ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:oCongestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]oLactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)]oEdema [see Warnings and Precautions (5.3)]oFractures [see Warnings and Precautions (5.7)]. oCongestive heart failure [see Boxed Warning and Warnings and Precautions (5.1)]. oLactic acidosis [see Boxed Warning and Warnings and Precautions (5.2)]. oEdema [see Warnings and Precautions (5.3)]. oFractures [see Warnings and Precautions (5.7)]. Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc., at 1-800-525-8747 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.PioglitazoneOver 8500 patients with type diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 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 TrialsA 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 PatientsPlaceboN=259PioglitazoneN=606Upper Respiratory Tract Infection8.513.2Headache6.99.1Sinusitis4.66.3Myalgia2.75.4Pharyngitis0.85.1Common Adverse Events: 16- to 24-Week Add-on Combination Therapy TrialsA 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 Metformin16-Week Placebo-Controlled TrialAdverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone Metformin than in Patients Treated with Placebo Metformin% of PatientsPlacebo MetforminN=160Pioglitazone 30 mg MetforminN=168Edema2.56Headache1.9624-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 MetforminN=411Pioglitazone 45 mg MetforminN=416Upper Respiratory Tract Infection12.413.5Edema5.813.9Headache5.45.8Weight Increased2.96.7Note: 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 TrialTable summarizes the incidence and types of adverse reactions reported in 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 3. Adverse Events (>=5% for Pioglitazone and Metformin Hydrochloride) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in 24-Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Administered Twice Daily% of PatientsPioglitazone and MetforminHydrochloride15/850 mgTwice DailyN=201Pioglitazone15 mgTwice DailyN=190Metformin850 mgTwice DailyN=209Diarrhea92.615.3Headache5.52.64.8In 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 TrialA 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 PatientsPlaceboN=2633PioglitazoneN=2605Hypoglycemia18.827.3Edema15.326.7Cardiac Failure6.18.1Pain in Extremity5.76.4Back Pain5.15.5Chest Pain55.1Mean duration of patient follow-up was 34.5 months.Congestive Heart FailureA summary of the incidence of adverse events related to congestive heart failure is provided in Table 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 MetforminNumber (%) of PatientsPlacebo-Controlled Trial(16 weeks)Non-Controlled Double-Blind Trial(24 weeks)Placebo MetforminN=160Pioglitazone 30 mg MetforminN=168Pioglitazone 30 mg MetforminN=411Pioglitazone 45 mg MetforminN=416At least one congestive heart failure event01 (0.6%)01 (0.2%)Hospitalized01 (0.6%)01 (0.2%)Table 6. Treatment-Emergent Adverse Events of Congestive Heart Failure (CHF)Patients Treated with Pioglitazone or Placebo Added on to SulfonylureaNumber (%) of PatientsPlacebo-Controlled Trial(16 weeks)Non-Controlled Double-Blind Trial(24 weeks)Placebo SulfonylureaN=187Pioglitazone 15 mg SulfonylureaN=184Pioglitazone 30 mg SulfonylureaN=189Pioglitazone 30 mg SulfonylureaN=351Pioglitazone 45 mg SulfonylureaN=351At least one congestive heart failure event2 (1.1%)001 (0.3%)6 (1.7%)Hospitalized2 (1.1%)0002 (0.6%)Patients Treated with Pioglitazone or Placebo Added on to InsulinNumber (%) of PatientsPlacebo-Controlled Trial(16 weeks)Non-Controlled Double-Blind Trial(24 weeks)Placebo InsulinN=187Pioglitazone15 mg InsulinN=191Pioglitazone30 mg InsulinN=188Pioglitazone30 mg InsulinN=345Pioglitazone45 mg InsulinN=345At least one congestive heart failure event02 (1%)2 (1.1%)3 (0.9%)5 (1.4%)Hospitalized02 (1%)1 (0.5%)1 (0.3%)3 (0.9%)Patients Treated with Pioglitazone or Placebo Added on to MetforminNumber (%) of PatientsPlacebo-Controlled Trial(16 weeks)Non-Controlled Double-Blind Trial(24 weeks)Placebo MetforminN=160Pioglitazone30 mg MetforminN=168Pioglitazone30 mg MetforminN=411Pioglitazone45 mg MetforminN=416At least one congestive heart failure event01 (0.6%)01 (0.2%)Hospitalized01 (0.6%)01 (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 GlyburideNumber (%) of SubjectsPioglitazoneN=262GlyburideN=256Death 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 study35 (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 TrialNumber (%) of PatientsPlaceboN=2633PioglitazoneN=2605At least one hospitalized congestive heart failure event108 (4.1%)149 (5.7%)Fatal22 (0.8%)25 (1%)Hospitalized, nonfatal86 (3.3%)124 (4.7%)Cardiovascular SafetyIn the PROactive trial, 5238 patients with type diabetes and 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 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 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 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. 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 0.90; 95% CI: 0.80, 1.02; p=0.10).Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of 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 EndpointCardiovascular EventsPlaceboN=2633PioglitazoneN=2605First Eventsn (%)Total eventsnFirst Eventsn (%)Total eventsnAny event572 (21.7)900514 (19.7)803 All-cause mortality122 (4.6)186110 (4.2)177 Nonfatal myocardial infarction (MI)118 (4.5)157105 (4)131 Stroke96 (3.6)11976 (2.9)92 Acute coronary syndrome63 (2.4)7842 (1.6)65 Cardiac intervention (CABG/PCI)101 (3.8)240101 (3.9)195 Major leg amputation15 (0.6)289 (0.3)28 Leg revascularization57 (2.2)9271 (2.7)115CABG coronary artery bypass grafting; PCI percutaneous interventionWeight GainDose-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 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 and metformin hydrochloride trial.Table 10. Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical TrialsControl Group(Placebo)Pioglitazone15 mgPioglitazone30 mgPioglitazone45 mgMedian(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=2560.9 (-0.5, 3.4)N=791 (-0.9, 3.4)N=1882.6 (0.2, 5.4)N=79Combination Therapy(16 to 24 weeks)Sulfonylurea-0.5 (-1.8, 0.7)N=1872 (0.2, 3.2)N=1833.1 (1.1, 5.4)N=5284.1 (1.8, 7.3)N=333Metformin-1.4 (-3.2, 0.3)N=160N/A0.9 (-1.3, 3.2)N=5671.8 (-0.9, 5)N=407Insulin0.2 (-1.4, 1.4)N=1822.3 (0.5, 4.3)N=1903.3 (0.9, 6.3)N=5224.1 (1.4, 6.8)N=338Table 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 TrialPlaceboPioglitazoneMedian(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=2560Note: 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 and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Diet and ExercisePioglitazone and Metformin Hydrochloride15/850 mgTwice DailyPioglitazone15 mgTwice DailyMetformin850 mgTwice DailyMedian(25th 75th percentile)Median(25th 75th percentile)Median(25th 75th percentile)Change from baseline to final visit (kg)1 (-1, 3)N=1981.35 (-0.7, 4.1)N=178-1 (-2.6, 0.4)N=203Note: Trial duration of 24 weeks.EdemaEdema 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 and metformin hydrochloride trial, edema was reported in 3% of patients in the pioglitazone 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 PioglitazoneNumber (%) of PatientsPlaceboPioglitazone15 mgPioglitazone30 mgPioglitazone45 mgMonotherapy(16 to 26 weeks)3 (1.2%)N=2592 (2.5%)N= 8113 (4.7%)N= 27511 (6.5%)N=169Combined Therapy(16 to 24 weeks)Sulfonylurea4 (2.1%)N=1873 (1.6%)N=18461 (11.3%)N=54081 (23.1%)N=351Metformin4 (2.5%)N=160N/A34 (5.9%)N=57958 (13.9%)N=416Insulin13 (7%)N=18724 (12.6%)N=191109 (20.5%)N=53390 (26.1%)N=345Note: 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 TrialNumber (%) of PatientsPlaceboN=2633PioglitazoneN=2605419 (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 EffectsThere 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. 