ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are discussed elsewhere in the labeling:o Congestive heart failure [see Boxed Warning, Warnings and Precautions (5.1)] Lactic acidosis [see Boxed Warning, Warnings and Precautions (5.2)] Edema [see Warnings and Precautions (5.3)] Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.4)] Hepatic Effects [see Warnings and Precautions (5.5)] Urinary Bladder Tumors [see Warnings and Precautions (5.6)] Fractures [see Warnings and Precautions (5.7)] Macular Edema [see Warnings and Precautions (5.8] Vitamin B12 Levels [see Warnings and Precautions (5.9] 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 8,500 patients with type diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2,605 patients with type diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial. In these trials, over 6,000 patients have been treated with pioglitazone for six months or longer, over 4,500 patients have been treated with pioglitazone for one year or longer, and over 3,000 patients have been treated with pioglitazone for at least two years.In six pooled 16 to 26 week placebo-controlled monotherapy and 16 to 24 week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients. The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%).In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients. Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo.Common Adverse Events: 16 to 26 Week Monotherapy TrialsA summary of the incidence and type of common adverse events reported in three pooled 16 to26 week placebo-controlled monotherapy trials of pioglitazone is provided in Table 2. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo. None of these adverse events were related to the pioglitazone dose.Table 2: Three Pooled 16 to 26 Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence >5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo% of PatientsPlaceboN=259 PioglitazoneN=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 3. Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone.Table 3: 16 to 24 Week Clinical Trials of Pioglitazone Add-on to Metformin16 Week Placebo-Controlled TrialAdverse Events Reported in >5% of Patients and More Commonly in Patients Treated with Pioglitazone Metforminthan in Patients Treated with Placebo Metformin% of PatientsPlacebo+MetforminN=160Pioglitazone 30 mg+ Metformin N=168Edema2.56.0Headache1.96.024 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 withPioglitazone 30 mg Metformin% of PatientsPioglitazone 30 mg+MetforminN=411Pioglitazone 45 mg+ MetforminN=416Upper RespiratoryTract Infection12.4 13.5Edema 5.8 13.9Headache 5.4 5.8Weight Increased 2.9 6.7Note: 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 Tablets Clinical TrialTable summarizes the incidence and types of adverse reactions reported in controlled, 24 week double-blind clinical trial of pioglitazone and metformin hydrochloride tablets dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).Table 4: Adverse Events (>=5% for Pioglitazone and Metformin Hydrochloride Tablets) Reported by Patients with Inadequate Glycemic Control on Diet and Exercise in 24 Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Tablets Administered Twice Daily% of PatientsPioglitazone and Metformin Hydrochloride Tablets 15/850 mgTwice DailyN=201Pioglitazone15 mgTwice DailyN=190Metformin850 mgTwice DailyN=209Diarrhea9.02.615.3Headache5.52.64.8In this 24 week trial, abdominal pain was reported in 2.0% of patients in the pioglitazone and metformin hydrochloride group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.Common Adverse Events: PROactive TrialA summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5. Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.Table 5: PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo% of PatientsPlaceboN=2,633Pioglitazone N=2,605Hypoglycemia18.827.3Edema15.326.7Cardiac Failure6.18.1Pain in Extremity5.76.4Back Pain5.15.5Chest Pain5.05.1Mean 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 6: 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-ControlledDouble-Blind Trial(24 weeks)Placebo Metformin N=160Pioglitazone 30 mg+ Metformin N=168Pioglitazone 30 mg+Metformin N=411Pioglitazone 45 mg+ Metformin N=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)Patients Treated with Pioglitazone or Placebo Added on to SulfonylureaNumber (%) of PatientsPlacebo- Controlled Trial(16 weeks)Non-Controlled Double-Blind Trial(24 weeks)Placebo+ Sulfonylurea N=187Pioglitazone15 mg+ Sulfonylurea N=184Pioglitazone30 mg+ Sulfonylurea N=189Pioglitazone30 mg+ Sulfonylurea N=351Pioglitazone45 mg+ Sulfonylurea N=351At least one congestive heart failure event2 (1.1%) 01 (0.3%)6 (1.7%)Hospitalized2 (1.1%) 0 02 (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+ Insulin N=187Pioglitazone15 mg+ Insulin N=191Pioglitazone30 mg+ Insulin N=188Pioglitazone30 mg+ InsulinN=345Pioglitazone45 mg+ Insulin N=345At least one congestive heart failure event02 (1.0%)2 (1.1%)3 (0.9%)5 (1.4%)Hospitalized02 (1.0%)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+ Metformin N=160Pioglitazone30 mg+ Metformin N=168Pioglitazone30 mg+ Metformin N=411At least one congestive heart failure event01 (0.6%) 0Hospitalized01 (0.6%) 0Table 8: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 9.Table 9: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 (1.0%)Hospitalized, nonfatal86 (3.3%)124 (4.7%)Cardiovascular SafetyIn the PROactive trial, 5,238 patients with type diabetes mellitus and history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) 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 and572 (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 10.Table 10:PROactive Trial: Number of First and Total Events for Each Component within the Cardiovascular Composite EndpointPlaceboN=2633PioglitazoneN=2605Cardiovascular EventsFirstEventsn (%)Total events nFirst Events (%)Total events Any event572 (21.7)900514 (19.7) 803 All-cause mortality122 (4.6)186110 (4.2) 177 Nonfatal myocardial infarction (MI)118 (4.5)157105 (4.0) 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 intervention.Weight 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 11, 12, and 13 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 24 week pioglitazone and metformin hydrochloride trial.Table 11: Weight Changes (kg) from Baseline During Randomized, Double- Blind Clinical TrialsControl Group(Placebo)Pioglitazone15 mgPioglitazone30 mgPioglitazone45 mgMedian (25 h, 75 h percentile)Median (25 h, 75 h percentile)Median (25 h, 75 h percentile)Median (25 h, 75 h percentile)Monotherapy(16 to 26 weeks)-1.4 (-2.7, 0.0) N=2560.9 (-0.5, 3.4) N=791.0 (-0.9, 3.4) N=1882.6 (0.2, 5.4) N=79Sulfonylurea-0.5 (-1.8, 0.7) N=1872.0 (0.2, 3.2) N=1833.1 (1.1, 5.4) N=5284.1 (1.8, 7.3) N=333CombinationTherapyMetformin-1.4 (-3.2, 0.3) N=160N/A0.9 (-1.3, 3.2) N=5671.8 (-0.9, 5.0) N=407(16 to 24 weeks)Insulin0.2 (-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 12:Median Change in Body Weight in Patients Treated with Pioglitazone vs Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive TrialPlaceboPioglitazoneMedian (25 h, 75 h percentile)Median (25 h, 75 h percentile)Change from baseline to final visit (kg)-0.5 (-3.3, 2.0) N=2581+3.6 (0.0, 7.5) N=2560Note: Median exposure for both pioglitazone and placebo was 2.7 years.Table 13: Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with Pioglitazone and Metformin Hydrochloride Tablets in Patients with Inadequate Glycemic Control on Diet and ExercisePioglitazone and Metformin Hydrochloride Tablets 15/850 mgTwice DailyPioglitazone 15 mgTwice DailyMetformin 850 mgTwice DailyMedian (25 h, 75 h percentile)Median (25 h, 75 h percentile)Median (25 h, 75 h percentile)Change from baseline to final visit (kg)1.00 (-1.0, 3.0) N=198 1.35 (-0.7, 4.1) N=178 -1.00 (-2.6, 0.4) N=203 Note: 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 co-existing congestive heart failure.In the 24 week pioglitazone and metformin hydrochloride tablets trial, edema was reported in 3.0% of patients in the pioglitazone and metformin hydrochloride tablets 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 14.Table 14:Adverse Events of Edema in Patients Treated with PioglitazoneNumber (%) of PatientsPlaceboPioglitazone15 mgPioglitazone30 mgPioglitazone45 mgMonotherapy(16 to 26 weeks) (1.2%) N=2592 (2.5%) N= 8113 (4.7%) N= 27511 (6.5%) N=169Sulfonylurea (2.1%) N=1873 (1.6%) N=184 61 (11.3%) N=540 81 (23.1%) N=351Combined Therapy(16 to 24 weeks)Metformin (2.5%) N=160N/A34 (5.9%) N=579 58 (13.9%) N=416Insulin 13 (7.0%) N=187 24 (12.6%) N=191 109 (20.5%) N=533 90 (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 15: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 3/1,051 (0.3%) patients treated with pioglitazone and 9/1,046 (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% vs 13.4%) and in the 24-week add-on to insulin trial (47.8% vs 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 of2,605 (0.54%) randomized to pioglitazone and out of 2,633 (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 (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% Cl: 0.59 1.72]) [see Warnings and Precautions (5.6)].Metformin HClIn double-blind clinical study of metformin in patients with type diabetes mellitus, total of 141 patients received metformin therapy (up to 2,550 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 16. In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.Table 16:Most Common Adverse Reactions (>5.0%) in Placebo-Controlled Clinical Study of Metformin MonotherapyMetforminMonotherapy(n=141)Placebo(n=145)Adverse Reaction% of PatientsDiarrhea53.2 11.7Nausea/Vomiting25.58.3Flatulence12.15.5Asthenia 9.25.5Indigestion 7.14.1Abdominal Discomfort 6.44.8Headache 5.74.8 Reactions that were more common in metformin than placebo-treated patients.Laboratory AbnormalitiesPioglitazoneHematologic 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.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 2,150 to 11,400 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.MetforminVitamin B12 ConcentrationsIn metformin clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of pioglitazone and/or metformin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.PioglitazoneCardiac Disorders: Rapid increases in weight, edema, congestive heart failure with and without previously known heart disease or concomitant insulin administrationEye Disorders: New onset or worsening diabetic macular edema with decreased visual acuityHepatobiliary Disorders: Fatal and nonfatal hepatic failureMetforminHepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.

