pioglitazone hydrochloride

Golden State Medical Supply
Golden State Medical Supply

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Pioglitazone Tablets, USP safely and effectively. See full prescribing information for Pioglitazone Tablets, USP. Pioglitazone Tablets, USP for oral use Initial U.S. Approval: 1999RECENT MAJOR CHANGES Indications and Usage   Important Limitations of Use (1.2) 01/2011 Dosage and Administration   Recommendations for All Patients (2.1) 01/2011   Coadministration with Strong CYP2C8 Inhibitors (2.3) 01/2011 Warnings and Precautions   Hepatic Effects (5.3) 01/2011   Urinary Bladder Tumors (5.5) 07/2011 BOXED WARNING WARNING: CONGESTIVE HEART FAILURE See full prescribing information for complete boxed warning. Thiazolidinediones, including Pioglitazone Tablets, USP, cause or exacerbate congestive heart failure in some patients. (5.1) After initiation of Pioglitazone Tablets, USP, and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea, and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of Pioglitazone Tablets, USP must be considered. (5.1) Pioglitazone Tablets, USP are not recommended in patients with symptomatic heart failure. Initiation of Pioglitazone Tablets, USP in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1) INDICATIONS AND USAGEPioglitazone Tablets, USP are a thiazolidinedione and an agonist for peroxisome proliferator- activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (1.1, 14)Important Limitation of Use: Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) DOSAGE AND ADMINISTRATION Initiate Pioglitazone Tablets, USP at 15 mg or 30 mg once daily. Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure. (2.1) If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily. (2.1) The maximum recommended dose of Pioglitazone Tablets, USP is 15 mg once daily in patients taking strong CYP2C8 inhibitors (e.g., gemfibrozil). (2.3, 7.1) Obtain liver tests before starting Pioglitazone Tablets, USP. If abnormal, use caution when treating with Pioglitazone Tablets, USP, investigate the probable cause, treat (if possible) and follow appropriately. Monitoring liver tests while on Pioglitazone Tablets, USP is not recommended in patients without liver disease. (5.3) DOSAGE FORMS AND STRENGTHSTablets: 15 mg, 30 mg, and 45 mg (3)CONTRAINDICATIONS Do not initiate Pioglitazone Tablets, USP in patients with established NYHA Class III or IV heart failure. (4) Do not use in patients with a history of a serious hypersensitivity reaction to Pioglitazone Tablets, USP or its ingredients. (4) WARNINGS AND PRECAUTIONS 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) Edema: Dose-related edema may occur. (5.2) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt Pioglitazone Tablets, USP and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart Pioglitazone Tablets, USP if liver injury is confirmed and no alternate etiology can be found. (5.3) Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.4) Bladder cancer: Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users. The observational data further suggest that the risk increases with duration of use. Do not use in patients with active bladder cancer. Use caution when using in patients with a prior history of bladder cancer (5.5) 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. (5.6) 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 Tablets, USP or any other anti-diabetic drug. (5.9) Side EffectsMost common adverse reactions (≥ 5% and at a rate higher than with placebo) include upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit Pioglitazone Tablets, USP dose to 15 mg daily. (2.3, 7.1) CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2) USE IN SPECIFIC POPULATIONS Pregnancy Category C: Based on animal data, may cause fetal harm (8.1) Nursing mothers: Discontinue drug or nursing, taking into consideration the importance of the drug to the mother (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 PIOGLITAZONE HYDROCHLORIDE INDICATIONS AND USAGE
  • 1.1 Monotherapy and Combination Therapy
  • 1.2 Important Limitation of Use
• 2 PIOGLITAZONE HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 Recommendations for all patients
  • 2.2 Concomitant use with an insulin secretagogue or insulin
  • 2.3 Coadministration with strong CYP2C8 inhibitors
• 3 DOSAGE FORMS AND STRENGTHS
• 4 PIOGLITAZONE HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Congestive Heart Failure
  • 5.2 Edema
  • 5.3 Hepatic Effects
  • 5.4 Fractures
  • 5.5 Urinary Bladder Tumors
  • 5.6 Hypoglycemia
  • 5.7 Macular Edema
  • 5.8 Ovulation
  • 5.9 Macrovascular Outcomes
• 6 PIOGLITAZONE HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Laboratory Abnormalities
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Strong CYP2C8 Inhibitors
  • 7.2 CYP2C8 Inducers
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
• 10 OVERDOSAGE
• 11 PIOGLITAZONE HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
  • 13.3 Reproductive and Developmental Toxicology
• 14 CLINICAL STUDIES
  • 14.1 Monotherapy
  • 14.2 Combination Therapy
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • Storage:
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Instructions
  • 17.2 FDA-Approved Medication Guide
• MEDICATION GUIDE
• PRINCIPAL DISPLAY PANEL - 30 mg Bottle Label
• PRINCIPAL DISPLAY PANEL - 45 mg Bottle Label

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

Pioglitazone Tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14)].

1.2 Important Limitation of Use

Pioglitazone Tablets, USP exert their antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone Tablets, USP should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it would not be effective in these settings.

Use caution in patients with liver disease [see Warnings and Precautions (5.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for all patients

Pioglitazone Tablets, USP should be taken once daily and can be taken without regard to meals.

The recommended starting dose for patients without congestive heart failure is 15 mg or 30 mg once daily.

The recommended starting dose for patients with congestive heart failure (NYHA Class I or II) is 15 mg once daily.

The dose can be titrated in increments of 15 mg up to a maximum of 45 mg once daily based on glycemic response as determined by HbA1c.

After initiation of Pioglitazone Tablets, USP or with dose increase, monitor patients carefully for adverse reactions related to fluid retention such as weight gain, edema, and signs and symptoms of congestive heart failure [see Boxed Warning and Warnings and Precautions (5.2)].

Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating Pioglitazone Tablets, USP. Routine periodic monitoring of liver tests during treatment with Pioglitazone Tablets, USP is not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of Pioglitazone Tablets, USP or who are found to have abnormal liver tests while taking Pioglitazone Tablets, USP should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

2.2 Concomitant use with an insulin secretagogue or insulin

If hypoglycemia occurs in a patient co-administered Pioglitazone Tablets, USP and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient co-administered Pioglitazone Tablets, USP and insulin, the dose of insulin should be decreased by 10% to 25%. Further adjustments to the insulin dose should be individualized based on glycemic response.

2.3 Coadministration with strong CYP2C8 inhibitors

Coadministration of Pioglitazone Tablets, USP and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of Pioglitazone Tablets, USP is 15 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Round tablet contains pioglitazone as follows:

• 15 mg: White to off-white, debossed with "PGZ" on one side and "15" on the other side
• 30 mg: White to off-white, debossed with "PGZ" on one side and "30" on the other side
• 45 mg: White to off-white, debossed with "PGZ" on one side and "45" on the other side

4 CONTRAINDICATIONS

Do not initiate in patients with NYHA Class III or IV heart failure [see Boxed Warning].

Do not use in patients with a history of a serious hypersensitivity reaction to Pioglitazone Tablets, USP or any of its ingredients.

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

Pioglitazone Tablets, USP, 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 Tablets, USP are 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 Tablets, USP must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions (6.1)].

5.2 Edema

In controlled clinical trials, edema was reported more frequently in patients treated with Pioglitazone Tablets, USP 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 Tablets, USP should be used with caution in patients with edema. Because thiazolidinediones, including Pioglitazone Tablets, USP, can cause fluid retention, which can exacerbate or lead to congestive heart failure, Pioglitazone Tablets, USP should be used with caution in patients at risk for congestive heart failure. Patients treated with Pioglitazone Tablets, USP should be monitored for signs and symptoms of congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1) and Patient Counseling Information (17.1)].

5.3 Hepatic Effects

There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking Pioglitazone Tablets, USP, although the reports contain insufficient information necessary to establish the probable cause. There has been no evidence of drug-induced hepatotoxicity in the Pioglitazone Tablets, USP 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 Tablets, USP therapy. In patients with abnormal liver tests, Pioglitazone Tablets, USP 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 Tablets, USP treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone Tablets, USP 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 Tablets, USP. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with Pioglitazone Tablets, USP can be used with caution.

5.4 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 Tablets, USP (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 Tablets, USP 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 Tablets, USP (1.7%) versus placebo (2.1%). The risk of fracture should be considered in the care of patients, especially female patients, treated with Pioglitazone Tablets, USP and attention should be given to assessing and maintaining bone health according to current standards of care.

5.5 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 two 3-year trials in which Pioglitazone Tablets, USP were compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone Tablets, USP compared to 5/3679 (0.14%) in patients not taking Pioglitazone Tablets, USP. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone Tablets, USP and two (0.05%) cases on placebo.

A five-year interim report of an ongoing 10-year observational cohort study found a non-significant increase in the risk of bladder cancer in subjects ever exposed to Pioglitazone Tablets, USP, compared to subjects never exposed to Pioglitazone Tablets, USP (HR 1.2 [95% CI 0.9-1.5]). Compared to never exposure, a duration of Pioglitazone Tablets, USP therapy longer than 12 months was associated with an increase in risk (HR 1.4 [95% CI 0.9-2.1]), which reached statistical significance after more than 24 months of Pioglitazone Tablets, USP use (HR 1.4 [95% CI 1.03-2.0]). Interim results from this study suggest that taking Pioglitazone Tablets, USP longer than 12 months increased the relative risk of developing bladder cancer in any given year by 40% which equates to an absolute increase of 3 cases in 10,000 (from approximately 7 in 10,000 [without Pioglitazone Tablets, USP] to approximately 10 in 10,000 [with Pioglitazone Tablets, USP]).

There are insufficient data to determine whether pioglitazone is a tumor promoter for urinary bladder tumors. Consequently, Pioglitazone Tablets, USP should not be used in patients with active bladder cancer and the benefits of glycemic control versus unknown risks for cancer recurrence with Pioglitazone Tablets, USP should be considered in patients with a prior history of bladder cancer.

5.6 Hypoglycemia

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

5.7 Macular Edema

Macular edema has been reported in postmarketing experience in diabetic patients who were taking Pioglitazone Tablets, USP 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 Ovulation

Therapy with Pioglitazone Tablets, USP, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Pioglitazone Tablets, USP [see Use in Specific Populations (8.1)]. This effect has not been investigated in clinical trials, so the frequency of this occurrence is not known. Adequate contraception in all premenopausal women treated with Pioglitazone Tablets, USP is recommended.

5.9 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Pioglitazone Tablets, USP or any other anti-diabetic 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 (5.2)]
• Fractures [see Warnings and Precautions (5.4)]

6.1 Clinical Studies 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 Tablets, USP in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes and macrovascular disease treated with Pioglitazone Tablets, USP in the PROactive clinical trial. In these trials, over 6000 patients have been treated with Pioglitazone Tablets, USP for 6 months or longer, over 4500 patients have been treated with Pioglitazone Tablets, USP for one year or longer, and over 3000 patients have been treated with Pioglitazone Tablets, USP for at least 2 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 Tablets, USP 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 Tablets, USP 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 Tablets, USP 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 Tablets, USP 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 Tablets, USP 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 Tablets, USP than in patients who received placebo. None of these adverse events were related to Pioglitazone Tablets, USP 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 Tablets, USP 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 Tablets, USP.

A summary of the overall incidence and types of common adverse events reported in trials of Pioglitazone Tablets, USP 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 Tablets, USP.

Table 4 summarizes the incidence and types of common adverse events reported in trials of Pioglitazone Tablets, USP 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 Tablets, USP.

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 Tablets, USP than in patients who received placebo.