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 serum ALT greater than three times the upper limit of the reference range and corresponding total bilirubin greater than two times the upper limit of the reference range, combination predictive of the potential for severe drug-induced liver injury.HypoglycemiaIn 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 patients 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 TumorsTumors 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 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 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, 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: 0.59-1.72) [see Warnings and Precautions (5.6)].Metformin hydrochlorideIn double-blind clinical study of metformin in patients with type diabetes, 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 Placebo-Controlled Clinical Study of Metformin MonotherapyReactions that were more common in metformin than placebo-treated patients.Adverse ReactionMetformin Monotherapy(n=141)Placebo(n=145)% of PatientsDiarrhea53.211.7Nausea/Vomiting25.58.3Flatulence12.15.5Asthenia9.25.5Indigestion7.14.1Abdominal Discomfort6.44.8Headache5.74.8Laboratory AbnormalitiesHematologic EffectsPioglitazone 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 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 ConcentrationsMetformin may lower serum vitamin B12 concentrations. 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 [see Warnings and Precautions (5.9)].Creatine PhosphokinaseDuring 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. The following adverse reactions have been identified during post-approval use of pioglitazone. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.PioglitazoneoNew onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.8)].oFatal and nonfatal hepatic failure [see Warnings and Precautions (5.5)].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 Warning and Warnings and Precautions (5.1)].MetforminCholestatic, hepatocellular, and mixed hepatocellular liver injury.. oNew onset or worsening diabetic macular edema with decreased visual acuity [see Warnings and Precautions (5.8)].. oFatal and nonfatal hepatic failure [see Warnings and Precautions (5.5)].

BOXED WARNING SECTION.

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS. Congestive Heart FailureoThiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].oAfter initiation of pioglitazone 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 and metformin hydrochloride must be considered [see Warnings and Precautions (5.1)].oPioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].oInitiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].Lactic AcidosisoPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than mcg/mL [see Warnings and Precautions (5.2)].oRisk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.oSteps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)]. oIf metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)]. oThiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].. oAfter initiation of pioglitazone 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 and metformin hydrochloride must be considered [see Warnings and Precautions (5.1)].. oPioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].. oInitiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].. oPost-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than mcg/mL [see Warnings and Precautions (5.2)].. oRisk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.. oSteps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)]. oIf metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)]. WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSISSee full prescribing information for complete boxed warningCongestive Heart FailureoThiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients. (5.1)oAfter initiation of pioglitazone 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 and metformin hydrochloride must be considered. (5.1)oPioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure. (5.1)oInitiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1)Lactic AcidosisoPost-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 mcg/mL. (5.2)oRisk 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)oIf lactic acidosis is suspected, discontinue pioglitazone and metformin hydrochloride and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.2). oThiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride, cause or exacerbate congestive heart failure in some patients. (5.1). oAfter initiation of pioglitazone 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 and metformin hydrochloride must be considered. (5.1). oPioglitazone and metformin hydrochloride is not recommended in patients with symptomatic heart failure. (5.1). oInitiation of pioglitazone and metformin hydrochloride in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1). oPost-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 mcg/mL. (5.2). oRisk 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). oIf lactic acidosis is suspected, discontinue pioglitazone and metformin hydrochloride and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pioglitazone and metformin hydrochloride combines two antidiabetic medications with different mechanisms of action to improve glycemic control in adults with type diabetes: pioglitazone, thiazolidinedione, and metformin hydrochloride, biguanide. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.PioglitazonePioglitazone is 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 (PPAR). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR nuclear receptors modulates the transcription of 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 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 hydrochlorideMetformin hydrochloride improves glucose tolerance in patients with type 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 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. PioglitazoneClinical 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 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 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 [see Warnings and Precautions (5.10) and Adverse Reactions (6.1)].In 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 mean increase in the placebo group. Mean HDL cholesterol increased to 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 26-Week Placebo-Controlled Monotherapy Dose-Ranging StudyPlaceboPioglitazone15 mgOnce DailyPioglitazone30 mgOnce DailyPioglitazone45 mgOnce DailyTriglycerides (mg/dL)N=79N=79N=84N=77Baseline (mean)263284261260Percent change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)4.8%-9%p <0.05 versus placebo -9.6% -9.3% HDL Cholesterol (mg/dL)N=79N=79N=83N=77Baseline (mean)42404141Percent change from baseline (adjusted mean)8.1%14.1% 12.2%19.1% LDL Cholesterol (mg/dL)N=65N=63N=74N=62Baseline (mean)139132136127Percent change from baseline (adjusted mean)4.8%7.2%5.2%6%Total Cholesterol (mg/dL)N=79N=79N=84N=77Baseline (mean)225220223214Percent 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. AbsorptionPioglitazone and Metformin Hydrochloride In bioequivalence studies of pioglitazone 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 single dose of the combination tablet were bioequivalent to pioglitazone 15 mg concomitantly administered with Glucophage (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.Administration of pioglitazone 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. 