PIOGLITAZONE HYDROCHLORIDE AND METFORMIN HYDROCHLORIDE - pioglitazone hydrochloride and metformin hydrochloride tablet, film coated 
Aurobindo Pharma Limited

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PIOGLITAZONE HYDROCHLORIDE and METFORMIN HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for PIOGLITAZONE HYDROCHLORIDE and METFORMIN HYDROCHLORIDE TABLETS.

PIOGLITAZONE HYDROCHLORIDE and METFORMIN HYDROCHLORIDE tablets for oral use
Initial U.S. Approval: 2005

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

See full prescribing information for complete boxed warning

Congestive Heart Failure

  • Thiazolidinediones, including pioglitazone, which is a component of pioglitazone hydrochloride and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients. (5.1)
  • After initiation of pioglitazone hydrochloride and metformin hydrochloride, 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 hydrochloride and metformin hydrochloride must be considered. (5.1)
  • Pioglitazone hydrochloride and metformin hydrochloride is not recommended in patients with symptomatic heart failure. (5.1)
  • Initiation of pioglitazone hydrochloride and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1)

Lactic Acidosis

  • Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. (5.2)
  • Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. (5.2)
  • If lactic acidosis is suspected, discontinue pioglitazone hydrochloride and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.2)

RECENT MAJOR CHANGES

Boxed Warning                                                                              5/2016
Dosage and Administration
Recommendations for Use in Renal Impairment (2.2)                 5/2016
Discontinuation for Iodinated Contrast Imaging
Procedures (2.4)                                                                            5/2016
Contraindications (4)                                                                    5/2016
Warnings and Precautions
Lactic Acidosis (5.2)                                                                      5/2016
Hepatic Effects (5.5)                                                                      5/2016
Urinary Bladder Tumors (5.6)                                                      12/2016

INDICATIONS AND USAGE


Pioglitazone hydrochloride and metformin hydrochloride tablets are a thiazolidinedione and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate. (1, 14)

Important Limitations of Use:

  • Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1)

DOSAGE AND ADMINISTRATION

  • Individualize the starting dose based on the patient's current regimen and adjust the dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of pioglitazone 45 mg and metformin 2550 mg. (2.1)
  • Give in divided daily doses with meals to reduce the gastrointestinal effects due to metformin. (2.1)
  • Monitor patients for adverse events related to fluid retention after initiation and dose increases. (2.1)
  • Obtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone hydrochloride and metformin hydrochloride, investigate the probable cause, treat (if possible), and follow appropriately. (2.1, 5.5)
  • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2)
    • Do not use in patients with eGFR below 30 mL/min/1.73 m2
    • Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2
    • Assess risk/benefit of continuing pioglitazone hydrochloride and metformin hydrochloride if eGFR falls below 45 mL/min/1.73 m2
    • Discontinue if eGFR falls below 30 mL/min/1.73 m2
  • Pioglitazone hydrochloride and metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4)

DOSAGE FORMS AND STRENGTHS


Tablets: 15 mg pioglitazone hydrochloride and 500 mg metformin hydrochloride and 15 mg pioglitazone hydrochloride and 850 mg metformin hydrochloride (3)

CONTRAINDICATIONS

  • Initiation in patients with established New York Heart Association (NYHA) Class III or IV heart failure [see Boxed Warning](4)
  • Severe renal impairment: (eGFR below 30 mL/min/1.73 m2). (4)
  • Use in patients with known hypersensitivity to pioglitazone, metformin or any other component of pioglitazone hydrochloride and metformin hydrochloride tablets. (4)
  • Metabolic acidosis, including diabetic ketoacidosis. (4, 5.2)

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)
  • Lactic acidosis: See boxed warning. (5.2)
  • Edema: Dose-related edema may occur. (5.3)
  • 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. (5.4)
  • Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone hydrochloride and metformin hydrochloride and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone hydrochloride and metformin hydrochloride if liver injury is confirmed and no alternate etiology can be found. (5.5)
  • 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. (5.6)
  • Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.7)
  • 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. (5.8)
  • Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. (5.9)
  • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone hydrochloride and metformin hydrochloride or any other antidiabetic drug. (5.10)

ADVERSE REACTIONS


Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 hydrochloride and metformin hydrochloride dose to 15 mg/850 mg daily. (2.3, 7.1)
  • CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2)
  • Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7.3)
  • Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine), may increase the accumulation of metformin. Consider more frequent monitoring. (7.4)
  • Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7.5)
  • Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. (7.6)

USE IN SPECIFIC POPULATIONS

  • Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
  • Pediatrics: Not recommended for use in pediatric patients. (8.4)
  • Geriatric Use: Assess renal function more frequently. (8.5)
  • Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 1/2017

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients

2.2 Recommendations for Use in Renal Impairment

2.3 Concomitant Use with Strong CYP2C8 Inhibitors

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

5.2 Lactic Acidosis

5.3 Edema

5.4 Hypoglycemia

5.5 Hepatic Effects

5.6 Urinary Bladder Tumors

5.7 Fractures

5.8 Macular Edema

5.9 Vitamin B12 Levels

5.10 Macrovascular Outcomes

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Strong CYP2C8 Inhibitors

7.2 CYP2C8 Inducers

7.3 Carbonic Anhydrase Inhibitors

7.4 Drugs that Reduce Metformin Clearance

7.5 Alcohol

7.6 Insulin Secretagogues or Insulin

7.7 Drugs Affecting Glycemic Control

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 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

14 CLINICAL STUDIES

14.1 Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone

14.2 Patients Previously Treated with Metformin

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS

Congestive Heart Failure

Lactic Acidosis

1 INDICATIONS AND USAGE

Pioglitazone hydrochloride and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate [see Clinical Studies (14)].

