Pioglitazole and Metformin Hydrochloride for Type 2 diabetes

INDICATIONS & USAGE 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 is not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis. Pioglitazone 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 ) Limitations of Use : • Not for treatment of type 1 diabetes or diabetic ketoacidosis. ( 1 )

DOSAGE AND ADMINISTRATION • 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 ) • Take orally with meals to reduce gastrointestinal adverse reactions with metformin ( 2.1 ) • Individualize the starting dose based on the patient’s current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. ( 2.2 ) • Recommended starting dosage in patients with NYHA Class I or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. ( 2.4 ) • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). ( 2.2 ) o Contraindicated in patients with eGFR below 30 mL/min o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min o Assess risk/benefit of continuing pioglitazone and metformin hydrochloride if eGFR falls below 45 mL/min o Discontinue if eGFR falls below 30 mL/min • Monitor patients for adverse events related to fluid retention after initiation and dose increases. ( 2.4 ) • Pioglitazone and metformin hydrochloride may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.6) 2.1 Important Dosage and Administration Information • Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions ( 5.5 )]. • Pioglitazone and metformin hydrochloride tablets contain 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet. • Take pioglitazone and metformin hydrochloride tablets with meals to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions ( 6.1 )]. • If a dose is missed, do not double the next dose 2.2 Recommended Dosage and Administration Recommended Starting Dosage Based on Current Regimen Individualize the starting dosage of pioglitazone and metformin hydrochloride tablets based on the patient's current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1). Table 1: Recommended Starting Dosage Based on the Patient’s Current Regimen Current Regimen Starting Dosage of pioglitazone and metformin Hydrochloride tablets (15 mg of pioglitazone and 850 mg of metformin HCl per tablet)* Not treated with either pioglitazone or metformin HCl One tablet orally once daily Metformin HCl One tablet orally once or twice daily. Select a dosage that is as close as possible to the current dosage of metformin HCl Pioglitazone One tablet orally once daily Pioglitazone and metformin HCl Select a dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. *For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration ( 2.3 , 2.4 ) Dosage Titration for Additional Glycemic Control Titrate the pioglitazone and metformin hydrochloride tablets dosage gradually, as needed, after assessing therapeutic response and tolerability. Pioglitazone and metformin hydrochloride tablets may be increased to a maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times a day to reduce gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )]. 2.3 Recommendations for Use in Patients with Renal Impairment • Assess renal function prior to initiation of pioglitazone and metformin hydrochloride tablets and periodically thereafter [see Use in Specific Populations ( 8.6 )]. • Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min. • Initiation of pioglitazone and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min is not recommended. • In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. • Discontinue pioglitazone and metformin hydrochloride tablets if the patient’s eGFR later falls below 30 mL/min [see Contraindications (4), Warnings and Precautions ( 5.2 )]. 2.4 Recommendations for Congestive Heart Failure Starting Dosage in Patients with NYHA Class I or II Congestive Heart Failure For patients with preexisting NYHA Class I or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets are 15 mg of pioglitazone and 850 mg of metformin [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart Failure After initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure). If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets [see Boxed Warning and Warnings and Precautions ( 5.1 )]. 2.5 Coadministration with Strong CYP2C8 Inhibitors The maximum recommended dosage of pioglitazone and metformin hydrochloride tablets are one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. 2.6 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; 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 )].

WARNINGS AND PRECAUTIONS • Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class I and II may increase risk. Monitor patients for signs and symptoms. ( 5.1 ) • Edema: Dose-related edema may occur. ( 5.3 ) • 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 tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets,or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets, [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 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), 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 tablets. 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 ( 2.2 ), Clinical Pharmacology ( 12.3 )]. • Before initiating pioglitazone and metformin hydrochloride tablets, obtain an eGFR. • P ioglitazone and metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30mL/min /1.73 m2. Initiation of pioglitazone and metformin hydrochloride tablets 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 tablets. 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 tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy. Drug Interactions The concomitant use of pioglitazone and metformin hydrochloride tablets 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 tablets 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 tablets 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 and metformin hydrochloride tablets 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 tablets. 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 in

DRUG INTERACTIONS • 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 tablets is 15 mg of pioglitazone and 850 mg of metformin HCl 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 tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride tablets, (45 mg of pioglitazone and 2,550 mg of metformin HCl) [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 tablets 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 tablets. 7.6 Insulin Secretagogues or Insulin Coadministration of pioglitazone and metformin hydrochloride tablets 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 tablets 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 tablets, 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 tablets, 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.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive heart failure [see Boxed Warning, and Warnings and Precautions ( 5.1 )] • Lactic acidosis [see Boxed Warning and Warnings, and Precautions ( 5.2 )] • Edema [see Warnings and Precautions ( 5.3 )] • Fractures [see Warnings and Precautions ( 5.7 )] • 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 Levels [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 Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 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 8500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes mellitus 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 (3.0%). In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% 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 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 6.0 Headache 1.9 6.0 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 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 Exercisein a 24-Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Administered Twice Daily % of Patients P ioglitazone 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 9.0 2.6 15.3 Headache 5.5 2.6 4.8 In this 24-week trial, abdominal pain was reported in 2.0% 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=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 5.0 5.1 Mean duration of patient follow-up was 34.5 months. Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to metformin trials. None of the events were fatal. Table 6. 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 7. 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-Con