1 INDICATIONS & USAGE Pioglitazone and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Limitations of Use Pioglitazone and metformin hydrochloride tablets is not recommended to treat type 1 diabetes mellitus or diabetic ketoacidosis.

Pioglitazone and metformin hydrochloride tablets are a thiazolidinedione and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate.

( 1 , 14 ) Limitations of Use : • Not for treatment of type 1 diabetes or diabetic ketoacidosis.

( 1 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Congestive heart failure [see Boxed Warning, and Warnings and Precautions ( 5.1 )] • Lactic acidosis [see Boxed Warning and Warnings, and Precautions ( 5.2 )] • Edema [see Warnings and Precautions ( 5.3 )] • Fractures [see Warnings and Precautions ( 5.7 )] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] • Hepatic Effects [see Warnings and Precautions ( 5.5 )] • Urinary Bladder Tumors [see Warnings and Precautions ( 5.6 )] • Fractures [see Warnings and Precautions ( 5.7 )] • Macular Edema [see Warnings and Precautions ( 5.8 ] • Vitamin B 12 Levels [see Warnings and Precautions ( 5.9 ] Most common adverse reactions (>5%) are upper respiratory tract infection, edema, diarrhea, headache and weight gain.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc.

at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Pioglitazone Over 8500 patients with type 2 diabetes mellitus have been treated with pioglitazone in randomized, double-blind, controlled clinical trials, including 2605 patients with type 2 diabetes mellitus and macrovascular disease treated with pioglitazone from the PROactive clinical trial.

In these trials, over 6000 patients have been treated with pioglitazone for six months or longer, over 4500 patients have been treated with pioglitazone for one year or longer, and over 3000 patients have been treated with pioglitazone for at least two years.

In six pooled 16- to 26-week placebo-controlled monotherapy and 16- to 24-week add-on combination therapy trials, the incidence of withdrawals due to adverse events was 4.5% for patients treated with pioglitazone and 5.8% for comparator-treated patients.

The most common adverse events leading to withdrawal were related to inadequate glycemic control, although the incidence of these events was lower (1.5%) with pioglitazone than with placebo (3.0%).

In the PROactive trial, the incidence of withdrawals due to adverse events was 9.0% for patients treated with pioglitazone and 7.7% for placebo-treated patients.

Congestive heart failure was the most common serious adverse event leading to withdrawal occurring in 1.3% of patients treated with pioglitazone and 0.6% of patients treated with placebo.

Common Adverse Events: 16- to 26-Week Monotherapy Trials A summary of the incidence and type of common adverse events reported in three pooled 16- to 26-week placebo-controlled monotherapy trials of pioglitazone is provided in Table 1.

Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

None of these adverse events were related to the pioglitazone dose.

Table 2.

Three Pooled 16- to 26-Week Placebo-Controlled Clinical Trials of Pioglitazone Monotherapy: Adverse Events Reported at an Incidence > 5% and More Commonly in Patients Treated with Pioglitazone than in Patients Treated with Placebo % of Patients Placebo N=259 Pioglitazone N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Pharyngitis 0.8 5.1 Common Adverse Events: 16- to 24-Week Add-on Combination Therapy Trials A summary of the overall incidence and types of common adverse events reported in trials of pioglitazone add-on to metformin is provided in Table 3.

Terms that are reported represent those that occurred at an incidence of >5% and more commonly with the highest tested dose of pioglitazone.

Table 3.

16- to 24-Week Clinical Trials of Pioglitazone Add-on to Metformin 16-Week Placebo-Controlled Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone + Metformin than in Patients Treated with Placebo + Metformin % of Patients Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Edema 2.5 6.0 Headache 1.9 6.0 24-Week Non-Controlled Double-Blind Trial Adverse Events Reported in > 5% of Patients and More Commonly in Patients Treated with Pioglitazone 45 mg + Metformin than in Patients Treated with Pioglitazone 30 mg + Metformin % of Patients Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 Upper Respiratory Tract Infection 12.4 13.5 Edema 5.8 13.9 Headache 5.4 5.8 Weight Increased 2.9 6.7 Note: The preferred terms of edema peripheral, generalized edema, pitting edema and fluid retention were combined to form the aggregate term of “edema.” Common Adverse Events: 24-Week pioglitazone and metformin hydrochloride Clinical Trial Table 4 summarizes the incidence and types of adverse reactions reported in a controlled, 24-week double-blind clinical trial of pioglitazone and metformin hydrochloride dosed twice daily in patients with inadequate glycemic control on diet and exercise (N=600).