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 Tablets, USP 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 Tablets, USP (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 Tablets, USP 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 Tablets, USP 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 Tablets, USP 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 Pioglitazone Tablets, USP. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.

Weight Gain:

Dose-related weight gain occurs when Pioglitazone Tablets, USP are used alone or in combination with other anti-diabetic 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 Tablets, USP 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.

Edema:

Edema induced from taking Pioglitazone Tablets, USP is reversible when Pioglitazone Tablets, USP are 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 Tablets, USP is provided in Table 12.

Hepatic Effects:

There has been no evidence of Pioglitazone Tablets, USP-induced hepatotoxicity in the Pioglitazone Tablets, USP controlled clinical trial database to date. One randomized, double-blind, 3-year trial comparing Pioglitazone Tablets, USP to glyburide as add-on to metformin and insulin therapy was specifically designed to evaluate the incidence of serum ALT elevation to greater than 3 times the upper limit of the reference range, measured every 8 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 Tablets, USP and 9/1046 (0.9%) patients treated with glyburide developed ALT values > 3 times the upper limit of the reference range. None of the patients treated with Pioglitazone Tablets, USP in the Pioglitazone Tablets, USP controlled clinical trial database to date have had a serum ALT > 3 times the upper limit of the reference range and a corresponding total bilirubin > 2 times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia:

In the Pioglitazone Tablets, USP 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 Tablets, USP 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 Tablets, USP 15 mg, 15.4% with Pioglitazone Tablets, USP 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with Pioglitazone Tablets, USP 45 mg compared to Pioglitazone Tablets, USP 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 Tablets, USP 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 Tablets, USP 45 mg in combination with sulfonylurea (n=2) or Pioglitazone Tablets, USP 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)]. In two 3-year trials in which Pioglitazone Tablets, USP were compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking Pioglitazone Tablets, USP compared to 5/3679 (0.14%) in patients not taking Pioglitazone Tablets, USP. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on Pioglitazone Tablets, USP and two (0.05%) cases on placebo. There are too few events of bladder cancer to establish causality.

6.2 Laboratory Abnormalities

Hematologic Effects:

Pioglitazone Tablets, USP 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 Tablets, USP 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 Tablets, USP 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 Tablets, USP clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in 9 (0.2%) patients treated with Pioglitazone Tablets, USP (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive Pioglitazone Tablets, USP, two patients were noted to have the CPK elevation on the last day of dosing and one patient discontinued Pioglitazone Tablets, USP due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to Pioglitazone Tablets, USP therapy is unknown.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Pioglitazone Tablets, USP. 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 (5.2)].
• Fatal and non-fatal hepatic failure [see Warnings and Precautions (5.3)].

Postmarketing reports of congestive heart failure have been reported in patients treated with Pioglitazone Tablets, USP, 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)].

7 DRUG INTERACTIONS

7.1 Strong CYP2C8 Inhibitors

An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life of pioglitazone. Therefore, the maximum recommended dose of Pioglitazone Tablets, USP is 15 mg daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

7.2 CYP2C8 Inducers

An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with Pioglitazone Tablets, USP, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for Pioglitazone Tablets, USP [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C.

There are no adequate and well-controlled studies of Pioglitazone Tablets, USP in pregnant women. Animal studies show increased rates of post-implantation loss, delayed development, reduced fetal weights, and delayed parturition at doses 10 to 40 times the maximum recommended human dose. Pioglitazone Tablets, USP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations:

Abnormal blood glucose concentrations during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality. Most experts recommend the use of insulin during pregnancy to maintain blood glucose concentrations as close to normal as possible for patients with diabetes.

Animal Data:

In animal reproductive studies, pregnant rats and rabbits received pioglitazone at doses up to approximately 17 (rat) and 40 (rabbit) times the maximum recommended human oral dose (MRHD) based on body surface area (mg/m²); no teratogenicity was observed [see Nonclinical Toxicology (13.3)]. Increases in embryotoxicity (increased postimplantation losses, delayed development, reduced fetal weights, and delayed parturition) occurred in rats that received oral doses approximately 10 or more times the MRHD (mg/m² basis). No functional or behavioral toxicity was observed in rat offspring. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in rat offspring at oral maternal doses approximately 2 or more times the MRHD (mg/m² basis). In rabbits, embryotoxicity occurred at oral doses approximately 40 times the MRHD (mg/m² basis).

8.3 Nursing Mothers

It is not known whether Pioglitazone Tablets, USP are secreted in human milk. Pioglitazone is secreted in the milk of lactating rats. Because many drugs are excreted in human milk, and because of the potential for Pioglitazone Tablets, USP to cause serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or discontinue Pioglitazone Tablets, USP, taking into account the importance of Pioglitazone Tablets, USP to the mother.

8.4 Pediatric Use

Safety and effectiveness of Pioglitazone Tablets, USP in pediatric patients have not been established.

Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with Pioglitazone Tablets, USP have not been determined in this population [see Warnings and Precautions (5.4)].

8.5 Geriatric Use

A total of 92 patients (15.2%) treated with Pioglitazone Tablets, USP in the three pooled 16 to 26-week double-blind, placebo-controlled, monotherapy, trials were ≥ 65 years old and 2 patients (0.3%) were ≥75 years old. In the two pooled 16 to 24-week add-on to sulfonylurea trials, 201 patients (18.7%) treated with Pioglitazone Tablets, USP were ≥ 65 years old and 19 (1.8%) were ≥ 75 years old. In the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with Pioglitazone Tablets, USP were ≥ 65 years old and 19 (1.9%) were ≥ 75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with Pioglitazone Tablets, USP were ≥ 65 years old and 22 (2.1%) were ≥ 75 years old.

In PROactive, 1068 patients (41.0%) treated with Pioglitazone Tablets, USP were ≥ 65 years old and 42 (1.6%) were ≥ 75 years old.