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.PioglitazoneFollowing 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 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 hydrochlorideThe absolute bioavailability of 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 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 mcg/mL, even at maximum doses.Food decreases the rate and extent of metformin absorption, as shown by 40% lower mean Cmax, 25% lower AUC, and 35-minute prolongation of Tmax following administration of single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.DistributionPioglitazoneThe 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 hydrochlorideThe 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 function of time.MetabolismPioglitazonePioglitazone 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 lesser degree, CYP3A4 with additional contributions from variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, strong CYP2C8 inhibitor, showed that pioglitazone is 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 strong CYP3A4 enzyme inducer.Metformin hydrochlorideIntravenous 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 EliminationPioglitazoneFollowing 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 (t 1/2 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 hydrochlorideRenal 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 plasma elimination 1/2 of approximately 6.2 hours. In blood, the elimination 1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.Specific PopulationsRenal ImpairmentPioglitazoneThe 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 hydrochlorideIn patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)].Hepatic ImpairmentPioglitazoneCompared 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 and metformin hydrochloride with caution in patients with liver disease [see Warnings and Precautions (5.5)].Metformin hydrochlorideNo pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].Geriatric PatientsPioglitazoneIn 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 1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of magnitude that would be considered clinically relevant.Metformin hydrochlorideLimited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the 1/2 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 change in renal function.PediatricsPioglitazoneSafety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].Metformin hydrochlorideAfter administration of single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 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.GenderPioglitazoneThe 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 hydrochlorideMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes, the antihyperglycemic effect of metformin was comparable in males and females.EthnicityPioglitazonePharmacokinetic data among various ethnic groups are not available.Metformin hydrochlorideNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).Drug-Drug InteractionsSpecific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.PioglitazoneTable 17. Effect of Pioglitazone Coadministration on Systemic Exposure of Other DrugsCoadministered DrugPioglitazone DosageRegimen (mg)Daily for days unless otherwise notedName and Dose RegimensChange in AUC% change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyChange in Cmax 45 mg(N 12)WarfarinPioglitazone had no clinically significant effect on prothrombin timeDaily loading then maintenance dosesbased PT and INR valuesQuicks Value 35 +- 5%R-Warfarin3%R-Warfarin2%S-Warfarin1%S-Warfarin1%45 mg(N 12)Digoxin0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, days)15%17%45 mg daily for 21 days(N 35)Oral Contraceptive [Ethinyl Estradiol (EE) 0.035 mg plusNorethindrone (NE) mg] for 21 daysEE11%EE13%NE3%NE7%45 mg(N 23)Fexofenadine60 mg twice daily for days30%37%45 mg(N 14)Glipizide5 mg daily for days3%8%45 mg daily for days(N 16)Metformin1000 mg single dose on Day 83%5%45 mg(N 21)Midazolam7.5 mg single dose on Day 1526%26%45 mg(N 24)Ranitidine150 mg twice daily for days1%1%45 mg daily for days(N 24)Nifedipine ER30 mg daily for days13%17%45 mg(N 25)Atorvastatin Ca80 mg daily for days14%23%45 mg(N 22)Theophylline400 mg twice daily for days2%5%Table 18. Effect of Coadministered Drugs on Pioglitazone Systemic ExposureCoadministered Drug and Dosage RegimenPioglitazoneDose Regimen(mg)Daily for days unless otherwise notedChange in AUCMean ratio (with/without coadministered drug and no change 1-fold) change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyChange in Cmax Gemfibrozil 600 mgtwice daily for days(N 12)15-mgsingle dose3.2-foldThe 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)] 6%Ketoconazole 200 mgtwice daily for days(N 28)45 mg34%14%Rifampin 600 mgdaily for days(N 10)30-mgsingle dose54%5%Fexofenadine 60 mgtwice daily for days(N 23)45 mg1%0%Ranitidine 150 mgtwice daily for days(N 23)45 mg13%16%Nifedipine ER 30 mgdaily for days(N 23)45 mg5%4%Atorvastatin Ca 80 mgdaily for days(N 24)45 mg24%31%Theophylline 400 mgtwice daily for days(N 22)45 mg4%2%Topiramate 96 mg twice daily for7 daysIndicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study (N 26)30 mg 15%Additional decrease in active metabolites; 60% for M-III and 16% for M-IV 0%Metformin hydrochlorideTable 19. Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered DrugDose of Coadministered DrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect 1.00AUC+ Cmax No dosing adjustments required for the following:Glyburide5 mg500 mg 0.98 0.99 Furosemide40 mg850 mg1.09 1.22 Nifedipine10 mg850 mg1.161.21Propranolol40 mg850 mg0.900.94Ibuprofen400 mg850 mg1.05 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)].Cimetidine400 mg850 mg1.401.61Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)].Topiramate100 mg 500 mg 1.25 1.17All metformin and coadministered drugs were given as single doses+AUC AUC0-Ratio of arithmetic meansMetformin hydrochloride extended-release tablets, 500 mgAt steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC0-12hTable 20. Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered DrugDose of Coadministered DrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect 1.00AUC+Cmax No dosing adjustments required for the following:Glyburide5 mg500 mg0.780.63Furosemide40 mg850 mg0.870.69Nifedipine10 mg850 mg1.101.08Propranolol40 mg850 mg1.010.94Ibuprofen400 mg850 mg0.971.01Cimetidine400 mg850 mg0.951.01All metformin and coadministered drugs were given as single doses+AUC AUC0- Ratio of arithmetic means, p-value of difference <0.05AUC0-24 hr reportedRatio of arithmetic means.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone. In 24-week, randomized, double-blind clinical trial, 600 patients with type diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were randomized to pioglitazone 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 and metformin hydrochloride compared to either pioglitazone or metformin alone (see Table 21).Table 21. Glycemic Parameters in 24-Week Study of Pioglitazone and Metformin Hydrochloride in Patients with Type Diabetes Mellitus Inadequately Controlled with Diet and ExerciseParameterTreatment GroupPioglitazone and metformin hydrochloride 15/850 mgTwice DailyPioglitazone15 mgTwice DailyMetformin850 mgTwice DailyHbA1c (%)N=188N=162N=193 Baseline (mean)8.98.78.7 Change from Baseline (adjusted meanAdjusted for baseline)-1.8-1-1 Difference between pioglitazone and metformin hydrochloride (adjusted mean) 95% Confidence Interval0.9p <=0.05 versus pioglitazone and metformin hydrochloride (0.5, 1.2)0.8 (0.5, 1.2) of patients with HbA1c <=7%644739Fasting Plasma Glucose (mg/dL)N=196N=176N=202 Baseline (mean)177171171 Change from Baseline (adjusted mean)-40-22-25 Difference between pioglitazone and metformin hydrochloride (adjusted mean) 95% Confidence Interval18 (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 and metformin hydrochloride with coadministered pioglitazone and metformin tablets was demonstrated for both pioglitazone 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 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 16-Week Placebo-Controlled, Add-on to Metformin TrialPlacebo MetforminPioglitazone30 mg MetforminTotal PopulationHbA1c (%)N=153N=161Baseline (mean)9.89.9Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)0.2-0.6Difference from placebo metformin (adjusted mean)95% Confidence Interval-0.8 <=0.05 vs. placebo metformin (-1.2, -0.5)Fasting Plasma Glucose (mg/dL)N=157N=165Baseline (mean)260254Change from baseline (adjusted mean)-5-43Difference 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 24-Week Add-on to Metformin StudyPioglitazone30 mg MetforminPioglitazone45 mg MetforminTotal PopulationHbA1c (%)N=400N=398Baseline (mean)9.99.8Change from baseline (adjusted meanAdjusted for baseline, pooled center, and pooled center by treatment interaction)-0.8-1Difference from 30 mg daily pioglitazone metformin (adjusted mean) (95% CI)-0.2(-0.5, 0.1)Fasting Plasma Glucose (mg/dL)N=398N=399Baseline (mean)233232Change from baseline (adjusted mean)-38-51Difference from 30 mg daily pioglitazone metformin (adjusted mean) (95% CI)-12p <=0.05 vs. 30 mg daily pioglitazone metformin (-21, -4)95% CI 95% confidence intervalThe therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oIndividualize the starting dose based on the patients 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)oGive in divided daily doses with meals to reduce the gastrointestinal effects due to metformin. (2.1)oMonitor