PIOGLITAZONEHYDROCHLORIDE (Page 2 of 9)

5.5 Edema

In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone hydrochloride than in placebo-treated patients and is dose-related [see Adverse Reactions (6.1)]. In postmarketing experience, reports of new onset or worsening edema have been received.

Pioglitazone hydrochloride should be used with caution in patients with edema. Because thiazolidinediones, including pioglitazone hydrochloride, can cause fluid retention, which can exacerbate or lead to congestive heart failure, pioglitazone hydrochloride should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone hydrochloride should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) and Patient Counseling Information (17)].

5.6 Fractures

In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 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. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone hydrochloride versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and persisted during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in the incidence of fracture was observed in men treated with pioglitazone hydrochloride (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone hydrochloride and attention should be given to assessing and maintaining bone health according to current standards of care.

5.7 Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone hydrochloride or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but others were diagnosed on routine ophthalmologic examination.

Most patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of the thiazolidinedione.

Patients with diabetes should have regular eye exams by an ophthalmologist according to current standards of care. Patients with diabetes who report any visual symptoms should be promptly referred to an ophthalmologist, regardless of the patient’s underlying medications or other physical findings [see Adverse Reactions (6.1)].

5.8 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone hydrochloride or any other antidiabetic drug.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

  • – Congestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]
  • – Edema [see Warnings and Precautions (5.5)]
  • – Fractures [see Warnings and Precautions (5.6)]

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.

Table 1 . Three Pooled 16 to 26 Week Placebo Controlled Clinical Trials of Pioglitazone Hydrochloride Monotherapy : Adverse Events Reported at an Incidence > 5 % and More Commonly in Patients Treated with Pioglitazone Hydrochloride than in Patients Treated with Placebo
(% of Patients )
Placebo N=259 Pioglitazone Hydrochloride N=606
Upper Respiratory Tract Infection 8.5 13.2
Headache 6.9 9.1
Sinusitis 4.6 6.3
Myalgia 2.7 5.4
Pharyngitis 0.8 5.1

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.”

Table 2 . 16 to 24 Week Clinical Trials of Pioglitazone Hydrochloride Add on to Sulfonylurea
16 Week Placebo Controlled Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride 30 mg + Sulfonylurea than in Patients Treated with Placebo + Sulfonylurea
% of Patients
Placebo + Sulfonylurea N=187 Pioglitazone Hydrochloride 15 mg + Sulfonylurea N=184 Pioglitazone Hydrochloride 30 mg + Sulfonylurea N=189
Edema 2.1 1.6 12.7
Headache 3.7 4.3 5.3
Flatulence 0.5 2.7 6.3
Weight Increased 0 2.7 5.3
24 Week Non Controlled Double Blind Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride 45 mg + Sulfonylurea than in Patients Treated with Pioglitazone Hydrochloride 30 mg + Sulfonylurea
% of Patients
PioglitazoneHydrochloride 30 mg + Sulfonylurea N=351 Pioglitazone Hydrochloride 45 mg + Sulfonylurea N=351
Hypoglycemia 13.4 15.7
Edema 10.5 23.1
Upper Respiratory Tract Infection 12.3 14.8
Weight Increased 9.1 13.4
Urinary Tract Infection 5.7 6.8

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 3 . 16 to 24 Week Clinical Trials of Pioglitazone Hydrochloride Add on to Metformin
16 Week Placebo Controlled Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride + Metformin than in Patients Treated with Placebo + Metformin
% of Patients
Placebo + Metformin N=160 Pioglitazone Hydrochloride30 mg + Metformin N=168
Edema 2.5 6.0
Headache 1.9 6.0
24 Week Non Controlled Double Blind Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride 45 mg + Metformin than in Patients Treated with Pioglitazone Hydrochloride 30 mg + Metformin
% of Patients
Pioglitazone Hydrochloride 30 mg + Metformin N = 411 Pioglitazone Hydrochloride 45 mg + Metformin N = 416
Upper Respiratory Tract Infection 12.4 13.5
Edema 5.8 13.9
Headache 5.4 5.8
Weight Increased 2.9 6.7

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.”