In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥ 65 years) and younger patients although small sample sizes for patients ≥ 75 years old limit conclusions [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

During controlled clinical trials, one case of overdose with Pioglitazone Tablets, USP was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

11 DESCRIPTION

Pioglitazone Tablets, USP are an oral antidiabetic medication.

Pioglitazone [(±)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy] phenyl] methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:

Pioglitazone hydrochloride, USP is an odorless white crystalline powder that has a molecular formula of C₁₉H₂₀N₂O₃S•HCl and a molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.

Pioglitazone Tablets, USP are available as tablets for oral administration containing 15 mg, 30 mg, or 45 mg of pioglitazone (as the base) formulated with the following excipients: lactose monohydrate NF, hydroxypropyl - cellulose NF, carboxymethylcellulose calcium NF, and magnesium stearate NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pioglitazone Tablets, USP are a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone Tablets, USP decrease insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.

In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.

12.2 Pharmacodynamics

Clinical studies demonstrate that Pioglitazone Tablets, USP improve insulin sensitivity in insulin-resistant patients. Pioglitazone Tablets, USP enhance cellular responsiveness to insulin, increase insulin-dependent glucose disposal and improve hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by Pioglitazone Tablets, USP results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, Pioglitazone Tablets, USP had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14.2)].

Patients with lipid abnormalities were included in clinical trials with Pioglitazone Tablets, USP. Overall, patients treated with Pioglitazone Tablets, USP had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with Pioglitazone Tablets, USP or any other antidiabetic medication [see Warnings and Precautions (5.9) and Adverse Reactions (6.1)].

In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the 15 mg, 30 mg, and 45 mg Pioglitazone Tablets, USP dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with Pioglitazone Tablets, USP than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with Pioglitazone Tablets, USP compared to placebo (Table 14).

Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study

	Placebo	Pioglitazone Tablets, USP 15 mg Once Daily	Pioglitazone Tablets, USP 30 mg Once Daily	Pioglitazone Tablets, USP 45 mg Once Daily
Triglycerides (mg/dL)	N=79	N=79	N=84	N=77
Baseline (mean)	263	284	261	260
Percent change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	4.8%	-9.0%p < 0.05 versus placebo	-9.6%p < 0.05 versus placebo	-9.3%p < 0.05 versus placebo
HDL Cholesterol (mg/dL)	N=79	N=79	N=83	N=77
Baseline (mean)	42	40	41	41
Percent change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	8.1%	14.1%p < 0.05 versus placebo	12.2%	19.1%p < 0.05 versus placebo
LDL Cholesterol (mg/dL)	N=65	N=63	N=74	N=62
Baseline (mean)	139	132	136	127
Percent change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	4.8%	7.2%	5.2%	6.0%
Total Cholesterol (mg/dL)	N=79	N=79	N=84	N=77
Baseline (mean)	225	220	223	214
Percent change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	4.4%	4.6%	3.3%	6.4%

In the two other monotherapy studies (16 weeks and 24 weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks ) or insulin (16 weeks and 24 weeks), the results were generally consistent with the data above.

12.3 Pharmacokinetics

Following once daily administration of Pioglitazone Tablets, USP, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within 7 days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC. Maximum serum concentration (C_max), AUC, and trough serum concentrations (C_min) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

Absorption:

Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within 2 hours. Food slightly delays the time to peak serum concentration (T_max) to 3 to 4 hours, but does not alter the extent of absorption (AUC).

Distribution:

The mean apparent volume of distribution (Vd/F) of pioglitazone following single-dose administration is 0.63 ± 0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (> 99%) in human serum, principally to serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III and M-IV are also extensively bound (> 98%) to serum albumin.

Metabolism:

Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans.

In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, a strong CYP2C8 inhibitor showed that pioglitazone is a CYP2C8 substrate [see Dosage and Administration (2.3) and Drug Interactions (7)]. Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with Pioglitazone Tablets, USP showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Excretion and Elimination:

Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5 to 7 L/hr.

Renal Impairment:

The serum elimination half-life of pioglitazone, M-III, and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) and severe (creatinine clearance < 30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dose adjustment in patients with renal impairment is required.

Hepatic Impairment:

Compared with healthy controls, subjects with impaired hepatic function (Child-Turcotte-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.

There are postmarketing reports of liver failure with Pioglitazone Tablets, USP and clinical trials have generally excluded patients with serum ALT > 2.5x the upper limit of the reference range. Use caution in patients with liver disease [see Warnings and Precautions (5.3)].

Geriatric Patients:

In healthy elderly subjects, peak serum concentrations of pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about 7 hours). These changes were not of a magnitude that would be considered clinically relevant.

Pediatric Patients:

Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone Tablets, USP are not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].

Gender:

The mean C_max and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, HbA1c decreases from baseline were generally greater for females than for males (average mean difference in HbA1c 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.

Ethnicity:

Pharmacokinetic data among various ethnic groups are not available.

Drug-Drug Interactions

Table 15: Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs

	Co-administered Drug
Pioglitazone Dosage Regimen (mg)Daily for 7 days unless otherwise noted	Name and Dose Regimens	Change in AUC% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.		Change in Cmax % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
45 mg (N = 12)	WarfarinPioglitazone had no clinically significant effect on prothrombin time
	Daily loading then maintenance doses based PT and INR values Quick's Value = 35 ± 5%	R-Warfarin	↓ 3%	R-Warfarin	↓ 2%
		S-Warfarin	↓ 1%	S-Warfarin	↑ 1%
45 mg (N = 12)	Digoxin
	0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, 7 days)	↑15%		↑17%
45 mg daily for 21 days (N = 35)	Oral Contraceptive
	[Ethinyl Estradiol (EE) 0.035 mg plus Norethindrone(NE) 1 mg] for 21 days	EE	↓ 11%	EE	↓ 13%
		NE	↑ 3%	NE	↓ 7%
45 mg (N = 23)	Fexofenadine
	60 mg twice daily for 7 days	↑ 30%		↑ 37%
45 mg (N = 14)	Glipizide
	5 mg daily for 7 days	↓ 3%		↓ 8%
45 mg daily for 8 days (N = 16)	Metformin
	1000 mg single dose on 8 days	↓ 3%		↓ 5%
45 mg (N = 21)	Midazolam
	7.5 mg single dose on day 15	↓ 26%		↓ 26%
45 mg (N = 24)	Ranitidine
	150 mg twice daily for 7 days	↑ 1%		↓ 1%
45 mg daily for 4 days (N = 24)	Nifedipine ER
	30 mg daily for 4 days	↓ 13%		↓ 17%
45 mg (N = 25)	Atorvastatin Ca
	80 mg daily for 7 days	↓ 14%		↓ 23%
45 mg (N = 22)	Theophylline
	400 mg twice daily for 7 days	↑ 2%		↑ 5%