BOXED WARNING SECTION.

WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSISSee full prescribing information for complete boxed warning.Congestive Heart Failureo Thiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride tablets, cause or exacerbate congestive heart failure in some patients. (5.1)o After initiation of pioglitazone and metformin hydrochloride tablets, 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 congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets. (5.1)o Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure. (5.1)o Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated. (4, 5.1)Lactic Acidosiso Postmarketing 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)o Risk factors include renal impairment, concomitant use of certain drugs, age >=65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the Full Prescribing Information. (5.2)o If lactic acidosis is suspected, discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended. (5.2). WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS. Congestive Heart Failureo Thiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].o After initiation of pioglitazone and metformin hydrochloride tablets, 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 congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions (5.1)].o Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].o Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4), Warnings and Precautions (5.1)].Lactic Acidosiso Postmarketing 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 than5 mcg/mL [see Warnings and Precautions (5.2)].o Risk 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.o Steps 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), Use in Specific Populations (8.6, 8.7)].o If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Pioglitazone and metformin hydrochloride tablets combine two antihyperglycemic agents: pioglitazone and metformin.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 mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.Metformin HClMetformin HCl improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.. 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 mellitus, 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 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 17). Adjusted for baseline, pooled center, and pooled center by treatment interaction+ < 0.05 vs placeboTable 17:Lipids in 26 Week Placebo-Controlled Monotherapy Dose-Ranging StudyPlaceboPioglitazone 15 mg Once DailyPioglitazone 30 mg Once DailyPioglitazone 45 mg Once DailyTriglycerides (mg/dL)N=79N=79N=84N=77Baseline (mean)263284261260Percent change from baseline (adjusted mean)4.8%-9.0% -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%6.0%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 tabletsIn bioequivalence studies of pioglitazone and metformin hydrochloride tablets 15 mg/500 mg and15 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 ACTOS 15 mg concomitantly administered with metformin HCl immediate release (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.Administration of pioglitazone and metformin hydrochloride tablets 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 mellitus, 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 HClThe 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 1,500 mg, and 850 mg to 2,550 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 HClThe 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.EliminationMetabolismPioglitazonePioglitazone 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), Drug Interactions (7.1)]. Urinary6-ss-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not strong CYP3A4 enzyme inducer.Metformin HClIntravenous 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.ExcretionPioglitazoneFollowing oral administration, approximately 15 to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.Metformin HClRenal clearance is approximately 3.5 times greater than creatinine clearance (CrCl), 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 t1/2 of approximately 6.2 hours. In blood, the elimination t1/2 is approximately17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.Specific PopulationsGeriatric 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 are not considered clinically relevant.Metformin HClLimited 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.Pediatric PatientsPioglitazoneSafety 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 HClAfter 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.Male and Female PatientsPioglitazoneThe mean Cmax and AUC values of pioglitazone were increased 20 to 60% in females compared to males. 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 dosage adjustment is recommended based on gender alone.Metformin HClMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.Racial or Ethnic GroupsPioglitazonePharmacokinetic data among various ethnic groups are not available.Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51), and Hispanics or Latinos (n=24).Patients with Renal ImpairmentPioglitazoneThe serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CrCl 30 to 50 mL/min) and severe (CrCl <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dosage adjustment in patients with renal impairment is required.Metformin HClIn 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 (2.3), Contraindications (4), Warnings and Precautions (5.2)].Patients with 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 dosage 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 tablets with caution in patients with liver disease [see Warnings and Precautions (5.5)].Metformin HClNo pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].Drug Interaction StudiesSpecific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride tablets have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.Pioglitazone Daily for days unless otherwise noted+% change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyPioglitazone had no clinically significant effect on prothrombin timeTable 18:Effect of Pioglitazone Coadministration on Systemic Exposure of Other DrugsCoadministered DrugPioglitazone Dosage Regimen (mg)Name and Dose RegimensChange in AUC+Change in m x +45 mg (N 12)WarfarinDaily loading then maintenance doses based PT and INR values Quicks 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 plusEE11%EE13%Norethindrone (NE) mg] for 21 daysNE3%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 Calcium80 mg daily for days14%23%45 mg (N 22)Theophylline400 mg twice daily for days2%5%Daily for days unless otherwise noted +Mean ratio (with/without coadministered drug and no change 1-fold) change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectively The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of studyAdditional decrease in active metabolites; 60% for M-III and 16% for M-IV Table 19: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Change in AUC Change in max +Gemfibrozil 600 mg twice daily for days (N 12)15-mg single dose3.2-fold6%Ketoconazole 200 mg twice daily for days (N 28)45 mg34%14%Rifampin 600 mg daily for5 days (N 10)30-mg single dose54%5%Fexofenadine 60 mg twice daily for days (N 23)45 mg1%0%Ranitidine 150 mg twice daily for days (N 23)45 mg13%16%Nifedipine ER 30 mg daily for days (N 23)45 mg5%4%Atorvastatin Calcium 80 mg daily for days (N 24)45 mg24%31%Theophylline 400 mg twice daily for days (N 22)45 mg4%2%Topiramate 96 mg twice daily for days (N 26)30 mg 15% 0%Metformin HClAll metformin and coadministered drugs were given as single doses+AUC AUC to Ratio of arithmetic meansMetformin HCl extended-release tablets, 500 mgAt steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC to 12h Table 20: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.00 AUC Cmax No dosing adjustments required for the following:Glyburide 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: use with caution [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 AUC to Ratio of arithmetic means, p-value of difference <0.05AUC to 24hr reportedRatio of arithmetic means Table 21: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.00 AUC C maxNo 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 mg0.951.01.

