FDA ALERT [8/2007] This Alert highlights important revisions to the full prescribing information for pioglitazone HCl, marketed as Actos, Actoplus Met, and Duetact. The updated information includes a new BOXED WARNING, and additional updated WARNINGS, PRECAUTIONS and CONTRAINDICATIONS to emphasize that pioglitazone may cause or exacerbate heart failure, particularly in certain patient populations. The implications of this new labeling for healthcare professionals who prescribe Actos are summarized below. This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

Recommendations and Considerations

• Thiazolidinediones, including Actos, Actoplus Met, and Duetact, may cause or exacerbate congestive heart failure in some patients.
• Initiation of these drugs in patients with established NYHA Class III or IV heart failure is contraindicated.
• After initiation of Actos, Actoplus Met, and 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 and heart failure is confirmed, appropriate management of heart failure should be initiated.  Discontinuation or dose reduction of Actos, Actoplus Met, or Duetact should be considered.

Information for the Patient

• Patients should be informed that Actos, alone or in combination with other antidiabetic agents, can cause fluid retention, which may exacerbate or lead to heart failure. 
• Patients should be asked to watch for and report to their healthcare professional any signs and symptoms of heart failure, including edema from fluid retention, shortness of breath or trouble breathing, unusually fast increase in weight, and unusual tiredness.

 Clinical Trial Data

In a 24-week study comparing Actos (n=262) to glyburide (n=256) in patients with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline), overnight hospitalization for congestive heart failure was reported in 9.9% of patients on Actos compared to 4.7% of patients on glyburide.  This adverse event was more marked in patients using insulin at baseline and in patients over 64 years of age.

In a long-term cardiovascular outcomes trial, 5238 patients were randomized to Actos (n=2605) or placebo (n=2633) in addition to their background anti-diabetic medications. The average duration of follow-up was 34.5 months. There was no statistically significant difference between the two treatment groups for the primary composite endpoint of all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, cardiac revascularization, major leg amputation, or leg revascularization. The percentage of patients who had a serious heart failure event 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 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.

Next Steps

Healthcare professionals should factor this new labeling information into their individual treatment decisions for their patients.  FDA will continue to monitor post-marketing reports of heart failure and will analyze any additional studies for this, as well as other important adverse effects.  The agency will consider further regulatory action and communication as additional information becomes available

Date created: August 14, 2007, updated August 22, 2007