Table 16: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure

Coadministered Drug and Dosage Regimen	Pioglitazone
	Dose Regimen (mg)Daily for 7 days unless otherwise noted	Change in AUCMean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.	Change in Cmax Mean ratio (with/without coadministered drug and no change = 1-fold) % change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively.
Gemfibrozil 600 mg twice daily for 2 days (N = 12)	30 mg single dose	↑ 3.4-foldThe half-life of pioglitazone increased from 6.5 h to 15.1 h in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7)]	↑ 6%
Ketoconazole 200 mg twice daily for 7 days (N = 28)	45 mg	↑ 34%	↑ 14%
Rifampin 600 mg daily for 5 days (N = 10)	30 mg single dose	↓ 54%	↓ 5%
Fexofenadine 60 mg twice daily for 7 days (N = 23)	45 mg	↑ 1%	0%
Ranitidine 150 mg twice daily for 4 days (N = 23)	45 mg	↓ 13%	↓ 16%
Nifedipine ER 30 mg daily for 7 days (N = 23)	45 mg	↑ 5%	↑ 4%
Atorvastatin Ca 80 mg daily for 7 days (N = 24)	45 mg	↓ 24%	↓ 31%
Theophylline 400 mg twice daily for 7 days (N = 22)	45 mg	↓ 4%	↓ 2%

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m²). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m²). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m²). No drug-induced tumors were observed in any organ.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.

No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m²).

13.2 Animal Toxicology and/or Pharmacology

Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m²). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m²). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m²), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m²).

13.3 Reproductive and Developmental Toxicology

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m², respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m²). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m²). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m²).

14 CLINICAL STUDIES

14.1 Monotherapy

Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of Pioglitazone Tablets, USP as monotherapy in patients with type 2 diabetes. These trials examined Pioglitazone Tablets, USP at doses up to 45 mg or placebo once daily in a total of 865 patients.

In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of Pioglitazone Tablets, USP, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of Pioglitazone Tablets, USP produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1 and Table 17).

Figure 1 shows the time course for changes in HbA1c in this 26-week study.

Figure 1 Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values)

Table 17: Glycemic Parameters in a 26 Week Placebo Controlled Dose

Ranging Monotherapy Trial

In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration Pioglitazone Tablets, USP treatment groups or a mock-titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one Pioglitazone Tablets, USP treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks). In the second Pioglitazone Tablets, USP treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with Pioglitazone Tablets, USP, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo.

Table 18: Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial

	Placebo	Pioglitazone Tablets, USP 30 mgFinal dose in forced titration Once Daily	Pioglitazone Tablets, USP 45 mgFinal dose in forced titration Once Daily
Total Population
HbA1c (%)	N=83	N=85	N=85
Baseline (mean)	10.8	10.3	10.8
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	0.9	-0.6	-0.6
Difference from placebo (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-1.5p ≤ 0.05 vs. placebo (-2.0, -1.0)	-1.5p ≤ 0.05 vs. placebo (-2.0, -1.0)
Fasting Plasma Glucose (mg/dL)	N=78	N=82	N=85
Baseline (mean)	279	268	281
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	18	-44	-50
Difference from placebo (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-62p ≤ 0.05 vs. placebo (-82, -.41)	-68p ≤ 0.05 vs. placebo (-88, -.48)

In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of Pioglitazone Tablets, USP or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of Pioglitazone Tablets, USP produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (Table 19).

Table 19: Glycemic Parameters in a 16-Week Placebo-Controlled Monotherapy Trial

	Placebo	Pioglitazone Tablets, USP 30 mg Once Daily
Total Population
HbA1c (%)	N=93	N=100
Baseline (mean)	10.3	10.5
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	0.8	-0.6
Difference from placebo (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-1.4p ≤ 0.050 vs. placebo (-1.8, -0.9)
Fasting Plasma Glucose (mg/dL)	N=91	N=99
Baseline (mean)	270	273
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	8	-50
Difference from placebo (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-58p ≤ 0.050 vs. placebo (-77, -38)

14.2 Combination Therapy

Three 16-week, randomized, double-blind, placebo-controlled clinical trials were conducted to evaluate the effects of Pioglitazone Tablets, USP (15 mg and/or 30 mg) on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin. In addition, three 24-week randomized, double-blind clinical trials were conducted to evaluate the effects of Pioglitazone Tablets, USP 30 mg vs. Pioglitazone Tablets, USP 45 mg on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.

Add-on to Sulfonylurea Trials:

Two clinical trials were conducted with Pioglitazone Tablets, USP in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on any dose of a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.

In the first study, 560 patients were randomized to receive 15 mg or 30 mg of Pioglitazone Tablets, USP or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. Treatment with Pioglitazone Tablets, USP as add-on to sulfonylurea produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to sulfonylurea (Table 20).