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 tablets 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 tablets compared to either pioglitazone or metformin alone (see Table 22).Adjusted for baseline+p <=0.05 vs pioglitazone and metformin hydrochloride tabletsTable 22: Glycemic Parameters in 24 Week Study of Pioglitazone and Metformin Hydrochloride Tablets in Patients with Type Diabetes Mellitus Inadequately Controlled with Diet and ExerciseParameterTreatment GroupPioglitazone and Metformin Hydrochloride Tablets 15/850 mg Twice DailyPioglitazone 15 mg Twice DailyMetformin 850 mg Twice DailyHbA1c (%)N=188N=162N=193Baseline (mean) 8.98.78.7Change from Baseline (adjusted mean) -1.8-1.0-1.0Difference between pioglitazone and metformin hydrochloride tablets (adjusted mean) 95% Confidence Interval 0.9+ (0.5, 1.2)0.8+ (0.5, 1.2)% of patients with HbA1c <=7% 644739Fasting Plasma Glucose (mg/dL)N=196N=176N=202Baseline (mean) 177171171Change from Baseline (adjusted mean) -40-22-25Difference between pioglitazone and metformin hydrochloride tablets (adjusted mean) 95% Confidence Interval 18+ (8, 28)15+ (6, 25). 14.2 Patients Previously Treated with Metformin. The efficacy and safety of pioglitazone as add-on to metformin therapy have been established in two clinical studies [see Clinical Pharmacology (12.3)].The two clinical trials testing pioglitazone as add-on to metformin therapy included patients with type diabetes mellitus 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 23). Adjusted for baseline, pooled center, and pooled center by treatment interaction+ <=0.05 vs. placebo metforminTable 23:Glycemic Parameters in 16 Week Placebo-Controlled, Add-on to Metformin TrialPlacebo MetforminPioglitazone 30 mg MetforminTotal PopulationHbA1c (%)N=153N=161Baseline (mean)9.89.9Change from baseline (adjusted mean)0.2-0.6Difference from placebo metformin (adjusted mean) 95% Confidence Interval-0.8 +(-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 1.0% for the 45 mg dose (see Table 24). 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.95% CI 95% confidence intervalAdjusted for baseline, pooled center, and pooled center by treatment interaction+p <=0.05 vs. 30 mg daily pioglitazone metforminTable 24:Glycemic Parameters in 24 Week Add-on to Metformin StudyPioglitazone 30 mg MetforminPioglitazone 45 mg MetforminTotal PopulationHbA1c (%)N=400N=398Baseline (mean)9.99.8Change from baseline (adjusted mean)-0.8-1.0Difference 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)-12 (-21, -4)The therapeutic effect of pioglitazone in combination with metformin was observed in patients regardless of the metformin dose.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Pioglitazone and metformin hydrochloride tablets, USP are thiazolidinediones and biguanide combination product that contains two oral antidiabetic medications: pioglitazone HCl and metformin HCl.Pioglitazone [(+-)-5-[[4-[2-(5-ethyl-2-pyridinyl) ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride contains one asymmetric carbon, and the compound is synthesized and used as the racemic mixture. The two enantiomers of pioglitazone interconvert in vivo. No differences were found in the pharmacologic activity between the two enantiomers. The structural formula is as shown:Pioglitazone HCl, USP is an odorless white crystalline powder that has molecular formula of 19H 20N 2O 3SoHCl and molecular weight of 392.90 daltons. It is soluble in N,N-dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water, and insoluble in ether.Metformin hydrochloride N,N-dimethylimidodicarbonimidic diamide HCl), USP is white crystalline powder with molecular formula of 4H 11N 5oHCl and molecular weight of 165.62. Metformin HCl is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of 1% aqueous solution of metformin HCl is 6.68. The structural formula is as shown:Pioglitazone and metformin hydrochloride tablets, USP are available as tablet for oral administration containing 15 mg pioglitazone (as the base) with 500 mg metformin hydrochloride (15 mg/500 mg) or 15 mg pioglitazone (as the base) with 850 mg metformin hydrochloride (15 mg/850 mg) formulated with the following excipients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, talc, and titanium dioxide.. 1. 2.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Obtain 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)o Take orally with meals to reduce gastrointestinal adverse reactions with metformin (2.1)o Individualize the starting dose based on the patients current regimen and titrate the dosage gradually, as needed after assessing therapeutic response and tolerability. The maximum recommended total daily dosage is pioglitazone 45 mg and metformin 2,550 mg. (2.2)o Recommended starting dosage in patients with NYHA Class or Class II congestive heart failure is 15 mg of pioglitazone and 850 mg of metformin HCl orally once daily. (2.4)o Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). (2.2)o Contraindicated in patients with eGFR below 30 mL/mino Initiation is not recommended in patients with eGFR between 30 to 45 mL/mino Assess risk/benefit of continuing pioglitazone and metformin hydrochloride tablets if eGFR falls below 45 mL/mino Discontinue if eGFR falls below 30 mL/mino Monitor patients for adverse events related to fluid retention after initiation and dose increases. (2.4)o Pioglitazone and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.6). 2.1 Important Dosage and Administration Information. Obtain liver tests (serum alanine and aspartate aminotransferases, alkaline phosphatase, and total bilirubin) prior to initiating pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions (5.5)].o Pioglitazone and metformin hydrochloride tablets contains 15 mg of pioglitazone and 500 mg of metformin hydrochloride (HCl) and 15 mg of pioglitazone and 850 mg of metformin hydrochloride (HCl) in each tablet.o Take pioglitazone and metformin hydrochloride tablets with meals to reduce gastrointestinal adverse reactions with metformin [see Adverse Reactions (6.1)]. If dose is missed, do not double the next dose. 2.2 Recommended Dosage and Administration. Recommended Starting Dosage Based on Current RegimenIndividualize the starting dosage of pioglitazone and metformin hydrochloride tablets based on the patients current regimen and the available strength of pioglitazone and metformin hydrochloride tablets (see Table 1).Table 1: Recommended Starting Dosage Based on the Patients Current RegimenCurrent RegimenStarting Dosage of pioglitazone and metformin hydrochloride tablets (15 mg of pioglitazone and 850 mg of metformin HCl per tablet)Not treated with either pioglitazone or metformin HCl One tablet orally once daily Metformin HCl One tablet orally once or twice daily. Select dosage that is as close as possible to the current dosage of metformin HCl Pioglitazone One tablet orally once daily Pioglitazone and metformin HCl Select dosage that is as close as possible to the current dosage of pioglitazone and metformin HCl while not exceeding three tablets orally per day. For dosage recommendations for patients with renal impairment and/or congestive heart failure, see Dosage and Administration (2.3, 2.4) Dosage Titration for Additional Glycemic ControlTitrate the pioglitazone and metformin hydrochloride tablets dosage gradually, as needed, after assessing therapeutic response and tolerability.Pioglitazone and metformin hydrochloride tablets may be increased to maximum recommended total daily dosage of three tablets per day (45 mg of pioglitazone and 2,550 mg of metformin HCl). Total daily dosages of 2,550 mg of metformin HCl may be taken in divided doses three times day to reduce gastrointestinal adverse reactions [see Adverse Reactions (6.1)] . 2.3 Recommendations for Use in Patients with Renal Impairment. Assess renal function prior to initiation of pioglitazone and metformin hydrochloride tablets and periodically thereafter [see Use in Specific Populations (8.6)].o Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min.o Initiation of pioglitazone and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min is not recommended.o In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min, assess the benefit and risk of continuing therapy. Discontinue pioglitazone and metformin hydrochloride tablets if the patients eGFR later falls below 30 mL/min [see Contraindications (4), Warnings and Precautions (5.2)].. 2.4 Recommendations for Congestive Heart Failure. Starting Dosage in Patients with NYHA Class or II Congestive Heart FailureFor patients with preexisting NYHA Class or II congestive heart failure, the recommended starting dosage of pioglitazone and metformin hydrochloride tablets is 15 mg of pioglitazone and 850 mg of metformin [see Boxed Warning and Warnings and Precautions (5.1)].Monitoring for Fluid Retention and Dosage Modifications for Congestive Heart FailureAfter initiation of pioglitazone and metformin hydrochloride tablets or with dosage increase, monitor patients carefully for adverse reactions related to fluid retention as has been seen with pioglitazone (e.g., weight gain, edema and signs and symptoms of congestive heart failure).If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets [see Boxed Warning and Warnings and Precautions (5.1)] . 2.5 Coadministration with Strong CYP2C8 Inhibitors. The maximum recommended dosage of pioglitazone and metformin hydrochloride tablet is one tablet (15 mg of pioglitazone and 850 mg of metformin HCl) once daily when used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Drug Interactions (7.1), Clinical Pharmacology (12.3)] . 2.6 Discontinuation for Iodinated Contrast Imaging Procedures. Discontinue pioglitazone and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Tablets: 15 mg pioglitazone/500 mg metformin hydrochloride and 15 mg pioglitazone/850 mg metformin hydrochloride (3). 15 mg of pioglitazone and 500 mg of metformin HCl tablets, USP: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/500 on one side and 1280 on other side.o 15 mg of pioglitazone and 850 mg of metformin HCl tablets, USP: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/850 on one side and 1281 on other side.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong CYP2C8 inhibitors (e.g., gemfibrozil): Limit pioglitazone and metformin hydrochloride tablets dose to 15 mg/850 mg daily. (7.1)o CYP2C8 inducers (e.g., rifampin) may decrease pioglitazone concentrations. (7.2)o Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7.3)o Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine), may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. (7.4)o Alcohol: Warn patients against excessive alcohol intake. (7.5)o Use of insulin secretagogues or insulin use may increase the risk for hypoglycemia and may require dose reduction. (7.6)o Topiramate may decrease pioglitazone concentrations. (7.8). 7.1 Strong CYP2C8 Inhibitors. An inhibitor of CYP2C8 (e.g., gemfibrozil) significantly increases the exposure (area under the serum concentration-time curve or AUC) and half-life (t1/2) of pioglitazone. Therefore, the maximum recommended dosage of pioglitazone and metformin hydrochloride tablets is 15 mg of pioglitazone and 850 mg of metformin HCl once daily if used in combination with gemfibrozil or other strong CYP2C8 inhibitors [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].. 7.2 CYP2C8 Inducers. An inducer of CYP2C8 (e.g., rifampin) may significantly decrease the exposure (AUC) of pioglitazone. Therefore, if an inducer of CYP2C8 is started or stopped during treatment with pioglitazone and metformin hydrochloride tablets, changes in diabetes treatment may be needed based on clinical response without exceeding the maximum recommended daily dosage of pioglitazone and metformin hydrochloride tablets (45 mg of pioglitazone and 2,550 mg of metformin HCl) [see Clinical Pharmacology (12.3)].. 7.3 Carbonic Anhydrase Inhibitors. Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes 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 tablets.. 7.6 Insulin Secretagogues or Insulin. Coadministration of pioglitazone and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. If hypoglycemia occurs in patient coadministered pioglitazone and metformin hydrochloride and an insulin secretagogue (e.g., sulfonylurea), the dose of the insulin secretagogue should be reduced.. 7.7 Drugs Affecting Glycemic Control. Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from patient receiving pioglitazone and metformin hydrochloride tablets, the patient should be observed closely for hypoglycemia.. 7.8 Topiramate. decrease in the exposure of pioglitazone and its active metabolites were noted with concomitant administration of pioglitazone and topiramate [see Clinical Pharmacology (12.3)]. The clinical relevance of this decrease is unknown; however, when pioglitazone and metformin hydrochloride and topiramate are used concomitantly, monitor patients for adequate glycemic control.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone and metformin hydrochloride tablets, may result in ovulation in some anovulatory women.