patients for adverse events related to fluid retention after initiation and dose increases. (2.1)oObtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride tablets, investigate the probable cause, treat (if possible), and follow appropriately. (2.1, 5.5)oPrior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2) oDo not use in patients with eGFR below 30 mL/min/1.73 m2 oInitiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2oAssess risk/benefit of continuing pioglitazone and metformin hydrochloride tablets if eGFR falls below 45 mL/min/1.73 m2oDiscontinue if eGFR falls below 30 mL/min/1.73 m2oPioglitazone and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4). oIndividualize the starting dose based on the patients 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). oGive in divided daily doses with meals to reduce the gastrointestinal effects due to metformin. (2.1). oMonitor patients for adverse events related to fluid retention after initiation and dose increases. (2.1). oObtain liver tests before initiation. If abnormal, use caution when treating with pioglitazone and metformin hydrochloride tablets, investigate the probable cause, treat (if possible), and follow appropriately. (2.1, 5.5). oPrior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2) oDo not use in patients with eGFR below 30 mL/min/1.73 m2 oInitiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2oAssess risk/benefit of continuing pioglitazone and metformin hydrochloride tablets if eGFR falls below 45 mL/min/1.73 m2oDiscontinue if eGFR falls below 30 mL/min/1.73 m2. oDo not use in patients with eGFR below 30 mL/min/1.73 m2 oInitiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2. oAssess risk/benefit of continuing pioglitazone and metformin hydrochloride tablets if eGFR falls below 45 mL/min/1.73 m2. oDiscontinue if eGFR falls below 30 mL/min/1.73 m2. oPioglitazone and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures (2.4). 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 combination tablet containing pioglitazone and metformin is considered appropriate the recommended starting dose is:o15 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,ofor patients with New York Heart Association (NYHA) Class 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,ofor 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,ofor 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,ofor 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 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 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)].. o15 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,. ofor patients with New York Heart Association (NYHA) Class 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,. ofor 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,. ofor 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,. ofor 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.. 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 m2.Initiation of pioglitazone 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 and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit risk of continuing therapy.Discontinue pioglitazone and metformin hydrochloride tablets if the patients 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 and metformin hydrochloride tablets) and gemfibrozil, strong CYP2C8 inhibitor, increases pioglitazone exposure approximately 3-fold. Therefore, the maximum recommended dose of pioglitazone and metformin hydrochloride tablets are 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 m2; in patients with 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)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oStrong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily. (2.3, 7.1)oCYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2)oCarbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7.3)oDrugs 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)oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7.5)oUse of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. (7.6)oTopiramate may decrease pioglitazone concentrations. (7.8). oStrong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone concentrations. Limit pioglitazone and metformin hydrochloride dose to 15 mg/850 mg daily. (2.3, 7.1). oCYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2). oCarbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7.3). oDrugs 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). oAlcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7.5). oUse of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. (7.6). oTopiramate 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 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 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 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 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 patient receiving pioglitazone and metformin hydrochloride, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-Approved Patient Labeling (Medication Guide).oIt is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.oTell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.oExplain to patients the risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted in the Warnings and Precautions (5.2) section. Advise patients to discontinue pioglitazone and metformin hydrochloride immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Instruct patients to inform their doctor that they are taking pioglitazone and metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation of pioglitazone and metformin hydrochloride may be required until renal function has been confirmed to be normal.oCounsel patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.oInform patients to immediately report symptoms of an unusually rapid increase in weight or edema, shortness of breath, or other symptoms of heart failure while receiving pioglitazone and metformin hydrochloride.oTell patients to promptly stop taking pioglitazone and metformin hydrochloride and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.oInform patients about the importance of regular testing of renal function and hematologic parameters when receiving treatment with pioglitazone and metformin hydrochloride.oInform female patients that treatment with pioglitazone and metformin hydrochloride may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].oPatients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of pioglitazone and metformin hydrochloride overdose.oCombination antihyperglycemic therapy may cause hypoglycemia. When initiating pioglitazone and metformin hydrochloride, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.oPatients should be told to take pioglitazone and metformin hydrochloride as prescribed and instructed that any change in dosing should only be done if directed by their physician. If dose is missed on one day, the dose should not be doubled the following day.. oIt is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.. oTell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.. oExplain to patients the risks of lactic acidosis, its symptoms and conditions that predispose to its development, as noted in the Warnings and Precautions (5.2) section. Advise patients to discontinue pioglitazone and metformin hydrochloride immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Instruct patients to inform their doctor that they are taking pioglitazone and metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation of pioglitazone and metformin hydrochloride may be required until renal function has been confirmed to be normal.. oCounsel patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.. oInform patients to immediately report symptoms of an unusually rapid increase in weight or edema, shortness of breath, or other symptoms of heart failure while receiving pioglitazone and metformin hydrochloride.. oTell patients to promptly stop taking pioglitazone and metformin hydrochloride and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.. oInform patients about the importance of regular testing of renal function and hematologic parameters when receiving treatment with pioglitazone and metformin hydrochloride.. oInform female patients that treatment with pioglitazone and metformin hydrochloride may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].. oPatients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of pioglitazone and metformin hydrochloride overdose.. oCombination antihyperglycemic therapy may cause hypoglycemia. When initiating pioglitazone and metformin hydrochloride, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.. oPatients should be told to take pioglitazone and metformin hydrochloride as prescribed and instructed that any change in dosing should only be done if directed by their physician. If dose is missed on one day, the dose should not be doubled the following day.