Table 4.

Adverse Events (≥5% for pioglitazone and metformin hydrochloride) Reported by Patients with Inadequate Glycemic Control on Diet and Exercisein a 24-Week Double-Blind Clinical Trial of Pioglitazone and Metformin Hydrochloride Administered Twice Daily % of Patients P ioglitazone and Metformin Hydrochloride 15/850 mg Twice Daily N=201 Pioglitazone 15 mg Twice Daily N=190 Metformin 850 mg Twice Daily N=209 Diarrhea 9.0 2.6 15.3 Headache 5.5 2.6 4.8 In this 24-week trial, abdominal pain was reported in 2.0% of patients in the pioglitazone and metformin hydrochloride group, 1.6% in the pioglitazone monotherapy group and 3.3% in the metformin monotherapy group.

Common Adverse Events: PROactive Trial A summary of the overall incidence and types of common adverse events reported in the PROactive trial is provided in Table 5.

Terms that are reported represent those that occurred at an incidence of >5% and more commonly in patients treated with pioglitazone than in patients who received placebo.

Table 5.

PROactive Trial: Incidence and Types of Adverse Events Reported in >5% of Patients Treated with Pioglitazone and More Commonly than Placebo % of Patients Placebo N=2633 Pioglitazone N=2605 Hypoglycemia 18.8 27.3 Edema 15.3 26.7 Cardiac Failure 6.1 8.1 Pain in Extremity 5.7 6.4 Back Pain 5.1 5.5 Chest Pain 5.0 5.1 Mean duration of patient follow-up was 34.5 months.

Congestive Heart Failure A summary of the incidence of adverse events related to congestive heart failure is provided in Table 6 for the 16- to 24-week add-on to metformin trials.

None of the events were fatal.

Table 6.

Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 7.

Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF) Patients Treated with Pioglitazone or Placebo Added on to a Sulfonylurea Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Sulfonylurea N=187 Pioglitazone 15 mg + Sulfonylurea N=184 Pioglitazone 30 mg + Sulfonylurea N=189 Pioglitazone 30 mg + Sulfonylurea N=351 Pioglitazone 45 mg + Sulfonylurea N=351 At least one congestive heart failure event 2 (1.1%) 0 0 1 (0.3%) 6 (1.7%) Hospitalized 2 (1.1%) 0 0 0 2 (0.6%) Patients Treated with Pioglitazone or Placebo Added on to Insulin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Insulin N=187 Pioglitazone 15 mg + Insulin N=191 Pioglitazone 30 mg + Insulin N=188 Pioglitazone 30 mg + Insulin N=345 Pioglitazone 45 mg + Insulin N=345 At least one congestive heart failure event 0 2 (1.0%) 2 (1.1%) 3 (0.9%) 5 (1.4%) Hospitalized 0 2 (1.0%) 1 (0.5%) 1 (0.3%) 3 (0.9%) Patients Treated with Pioglitazone or Placebo Added on to Metformin Number (%) of Patients Placebo-Controlled Trial (16 weeks) Non-Controlled Double-Blind Trial (24 weeks) Placebo + Metformin N=160 Pioglitazone 30 mg + Metformin N=168 Pioglitazone 30 mg + Metformin N=411 Pioglitazone 45 mg + Metformin N=416 At least one congestive heart failure event 0 1 (0.6%) 0 1 (0.2%) Hospitalized 0 1 (0.6%) 0 1 (0.2%) Table 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 Glyburide Number (%) of Subjects Pioglitazone N=262 Glyburide N=256 Death 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 study 35 (13.4%) 21 (8.2%) Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 8.

Table 9.

Treatment –Emergent Adverse Events of Congestive Heart Failure (CHF) in PROactive Trial Number (%) of Patients Placebo N=2633 Pioglitazone N=2605 At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%) Fatal 22 (0.8%) 25 (1.0%) Hospitalized, nonfatal 86 (3.3%) 124 (4.7%) Cardiovascular Safety In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care.

