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Questions & Answers
Side Effects & Adverse Reactions
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.
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.
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 placebo-treated 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.
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FDA Safety Alerts
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FDA Labeling Changes
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ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
There is currently no drug history available for this drug.
ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). Pharmacological studies indicate that ACTOS improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. ACTOS improves glycemic control while reducing circulating insulin levels.
Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride belongs to a different chemical class and has a different pharmacological action than the sulfonylureas, metformin, or the α-glucosidase inhibitors. The molecule contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:
Pioglitazone hydrochloride is an odorless white crystalline powder that has a molecular formula of C19H20N2O3S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.
ACTOS is available as a tablet for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropylcellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.
- Rebel Distributors Corp.
- Dispensing Solutions, Inc.
- Lake Erie Medical & Surgical Supply Dba Quality Care Products Llc
- Physicians Total Care, Inc.
- Remedyrepack Inc.
- Cardinal Health
- Takeda Pharmaceuticals America, Inc.
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