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPioglitazone and Metformin Hydrochloride In bioequivalence studies of pioglitazone 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 single dose of the combination tablet were bioequivalent to pioglitazone 15 mg concomitantly administered with Glucophage (500 mg or 850 mg respectively) tablets under fasted conditions in healthy subjects.Administration of pioglitazone 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. 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.PioglitazoneFollowing 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 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 hydrochlorideThe absolute bioavailability of 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 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 mcg/mL, even at maximum doses.Food decreases the rate and extent of metformin absorption, as shown by 40% lower mean Cmax, 25% lower AUC, and 35-minute prolongation of Tmax following administration of single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.DistributionPioglitazoneThe 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 hydrochlorideThe 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 function of time.MetabolismPioglitazonePioglitazone 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 lesser degree, CYP3A4 with additional contributions from variety of other isoforms, including the mainly extrahepatic CYP1A1. In vivo study of pioglitazone in combination with gemfibrozil, strong CYP2C8 inhibitor, showed that pioglitazone is 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 strong CYP3A4 enzyme inducer.Metformin hydrochlorideIntravenous 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 EliminationPioglitazoneFollowing 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 (t 1/2 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 hydrochlorideRenal 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 plasma elimination 1/2 of approximately 6.2 hours. In blood, the elimination 1/2 is approximately 17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.Specific PopulationsRenal ImpairmentPioglitazoneThe 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 hydrochlorideIn patients with decreased renal function, the plasma and blood t1/2 of metformin is prolonged and the renal clearance is decreased [see Dosage and Administration (2.2), Contraindications (4) and Warnings and Precautions (5.2)].Hepatic ImpairmentPioglitazoneCompared 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 and metformin hydrochloride with caution in patients with liver disease [see Warnings and Precautions (5.5)].Metformin hydrochlorideNo pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].Geriatric PatientsPioglitazoneIn 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 1/2 of pioglitazone was also prolonged in elderly subjects (about ten hours) as compared to younger subjects (about seven hours). These changes were not of magnitude that would be considered clinically relevant.Metformin hydrochlorideLimited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total CL/F is decreased, the 1/2 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 change in renal function.PediatricsPioglitazoneSafety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone and metformin hydrochloride is not recommended for use in pediatric patients [see Use in Specific Populations (8.4)].Metformin hydrochlorideAfter administration of single oral metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed less than 5% between pediatric type 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.GenderPioglitazoneThe 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 hydrochlorideMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes, the antihyperglycemic effect of metformin was comparable in males and females.EthnicityPioglitazonePharmacokinetic data among various ethnic groups are not available.Metformin hydrochlorideNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and Hispanics (n=24).Drug-Drug InteractionsSpecific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.PioglitazoneTable 17. Effect of Pioglitazone Coadministration on Systemic Exposure of Other DrugsCoadministered DrugPioglitazone DosageRegimen (mg)Daily for days unless otherwise notedName and Dose RegimensChange in AUC% change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyChange in Cmax 45 mg(N 12)WarfarinPioglitazone had no clinically significant effect on prothrombin timeDaily loading then maintenance dosesbased PT and INR valuesQuicks Value 35 +- 5%R-Warfarin3%R-Warfarin2%S-Warfarin1%S-Warfarin1%45 mg(N 12)Digoxin0.200 mg twice daily (loading dose) then 0.250 mg daily (maintenance dose, days)15%17%45 mg daily for 21 days(N 35)Oral Contraceptive [Ethinyl Estradiol (EE) 0.035 mg plusNorethindrone (NE) mg] for 21 daysEE11%EE13%NE3%NE7%45 mg(N 23)Fexofenadine60 mg twice daily for days30%37%45 mg(N 14)Glipizide5 mg daily for days3%8%45 mg daily for days(N 16)Metformin1000 mg single dose on Day 83%5%45 mg(N 21)Midazolam7.5 mg single dose on Day 1526%26%45 mg(N 24)Ranitidine150 mg twice daily for days1%1%45 mg daily for days(N 24)Nifedipine ER30 mg daily for days13%17%45 mg(N 25)Atorvastatin Ca80 mg daily for days14%23%45 mg(N 22)Theophylline400 mg twice daily for days2%5%Table 18. Effect of Coadministered Drugs on Pioglitazone Systemic ExposureCoadministered Drug and Dosage RegimenPioglitazoneDose Regimen(mg)Daily for days unless otherwise notedChange in AUCMean ratio (with/without coadministered drug and no change 1-fold) change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyChange in Cmax Gemfibrozil 600 mgtwice daily for days(N 12)15-mgsingle dose3.2-foldThe 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)] 6%Ketoconazole 200 mgtwice daily for days(N 28)45 mg34%14%Rifampin 600 mgdaily for days(N 10)30-mgsingle dose54%5%Fexofenadine 60 mgtwice daily for days(N 23)45 mg1%0%Ranitidine 150 mgtwice daily for days(N 23)45 mg13%16%Nifedipine ER 30 mgdaily for days(N 23)45 mg5%4%Atorvastatin Ca 80 mgdaily for days(N 24)45 mg24%31%Theophylline 400 mgtwice daily for days(N 22)45 mg4%2%Topiramate 96 mg twice daily for7 daysIndicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of study (N 26)30 mg 15%Additional decrease in active metabolites; 60% for M-III and 16% for M-IV 0%Metformin hydrochlorideTable 19. Effect of Coadministered Drug on Plasma Metformin Systemic ExposureCoadministered DrugDose of Coadministered DrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect 1.00AUC+ Cmax No dosing adjustments required for the following:Glyburide5 mg500 mg 0.98 0.99 Furosemide40 mg850 mg1.09 1.22 Nifedipine10 mg850 mg1.161.21Propranolol40 mg850 mg0.900.94Ibuprofen400 mg850 mg1.05 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)].Cimetidine400 mg850 mg1.401.61Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5) and Drug Interactions (7)].Topiramate100 mg 500 mg 1.25 1.17All metformin and coadministered drugs were given as single doses+AUC AUC0-Ratio of arithmetic meansMetformin hydrochloride extended-release tablets, 500 mgAt steady-state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC0-12hTable 20. Effect of Metformin on Coadministered Drug Systemic ExposureCoadministered DrugDose of Coadministered DrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect 1.00AUC+Cmax No dosing adjustments required for the following:Glyburide5 mg500 mg0.780.63Furosemide40 mg850 mg0.870.69Nifedipine10 mg850 mg1.101.08Propranolol40 mg850 mg1.010.94Ibuprofen400 mg850 mg0.971.01Cimetidine400 mg850 mg0.951.01All metformin and coadministered drugs were given as single doses+AUC AUC0- Ratio of arithmetic means, p-value of difference <0.05AUC0-24 hr reportedRatio of arithmetic means.