Important Limitations of Use

Pioglitazone exerts its antihyperglycemic effect only in the presence of endogenous insulin. Pioglitazone hydrochloride and metformin hydrochloride tablets should not be used to treat type 1 diabetes or diabetic ketoacidosis, as they would not be effective in these settings.

Use caution in patients with liver disease [see Warnings and Precautions (5.5)].

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients


Pioglitazone hydrochloride and metformin hydrochloride tablets should be taken with meals to reduce the gastrointestinal side effects associated with metformin.

If therapy with a combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:


  • 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
  • for patients with New York Heart Association (NYHA) Class I or Class II congestive heart failure: 15 mg/500 mg or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
  • for patients inadequately controlled on metformin monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once or twice daily (depending on the dose of metformin already being taken) and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
  • for patients inadequately controlled on pioglitazone monotherapy: 15 mg/500 mg twice daily or 15 mg/850 mg once daily and gradually titrated, as needed, after assessing adequacy of therapeutic response and tolerability,
  • for patients who are changing from combination therapy of pioglitazone plus metformin as separate tablets: pioglitazone hydrochloride and metformin hydrochloride tablets should be taken at doses that are as close as possible to the dose of pioglitazone and metformin already being taken.

Pioglitazone hydrochloride and metformin hydrochloride tablets may be titrated up to a maximum daily dose of 45 mg of pioglitazone and 2550 mg of metformin.

Metformin doses above 2000 mg may be better tolerated given three times a day.

After initiation of pioglitazone hydrochloride and metformin hydrochloride tablets 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 (5.1)]. Liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) should be obtained prior to initiating pioglitazone hydrochloride and metformin hydrochloride tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone hydrochloride and metformin hydrochloride tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone hydrochloride and metformin hydrochloride tablets or who are found to have abnormal liver tests while taking pioglitazone hydrochloride and metformin hydrochloride tablets should be managed as described under Warnings and Precautions [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

2.2 Recommendations for Use in Renal Impairment

Assess renal function prior to initiation of pioglitazone hydrochloride and metformin hydrochloride tablets and periodically thereafter.

Pioglitazone hydrochloride and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2.

Initiation of pioglitazone hydrochloride and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m2 is not recommended.

In patients taking pioglitazone hydrochloride and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.

Discontinue pioglitazone hydrochloride and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/min/1.73 m2[see Contraindications (4) and Warnings and Precautions (5.2)].

2.3 Concomitant Use with Strong CYP2C8 Inhibitors


Coadministration of pioglitazone (one of the ingredients in pioglitazone hydrochloride and metformin hydrochloride tablets) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone hydrochloride and metformin hydrochloride tablets is 15 mg/850 mg daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

2.4 Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue pioglitazone hydrochloride and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart pioglitazone hydrochloride and metformin hydrochloride tablets if renal function is stable [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS


5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure


Pioglitazone

Pioglitazone, 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 is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with pioglitazone hydrochloride and metformin hydrochloride 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 hydrochloride and metformin hydrochloride must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions (6.1)].

5.2 Lactic Acidosis

Metformin hydrochloride

Lactic Acidosis

There have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio;metformin plasma levels generally greater than 5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of pioglitazone hydrochloride and metformin hydrochloride. In pioglitazone hydrochloride and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue pioglitazone hydrochloride and metformin hydrochloride and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment

The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney [see Clinical Pharmacology (12.3)].

  • Before initiating pioglitazone hydrochloride and metformin hydrochloride, obtain an eGFR.
  • Pioglitazone hydrochloride and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Initiation of pioglitazone hydrochloride and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2.
  • Obtain an eGFR at least annually in all patients taking pioglitazone hydrochloride and metformin hydrochloride. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
  • In patients taking pioglitazone hydrochloride and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy [see Dosage and Administration (2.2)Contraindications (4) and Clinical Pharmacology (12.3)].

Drug Interactions

The concomitant use of pioglitazone hydrochloride and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.

Age 65 or Greater

The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].

Radiological Studies with Contrast

Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop pioglitazone hydrochloride and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart pioglitazone hydrochloride and metformin hydrochloride if renal function is stable.

Surgery and Other Procedures

Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. Pioglitazone hydrochloride and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue pioglitazone hydrochloride and metformin hydrochloride.

Excessive Alcohol Intake

Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving pioglitazone hydrochloride and metformin hydrochloride.

Hepatic Impairment

Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of pioglitazone hydrochloride and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

5.3 Edema


In controlled clinical trials with pioglitazone, 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 of edema have been received.

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

5.4 Hypoglycemia


Patients receiving pioglitazone hydrochloride and metformin 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 Drug Interactions (7.7)]

Hypoglycemia can also occur when caloric intake is deficient or when strenuous exercise is not compensated by caloric supplement. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.

5.5 Hepatic Effects

There have been postmarketing reports of fatal and nonfatal 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 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 hydrochloride and metformin hydrochloride therapy.

In patients with abnormal liver tests, pioglitazone hydrochloride and metformin 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 three times the upper limit of the reference range), pioglitazone hydrochloride and metformin hydrochloride treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone hydrochloride and metformin hydrochloride 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 hydrochloride and metformin hydrochloride. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone hydrochloride and metformin hydrochloride can be used with caution.