GERIATRIC USE SECTION.

8.5 Geriatric Use. PioglitazoneA total of 92 patients (15.2%) treated with pioglitazone in the three pooled 16 to 26 weekdouble-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 pooled16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were>=65 years old and 19 (1.9%) were >=75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were >=65 years old and 22 (2.1%) were >=75 years old.In PROactive Trial, 1,068 patients (41.0%) 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 HClControlled 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), Dosage and Administration (2.2)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Pioglitazone and metformin hydrochloride tablets, USP are available in 15 mg pioglitazone (as the base)/500 mg metformin HCl and 15 mg pioglitazone (as the base)/850 mg metformin HCl tablets as follows:15 mg/500 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/500 on one side and 1280 on other side, available in:Bottles of 60 NDC 13668-280-60Bottles of 180 NDC 13668-280-33Bottles of 500 NDC 13668-280-05Bottles of 1000 NDC 13668-280-1015 mg/850 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/850 on one side and 1281 on other side, available in:Bottles of 60 NDC 13668-281-60Bottles of 180 NDC 13668-281-33Bottles of 500 NDC 13668-281-05Bottles of 750 NDC 13668-281-49StorageStore at 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86 F) [see USP Controlled Room Temperature]. Keep container tightly closed, and protect from moisture.. 15 mg/500 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/500 on one side and 1280 on other side, available in:. 15 mg/850 mg tablet: white to off-white colored, capsule shaped, biconvex, film coated tablets debossed with 15/850 on one side and 1281 on other side, available in:.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).o Congestive Heart Failure: Inform patients of the signs and symptoms of heart failure. Instruct patients who experience an unusually rapid increase in weight or edema, shortness of breath, or other symptoms of heart failure while on pioglitazone and metformin hydrochloride tablets to immediately report these symptoms to their healthcare provider. [see Warnings and Precautions (5.1)].o Lactic Acidosis: Explain 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 tablets immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur.Counsel patients against excessive alcohol intake and inform patients about the importance of regular testing of renal function while receiving pioglitazone and metformin hydrochloride tablets.Inform patients about the importance of regular testing of renal function and hematologic parameters when receiving treatment with pioglitazone and metformin hydrochloride tabletsInstruct patients to inform their doctor that they are taking pioglitazone and metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation of pioglitazone and metformin hydrochloride tablets may be required until renal function has been confirmed to be normal.o Edema: Inform patients that pioglitazone and metformin hydrochloride tablets use can lead to new-onset or worsening of edema. Instruct patients to immediately report symptoms of rapid weight increase or worsening edema to their healthcare provider [see Warnings and Precautions (5.3)].o Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Inform patients that the risk of hypoglycemia is increased when pioglitazone and metformin hydrochloride tablets is used with insulin or insulin secretagogues (such as sulfonylurea). Educate patients on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.4)].o Hepatic Effects: Instruct patients to promptly stop taking pioglitazone and metformin hydrochloride tablets and seek immediate medical advice if they experience signs or symptoms of liver injury (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine) [see Warnings and Precautions (5.5)].o Urinary Bladder Tumors: Advise patients to promptly report any hematuria, dysuria or urinary urgency that develops or increases during treatment as these may be due to bladder cancer [see Warnings and Precautions (5.6)].o Fractures: Inform female patients about the risk of fractures while taking pioglitazone and metformin hydrochloride tablets. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.7)].o Macular Edema: Educate patients on the signs and symptoms of macular edema and advise them to seek medical attention from an ophthalmologist if they experience symptoms of macular edema [see Warnings and Precautions (5.8)].o Vitamin B12 Levels: Inform patients about the importance of obtaining regular hematological laboratory monitoring while receiving pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions (5.9)].o Females of Reproductive Age: Inform female patients that treatment with pioglitazone and metformin hydrochloride tablets may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)] Missed Dosage: Instruct patients if dose is missed, not to double their next dose.Trademarks are the property of their respective owners.Dispense with Medication Guide available at: https://torrentpharma.com/pi/usa/products/ Manufactured by:Torrent Pharmaceuticals LTD., India.Manufactured for:Torrent Pharma INC., Basking Ridge, NJ 079208099813 Revised: March 2025. 3.

