DOSAGE & ADMINISTRATION SECTION

Highlight: * 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 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 m 2
  • Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2
  • Assess risk/benefit of continuing pioglitazone and metformin hydrochloride if eGFR falls below 45 mL/min/1.73 m 2
  • Discontinue if eGFR falls below 30 mL/min/1.73 m 2
• Pioglitazone and metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.4)

2 DOSAGE AND ADMINISTRATION

2.1 Recommendations for All Patients

Pioglitazone 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 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 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 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 and metformin hydrochloride tablets. Routine periodic monitoring of liver tests during treatment with pioglitazone and metformin hydrochloride tablets are not recommended in patients without liver disease. Patients who have liver test abnormalities prior to initiation of pioglitazone and metformin hydrochloride tablets or who are found to have abnormal liver tests while taking pioglitazone 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 and metformin hydrochloride tablets and periodically thereafter.

Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2.

Initiation of pioglitazone and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m 2 is not recommended.

In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy.

Discontinue pioglitazone and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/min/1.73 m 2[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 and metformin hydrochloride tablets) and gemfibrozil, a strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone 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 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 m 2; 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 and metformin hydrochloride tablets if renal function is stable [see Warnings and Precautions (5.2)] .

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WARNINGS AND PRECAUTIONS SECTION

Highlight:

• 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 and metformin hydrochloride and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone 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 B 12 deficiency: Metformin may lower vitamin B 12 levels. Monitor hematologic parameters annually. ( 5.9)
• Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and metformin hydrochloride. ( 5.10)

5 WARNINGS AND PRECAUTIONS

5.1 Congestive Heart Failure

Pioglitazone

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****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 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 and metformin hydrochloride must be considered [see Boxed Warning, Contraindications (4), and Adverse Reactions (6.1)] .

5.2 Lactic Acidosis

Metformin hydrochloride

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** Lactic Acidosis**

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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 and metformin hydrochloride. In pioglitazone 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 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:

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** Renal Impairment**

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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. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].

• Before initiating pioglitazone and metformin hydrochloride, obtain an eGFR.
• Pioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2[see Contraindications (4)].
• Obtain an eGFR at least annually in all patients taking pioglitazone 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 and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit and risk of continuing therapy.

Drug Interactions

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The concomitant use of pioglitazone 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.

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** Age 65 or Greater**

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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)].

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** Radiological Studies with Contrast**

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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 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 m 2; 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 and metformin hydrochloride if renal function is stable.

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** Surgery and Other Procedures**

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

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** Hypoxic States**

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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 and metformin hydrochloride.

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** Excessive Alcohol Intake**

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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 and metformin hydrochloride.

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** Hepatic Impairment**

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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 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 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 and metformin hydrochloride should be used with caution in patients at risk for congestive heart failure. Patients treated with pioglitazone 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 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 and metformin hydrochloride therapy.

In patients with abnormal liver tests, pioglitazone 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 and metformin hydrochloride treatment should be interrupted and investigation done to establish the probable cause. Pioglitazone 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 and metformin hydrochloride. For patients with lesser elevations of serum ALT or bilirubin and with an alternate probable cause, treatment with pioglitazone 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 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 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 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 B 12 Levels

In controlled clinical trials of metformin of 29 weeks' duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone and metformin hydrochloride and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. In these patients, routine serum vitamin B 12 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 and metformin hydrochloride.

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DRUG INTERACTIONS SECTION

Highlight: * Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone 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 reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 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)
• Topiramate may decrease pioglitazone concentrations. (7.8)

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 (t 1/2) 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 and metformin hydrochloride may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

7.4 Drugs that Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)] . Consider the benefits and risks of concomitant use.

7.5 Alcohol

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

7.6 Insulin Secretagogues or Insulin

If hypoglycemia occurs in a patient coadministered pioglitazone 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 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 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 and metformin hydrochloride, the patient should be observed closely for hypoglycemia.

7.8 Topiramate

A decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3)]. The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Bottles of 90 NDC 42291-920-90

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

Bottles of 90 NDC 42291-921-90

Storage:****Store at20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed, and protect from moisture and humidity.

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