5.6 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 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 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. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1; [95% CI: 0.59 to 1.72]).

Findings regarding the risk of bladder cancer in patients exposed to pioglitazone vary among observational studies; some did not find an increased risk of bladder cancer associated with pioglitazone, while others did.

A large prospective10-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, compared to those never exposed to pioglitazone (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 and bladder cancer (HR: 1.63; [95% CI: 1.22 to 2.19]).

Associations between cumulative dose or cumulative duration of exposure to pioglitazone 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 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 and metformin 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 and metformin hydrochloride should be considered in patients with a prior history of bladder cancer.

5.7 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 hydrochloride and metformin hydrochloride and attention should be given to assessing and maintaining bone health according to current standards of care.

5.8 Macular Edema


Macular edema has been reported in postmarketing experience in diabetic patients who were taking pioglitazone 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)].

5.9 Vitamin B12 Levels


In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12  absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone hydrochloride and metformin hydrochloride and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful.

5.10 Macrovascular Outcomes


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

6 ADVERSE REACTIONS

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


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.


Pioglitazone

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 from the PROactive clinical trial. In these trials, over 6000 patients have been treated with pioglitazone 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 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%).


In the PROactive trial, the incidence of withdrawals due to adverse events was 9% for patients treated with pioglitazone 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 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 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 than in patients who received placebo. None of these adverse events were related to the pioglitazone dose. 


Table 1. Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo
% of Patients
 
Placebo
N=259
Pioglitazone
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 add-on to metformin 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 Add-on to Metformin
 
16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin
% of Patients
Placebo +
Metformin
N=160
Pioglitazone 30 mg + Metformin
N=168
Edema
2.5
6
Headache
1.9
6
 
24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin
% of Patients
Pioglitazone 30 mg + Metformin
N=411
Pioglitazone 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.”


Common Adverse Events: 24-Week Pioglitazone Hydrochloride and Metformin Hydrochloride Clinical Trial


Table 3 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of pioglitazone hydrochloride and metformin hydrochloride dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).



Table 3. Adverse Events (≥5% for Pioglitazone Hydrochloride and Metformin Hydrochloride) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24-Week Double-Blind Clinical Trial of Pioglitazone Hydrochloride and Metformin Hydrochloride Administered Twice Daily 
% of Patients
 
Pioglitazone Hydrochloride and Metformin Hydrochloride
15/850 mg
Twice Daily
N=201
Pioglitazone
15 mg
Twice Daily
N=190
Metformin
850 mg
Twice Daily
N=209
Diarrhea
9
2.6
15.3
Headache
5.5
2.6
4.8

In this 24-week trial, abdominal pain was reported in 2% of patients in the pioglitazone hydrochloride and metformin hydrochloride group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.


Common Adverse Events: PROactive Trial

A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 4. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

Table 4. PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo
 
% of Patients
Placebo
N=2633
Pioglitazone
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
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 5 for the 16- to 24-week add-on to metformin trials. None of the events were fatal.


Table 5. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin
 
Number (%) of Patients
Placebo-Controlled Trial
(16 weeks)
Non-Controlled
Double-Blind Trial
(24 weeks)
Placebo + Metformin
N=160
Pioglitazone
30 mg + Metformin
N=168
Pioglitazone
30 mg + Metformin
N=411
Pioglitazone
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%)



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



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 or Glyburide
 
Number (%) of Subjects
Pioglitazone
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
N=2605
At least one hospitalized congestive heart failure event
108 (4.1%)
149 (5.7%)
Fatal
22 (0.8%)
25 (1%)
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 (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 on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle, and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (HR 0.9; 95% CI: 0.8, 1.02; p=0.1).


Although there was no statistically significant difference between pioglitazone 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. The number of first occurrences and total individual events contributing to the primary composite endpoint is shown in Table 9.


Table 9. PROactive Trial: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint
Cardiovascular Events
Placebo
N=2633
Pioglitazone
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)
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 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, 11, and 12 summarize the changes in body weight with pioglitazone and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials, the PROactive trial, and the 24-week pioglitazone hydrochloride and metformin hydrochloride trial. 



Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials
 
Control Group
(Placebo)
Pioglitazone
15 mg
Pioglitazone
30 mg
Pioglitazone
45 mg
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
Monotherapy
(16 to 26 weeks)
 
-1.4
(-2.7, 0)
N=256
0.9
(-0.5, 3.4)
N=79
1
(-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
(0.2, 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)
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 Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial
 
Placebo
Pioglitazone
Median
(25th, 75th
percentile)
Median
(25th, 75th
percentile)
Change from baseline to final visit (kg)
-0.5
(-3.3, 2)
N=2581
+3.6
(0, 7.5)
N=2560

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



Table 12. Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with Pioglitazone Hydrochloride and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Diet and Exercise
 
Pioglitazone Hydrochloride and Metformin Hydrochloride
15/850 mg
Twice Daily
Pioglitazone
15 mg
Twice Daily
Metformin
850 mg
Twice Daily
Median (25th , 75th percentile)
Median (25th , 75th percentile)
Median (25th , 75th percentile)
Change from baseline to final visit (kg)
1 (-1, 3)
N=198
1.35 (-0.7, 4.1)
N=178
-1 (-2.6, 0.4)
N=203

Note: Trial duration of 24 weeks.