Table 20: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Sulfonylurea Trial

	Placebo + Sulfonylurea	Pioglitazone Tablets, USP 15 mg + Sulfonylurea	Pioglitazone Tablets, USP 30 mg + Sulfonylurea
Total Population
HbA1c (%)	N=181	N=176	N=182
Baseline (mean)	9.9	10.0	9.9
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	0.1	-0.8	-1.2
Difference from placebo + sulfonylurea (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-0.9p ≤ 0.05 vs. placebo + sulfonylurea (-1.2, -0.6)	-1.3p ≤ 0.05 vs. placebo + sulfonylurea (-1.6, -1.0)
Fasting Plasma Glucose (mg/dL)	N=182	N=179	N=186
Baseline (mean)	236	247	239
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	6	-34	-52
Difference from placebo + sulfonylurea (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-39p ≤ 0.05 vs. placebo + sulfonylurea (-52, -27)	-58p ≤ 0.05 vs. placebo + sulfonylurea (-70, -46)

In the second trial, 702 patients were randomized to receive 30 mg or 45 mg of Pioglitazone Tablets, USP once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.6% for the 30 mg dose and 1.7% for the 45 mg dose (see Table 21). The mean reduction from baseline at Week 24 in FPG was 52 mg/dL for the 30 mg dose and 56 mg/dL for the 45 mg dose.

The therapeutic effect of Pioglitazone Tablets, USP in combination with sulfonylurea was observed in patients regardless of the sulfonylurea dose.

Table 21: Glycemic Parameters in a 24-Week Add-on to Sulfonylurea Trial

	Pioglitazone Tablets, USP 30 mg + Sulfonylurea	Pioglitazone Tablets, USP 45 mg + Sulfonylurea
Total Population
95% CI = 95% confidence interval
HbA1c (%)	N=340	N=332
Baseline (mean)	9.8	9.9
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-1.6	-1.7
Difference from 30 mg daily Pioglitazone Tablets, USP + sulfonylurea (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-0.1 (-0.4, 0.1)
Fasting Plasma Glucose (mg/dL)	N=338	N=329
Baseline (mean)	214	217
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-52	-56
Difference from 30 mg daily Pioglitazone Tablets, USP + sulfonylurea (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-5 (-12, 3)

Add-on to Metformin Trials:

Two clinical trials were conducted with Pioglitazone Tablets, USP in combination with metformin. Both trials included patients with type 2 diabetes on any dose of metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn at least 3 weeks prior to starting study treatment.

In the first trial, 328 patients were randomized to receive either 30 mg of Pioglitazone Tablets, USP or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with Pioglitazone Tablets, USP as add-on to metformin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to metformin (see Table 22).

Table 22: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Metformin Trial

	Placebo + Metformin	Pioglitazone Tablets, USP 30 mg + Metformin
Total Population
HbA1c (%)	N=153	N=161
Baseline (mean)	9.8	9.9
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	0.2	-0.6
Difference from placebo + metformin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-0.8p ≤ 0.05 vs. placebo + metformin (-1.2, -0.5)
Fasting Plasma Glucose (mg/dL)	N=157	N=165
Baseline (mean)	260	254
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-5	-43
Difference from placebo + metformin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-38p ≤ 0.05 vs. placebo + metformin (-49, -26)

In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of Pioglitazone Tablets, USP once daily for 24 weeks in addition to their current metformin regimen. The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1.0% for the 45 mg dose (see Table 23). The mean reduction from baseline at Week 24 in FPG was 38 mg/dL for the 30 mg dose and 51 mg/dL for the 45 mg dose.

Table 23: Glycemic Parameters in a 24-Week Add-on to Metformin Study

	Pioglitazone Tablets, USP 30 mg + Metformin	Pioglitazone Tablets, USP 45 mg + Metformin
Total Population
95% CI = 95% confidence interval
HbA1C (%)	N=400	N=398
Baseline (mean)	9.9	9.8
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-0.8	-1.0
Difference from 30 mg daily Pioglitazone Tablets, USP + Metformin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-0.2 (-0.5, 0.1)
Fasting Plasma Glucose (mg/dL)	N=398	N=399
Baseline (mean)	233	232
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-38	-51
Difference from 30 mg daily Pioglitazone Tablets, USP + Metformin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-12p ≤ 0.05 vs. 30 mg daily Pioglitazone Tablets, USP + metformin (-21, -4)

The therapeutic effect of Pioglitazone Tablets, USP in combination with metformin was observed in patients regardless of the metformin dose.

Add-on to Insulin Trials:

Two clinical trials were conducted with Pioglitazone Tablets, USP in combination with insulin. Both trials included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first trial, 566 patients were randomized to receive either 15 mg or 30 mg of Pioglitazone Tablets, USP or placebo once daily for 16 weeks in addition to their insulin regimen. Treatment with Pioglitazone Tablets, USP as add-on to insulin produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo add-on to insulin (see Table 24). The mean daily insulin dose at baseline in each treatment group was approximately 70 units. The majority of patients (75% overall, 86% treated with placebo, 77% treated with Pioglitazone Tablets, USP 15 mg, and 61% treated with Pioglitazone Tablets, USP 30 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -3 units in the patients treated with Pioglitazone Tablets, USP 15 mg, -8 units in the patients treated with Pioglitazone Tablets, USP 30 mg, and -1 unit in patients treated with placebo.