Table 4 . 16 to 24 Week Clinical Trials of Pioglitazone Hydrochloride Add on to Insulin
16 Week Placebo Controlled Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride 30 mg + Insulin than in Patients Treated with Placebo + Insulin
% of Patients
Placebo + Insulin N=187 Pioglitazone Hydrochloride 15 mg + Insulin N = 191 Pioglitazone Hydrochloride 30 mg + Insulin N = 188
Hypoglycemia 4.8 7.9 15.4
Edema 7.0 12.6 17.6
Upper Respiratory Tract Infection 9.6 8.4 14.9
Headache 3.2 3.1 6.9
Weight Increased 0.5 5.2 6.4
Back Pain 4.3 2.1 5.3
Dizziness 3.7 2.6 5.3
Flatulence 1.6 3.7 5.3
24 Week Non Controlled Double Blind Trial Adverse Events Reported in > 5 % of Patients and More Commonly in Patients Treated with Pioglitazone Hydrochloride 45 mg + Insulin than in Patients Treated with Pioglitazone Hydrochloride 30 mg + Insulin
% of Patients
Pioglitazone Hydrochloride 30 mg + Insulin N=345 Pioglitazone Hydrochloride 45 mg + Insulin N=345
Hypoglycemia 43.5 47.8
Edema 22.0 26.1
Weight Increased 7.2 13.9
Urinary Tract Infection 4.9 8.7
Diarrhea 5.5 5.8
Back Pain 3.8 6.4
Blood Creatine Phosphokinase Increased 4.6 5.5
Sinusitis 4.6 5.5
Hypertension 4.1 5.5

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.

Table 5 . PROactive Trial : Incidence and Types of Adverse Events Reported in > 5 % of Patients Treated with Pioglitazone Hydrochloride and More Commonly than Placebo
% of Patients
Placebo N=2633 Pioglitazone Hydrochloride N=2605
Hypoglycemia 18.8 27.3
Edema 15.3 26.7
Cardiac Failure 6.1 8.1
Pain in Extremity 5.7 6.4
Back Pain 5.1 5.5
Chest Pain 5.0 5.1

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.

Table 6 . Treatment Emergent Adverse Events of Congestive Heart Failure ( CHF )
Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to a Sulfonylurea
Number (%) of Patients
Placebo Controlled Trial ( 16 weeks ) Non Controlled Double Blind Trial ( 24 weeks )
Placebo + Sulfonylurea N=187 Pioglitazone Hydrochloride 15 mg + Sulfonylurea N=184 Pioglitazone Hydrochloride 30 mg + Sulfonylurea N=189 Pioglitazone Hydrochloride 30 mg + Sulfonylurea N=351 Pioglitazone Hydrochloride 45 mg + Sulfonylurea N=351
At least one congestive heart failure event 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%)
Hospitalized 2 (1.1%) 0 0 0 2 (0.6%)
Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to Insulin
Number (%) of Patients
Placebo Controlled Trial ( 16 weeks ) Non Controlled Double Blind Trial ( 24 weeks )
Placebo + Insulin N=187 Pioglitazone Hydrochloride 15 mg + Insulin N=191 Pioglitazone Hydrochloride 30 mg + Insulin N=188 Pioglitazone Hydrochloride 30 mg + Insulin N=345 Pioglitazone Hydrochloride 45 mg + Insulin N=345
At least one congestive heart failure event 0 2 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%)
Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%)
Patients Treated with Pioglitazone Hydrochloride or Placebo Added on to Metformin
Number (%) of Patients
Placebo Controlled Trial ( 16 weeks ) Non Controlled Double Blind Trial ( 24 weeks )
Placebo + Metformin N=160 Pioglitazone Hydrochloride 30 mg + Metformin N=168 Pioglitazone Hydrochloride 30 mg + Metformin N=411 Pioglitazone Hydrochloride 45 mg + Metformin N=416
At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%)
Hospitalized 0 1 (0.6%) 0 1 (0.2%)

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 hydrochloride 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.