Edema

Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure.


In the 24-week pioglitazone hydrochloride and metformin hydrochloride trial, edema was reported in 3% of patients in the pioglitazone hydrochloride and metformin hydrochloride group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the metformin monotherapy group.


A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 13.



Table 13. Adverse Events of Edema in Patients Treated with Pioglitazone
 
Number (%) of Patients
Placebo
Pioglitazone
15 mg
Pioglitazone
30 mg
Pioglitazone
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)
Sulfonylurea
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%)
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 14. Adverse Events of Edema in Patients in the PROactive Trial
Number (%) of Patients
Placebo
N=2633
Pioglitazone
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 pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-year trial comparing pioglitazone 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 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 in the pioglitazone 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 clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.


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


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


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

Urinary Bladder Tumors

Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [see Nonclinical Toxicology (13.1)]. During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone 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 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. During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1; 95% CI: 0.59 to 1.72) [see Warnings and Precautions (5.6)].


Metformin hydrochloride

In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 15. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.



Table 15. Most Common Adverse Reactions (>5%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy*
Adverse Reaction
Metformin Monotherapy
(n=141)
Placebo
(n=145)
% of Patients
Diarrhea
53.2
11.7
Nausea/Vomiting
25.5
8.3
Flatulence
12.1
5.5
Asthenia
9.2
5.5
Indigestion
7.1
4.1
Abdominal Discomfort
6.4
4.8
Headache
5.7
4.8
*Reactions that were more common in metformin than placebo-treated patients.

Laboratory Abnormalities

Hematologic Effects

Pioglitazone 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 compared with a mean change in hemoglobin of -1% to +1% in placebo-treated patients. These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.

Vitamin B12 Concentrations

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone hydrochloride and metformin hydrochloride and any apparent abnormalities should be appropriately investigated and managed [see Warnings and Precautions (5.9)].

Creatine Phosphokinase

During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone 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 (values of 2150 to 11400 IU/L) and in no comparator-treated patients. Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to pioglitazone therapy is unknown.

6.2 Postmarketing Experience

Pioglitazone


The following adverse reactions have been identified during post-approval use of pioglitazone. 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.



Postmarketing reports of congestive heart failure have been reported in patients treated with pioglitazone, 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 Warnings 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 (t1/2) of pioglitazone. Therefore, the maximum recommended dose of pioglitazone 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, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dose of 45 mg for pioglitazone [see Clinical Pharmacology (12.3)].

7.3 Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with pioglitazone hydrochloride and metformin hydrochloride may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

7.4 Drugs that Reduce Metformin Clearance

Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have the potential for interaction with metformin by competing for common renal tubular transport systems, and may increase the accumulation of metformin and the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Consider more frequent monitoring of these patients.

7.5 Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving pioglitazone hydrochloride and metformin hydrochloride.

7.6 Insulin Secretagogues or Insulin

If hypoglycemia occurs in a patient coadministered pioglitazone hydrochloride and metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.

If hypoglycemia occurs in a patient coadministered pioglitazone hydrochloride and metformin hydrochloride 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.

7.7 Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving pioglitazone hydrochloride and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving pioglitazone hydrochloride and metformin hydrochloride, the patient should be observed closely for hypoglycemia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited data with pioglitazone hydrochloride and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

In animal reproduction studies, no adverse developmental effects were observed when pioglitazone was administered to pregnant rats and rabbits during organogenesis at exposures up to 5- and 35-times the 45 mg clinical dose, respectively, based on body surface area. No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- to 6-times, respectively, a 2000 mg clinical dose, based on body surface area [see Data].

The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20 to 25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Human Data

Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.

Animal Data

Pioglitazone and Metformin hydrochloride

Animal reproduction studies were not conducted with the combined products in pioglitazone hydrochloride and metformin hydrochloride. The following data are based on studies conducted with the individual components of pioglitazone hydrochloride and metformin hydrochloride.

Pioglitazone

Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg (~5-times the 45 mg clinical dose), but delayed parturition and reduced embryofetal viability at 40 and 80 mg/kg, or ≥9-times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35-times the 45 mg clinical dose), but reduced embryofetal viability at 160 mg/kg, or ~69-times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or ≥2-times the 45 mg clinical dose, by body surface area.

Metformin hydrochloride

Metformin hydrochloride did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- to 6-times a 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of pioglitazone hydrochloride and metformin hydrochloride or pioglitazone in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone is present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for pioglitazone hydrochloride and metformin hydrochloride and any potential adverse effects on the breastfed infant from pioglitazone hydrochloride and metformin hydrochloride or from the underlying maternal condition.

Data

Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone hydrochloride and metformin hydrochloride, may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Safety and effectiveness of pioglitazone hydrochloride and metformin hydrochloride in pediatric patients have not been established.


Pioglitazone hydrochloride and metformin hydrochloride is not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures, and urinary bladder tumors [see Warnings and Precautions (5.1, 5.3, 5.6, 5.7)].

8.5 Geriatric Use


Pioglitazone
 
A total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16- to 26­-week double-blind, placebo-controlled, monotherapy trials were ≥ 65 years old and two 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 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 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 were ≥ 65 years old and 22 (2.1%) were ≥ 75 years old.

In PROactive Trial, 1068 patients (41%) treated with pioglitazone 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 [see Clinical Pharmacology (12.3)].