LACTATION SECTION.

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 tablets and any potential adverse effects on the breastfed infant from pioglitazone and metformin hydrochloride tablets 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Pioglitazone and metformin hydrochloride tablets combine two antihyperglycemic agents: pioglitazone and metformin.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 mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.Metformin HClMetformin HCl improves glucose tolerance in patients with type diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in either patients with type diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Pioglitazone and metformin hydrochloride tabletsNo animal studies have been conducted with pioglitazone and metformin hydrochloride. The following data are based on findings in studies performed with pioglitazone or metformin individually.PioglitazoneA two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder of male rats. Benign and/or malignant transitional cell neoplasms were observed in male rats at mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats. two year mechanistic study in male rats utilizing dietary acidification to reduce calculi formation was completed in 2009. Dietary acidification decreased but did not abolish the hyperplastic changes in the bladder. The presence of calculi exacerbated the hyperplastic response to pioglitazone but was not considered the primary cause of the hyperplastic changes.The relevance to humans of the bladder findings in the male rat cannot be excluded.A two year carcinogenicity study was also conducted in male and female mice at oral doses up to100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ.Pioglitazone HCl was not mutagenic in battery of genetic toxicology studies, including the Ames bacterial assay, mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m2).Metformin HClLong-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately four times human daily dose of 2000 mg of the metformin component of pioglitazone and metformin hydrochloride tablets based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with900 mg/kg/day.There was no evidence of mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose of the metformin component of pioglitazone and metformin hydrochloride tablets based on body surface area comparisons.. 13.2 Animal Toxicology and/or Pharmacology. Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately 11, one, and two times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In one year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in 13 week study in monkeys at oral doses of 8.9 mg/kg and above (approximately four times the maximum recommended human oral dose based on mg/m2), but not in 52 week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2).

OVERDOSAGE SECTION.

10 OVERDOSAGE. PioglitazoneDuring controlled clinical trials, one case of overdose with pioglitazone was reported. male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.Metformin HClOverdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.2)]. Metformin is dialyzable with clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated metformin from patients in whom metformin overdosage is suspected.In the event of overdosage, contact the Poison Help Line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations. Appropriate supportive treatment should be initiated according to the patients clinical signs and symptoms.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. Pioglitazone and Metformin Hydrochloride Tablets 15 mg 500 mgPioglitazone and Metformin Hydrochloride Tablets 15 mg 850 mg. 1. 2.

PEDIATRIC USE SECTION.

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)].

PHARMACODYNAMICS SECTION.

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 mellitus, 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 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 17). Adjusted for baseline, pooled center, and pooled center by treatment interaction+ < 0.05 vs placeboTable 17:Lipids in 26 Week Placebo-Controlled Monotherapy Dose-Ranging StudyPlaceboPioglitazone 15 mg Once DailyPioglitazone 30 mg Once DailyPioglitazone 45 mg Once DailyTriglycerides (mg/dL)N=79N=79N=84N=77Baseline (mean)263284261260Percent change from baseline (adjusted mean)4.8%-9.0% -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%6.0%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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionPioglitazone and metformin hydrochloride tabletsIn bioequivalence studies of pioglitazone and metformin hydrochloride tablets 15 mg/500 mg and15 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 ACTOS 15 mg concomitantly administered with metformin HCl immediate release (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.Administration of pioglitazone and metformin hydrochloride tablets 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 mellitus, 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 HClThe 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 1,500 mg, and 850 mg to 2,550 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 HClThe 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.EliminationMetabolismPioglitazonePioglitazone 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), Drug Interactions (7.1)]. Urinary6-ss-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not strong CYP3A4 enzyme inducer.Metformin HClIntravenous 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.ExcretionPioglitazoneFollowing oral administration, approximately 15 to 30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.The mean serum half-life (t1/2) of pioglitazone and its metabolites (M-III and M-IV) range from three to seven hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be five to seven L/hr.Metformin HClRenal clearance is approximately 3.5 times greater than creatinine clearance (CrCl), 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 t1/2 of approximately 6.2 hours. In blood, the elimination t1/2 is approximately17.6 hours, suggesting that the erythrocyte mass may be compartment of distribution.Specific PopulationsGeriatric 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 are not considered clinically relevant.Metformin HClLimited 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.Pediatric PatientsPioglitazoneSafety 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 HClAfter 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.Male and Female PatientsPioglitazoneThe mean Cmax and AUC values of pioglitazone were increased 20 to 60% in females compared to males. 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 dosage adjustment is recommended based on gender alone.Metformin HClMetformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.Racial or Ethnic GroupsPioglitazonePharmacokinetic data among various ethnic groups are not available.Metformin HClNo studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Blacks or African Americans (n=51), and Hispanics or Latinos (n=24).Patients with Renal ImpairmentPioglitazoneThe serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CrCl 30 to 50 mL/min) and severe (CrCl <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore, no dosage adjustment in patients with renal impairment is required.Metformin HClIn 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 (2.3), Contraindications (4), Warnings and Precautions (5.2)].Patients with 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 dosage 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 tablets with caution in patients with liver disease [see Warnings and Precautions (5.5)].Metformin HClNo pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment [see Warnings and Precautions (5.5)].Drug Interaction StudiesSpecific pharmacokinetic drug interaction studies with pioglitazone and metformin hydrochloride tablets have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.Pioglitazone Daily for days unless otherwise noted+% change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectivelyPioglitazone had no clinically significant effect on prothrombin timeTable 18:Effect of Pioglitazone Coadministration on Systemic Exposure of Other DrugsCoadministered DrugPioglitazone Dosage Regimen (mg)Name and Dose RegimensChange in AUC+Change in m x +45 mg (N 12)WarfarinDaily loading then maintenance doses based PT and INR values Quicks 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 plusEE11%EE13%Norethindrone (NE) mg] for 21 daysNE3%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 Calcium80 mg daily for days14%23%45 mg (N 22)Theophylline400 mg twice daily for days2%5%Daily for days unless otherwise noted +Mean ratio (with/without coadministered drug and no change 1-fold) change (with/without coadministered drug and no change 0%); symbols of and indicate the exposure increase and decrease, respectively The half-life of pioglitazone increased from 8.3 hours to 22.7 hours in the presence of gemfibrozil [see Dosage and Administration (2.3) and Drug Interactions (7.1)]Indicates duration of concomitant administration with highest twice-daily dose of topiramate from Day 14 onwards over the 22 days of studyAdditional decrease in active metabolites; 60% for M-III and 16% for M-IV Table 19: Effect of Coadministered Drugs on Pioglitazone Systemic Exposure Coadministered Drug and Dosage Regimen Pioglitazone Dose Regimen (mg) Change in AUC Change in max +Gemfibrozil 600 mg twice daily for days (N 12)15-mg single dose3.2-fold6%Ketoconazole 200 mg twice daily for days (N 28)45 mg34%14%Rifampin 600 mg daily for5 days (N 10)30-mg single dose54%5%Fexofenadine 60 mg twice daily for days (N 23)45 mg1%0%Ranitidine 150 mg twice daily for days (N 23)45 mg13%16%Nifedipine ER 30 mg daily for days (N 23)45 mg5%4%Atorvastatin Calcium 80 mg daily for days (N 24)45 mg24%31%Theophylline 400 mg twice daily for days (N 22)45 mg4%2%Topiramate 96 mg twice daily for days (N 26)30 mg 15% 0%Metformin HClAll metformin and coadministered drugs were given as single doses+AUC AUC to Ratio of arithmetic meansMetformin HCl extended-release tablets, 500 mgAt steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC AUC to 12h Table 20: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.00 AUC Cmax No dosing adjustments required for the following:Glyburide 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: use with caution [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 AUC to Ratio of arithmetic means, p-value of difference <0.05AUC to 24hr reportedRatio of arithmetic means Table 21: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug Dose of Metformin Geometric Mean Ratio (ratio with/without coadministered drug) No effect 1.00 AUC C maxNo 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 mg0.951.01.

