Managed Care - January 2008 - (Page 1) ACTOS® (pioglitazone hydrochloride) Tablets Brief Summary of Prescribing Information. Please see package insert for Complete Prescribing Information. WARNING: CONGESTIVE HEART FAILURE • Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients (see WARNINGS). 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 the current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered. • 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 (see CONTRAINDICATIONS and WARNINGS). INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING). ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. 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 (see BOXED WARNING). Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and ACTOS is not recommended in these patients (see BOXED WARNING and CONTRAINDICATIONS). In one 16-week, U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study, two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week, dose-controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetes and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see ADVERSE REACTIONS). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebotreated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see BOXED WARNING, WARNINGS, and PRECAUTIONS, Information for Patients). Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with ot her hypoglycemic agents (Table 1). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation. Table 1 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS Control Group (Placebo) Median (25th/75th percentile) Monotherapy Sulfonylurea Combination Therapy ACTOS 15 mg Median (25th/75th percentile) 0.9 (-0.5/3.4) n=79 2.0 (0.2/3.2) n=183 N/A 2.3 (0.5/4.3) n=190 ACTOS 30 mg Median (25th/75th percentile) 1.0 (-0.9/3.4) n=188 3.1 (1.1/5.4) n=528 0.9 (-0.3/3.2) n=567 3.3 (0.9/6.3) n=522 ACTOS 45 mg Median (25th/75th percentile) 2.6 (0.2/5.4) n=79 4.1 (1.8/7.3) n=333 1.8 (-0.9/5.0) n=407 4.1 (1.4/6.8) n=338 -1.4 (-2.7/0.0) n=256 -0.5 (-1.8/0.7) n=187 -1.4 (-3.2/0.3) n=160 0.2 (-1.4/1.4) n=182 Metformin Insulin Note: Trial durations of 16 to 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were
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