DailyMed - PIOGLITAZONE tablet (2024)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Over 8500 patients with type 2 diabetes have been treated with pioglitazone hydrochloride in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with pioglitazone hydrochloride in the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone hydrochloride for six months or longer, over 4500 patients have been treated with pioglitazone hydrochloride for one year or longer, and over 3000 patients have been treated with pioglitazone hydrochloride for at least two years.

In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone hydrochloride and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone hydrochloride than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone hydrochloride and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone hydrochloride and 0.6% of patients treated with placebo.

Common Adverse Events: 16 to 26 Week Monotherapy Trials

A summary of the incidence and type of common adverse events reported in three pooled 16 to 26 week placebo-controlled monotherapy trials of pioglitazone hydrochloride is provided in Table 1. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with pioglitazone hydrochloride than in patients who received placebo. None of these adverse events were related to pioglitazone hydrochloride dose.

Common Adverse Events: 16 to 24 Week Add-on Combination Therapy Trials

A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone hydrochloride add-on to sulfonylurea is provided in Table 2. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone hydrochloride.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone hydrochloride add-on to metformin is provided in Table 3. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone hydrochloride.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

Table 4 summarizes the incidence and types of common adverse events reported in trials of pioglitazone hydrochloride add-on to insulin. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly with the highest tested dose of pioglitazone hydrochloride.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of > 5% and more commonly in patients treated with pioglitazone hydrochloride than in patients who received placebo.

Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure

A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16 to 24 week add-on to sulfonylurea trials, for the 16 to 24 week add-on to insulin trials, and for the 16 to 24 week add-on to metformin trials. None of the events were fatal.

Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (n = 262) or glyburide at daily doses of 10 mg to 15 mg (n = 256). A summary of the incidence of adverse events related to congestive heart failure reported in this study is provided in Table 7.

Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone hydrochloride (N = 2605), force-titrated up to 45 mg daily or placebo (N = 2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years, and mean HbA1c of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone hydrochloride on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone hydrochloride and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p = 0.10).

Although there was no statistically significant difference between pioglitazone hydrochloride and placebo for the three- year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone hydrochloride. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

CABG = coronary artery bypass grafting; PCI = percutaneous intervention

Weight Gain

Dose-related weight gain occurs when pioglitazone hydrochloride is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Tables 10 and 11 summarize the changes in body weight with pioglitazone hydrochloride and placebo in the 16 to 26 week randomized, double-blind monotherapy and 16 to 24 week combination add-on therapy trials and in the PROactive trial.

Note: Median exposure for both pioglitazone hydrochloride and Placebo was 2.7 years.

Edema

Edema induced from taking pioglitazone hydrochloride is reversible when pioglitazone hydrochloride is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure. A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone hydrochloride is provided in Table 12.

Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.”

Hepatic Effects

There has been no evidence of induced hepatotoxicity with pioglitazone hydrochloride in the pioglitazone hydrochloride controlled clinical trial database to date. One randomized, double-blind 3 year trial comparing pioglitazone hydrochloride to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone hydrochloride and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone hydrochloride in the pioglitazone hydrochloride controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the pioglitazone hydrochloride clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16 week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16 week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24 week add-on to sulfonylurea trial (15.7% vs. 13.4%) and in the 24 week add-on to insulin trial (47.8% vs. 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receiving pioglitazone 30 mg (0.9%) in the 24 week add-on to insulin trial. An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient’s usual activities) that did not require hospitalization. These patients were receiving pioglitazone 45 mg in combination with sulfonylurea (n = 2) or pioglitazone 30 mg or 45 mg in combination with insulin (n = 12).

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone hydrochloride and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone hydrochloride and two (0.08%) cases on placebo. After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone hydrochloride. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone hydrochloride or placebo (HR = 1.00; 95% CI: 0.59 to 1.72) [see Warnings and Precautions (5.4)].

Laboratory Abnormalities

Hematologic Effects

Pioglitazone hydrochloride may cause decreases in hemoglobin and hematocrit. In placebo-controlled monotherapy trials, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone hydrochloride compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. 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 associated with pioglitazone hydrochloride therapy and are not likely to be associated with any clinically significant hematologic effects.

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone hydrochloride clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone hydrochloride (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone hydrochloride, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued pioglitazone hydrochloride due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone hydrochloride therapy is unknown.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of pioglitazone hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• New onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.7)].
• Fatal and nonfatal hepatic failure [see Warnings and Precautions (5.3)].

Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone hydrochloride, both with and without previously known heart disease and both with and without concomitant insulin administration.

In postmarketing experience, there have been reports of unusually rapid increases in weight and increases in excess of that generally observed in clinical trials. Patients who experience such increases should be assessed for fluid accumulation and volume-related events such as excessive edema and congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)].