PREGNANCY SECTION.

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 and 35 times the45 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 to times, respectively, 2,000 mg clinical dose, based on body surface area (see Data).The estimated background risk of major birth defects is to 10% in women with pregestational 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 US 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 ConsiderationsDisease-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.DataHuman DataPublished data from postmarketing 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 DataPioglitazone and Metformin HClAnimal reproduction studies were not conducted with the combined products in pioglitazone and metformin hydrochloride tablets. The following data are based on studies conducted with the individual components of pioglitazone and metformin hydrochloride tablets.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 embryo-fetal viability at 40 and 80 mg/kg, or >=9 times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryo-fetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or >=2 times the 45 mg clinical dose, by body surface area.Metformin HClMetformin HCl 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 to times 2,000 mg clinical dose based on body surface area (mg/m2) for rats and rabbits, respectively.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Dosage and AdministrationImportant Dosage and Administration Information (2.1).............06/2024Recommended Dosage and Administration (2.2).....................06/2024Recommendations for Use in Patients with Renal Impairment (2.3)......... 06/2024Recommendations for Congestive Heart Failure (2.4)...............06/2024Coadministration with Strong CYP2C8 Inhibitors (2.5)..................06/2024.

SPL MEDGUIDE SECTION.

Dispense with Medication Guide available at: https://torrentpharma.com/pi/usa/products/ MEDICATION GUIDEPIOGLITAZONE AND METFORMIN HYDROCHLORIDE (PYE GLI ta zone and met FOR min HYE-droe-KLOR-ide) TABLETS, USPRead 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 healthcare provider about your medical condition or your treatment. If you have any questions about pioglitazone and metformin hydrochloride tablets, ask your healthcare provider or pharmacist.What is the most important information should know aboutpioglitazone and metformin hydrochloride tablets Pioglitazone and metformin hydrochloride tablets can cause serious side effects, including: 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.Before you start taking pioglitazone and metformin hydrochloride tablets:Tell your healthcare provider if you have ever had heart failure or have problems with your kidneysCall your healthcare provider right away if you have any of the following: increasing shortness of breath or trouble breathing, especially when you lie downan unusually fast increase in weightswelling or fluid retention, especially in the ankles or legsunusual tirednessThese may be symptoms of heart failure.Lactic 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.Stop taking pioglitazone and metformin hydrochloride tablets and call your healthcare provider right away if you have any of the following symptoms, which could be signs of lactic acidosis:feel very weak or tiredhave unusual (not normal) muscle painhave trouble breathinghave unusual sleepiness or sleep longer than usualhave unexplained stomach or intestinal problems with nausea, vomiting, or diarrheafeel cold, especially in your arms and legsfeel dizzy or lightheadedhave slow or irregular heartbeatMost people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have higher chance for getting lactic acidosis with pioglitazone and metformin hydrochloride tablets if you:have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.have liver problemsdrink alcohol very often, or drink lot of alcohol in short-term (binge drinking)get 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 fluidshave surgeryhave heart attack, severe infection, or strokeare 65 years of age or olderThe best way to keep from having problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider 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 arepioglitazone and metformin hydrochloride tablets Pioglitazone and metformin hydrochloride tablets are prescription medicine that contains diabetes medicines, pioglitazone (ACTOS) and metformin hydrochloride (GLUCOPHAGE). Pioglitazone and metformin hydrochloride tablets are used along 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 takepioglitazone and metformin hydrochloride tabletsSee What is the most important information should know about pioglitazone and metformin hydrochloride tablets.Do not take pioglitazone and metformin hydrochloride tablets if you:have severe heart failurehave severe kidney problemshave condition called acute or chronic metabolic acidosis, including diabetic ketoacidosis.are allergic to pioglitazone, metformin, or any of the ingredients in pioglitazone and metformin hydrochloride tablets or have had serious allergic (hypersensitivity) reaction to pioglitazone or metformin. See the end of this Medication Guide for complete list of ingredients in pioglitazone and metformin hydrochloride tablets. Symptoms of serious allergic reaction to pioglitazone and metformin hydrochloride tablets may include:o swelling of your face, lips, throat and other areas on difficulty with swallowing or your skin breathingo raised, red areas on your skin (hives) skin rash, itching, flaking or peelingIf you have these symptoms, stop taking pioglitazone and metformin hydrochloride tablets and contact your healthcare provider or go to the nearest hospital emergency room right away.Tell your healthcare provider before taking pioglitazone and metformin hydrochloride tablets if you have any of these conditions.What should tell my healthcare provider before takingpioglitazone and metformin hydrochloride tablets Before you take pioglitazone and metformin hydrochloride tablets, tell your healthcare provider if you:have heart failurehave kidney or liver problemsare going to have dye injected into vein for an x-ray, CAT scan, heart study, or other type of scanningwill be undergoing surgical proceduredrink lot of alcohol (all the time or short binge drinking)have type (juvenile) diabetes or had diabetic ketoacidosishave type of diabetic eye disease that causes swelling in the back of the eye (macular edema)have low levels of vitamin B12 in your bloodhave or have had cancer of the bladderare pregnant or plan to become pregnant. It is not known if pioglitazone and metformin hydrochloride tablets can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnantare woman who has not gone through menopause (premenopausal), who does not have periods regularly or at all. Pioglitazone and metformin hydrochloride tablets may increase your chance of becoming pregnant. Talk to your healthcare provider about birth control choices while taking pioglitazone and metformin hydrochloride tablets. Tell your healthcare provider right away if you become pregnant while taking pioglitazone and metformin hydrochloride tabletsare 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 healthcare provider about the best way to control your blood glucose levels while breastfeeding Tell your healthcare provider about all the medicines you take, including prescription and over the counter medicines, vitamins, and herbal supplements.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider 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.Pioglitazone and metformin hydrochloride tablets may affect the way other medicines work, and other medicines may affect how pioglitazone and metformin hydrochloride tablets work. Contact your healthcare provider before you start or stop other types of medicines.How should takepioglitazone and metformin hydrochloride tablets Take pioglitazone and metformin hydrochloride tablets exactly as your healthcare provider tells you to take itYour healthcare provider may need to change your dose of pioglitazone and metformin hydrochloride tablets. Do not change your pioglitazone and metformin hydrochloride tablets dose unless your healthcare provider tells you toTake pioglitazone and metformin hydrochloride tablets with meals to lower your chance of an upset stomachIf you miss dose of pioglitazone and metformin hydrochloride tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take two doses at one time the next dayIf you take too much pioglitazone and metformin hydrochloride tablets, call your healthcare provider or go to the nearest hospital emergency room right awayIf 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 healthcare provider right awayStay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone and metformin hydrochloride tabletsYour healthcare provider should do certain blood tests before you start and while you take pioglitazone and metformin hydrochloride tabletsYour healthcare provider should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone and metformin hydrochloride tabletsYour healthcare provider 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: See What is the most important information should know about pioglitazone and metformin hydrochloride tabletsLow blood sugar (hypoglycemia). If you take pioglitazone and metformin hydrochloride tablets withanother medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take pioglitazone and metformin hydrochloride tablets. Signs and symptoms of low blood sugar may include: shaking or feeling jitteryo change in visiono change in moodo sweatingo hungero confusion fast heartbeato headacheo dizzinessLiver problems. Call your healthcare provider right away or go to the nearest hospital emergency room if you have unexplained symptoms such as:o nausea