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEPioglitazone and Metformin Hydrochloride Tablets, USP(pie-oh-GLIT-ah-zohn and met-FORE-min)Read this Medication Guide carefully before you start taking pioglitazone and metformin hydrochloride tablets and each time you get 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 and metformin hydrochloride, ask your doctor or pharmacist.What is the most important information should know about pioglitazone and metformin hydrochloride tabletsPioglitazone and metformin hydrochloride tablets can cause serious side effects, including:onew or worse heart failure. Pioglitazone, one of the medicines in pioglitazone and metformin hydrochloride tablets, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.oDo not take pioglitazone and metformin hydrochloride tablets if you have severe heart failureoIf you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, pioglitazone and metformin hydrochloride tablets may not be right for you. Call your doctor right away if you have any of the following:o swelling or fluid retention, especially in the ankles or legso shortness of breath or trouble breathing, especially when you lie downo an unusually fast increase in weighto unusual tirednessolactic acidosis. Metformin, one of the medicines in pioglitazone and metformin hydrochloride tablets, can cause rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:o you feel cold in your hands or feeto you feel dizzy or lightheadedo you have slow or irregular heartbeato you feel very weak or tiredo you have unusual (not normal) muscle paino you have trouble breathingo you feel sleepy or drowsyo you have stomach pains, nausea, or vomitingMost 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 higher chance for getting lactic acidosis with pioglitazone and metformin hydrochloride tablets if you:ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. ohave liver problemsodrink alcohol very often, or drink lot of alcohol in short-term binge drinkingoget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluidsohave surgeryohave heart attack, severe infection, or strokeThe best way to keep from having 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 and metformin hydrochloride tablets for while if you have any of these things.Pioglitazone and metformin hydrochloride tablets can have other serious side effects. See What are the possible side effects of pioglitazone and metformin hydrochloride tabletsWhat are pioglitazone and metformin hydrochloride tabletsPioglitazone and metformin hydrochloride tablets contains two prescription diabetes medicines called pioglitazone and metformin hydrochloride. Pioglitazone and metformin hydrochloride tablets can be used with diet and exercise to improve blood sugar (glucose) control in adults with type diabetes.Pioglitazone and metformin hydrochloride tablets are not for people with type diabetes.Pioglitazone and metformin hydrochloride tablets are not for people with diabetic ketoacidosis (increased ketones in your blood or urine).It is not known if pioglitazone and metformin hydrochloride tablets are safe and effective in children under the age of 18. Pioglitazone and metformin hydrochloride tablets are not recommended for use in children.Who should not take pioglitazone and metformin hydrochloride tabletsSee What is the most important information should know about pioglitazone and metformin hydrochloride tabletsDo not take pioglitazone and metformin hydrochloride tablets if you:ohave severe heart failureoare allergic to pioglitazone, metformin, or any of the ingredients in pioglitazone and metformin hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in pioglitazone and metformin hydrochloride tabletsohave severe kidney problemsohave condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulinTell your doctor before taking pioglitazone and metformin hydrochloride tablets if you have any of these conditions.What should tell my doctor before taking pioglitazone and metformin hydrochloride tabletsBefore you take pioglitazone and metformin hydrochloride tablets, tell your doctor if you:ohave heart failureohave severe kidney problemsoare going to have dye injected into vein for an x-ray, CAT scan, heart study, or other type of scanningowill be undergoing surgical procedureodrink lot of alcohol (all the time or short binge drinking)ohave type (juvenile) diabetes or had diabetic ketoacidosisohave type of diabetic eye disease that causes swelling in the back of the eye (macular edema)ohave liver problemsohave or have had cancer of the bladderoare pregnant or plan to become pregnant. It is not known if pioglitazone and metformin hydrochloride tablets can harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnantoare premenopausal woman (before the change of life) who does not have periods regularly or at all. Pioglitazone and metformin hydrochloride tablets may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking pioglitazone and metformin hydrochloride tablets. Tell your doctor right away if you become pregnant while taking pioglitazone and metformin hydrochloride tablets oare breastfeeding or plan to breastfeed. It is not known if pioglitazone and metformin hydrochloride passes into your milk and if it can harm your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeedingTell your doctor about all the medicines you take, including prescription and over the counter medicines, vitamins, and herbal supplements.Pioglitazone and metformin hydrochloride tablets and some of your other medicines can affect each other. You may need to have your dose of pioglitazone and metformin hydrochloride tablets or certain other medicines changed.Know the medicines you take. Keep list of your medicines and show it to your doctor and pharmacist before you start new medicine. They will tell you if it is okay to take pioglitazone and metformin hydrochloride tablets with other medicines.How should take pioglitazone and metformin hydrochlorideoTake pioglitazone and metformin hydrochloride tablets exactly as your doctor tells you to take itoYour doctor may need to change your dose of pioglitazone and metformin hydrochloride tablets. Do not change your pioglitazone and metformin hydrochloride tablets dose unless your doctor tells you tooPioglitazone and metformin hydrochloride tablets may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlledoTake pioglitazone and metformin hydrochloride tablets with meals to lower your chance of an upset stomachoIf you miss dose of pioglitazone and metformin hydrochloride tablets, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next dayoIf you take too much pioglitazone and metformin hydrochloride, call your doctor or go to the nearest hospital emergency room right awayoIf your body is under stress such as from fever, infection, accident, or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right awayoStay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone and metformin hydrochloride tablets.oYour doctor should do certain blood tests before you start and while you take pioglitazone and metformin hydrochloride tabletsoYour doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone and metformin hydrochloride tabletsoYour doctor should check your eyes regularly while you take pioglitazone and metformin hydrochloride tabletsWhat are the possible side effects of pioglitazone and metformin hydrochloride tabletsPioglitazone and metformin hydrochloride tablets may cause serious side effects, including:oSee What is the most important information should know about pioglitazone and metformin hydrochloride tabletsolow blood sugar (hypoglycemia). This can happen if you skip meals, if you also use another medicine that lowers blood sugar, or if you have certain medical problems. Lightheadedness, dizziness, shakiness, or hunger may happen if your blood sugar is too low. Call your doctor if low blood sugar levels are problem for youoliver problems. Call your doctor right away if you have:onausea or vomitingostomach painounusual or unexplained tirednessoloss of appetiteodark urineoyellowing of your skin or the whites of your eyesobladder cancer. There may be an increased chance of having bladder cancer when you take