Table 7 . Treatment Emergent Adverse Events of Congestive Heart Failure ( CHF ) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone Hydrochloride or Glyburide
Number (%) of Subjects
Pioglitazone Hydrochloride N=262 Glyburide N=256
Death due to cardiovascular causes (adjudicated) 5 (1.9%) 6 (2.3%)
Overnight hospitalization for worsening CHF (adjudicated) 26 (9.9%) 12 (4.7%)
Emergency room visit for CHF (adjudicated) 4 (1.5%) 3 (1.2%)
Patients experiencing CHF progression during study 35 (13.4%) 21 (8.2%)

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

Table 8 . Treatment Emergent Adverse Events of Congestive Heart Failure ( CHF ) in PROactive Trial
Number (%) of Patients
Placebo N=2633 Pioglitazone Hydrochloride N=2605
At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%)
Fatal 22 (0.8%) 25 (1.0%)
Hospitalized, nonfatal 86 (3.3%) 124 (4.7%)

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

Table 9 . PROactive : Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint
Cardiovascular Events Placebo N = 2633 Pioglitazone Hydrochloride N = 2605
First Events n (%) Total events n First Events n (%) Total events n
Any event 572 (21.7) 900 514 (19.7) 803
All-cause mortality 122 (4.6) 186 110 (4.2) 177
Nonfatal myocardial infarction (MI) 118 (4.5) 157 105 (4.0) 131
Stroke 96 (3.6) 119 76 (2.9) 92
Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65
Cardiac intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195
Major leg amputation 15 (0.6) 28 9 (0.3) 28
Leg revascularization 57 (2.2) 92 71 (2.7) 115

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.

Table 10 . Weight Changes ( kg ) from Baseline During Randomized , Double Blind Clinical Trials
Control Group ( Placebo ) Pioglitazone Hydrochloride 15 mg Pioglitazone Hydrochloride 30 mg Pioglitazone Hydrochloride 45 mg
Median (25 t h /75 t h percentile) Median (25 t h /75 t h percentile) Median (25 t h /75 t h percentile) Median (25 t h /75 t h percentile)
Monotherapy ( 16 to 26 weeks ) -1.4 (-2.7/0.0) N=256 0.9 (-0.5/3.4) N = 79 1.0 (-0.9/3.4) N=188 2.6 (0.2/5.4) N = 79
Combination Therapy Sulfonylurea -0.5 (-1.8/0.7) N=187 2.0 (0.2/3.2) N=183 3.1 (1.1/5.4) N=528 4.1 (1.8/7.3) N=333
( 16 to 24 weeks ) Metformin -1.4 (-3.2/0.3) N=160 N/A 0.9 (-1.3/3.2) N=567 1.8 (-0.9/5.0) N=407
Insulin 0.2 (-1.4/1.4) N=182 2.3 (0.5/4.3) N=190 3.3 (0.9/6.3) N=522 4.1 (1.4/6.8) N=338

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

Table 11 . Median Change in Body Weight in Patients Treated with Pioglitazone Hydrochloride Versus Patients Treated with Placebo During the Double Blind Treatment Period in the PROactive Trial
Placebo Pioglitazone Hydrochloride
Median (25 t h /75 t h percentile) Median (25 t h /75 t h percentile)
Change from baseline to final visit (kg) -0.5 (-3.3, 2.0) N=2581 +3.6 (0.0, 7.5) N=2560

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.”

Table 12 . Adverse Events of Edema in Patients Treated with Pioglitazone Hydrochloride
Number (%) of Patients
Placebo Pioglitazone Hydrochloride 15 mg Pioglitazone Hydrochloride 30 mg Pioglitazone Hydrochloride 45 mg
Monotherapy (16 to 26 weeks) 3 (1.2%) N=259 2(2.5%) N= 81 13 (4.7%) N= 275 11 (6.5%) N=169
Combined Therapy Sulfonylurea 4 (2.1%) N=187 3(1.6%) N=184 61 (11.3%) N=540 81 (23.1%) N=351
(16 to 24 weeks) Metformin 4 (2.5%) N=160 N/A 34 (5.9%) N=579 58 (13.9%) N=416
Insulin 13(7.0%) N=187 24(12.6%) N=191 109(20.5%) N=533 90 (26.1%) N=345

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

Table 13 . Adverse Events of Edema in Patients in the PROactive Trial
Number (%) of Patients
Placebo N=2633 Pioglitazone Hydrochloride N=2605
419 (15.9%) 712 (27.3%)

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 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 hydrochloride 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 hydrochloride 15 mg, 15.4% with pioglitazone hydrochloride 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone hydrochloride 45 mg compared to pioglitazone hydrochloride 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 hydrochloride 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 hydrochloride 45 mg in combination with sulfonylurea (n=2) or pioglitazone hydrochloride 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: 0.59-1.72) [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.

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