Pioglitazone Hydrochloride and Metformin Hydrochloride

Pioglitazone and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Pioglitazone and metformin hydrochloride tablets are not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis. Pioglitazone and metformin hydrochloride tablets are a combination of pioglitazone, a thiazolidinedione agonist of peroxisome proliferator receptor gamma, and metformin hydrochloride, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use: Not recommended for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )

15 mg/500 mg tablets: White to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘92’ on other side. 15 mg/850 mg tablets: White to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘93’ on other side. Tablets: 15 mg pioglitazone hydrochloride and 500 mg metformin hydrochloride and 15 mg pioglitazone hydrochloride and 850 mg metformin hydrochloride. (3)

Pioglitazone and metformin hydrochloride are contraindicated in patients with: Established NYHA Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation [see Boxed Warning ] . Severe renal impairment (eGFR below 30 mL/min) [see Warnings and Precautions (5.2) ] . A history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excipients in pioglitazone and metformin hydrochloride tablets. Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.2) ]. In patients with established New York Heart Association (NYHA) Class III or IV heart failure at the time of pioglitazone and metformin hydrochloride initiation [see Boxed Warning ]. ( 4 ) In patients with severe renal impairment: (eGFR below 30 mL/min). ( 4 ) In patients with a history of serious hypersensitivity to pioglitazone, metformin hydrochloride, or any of the excepients in pioglitazone and metformin hydrochloride tablets. ( 4 ) In patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis. ( 4 )

Congestive Heart Failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 ) Edema: Dose-related edema may occur. ( 5.3 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with pioglitazone and metformin hydrochloride. ( 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 ) Urinary Bladder Tumors: 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 and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.9 )

5.1 Congestive Heart Failure 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. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride, consider discontinuation of pioglitazone and metformin hydrochloride or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Boxed Warning , Contraindications (4) , Adverse Reactions (6.1) ] .

5.2 Lactic Acidosis Lactic Acidosis There have been postmarketing 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 bradyarrhythmia's 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), an increased lactate/pyruvate ratio; and 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: 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. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.3) , 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. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min [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, assess the benefit and risk of continuing therapy. Drug Interactions 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. 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 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; 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. Surgery and Other Procedures Withholding 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. 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 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 and metformin hydrochloride. Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. […]

The following serious adverse reactions are discussed elsewhere in the labeling: Congestive heart failure [see Boxed Warning , Warnings and Precautions (5.1) ] Lactic acidosis [see Boxed Warning , Warnings and Precautions (5.2) ] Edema [see Warnings and Precautions (5.3) ] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4) ] Hepatic Effects [see Warnings and Precautions (5.5) ] Urinary Bladder Tumors [see Warnings and Precautions (5.6) ] Fractures [see Warnings and Precautions (5.7) ] Macular Edema [see Warnings and Precautions (5.8) ] Vitamin B 12 Deficiency [see Warnings and Precautions (5.9) ] 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.

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 8,500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 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 2. 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 2: 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 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone. Table 3: 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 and Metformin Hydrochloride Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24 week double-blind clinical trial of pioglitazone and metformin hydrochloride dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600). Table 4: Adverse Events (≥5% for Pioglitazone and Metformin Hydrochloride) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in a 24 Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Administered Twice Daily % of Patients Pioglitazone 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 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 5. 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 5: 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=2,633 Pioglitazone N=2,605 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 6 for the 16 to 24 week add-on to metformin trials. None of the events were fatal. […]

Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily. ( 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: 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 )

7.1 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 dosage of pioglitazone and metformin hydrochloride is 15 mg of pioglitazone and 850 mg of metformin hydrochloride once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3) , 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 and metformin hydrochloride, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride (45 mg of pioglitazone and 2,550 mg of metformin hydrochloride) [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 Coadministration of pioglitazone and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. 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.

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.

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

8.1 Pregnancy Risk Summary Limited data with pioglitazone 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 2,000 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 postmarketing 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 and metformin hydrochloride. The following data are based on studies conducted with the individual components of pioglitazone 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 embryo-fetal 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 embryo-fetal 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 2,000 mg clinical dose based on body surface area (mg/m 2 ) for rats and rabbits, respectively.

8.2 Lactation Risk Summary There is no information regarding the presence of pioglitazone 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 and metformin hydrochloride and any potential adverse effects on the breastfed infant from pioglitazone 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 and metformin hydrochloride, may result in ovulation in some anovulatory women.

8.4 Pediatric Use Safety and effectiveness of pioglitazone and metformin hydrochloride in pediatric patients have not been established. Pioglitazone 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, 1,068 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. […]

Pioglitazone and metformin hydrochloride combines two antihyperglycemic agents: pioglitazone and metformin. 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 mellitus. 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 mellitus, 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 mellitus 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.