or vomitingo stomach paino unusual or unexplained tirednesso loss of appetiteo dark urineo yellowing of your skin or the whites of your eyesBladder tumors. There may be an increased chance of having bladder cancer when you take pioglitazone and metformin hydrochloride tablets. You should not take pioglitazone and metformin hydrochloride tablets if you are receiving treatment for bladder cancer. Tell your healthcare provider right away if you have any of the following symptoms of bladder cancer: blood or red color in your urine an increased need to urinate pain while you urinateBroken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your healthcare provider for advice on how to keep your bones healthyDiabetic eye disease with swelling in the back of the eye (macular edema). Tell your healthcare provider right away if you have any changes in your vision. Your healthcare provider should check your eyes regularlyRelease 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.Low vitamin B12 (vitamin B12 deficiency). Using metformin, one of the medicines in pioglitazone and metformin hydrochloride tablets for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels. The most common side effects of pioglitazone and metformin hydrochloride tablets include:cold-like symptoms (upper respiratory tract infection)swelling (edema)diarrheaheadacheincreased weightTell your healthcare provider 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 healthcare provider 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 storepioglitazone and metformin hydrochloride tablets Store pioglitazone and metformin hydrochloride tablets at 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86 F) [see USP Controlled Room Temperature].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 dry.Keep 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.You can ask your healthcare provider or pharmacist for information about pioglitazone and metformin hydrochloride tablets that is written for health professionals.What are the ingredients inpioglitazone and metformin hydrochloride tablets Active Ingredients: pioglitazone hydrochloride, USP and metformin hydrochloride, USPInactive Ingredients: croscarmellose sodium, hypromellose, magnesium stearate, microcrystallinecellulose, polyethylene glycol, povidone, talc, and titanium dioxideTrademarks are the property of their respective owners.For more information, call 1-800-912-9561. Manufactured by:Torrent Pharmaceuticals LTD., India.Manufactured for: Torrent Pharma INC., Basking Ridge, NJ079208099814 Revised: March 2025This Medication Guide has been approved by the U.S. Food and Drug Administration.. 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.. increasing shortness of breath or trouble breathing, especially when you lie down. an unusually fast increase in weight. swelling or fluid retention, especially in the ankles or legs. unusual tiredness. Lactic 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.. feel very weak or tired. have unusual (not normal) muscle pain. have trouble breathing. have unusual sleepiness or sleep longer than usual. have unexplained stomach or intestinal problems with nausea, vomiting, or diarrhea. feel cold, especially in your arms and legs. feel dizzy or lightheaded. have slow or irregular heartbeat. have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye.. have liver problems. drink alcohol very often, or drink lot of alcohol in short-term (binge drinking). get 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. have surgery. have heart attack, severe infection, or stroke. are 65 years of age or older. have severe heart failure. have severe kidney problems. have condition called acute or chronic metabolic acidosis, including diabetic ketoacidosis.. are allergic to pioglitazone, metformin, or any of the ingredients in pioglitazone and metformin hydrochloride tablets or have had serious allergic (hypersensitivity) reaction to pioglitazone or metformin. See the end of this Medication Guide for complete list of ingredients in pioglitazone and metformin hydrochloride tablets. Symptoms of serious allergic reaction to pioglitazone and metformin hydrochloride tablets may include:. If you have these symptoms, stop taking pioglitazone and metformin hydrochloride tablets and contact your healthcare provider or go to the nearest hospital emergency room right away.. have heart failure. have kidney or liver problems. will be undergoing surgical procedure. drink lot of alcohol (all the time or short binge drinking). have type (juvenile) diabetes or had diabetic ketoacidosis. have type of diabetic eye disease that causes swelling in the back of the eye (macular edema). have low levels of vitamin B12 in your blood. have or have had cancer of the bladderare pregnant or plan to become pregnant. It is not known if pioglitazone and metformin hydrochloride tablets can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnantare woman who has not gone through menopause (premenopausal), who does not have periods regularly or at all. Pioglitazone and metformin hydrochloride tablets may increase your chance of becoming pregnant. Talk to your healthcare provider about birth control choices while taking pioglitazone and metformin hydrochloride tablets. Tell your healthcare provider right away if you become pregnant while taking pioglitazone and metformin hydrochloride tabletsare 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 healthcare provider about the best way to control your blood glucose levels while breastfeeding are pregnant or plan to become pregnant. It is not known if pioglitazone and metformin hydrochloride tablets can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant about the best way to control your blood glucose levels while pregnant. are woman who has not gone through menopause (premenopausal), who does not have periods regularly or at all. Pioglitazone and metformin hydrochloride tablets may increase your chance of becoming pregnant. Talk to your healthcare provider about birth control choices while taking pioglitazone and metformin hydrochloride tablets. Tell your healthcare provider right away if you become pregnant while taking pioglitazone and metformin hydrochloride tablets. are 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 healthcare provider about the best way to control your blood glucose levels while breastfeeding. Take pioglitazone and metformin hydrochloride tablets exactly as your healthcare provider tells you to take it. Your healthcare provider may need to change your dose of pioglitazone and metformin hydrochloride tablets. Do not change your pioglitazone and metformin hydrochloride tablets dose unless your healthcare provider tells you to. Take pioglitazone and metformin hydrochloride tablets with meals to lower your chance of an upset stomach. If you miss dose of pioglitazone and metformin hydrochloride tablets, take your next dose as prescribed unless your healthcare provider tells you differently. Do not take two doses at one time the next day. If you take too much pioglitazone and metformin hydrochloride tablets, call your healthcare provider or go to the nearest hospital emergency room right away. If 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 healthcare provider right away. Stay on your diet and exercise programs and test your blood sugar regularly while taking pioglitazone and metformin hydrochloride tablets. Your healthcare provider should do certain blood tests before you start and while you take pioglitazone and metformin hydrochloride tablets. Your healthcare provider should also do hemoglobin A1C testing to check how well your blood sugar is controlled with pioglitazone and metformin hydrochloride tablets. Your healthcare provider should check your eyes regularly while you take pioglitazone and metformin hydrochloride tablets. See What is the most important information should know about pioglitazone and metformin hydrochloride tablets. Low blood sugar (hypoglycemia). If you take pioglitazone and metformin hydrochloride tablets withanother medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take pioglitazone and metformin hydrochloride tablets. Signs and symptoms of low blood sugar may include: Liver problems. Call your healthcare provider right away or go to the nearest hospital emergency room if you have unexplained symptoms such as:. Bladder tumors. There may be an increased chance of having bladder cancer when you take pioglitazone and metformin hydrochloride tablets. You should not take pioglitazone and metformin hydrochloride tablets if you are receiving treatment for bladder cancer. Tell your healthcare provider right away if you have any of the following symptoms of bladder cancer:. Broken bones (fractures). Usually in the hand, upper arm, or foot in women. Talk to your healthcare provider for advice on how to keep your bones healthy. Diabetic eye disease with swelling in the back of the eye (macular edema). Tell your healthcare provider right away if you have any changes in your vision. Your healthcare provider should check your eyes regularly. Release 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.. Low vitamin B12 (vitamin B12 deficiency). Using metformin, one of the medicines in pioglitazone and metformin hydrochloride tablets for long periods of time may cause decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels. The most common side effects of pioglitazone and metformin hydrochloride tablets include:. cold-like symptoms (upper respiratory tract infection). swelling (edema). diarrhea. headache. increased weight. Store pioglitazone and metformin hydrochloride tablets at 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86 F) [see USP Controlled Room Temperature].. 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 dry.. 4.