pioglitazone and metformin hydrochloride. You should not take pioglitazone and metformin hydrochloride tablets if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:oblood or red color in your urineoan increased need to urinateopain while you urinateobroken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthyodiabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularlyorelease of an egg from an ovary in woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take pioglitazone and metformin hydrochloride tablets. This can increase your chance of getting pregnant.olow red blood cell count (anemia).The most common side effects of Pioglitazone and metformin hydrochloride include:ocold-like symptoms (upper respiratory tract infection)oswelling (edema)odiarrheaoheadacheoincreased weightTell 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 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 store pioglitazone and metformin hydrochloride tabletsoStore pioglitazone and metformin hydrochloride tablets at 68F to 77F (20C to 25C). Keep pioglitazone and metformin hydrochloride tablets in the original container and protect from light.Keep the pioglitazone and metformin hydrochloride tablets bottle tightly closed and keep tablets dryKeep pioglitazone and metformin hydrochloride tablets and all medicines out of the reach of children.General information about the safe and effective use of pioglitazone and metformin hydrochloride tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use pioglitazone and metformin hydrochloride tablets for condition for which it was not prescribed. Do not give pioglitazone 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 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 and metformin hydrochloride tablets that is written for healthcare professionals.For more information, go to www.us.sandoz.com or call 1-800-525-8747.What are the ingredients in pioglitazone and metformin hydrochloride tabletsActive Ingredients: pioglitazone hydrochloride and metformin hydrochlorideInactive Ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.The brands listed are trademarks of their respective owners and are not trademark of Sandoz Inc. This Medication Guide has been approved by the U.S. Food and Drug Administration.Finished drug product manufactured byLek Pharmaceuticals d.d., SI-1526 Ljubljana, Slovenia forSandoz Inc., Princeton, NJ 08540Rev. June 2018. onew or worse heart failure. Pioglitazone, one of the medicines in pioglitazone and metformin hydrochloride tablets, can cause your body to keep extra fluid (fluid retention), which leads to swelling (edema) and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. Heart failure means your heart does not pump blood well enough.. oDo not take pioglitazone and metformin hydrochloride tablets if you have severe heart failure. oIf you have heart failure with symptoms (such as shortness of breath or swelling), even if these symptoms are not severe, pioglitazone and metformin hydrochloride tablets may not be right for you.. Call your doctor right away if you have any of the following:. swelling or fluid retention, especially in the ankles or legs. shortness of breath or trouble breathing, especially when you lie down. an unusually fast increase in weight. unusual tiredness. olactic acidosis. Metformin, one of the medicines in pioglitazone and metformin hydrochloride tablets, can cause rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital.. Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:. you feel cold in your hands or feet. you feel dizzy or lightheaded. you have slow or irregular heartbeat. you feel very weak or tired. you have unusual (not normal) muscle pain. you have trouble breathing. you feel sleepy or drowsy. you have stomach pains, nausea, or vomiting. ohave severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye. ohave liver problems. odrink alcohol very often, or drink lot of alcohol in short-term binge drinking. oget dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids. ohave surgery. ohave heart attack, severe infection, or stroke. ohave severe heart failure. oare allergic to pioglitazone, metformin, or any of the ingredients in pioglitazone and metformin hydrochloride tablets. See the end of this Medication Guide for complete list of ingredients in pioglitazone and metformin hydrochloride tablets. ohave severe kidney problems. ohave condition called metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin. ohave heart failure. ohave severe kidney problems. oare going to have dye injected into vein for an x-ray, CAT scan, heart study, or other type of scanning. owill be undergoing surgical procedure. odrink lot of alcohol (all the time or short binge drinking). ohave type (juvenile) diabetes or had diabetic ketoacidosis. ohave type of diabetic eye disease that causes swelling in the back of the eye (macular edema). ohave liver problems. ohave or have had cancer of the bladder. oare pregnant or plan to become pregnant. It is not known if pioglitazone and metformin hydrochloride tablets can harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant. oare premenopausal woman (before the change of life) who does not have periods regularly or at all. Pioglitazone and metformin hydrochloride tablets may increase your chance of becoming pregnant. Talk to your doctor about birth control choices while taking pioglitazone and metformin hydrochloride tablets. Tell your doctor right away if you become pregnant while taking pioglitazone and metformin hydrochloride tablets oare breastfeeding or plan to breastfeed. It is not known if pioglitazone and metformin hydrochloride passes into your milk and if it can harm your baby. Talk to your doctor about the best way to control your blood glucose levels while breastfeeding. oTake pioglitazone and metformin hydrochloride tablets exactly as your doctor tells you to take it. oYour doctor may need to change your dose of pioglitazone and metformin hydrochloride tablets. Do not change your pioglitazone and metformin hydrochloride tablets dose unless your doctor tells you to. oPioglitazone and metformin hydrochloride tablets may be prescribed alone or with other diabetes medicines. This will depend on how well your blood sugar is controlled. oTake pioglitazone and metformin hydrochloride tablets with meals to lower your chance of an upset stomach. oIf you miss dose of pioglitazone and metformin hydrochloride tablets, take your next dose as prescribed unless your doctor tells you differently. Do not take two doses at one time the next day. oIf you take too much pioglitazone and metformin hydrochloride, call your doctor or go to the nearest hospital emergency room right away. oIf your body is under stress such as from fever, infection, accident, or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away. oStay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone and metformin hydrochloride tablets.. oYour doctor should do certain blood tests before you start and while you take pioglitazone and metformin hydrochloride tablets. oYour doctor should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone and metformin hydrochloride tablets. oYour doctor should check your eyes regularly while you take pioglitazone and metformin hydrochloride tablets. oSee What is the most important information should know about pioglitazone and metformin hydrochloride tablets. olow blood sugar (hypoglycemia). This can happen if you skip meals, if you also use another medicine that lowers blood sugar, or if you have certain medical problems. Lightheadedness, dizziness, shakiness, or hunger may happen if your blood sugar is too low. Call your doctor if low blood sugar levels are problem for you. oliver problems. Call your doctor right away if you have:. onausea or vomiting. ostomach pain. ounusual or unexplained tiredness. oloss of appetite. odark urine. oyellowing of your skin or the whites of your eyes. obladder cancer. There may be an increased chance of having bladder cancer when you take pioglitazone and metformin hydrochloride. You should not take pioglitazone and metformin hydrochloride tablets if you are receiving treatment for bladder cancer. Tell your doctor right away if you have any of the following symptoms of bladder cancer:. oblood or red color in your urine. oan increased need to urinate. opain while you urinate. obroken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your doctor for advice on how to keep your bones healthy. odiabetic eye disease with swelling in the back of the eye (macular edema). Tell your doctor right away if you have any changes in your vision. Your doctor should check your eyes regularly. orelease of an egg from an ovary in woman (ovulation) leading to pregnancy. Ovulation may happen when premenopausal women who do not have regular monthly periods take pioglitazone and metformin hydrochloride tablets. This can increase your chance of getting pregnant.. olow red blood cell count (anemia).. ocold-like symptoms (upper respiratory tract infection). oswelling (edema). odiarrhea. oheadache. oincreased weight. oStore pioglitazone and metformin hydrochloride tablets at 68F to 77F (20C to 25C). Keep pioglitazone and metformin hydrochloride tablets in the original container and protect from light.