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Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.

The most common adverse events reported in at least 5% of patients in the controlled 16-week clinical trial between placebo plus metformin and pioglitazone 30 mg plus metformin were upper respiratory tract infection (15.6% and 15.5%), diarrhea (6.3% and 4.8%), combined edema/peripheral edema (2.5% and 6.0%) and headache (1.9% and 6.0%), respectively.

The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus metformin and pioglitazone 45 mg plus metformin are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 7.8% and 7.7%, respectively.

Table 4: Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study

Adverse Event
Preferred Term
Pioglitazone 30 mg + metformin
N=411 n (%)
Pioglitazone 45 mg + metformin
N=416 n (%)
Upper Respiratory Tract Infection 51 (12.4) 56 (13.5)
Diarrhea 24 (5.8) 20 (4.8)
Nausea 24 (5.8) 15 (3.6)
Headache 19 (4.6) 22 (5.3)
Urinary Tract Infection 24 (5.8) 22 (5.3)
Sinusitis 18 (4.4) 21 (5.0)
Dizziness 22 (5.4) 20 (4.8)
Edema Lower Limb 12 (2.9) 47 (11.3)
Weight Increased 12 (2.9) 28 (6.7)

Most clinical adverse events were similar between groups treated with pioglitazone in combination with metformin and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical trials between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.

In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus metformin (see PRECAUTIONS, General: Pioglitazone hydrochloride).

In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General: Pioglitazone hydrochloride).

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 daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS 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 the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.

Table 5: Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint

Cardiovascular Events Placebo
First Events (N) Total events (N) First Events (N) Total events (N)
Any event 572 900 514 803
All-cause mortality 122 186 110 177
Non-fatal MI 118 157 105 131
Stroke 96 119 76 92
ACS 63 78 42 65
Cardiac intervention 101 240 101 195
(Major leg amputation 15 28 9 28
Leg revascularization 57 92 71 115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General: Pioglitazone hydrochloride).

Laboratory Abnormalities

Hematologic: Pioglitazone may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with pioglitazone appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with pioglitazone. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and have rarely been associated with any significant hematologic clinical effects (see PRECAUTIONS, General: Pioglitazone hydrochloride).

In controlled clinical trials of metformin at 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12 -intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation (see PRECAUTIONS, General: Metformin hydrochloride).

Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with pioglitazone had ALT values ≥ 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with pioglitazone, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with pioglitazone were withdrawn from clinical trials in the U.S. due to abnormal liver function tests.

In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General: Pioglitazone hydrochloride).

CPK Levels: During required laboratory testing in clinical trials with pioglitazone, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive pioglitazone, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.