Although clinical experiences have not identified differences in effectiveness and safety between the elderly (≥ 65 years) and younger patients, these conclusions are limited by small sample sizes for patients ≥75 years old. 

Metformin hydrochloride

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions (5.2) and Dosage and Administration (2.2)].

8.6 Renal Impairment

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Pioglitazone hydrochloride and metformin hydrochloride is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/min/1.73 m2[see Dosage and Administration (2.2), Contraindications (4)Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Pioglitazone hydrochloride and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)].

10 OVERDOSAGE


Pioglitazone

During controlled clinical trials, one case of overdose with pioglitazone 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.

Metformin hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.2)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.

11 DESCRIPTION

Pioglitazone hydrochloride and metformin hydrochloride tablets are a thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone hydrochloride and metformin hydrochloride.

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:


Piomet Structure1

Pioglitazone hydrochloride USP is an off-white to pale yellow color 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.

Metformin hydrochloride USP (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a white crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown: 


Piomet Structure2

Pioglitazone hydrochloride and metformin hydrochloride is available as a tablet for oral administration containing 15 mg pioglitazone hydrochloride USP (as the base) with 500 mg metformin hydrochloride USP (15 mg/500 mg) or 15 mg pioglitazone hydrochloride USP (as the base) with 850 mg metformin hydrochloride USP (15 mg/850 mg) formulated with the following excipients: carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 6000, talc, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


Pioglitazone hydrochloride and metformin hydrochloride combines two antidiabetic medications with different mechanisms of action to improve glycemic control in adults with type 2 diabetes: pioglitazone, a thiazolidinedione, and metformin hydrochloride, a biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production. 

Pioglitazone

Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases 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.

Metformin hydrochloride

Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type 2 diabetes or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

12.2 Pharmacodynamics


Pioglitazone

Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14)].

Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone 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 or any other antidiabetic medication [see Warnings and Precautions (5.10) 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 dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 16).



Table 16. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study
  Placebo Pioglitazone
15 mg
Once Daily
Pioglitazone
30 mg
Once Daily
Pioglitazone
45 mg
Once Daily
* Adjusted for baseline, pooled center, and pooled center by treatment interaction
† p < 0.05 versus placebo
 Triglycerides (mg/dL)
N=79
N=79
N=84
N=77
 Baseline (mean)
263
284
261
260
 Percent change from baseline (adjusted mean*)
4.8%
-9%
-9.6%
-9.3%
 HDL Cholesterol (mg/dL)
N=79
N=79
N=83
N=77
 Baseline (mean)
42
40
41
41
 Percent change from baseline (adjusted mean*)
8.1%
14.1%
12.2%
19.1%
 LDL Cholesterol (mg/dL)
N=65
N=63
N=74
N=62
 Baseline (mean)
139
132
136
127
 Percent change from baseline (adjusted mean*)
4.8%
7.2%
5.2%
6%
 Total Cholesterol (mg/dL)
N=79
N=79
N=84
N=77
 Baseline (mean)
225
220
223
214
 Percent change from baseline (adjusted mean*)
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 metformin (16 weeks and 24 weeks), the results were generally consistent with the data above.

12.3 Pharmacokinetics


Absorption

Pioglitazone Hydrochloride and Metformin Hydrochloride

In bioequivalence studies of pioglitazone hydrochloride and metformin hydrochloride 15 mg/ 500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone hydrochloride 15 mg concomitantly administered with metformin hydrochloride (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.

Administration of pioglitazone hydrochloride and metformin hydrochloride 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hours for pioglitazone and 0.8 hours for metformin) under fed conditions. These changes are not likely to be clinically significant.

Pioglitazone


Following once-daily administration of pioglitazone, 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 seven 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.

Cmax, AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.

Following oral administration of pioglitazone, Tmax of pioglitazone was within two hours. Food delays the Tmax to three to four hours, but does not alter the extent of absorption (AUC).

Metformin hydrochloride


The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean Cmax, a 25% lower AUC, and a 35-minute prolongation of Tmax following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution


Pioglitazone

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.

Metformin hydrochloride


The Vd/F of metformin following single oral doses of 850 mg immediate-release metformin averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.

Metabolism 

Pioglitazone

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 which include 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 (7.1)]. Urinary 6ß­-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.

Metformin hydrochloride


Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion and Elimination


Pioglitazone

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 (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.

Metformin hydrochloride


Renal clearance is approximately 3.5 times greater than creatinine clearance (CLcr), which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination t1/2 of approximately 6.2 hours. In blood, the elimination t1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Specific Populations


Renal Impairment

Pioglitazone

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

Metformin hydrochloride


In patients with decreased renal function (based on eGFR), the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in eGFR [see Dosage and Administration (2.2)Contraindications (4) and Warnings and Precautions (5.2)].

Hepatic Impairment


Pioglitazone

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 Cmax 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 and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use pioglitazone hydrochloride and metformin hydrochloride with caution in patients with liver disease [see Warnings and Precautions (5.5)].

Metformin hydrochloride


No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].

Geriatric Patients


Pioglitazone


In healthy elderly subjects, Cmax of pioglitazone was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects. The mean t1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of a magnitude that would be considered clinically relevant.

Metformin hydrochloride
 


Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the t1/2 is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatrics


Pioglitazone

Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone hydrochloride and metformin hydrochloride is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].

Metformin hydrochloride


After administration of a single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), and all with normal renal function.

Gender


Pioglitazone

The mean Cmax 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.