SPL UNCLASSIFIED SECTION.

WARNING: CONGESTIVE HEART FAILURE AND LACTIC ACIDOSIS. Congestive Heart Failureo Thiazolidinediones, including pioglitazone, which is component of pioglitazone and metformin hydrochloride tablets, cause or exacerbate congestive heart failure in some patients [see Warnings and Precautions (5.1)].o After initiation of pioglitazone and metformin hydrochloride tablets, 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 congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride tablets [see Warnings and Precautions (5.1)].o Pioglitazone and metformin hydrochloride tablets are not recommended in patients with symptomatic heart failure [see Warnings and Precautions (5.1)].o Initiation of pioglitazone and metformin hydrochloride tablets in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated [see Contraindications (4), Warnings and Precautions (5.1)].Lactic Acidosiso Postmarketing 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 than5 mcg/mL [see Warnings and Precautions (5.2)].o Risk 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.o Steps 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), Use in Specific Populations (8.6, 8.7)].o If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone and metformin hydrochloride tablets and institute general supportive measures in hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)o Pediatrics: Safety and effectiveness have not been established. (8.4)o Geriatric Use: Assess renal function more frequently. (8.5)o Hepatic 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 and 35 times the45 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 to times, respectively, 2,000 mg clinical dose, based on body surface area (see Data).The estimated background risk of major birth defects is to 10% in women with pregestational 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 US 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 ConsiderationsDisease-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.DataHuman DataPublished data from postmarketing 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 DataPioglitazone and Metformin HClAnimal reproduction studies were not conducted with the combined products in pioglitazone and metformin hydrochloride tablets. The following data are based on studies conducted with the individual components of pioglitazone and metformin hydrochloride tablets.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 embryo-fetal viability at 40 and 80 mg/kg, or >=9 times the 45 mg clinical dose, by body surface area. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg (~35 times the 45 mg clinical dose), but reduced embryo-fetal viability at 160 mg/kg, or ~69 times the 45 mg clinical dose, by body surface area. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above or >=2 times the 45 mg clinical dose, by body surface area.Metformin HClMetformin HCl 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 to times 2,000 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 tablets and any potential adverse effects on the breastfed infant from pioglitazone and metformin hydrochloride tablets 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 tablets, 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 weekdouble-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 pooled16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were>=65 years old and 19 (1.9%) were >=75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were >=65 years old and 22 (2.1%) were >=75 years old.In PROactive Trial, 1,068 patients (41.0%) 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 HClControlled 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), 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 tablets are contraindicated in severe renal impairment, which includes patients with an eGFR below 30 mL/min[see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.2), 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 tablets are not recommended in patients with hepatic impairment [see Warnings and Precautions (5.2)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Congestive heart failure: Fluid retention may occur and can exacerbate or lead to congestive heart failure. Combination use with insulin and use in congestive heart failure NYHA Class and II may increase risk. Monitor patients for signs and symptoms. (5.1)o Edema: Dose-related edema may occur. (5.3)o Hypoglycemia: Consider lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with pioglitazone and metformin hydrochloride tablets. (5.4)o Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt pioglitazone and metformin hydrochloride tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart pioglitazone and metformin hydrochloride tablets if liver injury is confirmed and no alternate etiology can be found. (5.5)o Urinary Bladder Tumors: May increase the risk of bladder cancer. Do not use in patients with active bladder cancer. Use caution when using in patients with prior history of bladder cancer. (5.6)o Fractures: Increased incidence in female patients. Apply current standards of care for assessing and maintaining bone health. (5.7)o Macular edema: Postmarketing reports. Recommend regular eye exams in all patients with diabetes according to current standards of care with prompt evaluation for acute visual changes. (5.8)o Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually and vitamin B12 at to year intervals and manage any abnormalities. (5.9). 5.1 Congestive Heart Failure. Pioglitazone, like other thiazolidinediones, can cause dose-related fluid retention when used alone or in combination with other antidiabetic medications and is most common when pioglitazone is used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Observe patients for signs and symptoms of congestive heart failure. If congestive heart failure develops while taking pioglitazone and metformin hydrochloride tablets, consider discontinuation of pioglitazone and metformin hydrochloride tablets or dosage reduction of pioglitazone in pioglitazone and metformin hydrochloride [see Boxed Warning, Contraindications (4), Adverse Reactions (6.1)].. 5.2 Lactic Acidosis. Lactic AcidosisThere have been postmarketing 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), an increased lactate:pyruvate ratio, and 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 tablets. In pioglitazone and metformin hydrochloride tablets-treated patients with diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl 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 tablets 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 (2.3), Clinical Pharmacology (12.3)].o Before initiating pioglitazone and metformin hydrochloride tablets, obtain an eGFR.o Pioglitazone and metformin hydrochloride tablets are contraindicated in patients with an eGFR less than 30 mL/min. Initiation of pioglitazone and metformin hydrochloride tablets is not recommended in patients with eGFR between 30 to 45 mL/min [see Contraindications (4)].o Obtain an eGFR at least annually in all patients taking pioglitazone and metformin hydrochloride tablets. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.o In patients taking pioglitazone and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min, 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 tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min; in patients with history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.Re-evaluate eGFR 48 hours after the imaging procedure, and restart pioglitazone and metformin hydrochloride tablets if renal function is stable.Surgery and Other 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 tablets 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 tablets.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 tablets.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 tablets 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)].. 5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues. Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with pioglitazone and metformin hydrochloride [see Drug Interactions (7.6, 7.7)].. 5.5 Hepatic Effects. There have been postmarketing reports of fatal and non-fatal 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 mellitus 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 clinically significant liver enzyme elevations (serum ALT greater than three times the ULN) and if abnormal liver tests persist or worsen, pioglitazone and metformin hydrochloride 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.. 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 2,605 (0.54%) randomized to pioglitazone and out of 2,633 (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 (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 [Hazard Ratio (HR) 1.00; (95% Confidence Interval (Cl): 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 prospective 10 year observational cohort study conducted in the United States (U.S) 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% Cl: 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% Cl: 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 tablets 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 tablets should be considered in patients with prior history of bladder cancer.. 5.7 Fractures. In PROactive (the Prospective Pioglitazone Clinical Trial in Macrovascular Events), 5,238 patients with type diabetes mellitus and history of macrovascular disease were randomized to pioglitazone (N=2,605), force-titrated up to 45 mg daily or placebo (N=2,633) 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 metformin clinical trials of 29-week duration, decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at to year intervals in patients on pioglitazone and metformin hydrochloride and manage any abnormalities [see Adverse Reactions (6.1)].