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 a 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 2 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 a cardiovascular composite endpoint that included all-cause mortality, non-fatal 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.

A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (HR 0.90; 95% CI: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a 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 Endpoint Cardiovascular Events Placebo N=2633 Pioglitazone N=2605 First Events n (%) Total events n First Events n (%) Total events n Any event 572 (21.7) 900 514 (19.7) 803 All-cause mortality 122 (4.6) 186 110 (4.2) 177 Nonfatal myocardial infarction (MI) 118 (4.5) 157 105 (4.0) 131 Stroke 96 (3.6) 119 76 (2.9) 92 Acute coronary syndrome 63 (2.4) 78 42 (1.6) 65 Cardiac intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195 Major leg amputation 15 (0.6) 28 9 (0.3) 28 Leg revascularization 57 (2.2) 92 71 (2.7) 115 CABG = coronary artery bypass grafting; PCI = percutaneous intervention Weight Gain Dose-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 a combination of fluid retention and fat accumulation.

Tables 10, 11, and 12 summarize the changes in body weight with pioglitazone and placebo in the 16- to 26-week randomized, double-blind monotherapy and 16- to 24-week combination add-on therapy trials, the PROactive trial, and the 24-week pioglitazone and metformin hydrochloride trial.

Table 11.

Weight Changes (kg) from Baseline During Randomized, Double-Blind Clinical Trials Control Group (Placebo) Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Monotherapy (16 to 26 weeks) -1.4 (-2.7, 0.0) N=256 0.9 (-0.5, 3.4) N=79 1.0 (-0.9, 3.4) N=188 2.6 (0.2, 5.4) N=79 Combination Therapy (16 to 24 weeks) Sulfonylurea -0.5 (-1.8, 0.7) N=187 2.0 (0.2, 3.2) N=183 3.1 (1.1, 5.4) N=528 4.1 (1.8, 7.3) N=333 Metformin -1.4 (-3.2, 0.3) N=160 N/A 0.9 (-1.3, 3.2) N=567 1.8 (-0.9, 5.0) N=407 Insulin 0.2 (-1.4, 1.4) N=182 2.3 (0.5, 4.3) N=190 3.3 (0.9, 6.3) N=522 4.1 (1.4, 6.8) N=338 Table 12.

Median Change in Body Weight in Patients Treated with Pioglitazone Versus Patients Treated with Placebo During the Double-Blind Treatment Period in the PROactive Trial Placebo Pioglitazone Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Change from baseline to final visit (kg) -0.5 (-3.3, 2.0) N=2581 +3.6 (0.0, 7.5) N=2560 Note: Median exposure for both pioglitazone and placebo was 2.7 years.

Table 13.

Weight Changes (kg) from Baseline During Double-Blind Clinical Trial with P ioglitazone and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Diet and Exercise P ioglitazone and Metformin Hydrochloride 15/850 mg Twice Daily Pioglitazone 15 mg Twice Daily Metformin 850 mg Twice Daily Median (25 th , 75 th percentile) Median (25 th , 75 th percentile) Median (25 th , 75 th 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.

Edema Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued.

The edema usually does not require hospitalization unless there is coexisting congestive heart failure.

In the 24-week pioglitazone and metformin hydrochloride trial, edema was reported in 3.0% of patients in the pioglitazone and metformin hydrochloride group, 4.2% in the pioglitazone monotherapy group, and 1.4% in the metformin monotherapy group.

A summary of the frequency and types of edema adverse events occurring in clinical investigations of pioglitazone is provided in Table 14.

Table 14.

Adverse Events of Edema in Patients Treated with Pioglitazone Number (%) of Patients Placebo Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg Monotherapy (16 to 26 weeks) 3 (1.2%) N=259 2 (2.5%) N= 81 13 (4.7%) N= 275 11 (6.5%) N=169 Combined Therapy (16 to 24 weeks) Sulfonylurea 4 (2.1%) N=187 3 (1.6%) N=184 61 (11.3%) N=540 81 (23.1%) N=351 Metformin 4 (2.5%) N=160 N/A 34 (5.9%) N=579 58 (13.9%) N=416 Insulin 13 (7.0%) N=187 24 (12.6%) N=191 109 (20.5%) N=533 90 (26.1%) N=345 Note: 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 Trial Number (%) of Patients Placebo N=2633 Pioglitazone N=2605 419 (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 Effects There 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.