Metformin hydrochloride


Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Ethnicity


Pioglitazone

Pharmacokinetic data among various ethnic groups are not available.

Metformin hydrochloride


No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).

Drug-Drug Interactions
 
Specific pharmacokinetic drug interaction studies with pioglitazone hydrochloride and metformin hydrochloride have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.

Pioglitazone



Table 17. Effect of Pioglitazone Coadministration on Systemic Exposure of Other Drugs
Coadministered Drug
Pioglitazone
Dosage Regimen (mg)*
Name and Dose Regimens Change
in AUC
Change
in Cmax
* Daily for 7 days unless otherwise noted
% change (with/without coadministered drug and no change = 0%); symbols of ↑ and ↓ indicate the exposure increase and decrease, respectively
Pioglitazone had no clinically significant effect on prothrombin time
 45 mg
 (N = 12)
 Warfarin
 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
 0.2 mg twice daily (loading
 dose) then 0.25 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 Day 8
↓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 18. Effect of Coadministered Drugs on Pioglitazone Systemic Exposure
Coadministered Drug
and Dosage Regimen
Pioglitazone
Dose Regimen
(mg)*
Change
in AUC
Change
in Cmax†
* Daily for 7 days unless otherwise noted
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
The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]
Gemfibrozil 600 mg
twice daily for 2 days
(N = 12)
15 mg
single dose
↑ 3.2-fold
↑ 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%

Metformin hydrochloride

Table 19. Effect of Coadministered Drug on Plasma Metformin Systemic Exposure
Coadministered
Drug
Dose of
Coadministered
Drug*
Dose of
Metformin*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No effect = 1
AUC Cmax
* All metformin and coadministered drugs were given as single doses
AUC = AUC0–∞
Ratio of arithmetic means
§ Metformin hydrochloride extended-release tablets, 500 mg
At steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h
 No dosing adjustments required for the following:
 Glyburide
5 mg
500 mg§
0.98
0.99
 Furosemide
40 mg
850 mg
1.09
1.22
 Nifedipine
10 mg
850 mg
1.16
1.21
 Propranolol
40 mg
850 mg
0.9
0.94
 Ibuprofen
400 mg
850 mg
1.05
1.07
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Warnings and Precautions (5) and Drug Interactions (7)].
 Cimetidine
400 mg
850 mg
1.4
1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)].
 Topiramate
100 mg
500 mg
1.25
1.17
Table 20. Effect of Metformin on Coadministered Drug Systemic Exposure
Coadministered
Drug
Dose of
Coadministered
Drug*
Dose of
Metformin*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No effect = 1
AUC Cmax
* All metformin and coadministered drugs were given as single doses
AUC = AUC0–∞
Ratio of arithmetic means, p-value of difference <0.05
§ AUC0-24 hr reported
Ratio of arithmetic means
 No dosing adjustments required for the following:
 Glyburide
5 mg
500 mg§
0.78
0.63
 Furosemide
40 mg
850 mg
0.87
0.69
 Nifedipine
10 mg
850 mg
1.1§
1.08
 Propranolol
40 mg
850 mg
1.01§
0.94
 Ibuprofen
400 mg
850 mg
0.97
1.01
 Cimetidine
400 mg
850 mg
0.95§
1.01

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Pioglitazone Hydrochloride and Metformin Hydrochloride

No animal studies have been conducted with pioglitazone hydrochloride and metformin hydrochloride. The following data are based on findings in studies performed with pioglitazone or metformin individually.

Pioglitazone

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 of male rats. 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). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. A two-year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes. 

The relevance to humans of the bladder findings in the male rat cannot be excluded.

A two-year carcinogenicity study was also 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 nine times the maximum recommended human oral dose based on mg/m2).

Metformin hydrochloride

Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times a human daily dose of 2000 mg of the metformin component of pioglitazone hydrochloride and metformin hydrochloride based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day. 

There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative. 

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of pioglitazone hydrochloride and metformin hydrochloride based on body surface area comparisons.

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, one, and two 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 four 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).

14 CLINICAL STUDIES

14.1 Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone

In a 24-week, randomized, double-blind clinical trial, 600 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were randomized to pioglitazone hydrochloride and metformin hydrochloride 15/850 mg, pioglitazone 15 mg, or metformin 850 mg twice daily. Statistically significant improvements in HbA1c and fasting plasma glucose (FPG) were observed in patients treated with pioglitazone hydrochloride and metformin hydrochloride compared to either pioglitazone or metformin alone (see Table 21).


Table 21. Glycemic Parameters in 24-Week Study of Pioglitazone Hydrochloride and Metformin Hydrochloride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise
* Adjusted for baseline
p ≤0.05 versus pioglitazone hydrochloride and metformin hydrochloride
Parameter
Treatment Group
Pioglitazone Hydrochloride and Metformin Hydrochloride
15/850 mg
Twice Daily
Pioglitazone
15 mg
Twice Daily
Metformin
850 mg
Twice Daily
HbA1c (%)
N=188
N=162
N=193
Baseline (mean)
8.9
8.7
8.7
Change from Baseline
(adjusted mean*)
-1.8
-1
-1
Difference between pioglitazone hydrochloride and metformin hydrochloride (adjusted mean*) 95% Confidence Interval
 
0.9
(0.5, 1.2)
0.8
(0.5, 1.2)
% of patients with HbA1c ≤7%
64
47
39
Fasting Plasma Glucose (mg/dL)
N=196
N=176
N=202
Baseline (mean)
177
171
171
Change from Baseline
(adjusted mean*)
-40
-22
-25
Difference between pioglitazone hydrochloride and metformin hydrochloride (adjusted mean*)
95% Confidence Interval
 
18
(8, 28)
15
(6, 25)

14.2 Patients Previously Treated with Metformin


The efficacy and safety of pioglitazone as add-on to metformin therapy have been established in two clinical studies. Bioequivalence of pioglitazone hydrochloride and metformin hydrochloride with coadministered pioglitazone and metformin tablets was demonstrated for both pioglitazone hydrochloride and metformin hydrochloride strengths [see Clinical Pharmacology (12.3)].

