 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.[1]
Other considerations
ACTOS 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 ACTOS. The risk of fracture should be considered in the care of patients treated with ACTOS, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.[1]
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]
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] • ACTOS 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]
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.[2] Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.[3] Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.[4]
References:
1. ACTOS package insert, Takeda Pharmaceuticals America, Inc. 2. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674-682. 3. American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S68-S71. 4. American Diabetes Association. Standards of medical care in diabetes–2008. Diabetes Care. 2008;31(suppl 1):S12-S54.