WARNINGS AND PRECAUTIONS

Cardiac Failure and Other Cardiac Effects

Like other TZDs, pioglitazone can cause fluid retention which may exacerbate or lead to heart failure.  Weight gain, which may also be associated with fluid retention, has also been reported with pioglitazone. 

CHF has occurred in patients taking pioglitazone, especially in combination with insulin. Incidence of heart failure increases in patients with history of cardiac disease such as CAD, previous coronary artery bypass graft procedures, and MI. 

Risk of hospitalization for CHF is higher in patients with the following conditions:

• CHF New York Heart Association (NYHA) Class II and III
• Poorly controlled diabetes
• Age more than 64 yrs
• Using insulin at baseline

Use pioglitazone with caution in patients with existing edema or heart failure. Avoid pioglitazone use in patients with NYHA Class III or IV heart failure.

Initiate pioglitazone therapy at the lowest approved dose if prescribed for T2DM patients with systolic heart failure (NYHA Class II). Gradually increase dose only after several mos of treatment and carefully monitor weight gain, edema, or signs and symptoms of exacerbation of CHF if subsequent dose escalation is necessary.

Observe patients for signs and symptoms of heart failure such as dyspnea, rapid weight gain, and edema. Manage heart failure according to current standards of care if these signs and symptoms develop. Consider discontinuation of pioglitazone or dose reduction. (see BOXED WARNING)  Pioglitazone is not recommended in patients with established NYHA Class III or IV heart failure. (see BOXED WARNING and CONTRAINDICATIONS)

In the published Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) Study, the event of serious heart failure in T2DM patients with a history of macrovascular disease was higher in patients who received pioglitazone (5.7%) than for patients treated with placebo (4.1%). Deaths associated with serious heart failure were reported in about 1.5% in pioglitazone-treated patients and 1.4% of placebo-treated patients. Incidence of serious heart failure in patients who were treated with an insulin-containing regimen at baseline was 6.3% in the pioglitazone group and 5.2% in the placebo group. In patients who were treated with sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% in the pioglitazone group and 4.4% in the placebo group.

Type 1 DM or Diabetic Ketoacidosis

Pioglitazone is active only in the presence of endogenous insulin and should therefore not be used in patients with type 1 DM or for the treatment of diabetic ketoacidosis.

Hypoglycemia

Use of pioglitazone in combination with other hypoglycemic agents such as sulfonylureas may increase the risk for hypoglycemia. Reduction in the dose of the concomitant agent may be necessary. 

Edema and Weight Gain

Use pioglitazone with caution in patients with existing edema. (See CV Effects) Use pioglitazone with caution in patients at risk for heart failure since the drug can cause fluid retention which can exacerbate or lead to CHF.  Monitor patients for signs and symptoms of heart failure. (see BOXED WARNING, WARNINGS AND PRECAUTIONS)

Weight gain, usually dose dependent and probably due to a combination of fluid retention and fat accumulation, has been reported with pioglitazone use. Patients who experience weight gain should be assessed for fluid accumulation and volume-related events such as excessive edema and CHF. (See CV Effects). 

Ocular Effects

Macular edema, some with decreased visual acuity, has been reported in patients receiving pioglitazone or other TZDs. Peripheral edema has also been seen in some patients at the time the macular edema was diagnosed. In some patients, macular edema improved after discontinuation of TZD treatment.

Although it is not known whether there is causal relationship between pioglitazone and macular edema, regular eye examination by an ophthalmologist is recommended for all diabetic patients. Promptly report and refer any visual symptom to an ophthalmologist. 

Hematologic

Pioglitazone may cause dose-related decreases in hemoglobin and hematocrit which usually become evident within the first 3 mos of starting treatment. These hematologic effects may be related to plasma volume expansion. 

Ovulation

Pioglitazone, like other TZDs, may cause ovulation in anovulatory premenopausal women with insulin resistance. These women have an increased possibility of pregnancy unless contraceptive methods are initiated.  

Hepatic Effects

Hepatitis, elevations in hepatic enzymes up to 3 or more times the upper limit of normal, and very rarely, liver failure with or without fatal outcome have been associated with pioglitazone. 

Perform periodic liver function tests (before therapy, then periodically according to the clinician’s judgement) in patients receiving pioglitazone. (see STATEMENT ON USAGE FOR HIGH-RISK GROUPS)

In patients with mild hepatic impairment (ALT not exceeding 2.5 times the upper limit of normal), close clinical follow-up and more frequent liver enzyme monitoring is recommended. 

Recheck liver function if manifestations suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, dark urine) develop in patients receiving pioglitazone.  Discontinue pioglitazone therapy if ALT increases to three times the upper limit of normal during therapy and remains elevated, or if jaundice develops.

Increased Risk of Fracture in Women

In clinical trials, there were more reports of fractures in female patients taking TZDs, including pioglitazone, than those taking a comparator (either placebo or active). Fracture incidence was about 1.9 fractures per 100 patient-years in the pioglitazone group and about 1.1 fractures per 100 patient-years in the comparator-treated group. Thus, the observed excess risk of fracture for women is 0.8 fractures per 100 patient-years. Majority of fractures observed were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia).

There was no increased risk of fracture identified in men.

Consider the risk of fracture in caring for female patients with T2DM who are currently being treated with pioglitazone or when starting pioglitazone treatment.