A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range.

None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia In the pioglitazone clinical trials, adverse events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick glucose testing.

In the 16-week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo.

In the 16-week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg, and 4.8% with placebo.

The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24-week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24-week add-on to insulin trial (47.8% versus 43.5%).

Three patients in these four trials were hospitalized due to hypoglycemia.

All three patients were receiving pioglitazone 30 mg (0.9%) in the 24-week add-on to insulin trial.

An additional 14 patients reported severe hypoglycemia (defined as causing considerable interference with patient's 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 Tumors Tumors were observed in the urinary bladder of male rats in the two-year carcinogenicity study [ see Nonclinical Toxicology ( 13.1 ) ].

During the three year PROactive clinical trial, 14 patients out of 2605 (0.54%) randomized to pioglitazone and 5 out of 2633 (0.19%) randomized to placebo were diagnosed with bladder cancer.

After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were 6 (0.23%) cases on pioglitazone and two (0.08%) cases on placebo.

After completion of the trial, a large subset of patients was observed for up to 10 additional years, with little additional exposure to pioglitazone.

During the 13 years of both PROactive and observational follow-up, the occurrence of bladder cancer did not differ between patients randomized to pioglitazone or placebo (HR =1.00; 95% CI: 0.59-1.72) [ see Warnings and Precautions ( 5.6 ) ].

Metformin hydrochloride In a double-blind clinical study of metformin in patients with type 2 diabetes, a total of 141 patients received metformin therapy (up to 2550 mg per day) and 145 patients received placebo.

Adverse reactions reported in greater than 5% of the metformin patients, and that were more common in metformin than placebo-treated patients, are listed in Table 15.

In this trial, diarrhea led to discontinuation of study medication in 6% of patients treated with metformin.

Table 15.

Most Common Adverse Reactions (>5.0%) in a Placebo-Controlled Clinical Study of Metformin Monotherapy* Adverse Reaction Metformin Monotherapy (n=141) Placebo (n=145) % of Patients Diarrhea 53.2 11.7 Nausea/Vomiting 25.5 8.3 Flatulence 12.1 5.5 Asthenia 9.2 5.5 Indigestion 7.1 4.1 Abdominal Discomfort 6.4 4.8 Headache 5.7 4.8 * Reactions that were more common in metformin than placebo-treated patients.

Laboratory Abnormalities Hematologic Effects Pioglitazone 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 a mean change in hemoglobin of -1% to +1% in placebo-treated patients.

These changes primarily occurred within the first four to 12 weeks of therapy and remained relatively constant thereafter.

These changes may be related to increased plasma volume associated with pioglitazone therapy and are not likely to be associated with any clinically significant hematologic effects.

Vitamin B 12 Concentrations Metformin may lower serum vitamin B 12 concentrations.

Measurement of hematologic parameters on an annual basis is advised in patients on pioglitazone and metformin hydrochloride tablets and any apparent abnormalities should be appropriately investigated and managed [ see Warnings and Precautions ( 5.9 ) ].

Creatine Phosphokinase During protocol-specified measurement of serum creatine phosphokinase (CPK) in pioglitazone clinical trials, an isolated elevation in CPK to greater than 10 times the upper limit of the reference range was noted in nine (0.2%) patients treated with pioglitazone (values of 2150 to 11400 IU/L) and in no comparator-treated patients.

Six of these nine patients continued to receive pioglitazone, two patients were noted to have the CPK elevation on the last day of dosing, and one patient discontinued pioglitazone due to the elevation.

These elevations resolved without any apparent clinical sequelae.

The relationship of these events to pioglitazone therapy is unknown.

Metformin Vitamin B 12 Concentrations In metformin clinical trials of 29-week duration, a 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pioglitazone Cardiac Disorder s: Rapid increases in weight, edema, congestive heart failure with and without previously known heart disease or concomitant insulin administration Eye Disorders : New onset or worsening diabetic macular edema with decreased visual acuity Hepatobiliary Disorders : Fatal and nonfatal hepatic failure Metformin Hepatobiliary Disorder s: Cholestatic, hepatocellular, and mixed hepatocellular liver injury