Table 24: Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Insulin Trial

	Placebo + Insulin	Pioglitazone Tablets, USP 15 mg + Insulin	Pioglitazone Tablets, USP 30 mg + Insulin
Total Population
HbA1C (%)	N=177	N=177	N=185
Baseline (mean)	9.8	9.8	9.8
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-0.3	-1.0	-1.3
Difference from placebo + Insulin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-0.7p ≤ 0.05 vs. placebo + insulin (-1.0, -0.5)	-1.0p ≤ 0.05 vs. placebo + insulin (-1.3, -0.7)
Fasting Plasma Glucose (mg/dL)	N=179	N=183	N=184
Baseline (mean)	221	222	229
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	1	-35	-48
Difference from placebo + Insulin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) 95% Confidence Interval		-35p ≤ 0.05 vs. placebo + insulin (-51, -19)	-49p ≤ 0.05 vs. placebo + insulin (-65, -33)

In the second trial, 690 patients receiving a median of 60 units per day of insulin were randomized to receive either 30 mg or 45 mg of Pioglitazone Tablets, USP once daily for 24 weeks in addition to their current insulin regimen. The mean reduction from baseline at Week 24 in HbA1c was 1.2% for the 30 mg dose and 1.5% for the 45 mg dose. The mean reduction from baseline at Week 24 in FPG was 32 mg/dL for the 30 mg dose and 46 mg/dL for the 45 mg dose (see Table 25). The mean daily insulin dose at baseline in both treatment groups was approximately 70 units. The majority of patients (55% overall, 58% treated with Pioglitazone Tablets, USP 30 mg, and 52% treated with Pioglitazone Tablets, USP 45 mg) had no change in their daily insulin dose from baseline to the final study visit. The mean change from baseline in daily dose of insulin (including patients with no insulin dose modifications) was -5 units in the patients treated with Pioglitazone Tablets, USP 30 mg and -8 units in the patients treated with Pioglitazone Tablets, USP 45 mg.

The therapeutic effect of Pioglitazone Tablets, USP in combination with insulin was observed in patients regardless of the insulin dose.

Table 25: Glycemic Parameters in a 24-Week Add-on to Insulin Trial

	Pioglitazone Tablets, USP 30 mg + Insulin	Pioglitazone Tablets, USP 45 mg + Insulin
Total Population
95% CI = 95% confidence interval
HbA1c (%)	N=328	N=328
Baseline (mean)	9.9	9.7
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-1.2	-1.5
Difference from 30 mg daily Pioglitazone Tablets, USP+Insulin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-0.3p ≤ 0.05 vs. 30 mg daily Pioglitazone Tablets, USP + insulin (-0.5, -0.1)
Fasting Plasma Glucose (mg/dL)	N=325	N=327
Baseline (mean)	202	199
Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)	-32	-46
Difference from 30 mg daily Pioglitazone Tablets, USP + Insulin (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction) (95% CI)		-14p ≤ 0.05 vs. 30 mg daily Pioglitazone Tablets, USP + insulin (-25, -3)

16 HOW SUPPLIED/STORAGE AND HANDLING

Pioglitazone Tablets, USP are available in 15 mg, 30 mg, and 45 mg tablets as follows:

15 mg tablet: White to off-white, round tablet debossed with "PGZ" on one side and "15" on the other side, available in:

NDC 60429-330-30 Bottles of 30
NDC 60429-330-90 Bottles of 90
NDC 60429-330-10 Bottles of 1000

30 mg tablet: White to off-white, round tablet debossed with "PGZ" on one side and "30" on the other side, available in:

NDC 60429-331-30 Bottles of 30
NDC 60429-331-90 Bottles of 90
NDC 60429-331-10 Bottles of 1000

45 mg tablet: White to off-white, round tablet debossed with "PGZ" on one side and "45" on the other side, available in:

NDC 60429-332-30 Bottles of 30
NDC 60429-332-90 Bottles of 90
NDC 60429-332-10 Bottles of 1000

Storage:

Store at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from light, moisture and humidity.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide (17.2).

17.1 Instructions

• It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
• Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on Pioglitazone Tablets, USP should immediately report these symptoms to a physician.
• Tell patients to promptly stop taking Pioglitazone Tablets, USP and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
• Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
• Tell patients to take Pioglitazone Tablets, USP once daily. Pioglitazone Tablets, USP can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day.
• When using combination therapy with insulin or other antidiabetic medications, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
• Therapy with Pioglitazone Tablets, USP, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking Pioglitazone Tablets, USP. Therefore, adequate contraception should be recommended for all pre-menopausal women who are prescribed Pioglitazone Tablets, USP.

17.2 FDA-Approved Medication Guide

See attached leaflet.

Manufactured by:
Rottendorf Pharma GmbH
Ennigerloh, Germany
Made in Germany

Distributed by:
Breckenridge Pharmaceutical, Inc.
Boca Raton, FL 33487

Marketed/Packaged by:
GSMS, Inc.
Camarillo, CA 93012

Issue Date: 09/2012

PI-5019-0

Leaflet (PI): PGZ 15; 30; 45mg BRE US
Material Number: 305053

MEDICATION GUIDE

Pioglitazone Tablets, USP

Read this Medication Guide carefully before you start taking Pioglitazone Tablets, USP and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about Pioglitazone Tablets, USP, ask your doctor or pharmacist.

What is the most important information I should know about Pioglitazone Tablets, USP?

Pioglitazone Tablets, USP can cause serious side effects, including new or worse heart failure.

• Pioglitazone Tablets, USP can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough
• Do not take Pioglitazone Tablets, USP if you have severe heart failure
• If you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, Pioglitazone Tablets, USP may not be right for you

Call your doctor right away if you have any of the following:

• swelling or fluid retention, especially in the ankles or legs
• shortness of breath or trouble breathing, especially when you lie down
• an unusually fast increase in weight
• unusual tiredness

Pioglitazone Tablets, USP can have other serious side effects. See "What are the possible side effects of Pioglitazone Tablets, USP?"

What are Pioglitazone Tablets, USP?

Pioglitazone Tablets, USP are a prescription medicine used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes. Pioglitazone Tablets, USP are a diabetes medicine called pioglitazone hydrochloride that may be taken alone or with other diabetes medicines.

It is not known if Pioglitazone Tablets, USP are safe and effective in children.

Who should not take Pioglitazone Tablets, USP?

See "What is the most important information I should know about Pioglitazone Tablets, USP?"

Do not take Pioglitazone Tablets, USP if you:

• have severe heart failure
• are allergic to any of the ingredients in Pioglitazone Tablets, USP. See the end of this Medication Guide for a complete list of ingredients in Pioglitazone Tablets, USP

Talk to your doctor before taking Pioglitazone Tablets, USP if you have either of these conditions.

