Pioglitazone Dailymed

•Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. (5.1) • Hypoglycemia: When used with insulin or an insulin secretagogue, a lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. (5.2) • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone hydrochloride and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone if liver injury is confirmed and no alternate etiology can be found. (5.3) • Bladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer. (5.4) • Edema: Dose-related edema may occur. (5.5) • Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.6) •Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. (5.7) Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone hydrochloride. (5.8)

5.1 Congestive Heart Failure

Pioglitazone hydrochloride, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone hydrochloride is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients should be observed for signs and symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone must be considered [see Boxed Warning, Contraindications (4) , and Adverse Reactions (6.1)].

5.2 Hypoglycemia

Patients receiving pioglitazone hydrochloride in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia. A reduction in the dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia [see Dosage and Administration ( 2.2 )].

5.3 Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking pioglitazone, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the pioglitazone hydrochloride controlled clinical trial database to date [see Adverse Reactions (6.1)].

Patients with type 2 diabetes may have fatty liver disease or cardiac disease with episodic congestive heart failure, both of which may cause liver test abnormalities, and they may also have other forms of liver disease, many of which can be treated or managed. Therefore, obtaining a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) and assessing the patient is recommended before initiating pioglitazone therapy. In patients with abnormal liver tests, pioglitazone hydrochloride should be initiated with caution.

Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. In this clinical context, if the patient is found to have abnormal liver tests (ALT greater than 3 times the upper limit of the reference range),  pioglitazone hydrochloride treatment should be interrupted and investigation done to establish the probable cause.  Pioglitazone tablets should not be restarted in these patients without another explanation for the liver test abnormalities.

Patients who have serum ALT greater than three times the reference range with serum total bilirubin greater than two times the reference range without alternative etiologies are at risk for severe drug-induced liver injury, and should not be restarted on  pioglitazone. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone can be used with caution.

5.4 Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. In addition, 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]). Findings regarding the risk of bladder cancer in patients exposed to pioglitazone hydrochloride vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone hydrochloride, while others did.

A large prospective 10-year observational cohort study conducted in the United States found no statistically significant increase in the risk of bladder cancer in diabetic patients ever exposed to pioglitazone  hydrochloride, compared to those never exposed to pioglitazone hydrochloride (HR =1.06 [95% CI 0.89 to 1.26]).

A retrospective cohort study conducted with data from the United Kingdom found a statistically significant association between ever exposure to pioglitazone hydrochloride and bladder cancer (HR: 1.63; [95% CI: 1.22 to 2.19]).

Associations  between cumulative dose or cumulative duration of exposure to pioglitazone hydrochloride and bladder cancer were not detected in some studies including the 10-year observational study in the U.S., but were in others. Inconsistent findings and limitations inherent in these and other studies preclude conclusive interpretations of the observational data.

Pioglitazone hydrochloride may be associated with an increase in the risk of urinary bladder tumors. There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors.

Consequently, pioglitazone hydrochloride should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with pioglitazone  hydrochloride should be considered in patients with a prior history of bladder cancer.

5.5 Edema

In controlled clinical trials, edema was reported more frequently in patients treated with pioglitazone 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 tablets 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 (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 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 (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone 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.

6 Adverse Reactions

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

• Congestive heart failure [see Boxed Warningand Warnings and Precautions ( 5.1 )]
• Edema [see Warnings and Precautions ( 5.5 )]

• Fractures [see Warnings and Precautions ( 5.6 ) ]

Most common adverse reactions (≥ 5% )are upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact NorthStar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

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

Table 2. 16- to 24-Week Clinical Trials of   Pioglitazone Hydrochloride Add-on to Sulfonylurea

Â	16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 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
Â	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
	  Pioglitazone Hydrochloride  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

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. 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 Hydrochloride 30 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

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. 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 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
Â	24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with P ioglitazone 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

 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.

Table 5. PROactive Trial: Incidence and Types of Adverse Events Reported in > 5% of Patients Treated with Pioglitazone Hydrochloride and More Commonly than Placebo

Â	% 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

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. Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)

Patients Treated with  Pioglitazone Hydrochloride or Placebo Added on to a Sulfonylurea
Â	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
Â	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
Â	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, non-fatal 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. 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

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. 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 (25th/75th percentile)	Median (25th/75th percentile)	Median (25th/75th percentile)	Median (25th/75th percentile)
Mono therapy (16 to 26 weeks)	Â	-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 (16 to 24 weeks)	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
	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

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 HydrochlorideÂ
	Median (25th/75th percentile)	Median (25th/75th percentile)
Change from Baseline to final visit (kg)	-0.5 (-3.3, 2.0) N=2581	+3.6 (0.0, 7.5) N=2560

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 is provided in Table 12. 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 (16 to 24 weeks)	Sulfonyl urea	4 (2.1%) N=187	3 (1.6%) N=184	61 (11.3%) N=540	81 (23.1%) N=351
	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%)

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 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 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 )].