The two clinical trials testing pioglitazone as add-on to metformin therapy 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 three weeks prior to starting study treatment.

In the first trial, 328 patients were randomized to receive either 30 mg of pioglitazone or placebo once daily for 16 weeks in addition to their current metformin regimen. Treatment with pioglitazone 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
30 mg +
Metformin
* Adjusted for baseline, pooled center, and pooled center by treatment interaction
p ≤ 0.05 vs. placebo + metformin
 Total Population
 HbA1c (%)
N=153
N=161
 Baseline (mean)
9.8
9.9
 Change from baseline (adjusted mean*)
0.2
-0.6
 Difference from placebo + metformin (adjusted mean*)
 95% Confidence Interval
 
-0.8
(-1.2, -0.5)
 Fasting Plasma Glucose (mg/dL)
N=157
N=165
 Baseline (mean)
260
254
 Change from baseline (adjusted mean*)
-5
-43
 Difference from placebo + metformin (adjusted mean*)
 95% Confidence Interval
 
-38
(-49, -26)

In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone 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% 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
30 mg +
Metformin
Pioglitazone
45 mg +
Metformin
95% CI = 95% confidence interval
*Adjusted for baseline, pooled center, and pooled center by treatment interaction
p ≤ 0.05 vs. 30 mg daily pioglitazone + metformin
 Total Population
 HbA1c (%)
N=400
N=398
 Baseline (mean)
9.9
9.8
 Change from baseline (adjusted mean*)
-0.8
-1
 Difference from 30 mg daily pioglitazone +
 metformin (adjusted mean*) (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 mean*)
-38
-51
 Difference from 30 mg daily pioglitazone +
 metformin (adjusted mean*) (95% CI)
 
-12
(-21, -4)

The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose.

16 HOW SUPPLIED/STORAGE AND HANDLING


Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets, 15 mg/500 mg are white to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘92’ on other side.

      Bottles of 60                               NDC 65862-525-60
      Bottles of 180                             NDC 65862-525-18 

Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets, 15 mg/850 mg are white to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘93’ on other side.

      Bottles of 60                               NDC 65862-526-60
      Bottles of 180                             NDC 65862-526-18 

Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture and humidity.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide).



Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

MEDICATION GUIDE

Pioglitazone Hydrochloride and Metformin Hydrochloride Tablets

(pye'' oh gli' ta zone hye'' droe klor' ide and met for' min hye'' droe klor' ide)


Read this Medication Guide carefully before you start taking pioglitazone hydrochloride and metformin hydrochloride tablets 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 hydrochloride and metformin hydrochloride tablets, ask your doctor or pharmacist.


What is the most important information I should know about pioglitazone hydrochloride and metformin hydrochloride tablets?

Pioglitazone hydrochloride and metformin hydrochloride tablets can cause serious side effects, including:


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



Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:


Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with pioglitazone hydrochloride and metformin hydrochloride tablets if you:



The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your pioglitazone hydrochloride and metformin hydrochloride tablets for a while if you have any of these things.


Pioglitazone hydrochloride and metformin hydrochloride tablets can have other serious side effects. See “What are the possible side effects of pioglitazone hydrochloride and metformin hydrochloride tablets?”


What are pioglitazone hydrochloride and metformin hydrochloride tablets?

Pioglitazone hydrochloride and metformin hydrochloride tablets contain two prescription diabetes medicines called pioglitazone tablets and metformin hydrochloride tablets. Pioglitazone hydrochloride and metformin hydrochloride tablets can be used with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.


Pioglitazone hydrochloride and metformin hydrochloride tablets are not for people with type 1 diabetes.


Pioglitazone hydrochloride and metformin hydrochloride tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).


It is not known if pioglitazone hydrochloride and metformin hydrochloride tablets are safe and effective in children under the age of 18. Pioglitazone hydrochloride and metformin hydrochloride tablets are not recommended for use in children.


Who should not take pioglitazone hydrochloride and metformin hydrochloride tablets?

See “What is the most important information I should know about pioglitazone hydrochloride and metformin hydrochloride tablets?”


Do not take pioglitazone hydrochloride and metformin hydrochloride tablets if you:


Tell your doctor before taking pioglitazone hydrochloride and metformin hydrochloride tablets if you have any of these conditions.


What should I tell my doctor before taking pioglitazone hydrochloride and metformin hydrochloride tablets?

 

Before you take pioglitazone hydrochloride and metformin hydrochloride tablets, tell your doctor if you:


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


Pioglitazone hydrochloride and metformin hydrochloride tablets and some of your other medicines can affect each other. You may need to have your dose of pioglitazone hydrochloride and metformin hydrochloride tablets 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 hydrochloride and metformin hydrochloride tablets with other medicines.