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)oPediatrics: Not recommended for use in pediatric patients. (8.4)oGeriatric Use: Assess renal function more frequently. (8.5)oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). oFemales and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3). oPediatrics: Not recommended for use in pediatric patients. (8.4). oGeriatric Use: Assess renal function more frequently. (8.5). oHepatic Impairment: Avoid use in patients with hepatic impairment. (8.7). 8.1 Pregnancy. Risk SummaryLimited data with pioglitazone and metformin hydrochloride or pioglitazone in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported 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, 2000 mg clinical dose, based on body surface area [see Data]. The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20 to 25% in women with 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 to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly 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 DataPublished data from post-marketing studies have not reported 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 HydrochlorideAnimal 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.. PioglitazonePioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at 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 hydrochlorideMetformin 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 2000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.. 8.2 Lactation. Risk SummaryThere 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 mothers 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.. DataPublished 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 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. PioglitazoneA 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 hydrochlorideControlled 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 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 and metformin hydrochloride is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oCongestive 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 and II may increase risk. Monitor patients for signs and symptoms. (5.1)oLactic acidosis: See boxed warning. (5.2)oEdema: Dose-related edema may occur. (5.3)oHypoglycemia: When used with insulin or an insulin secretagogue, lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. (5.4)oHepatic 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)oBladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with prior history of bladder cancer. (5.6)oFractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.7)oMacular 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)oVitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. (5.9)oMacrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and metformin hydrochloride. (5.10). oCongestive 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 and II may increase risk. Monitor patients for signs and symptoms. (5.1). oLactic acidosis: See boxed warning. (5.2). oEdema: Dose-related edema may occur. (5.3). oHypoglycemia: When used with insulin or an insulin secretagogue, lower dose of the insulin or insulin secretagogue may be needed to reduce the risk of hypoglycemia. (5.4). oHepatic 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). oBladder cancer: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with prior history of bladder cancer. (5.6). oFractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.7). oMacular 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). oVitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually. (5.9). oMacrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with pioglitazone and metformin hydrochloride. (5.10). 5.1 Congestive Heart Failure. PioglitazonePioglitazone, 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 hydrochlorideLactic AcidosisThere have been post-marketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had 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 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 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 hospital setting, along with immediate discontinuation of pioglitazone and metformin hydrochloride. In pioglitazone and metformin hydrochloride -treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with 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 ImpairmentThe 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 patients renal function include [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) ].oBefore initiating pioglitazone and metformin hydrochloride, obtain an eGFR.oPioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30mL/min /1.73 m2. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2 [see Contraindications (4) ].oObtain 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.oIn patients taking pioglitazone and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.. oBefore initiating pioglitazone and metformin hydrochloride, obtain an eGFR.. oPioglitazone and metformin hydrochloride is contraindicated in patients with an eGFR less than 30mL/min /1.73 m2. Initiation of pioglitazone and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m2 [see Contraindications (4) ].. oObtain 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.. oIn patients taking pioglitazone and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.. Drug InteractionsThe 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 GreaterThe risk of metformin-associated lactic acidosis increases with the patients age because elderly patients have 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 ContrastAdministration 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 m2; in patients with 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 ProceduresWithholding 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.. Hypoxic StatesSeveral 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 IntakeAlcohol 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 ImpairmentPatients 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 (17.1)].. 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. 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 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 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 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 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo. After completion of the trial, 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 =1.00; [95% CI: 0.59-1.72]).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 0.89-1.26]).A retrospective cohort study conducted with data from the United Kingdom found statistically significant association between ever exposure to pioglitazone and bladder cancer (HR: 1.63; [95% CI: 1.22-2.19]).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 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 prior history of bladder cancer.. 5.7 Fractures. In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5238 patients with type diabetes and 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 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 patients 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, 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 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 and metformin hydrochloride.