What should I tell my doctor before taking Pioglitazone Tablets, USP?

Before you take starting Pioglitazone Tablets, USP, tell your doctor if you:

• have heart failure
• have type 1 ("juvenile") diabetes or had diabetic ketoacidosis
• have a type of diabetic eye disease that causes swelling in the back of the eye (macular edema)
• have liver problems
• are pregnant or plan to become pregnant. It is not known if Pioglitazone Tablets, USP will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant
• are a premenopausal woman (before the "change of life") who does not have periods regularly or at all. Pioglitazone Tablets, USP may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking Pioglitazone Tablets, USP. Tell your doctor right away if you become pregnant while taking Pioglitazone Tablets, USP
• are breast-feeding or plan to breast-feed. It is not known if Pioglitazone Tablets, USP passes into your milk and if it can harm your baby. You should not take Pioglitazone Tablets, USP if you breastfeed your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Pioglitazone Tablets, USP and some of your other medicines can affect each other. You may need to have your dose of Pioglitazone Tablets, USP or certain other medicines changed.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist before you start a new medicine. They will tell you if it is okay to take Pioglitazone Tablets, USP with other medicines.

How should I take Pioglitazone Tablets, USP?

• Take Pioglitazone Tablets, USP exactly as your doctor tells you to take it
• Your doctor may change your dose of Pioglitazone Tablets, USP. Do not change your Pioglitazone Tablets, USP dose unless your doctor tells you to
• Pioglitazone Tablets, USP may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled
• Take Pioglitazone Tablets, USP 1 time each day, with or without food
• If you miss a dose of Pioglitazone Tablets, USP, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day
• If you take too much Pioglitazone Tablets, USP, call your doctor or go to the nearest hospital emergency room right away
• If your body is under stress such as from a fever, infection, accident, or surgery the dose of your diabetes medicines may need to be changed. Call your doctor right away
• Stay on your diet and exercise programs and test your blood sugar regularly while taking Pioglitazone Tablets, USP
• Your doctor should do certain blood tests before you start and while you take Pioglitazone Tablets, USP
• Your doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with Pioglitazone Tablets, USP
• Your doctor should check your eyes regularly while you take Pioglitazone Tablets, USP
• It may take 2 to 3 months to see the full effect of Pioglitazone Tablets, USP on your blood sugar level.

What are the possible side effects of Pioglitazone Tablets, USP?

Pioglitazone Tablets, USP may cause serious side effects including:

• See "What is the most important information about Pioglitazone Tablets, USP."
• liver problems. Call your doctor right away if you have:
  • nausea or vomiting
  • stomach pain
  • unusual or unexplained tiredness
  • loss of appetite
  • dark urine
  • yellowing of your skin or the whites of your eyes
• broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy
• bladder cancer. There may be an increased chance of having bladder cancer when you take Pioglitazone Tablets, USP. You should not take Pioglitazone Tablets, USP if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:
  • blood or a red color in your urine
  • an increased need to urinate
  • pain while you urinate
• low blood sugar (hypoglycemia). This can happen if you skip meals, if you also use another medicine that lowers blood sugar, or if you have certain medical problems. Light-headedness, dizziness, shakiness, or hunger may happen if your blood sugar is too low. Call your doctor if low blood sugar levels are a problem for you
• diabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly
• release of an egg from an ovary in a woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take Pioglitazone Tablets, USP. This can increase your chance of getting pregnant

The most common side effects of Pioglitazone Tablets, USP include:

• cold-like symptoms (respiratory tract infection)
• headache
• sinus infection
• muscle pain
• sore throat

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the side effects of Pioglitazone Tablets, USP. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Pioglitazone Tablets, USP?

• Store Pioglitazone Tablets, USP at 59°F to 86°F (15°C to 30°C). Keep Pioglitazone Tablets, USP in the original container and protect from light
• Keep the Pioglitazone Tablets, USP bottle tightly closed and protect from getting wet (away from moisture and humidity)
• Keep Pioglitazone Tablets, USP and all medicines out of the reach of children

General information about the safe and effective use of Pioglitazone Tablets, USP Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Pioglitazone Tablets, USP for a condition for which it was not prescribed. Do not give Pioglitazone Tablets, USP to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about Pioglitazone Tablets, USP. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Pioglitazone Tablets, USP that is written for healthcare professionals. For more information, call Breckenridge Pharmaceutical, Inc. at 1-800-367-3395.

What are the ingredients in Pioglitazone Tablets, USP?

Active Ingredient: pioglitazone hydrochloride, USP Inactive Ingredients: lactose monohydrate, hydroxypropylcellulose, carboxymethylcellulose calcium, and magnesium stearate.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Rottendorf Pharma GmbH
Ennigerloh, Germany
Made in Germany

Distributed by:
Breckenridge Pharmaceutical, Inc.
Boca Raton, FL 33487

Marketed/Packaged by:
GSMS, Inc.
Camarillo, CA 93012

Issue Date: 09/2012

MG-5020-0

Breckenridge
Pharmaceutical, Inc.

NDC 60429-330-30

Pioglitazone Tablets USP

15 mg

PHARMACIST: PLEASE DISPENSE WITH
ATTACHED MEDICATION GUIDE.

Rx Only

30 Tablets

PRINCIPAL DISPLAY PANEL - 30 mg Bottle Label

Breckenridge
Pharmaceutical, Inc.

NDC 60429-331-30

Pioglitazone Tablets USP

30 mg

PHARMACIST: PLEASE DISPENSE WITH
ATTACHED MEDICATION GUIDE.

Rx Only

30 Tablets

PRINCIPAL DISPLAY PANEL - 45 mg Bottle Label

Breckenridge
Pharmaceutical, Inc.

NDC 60429-332-30

Pioglitazone Tablets USP

45 mg

PHARMACIST: PLEASE DISPENSE WITH
ATTACHED MEDICATION GUIDE.

Rx Only

30 Tablets