How should I take pioglitazone hydrochloride and metformin hydrochloride tablets?


What are the possible side effects of pioglitazone hydrochloride and metformin hydrochloride tablets? 

Pioglitazone hydrochloride and metformin hydrochloride tablets may cause serious side effects, including:


The most common side effects of pioglitazone hydrochloride and metformin hydrochloride tablets include:


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 hydrochloride and metformin hydrochloride tablets. 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 hydrochloride and metformin hydrochloride tablets?



Keep the pioglitazone hydrochloride and metformin hydrochloride tablets bottle tightly closed and keep tablets dry


Keep pioglitazone hydrochloride and metformin hydrochloride tablets and all medicines out of the reach of children.


General information about the safe and effective use of pioglitazone hydrochloride and metformin hydrochloride tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use pioglitazone hydrochloride and metformin hydrochloride tablets for a condition for which it was not prescribed. Do not give pioglitazone hydrochloride and metformin hydrochloride tablets 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 hydrochloride and metformin hydrochloride tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about pioglitazone hydrochloride and metformin hydrochloride tablets that is written for healthcare professionals.


For more information, call 1-866-850-2876.


What are the ingredients in pioglitazone hydrochloride and metformin hydrochloride tablets?

Active Ingredients: pioglitazone hydrochloride and metformin hydrochloride


Inactive Ingredients: carboxymethylcellulose calcium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol 6000, talc, and titanium dioxide.


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

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Manufactured for:
Aurobindo Pharma USA, Inc.
2400 Route 130 North
Dayton, NJ 08810

Manufactured by:
Aurobindo Pharma Limited
Unit-VII (SEZ)
Mahaboob Nagar (Dt)-509302
India

Licensed - United States Patents Nos. 5,965,584, 6,166,042, 6,166,043, and 6,172,090.

Revised: 01/2017

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg/500 mg (60 Tablet Bottle)


NDC 65862-525-60
Pioglitazone Hydrochloride
and Metformin Hydrochloride Tablets

15 mg*/500 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Rx only             60 Tablets
AUROBINDO
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg/500 mg (60 Tablet Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg/850 mg (60 Tablet Bottle)


NDC 65862-526-60
Pioglitazone Hydrochloride
and Metformin Hydrochloride Tablets

15 mg*/850 mg
PHARMACIST: Dispense the Medication Guide provided separately to each patient.
Rx only             60 Tablets
AUROBINDO

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg/850 mg (60 Tablet Bottle)

PIOGLITAZONE HYDROCHLORIDE AND METFORMIN HYDROCHLORIDE 
pioglitazone hydrochloride and metformin hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-525
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIOGLITAZONE HYDROCHLORIDE (UNII: JQT35NPK6C) (PIOGLITAZONE - UNII:X4OV71U42S) PIOGLITAZONE 15 mg
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N) METFORMIN HYDROCHLORIDE 500 mg
Inactive Ingredients
Ingredient Name Strength
CARBOXYMETHYLCELLULOSE CALCIUM (UNII: UTY7PDF93L)  
HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape CAPSULE (Oblong, Biconvex) Size 15mm
Flavor Imprint Code H;92
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:65862-525-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 02/13/2013
2 NDC:65862-525-18 180 in 1 BOTTLE; Type 0: Not a Combination Product 02/13/2013
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200823 02/13/2013
PIOGLITAZONE HYDROCHLORIDE AND METFORMIN HYDROCHLORIDE 
pioglitazone hydrochloride and metformin hydrochloride tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-526
Route of Administration ORAL
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
PIOGLITAZONE HYDROCHLORIDE (UNII: JQT35NPK6C) (PIOGLITAZONE - UNII:X4OV71U42S) PIOGLITAZONE 15 mg
METFORMIN HYDROCHLORIDE (UNII: 786Z46389E) (METFORMIN - UNII:9100L32L2N) METFORMIN HYDROCHLORIDE 850 mg
Inactive Ingredients
Ingredient Name Strength
CARBOXYMETHYLCELLULOSE CALCIUM (UNII: UTY7PDF93L)  
HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P)  
HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE)  
TALC (UNII: 7SEV7J4R1U)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Color WHITE (White to Off-white) Score no score
Shape CAPSULE (Oblong, Biconvex) Size 19mm
Flavor Imprint Code H;93
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:65862-526-60 60 in 1 BOTTLE; Type 0: Not a Combination Product 02/13/2013
2 NDC:65862-526-18 180 in 1 BOTTLE; Type 0: Not a Combination Product 02/13/2013
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA200823 02/13/2013
Labeler - Aurobindo Pharma Limited (650082092)
Establishment
Name Address ID/FEI Business Operations
Aurobindo Pharma Limited 650381903 ANALYSIS(65862-525, 65862-526) , MANUFACTURE(65862-525, 65862-526)
Establishment
Name Address ID/FEI Business Operations
Aurobindo Pharma Limited 918917647 API MANUFACTURE(65862-525, 65862-526)
Establishment
Name Address ID/FEI Business Operations
Aurobindo Pharma Limited 918917626 API MANUFACTURE(65862-525, 65862-526)

Revised: 1/2017
Document Id: 989bccec-a1de-4e78-814b-053ea842ba16
Set id: 1fa2703e-fb73-44d5-aaa2-b12b1090d42c
Version: 5
Effective Time: 20170106
 
Aurobindo Pharma Limited