Pioglitazone Hydrochloride and Metformin 15 mg; 850 mg Tablet, Film Coated, 60-count — NDC 65862-526-60 (Billing 65862-0526-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pioglitazone and metformin hydrochloride combines two antihyperglycemic agents: pioglitazone and metformin. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.

Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Metformin hydrochloride Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4) ] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

12.2Pharmacodynamics Pioglitazone Clinical 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 2 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 a 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 a 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 a mean increase in the placebo group. Mean HDL cholesterol increased to a 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) . Table 17: Lipids in a 26 Week Placebo-Controlled Monotherapy Dose-Ranging Study Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily * Adjusted for baseline, pooled center, and pooled center by treatment interaction. †p<0.05 vs placebo. Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Pioglitazone and metformin hydrochloride combines two antihyperglycemic agents: pioglitazone and metformin. Pioglitazone Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

Pioglitazone is not an insulin secretagogue. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.

Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. In animal models of diabetes, pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes mellitus. The metabolic changes produced by pioglitazone result in increased responsiveness of insulin-dependent tissues and are observed in numerous animal models of insulin resistance.

Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin. Metformin hydrochloride Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Metformin does not produce hypoglycemia in either patients with type 2 diabetes mellitus or healthy subjects [except in specific circumstances, see Warnings and Precautions (5.4) ] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

12.3Pharmacokinetics Absorption Pioglitazone and Metformin Hydrochloride In bioequivalence studies of pioglitazone and metformin hydrochloride 15 mg/500 mg and 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (C max ) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to pioglitazone hydrochloride 15 mg concomitantly administered with metformin hydrochloride immediate release (500 mg or 850 mg, respectively) tablets under fasted conditions in healthy subjects.

Administration of pioglitazone and metformin hydrochloride 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC; however, mean peak serum concentration of metformin was decreased by 28% when administered with food. A 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. Pioglitazone Following 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 2 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. C max , AUC, and trough serum concentrations (C min ) 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, T max of pioglitazone was within two hours.

Food delays the T max to three to four hours, but does not alter the extent of absorption (AUC). Metformin hydrochloride The absolute bioavailability of a 500 mg metformin tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg, and 850 mg to 2,550 mg, indicate that there is a 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 5 mcg/mL, even at maximum doses. Food decreases the rate and extent of metformin absorption, as shown by a 40% lower mean C max , a 25% lower AUC, and a 35 minute prolongation of T max following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting.

The clinical relevance of these decreases is unknown. Distribution Pioglitazone The 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 hydrochloride The 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 a function of time. Elimination Metabolism Pioglitazone Pioglitazone 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 i… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Pioglitazone Clinical 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 2 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 a 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 a 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 a mean increase in the placebo group. Mean HDL cholesterol increased to a 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) . Table 17: Lipids in a 26 Week Placebo-Controlled Monotherapy Dose-Ranging Study Placebo Pioglitazone 15 mg Once Daily Pioglitazone 30 mg Once Daily Pioglitazone 45 mg Once Daily * Adjusted for baseline, pooled center, and pooled center by treatment interaction. †p<0.05 vs placebo. Triglycerides (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 263 284 261 260 Percent change from baseline (adjusted mean*) 4.8% -9% † -9.6% † -9.3% † HDL Cholesterol (mg/dL) N=79 N=79 N=83 N=77 Baseline (mean) 42 40 41 41 Percent change from baseline (adjusted mean*) 8.1% 14.1% † 12.2% 19.1% † LDL Cholesterol (mg/dL) N=65 N=63 N=74 N=62 Baseline (mean) 139 132 136 127 Percent change from baseline (adjusted mean*) 4.8% 7.2% 5.2% 6% Total Cholesterol (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 225 220 223 214 Percent 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.

14 CLINICAL STUDIES

14.1Patients Who Have Inadequate Glycemic Control with Diet and Exercise Alone In a 24-week, randomized, double-blind clinical trial, 600 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise alone (mean baseline HbA1c 8.7%) were randomized to pioglitazone and metformin hydrochloride 15/850 mg, pioglitazone 15 mg, or metformin 850 mg twice daily. Statistically significant improvements in HbA1c and fasting plasma glucose (FPG) were observed in patients treated with pioglitazone and metformin hydrochloride compared to either pioglitazone or metformin alone (see Table 22).

Table 22: Glycemic Parameters in 24 Week Study of Pioglitazone and Metformin Hydrochloride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise * Adjusted for baseline. † p ≤ 0.05 vs pioglitazone and metformin hydrochloride. Parameter Treatment Group Pioglitazone and Metformin Hydrochloride 15/850 mg Twice Daily Pioglitazone 15 mg Twice Daily Metformin 850 mg Twice Daily HbA1c (%) N=188 N=162 N=193 Baseline (mean) 8.9 8.7

8.7Change from Baseline (adjusted mean * ) -1.8 -1 -1 Difference between pioglitazone and metformin hydrochloride (adjusted mean * ) 95% Confidence Interval 0.9 † (0.5, 1.2) 0.8 † (0.5, 1.2) % of patients with HbA1c ≤ 7% 64 47 39 Fasting Plasma Glucose (mg/dL) N=196 N=176 N=202 Baseline (mean) 177 171 171 Change from Baseline (adjusted mean*) -40 -22 -25 Difference between pioglitazone and metformin hydrochloride (adjusted mean*) 95% Confidence Interval 18 † (8, 28) 15 † (6, 25)

14.2Patients 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 2 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) . Table 23: Glycemic Parameters in a 16 Week Placebo-Controlled, Add-on to Metformin Trial Placebo + Metformin Pioglitazone 30 mg + Metformin * Adjusted for baseline, pooled center, and pooled center by treatment interaction. † p ≤0.05 vs placebo + metformin.

Total Population HbA1c (%) N=153 N=161 Baseline (mean) 9.8

9.9Change from baseline (adjusted mean*) 0.2 -0.6 Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval -0.8 † (-1.2, -0.5) Fasting Plasma Glucose (mg/dL) N=157 N=165 Baseline (mean) 260 254 Change from baseline (adjusted mean*) -5 -43 Difference from placebo + metformin (adjusted mean*) 95% Confidence Interval -38 † (-49, -26) In the second trial, 827 patients were randomized to receive either 30 mg or 45 mg of pioglitazone once daily for 24 weeks in addition to their current metformin regimen.

The mean reduction from baseline at Week 24 in HbA1c was 0.8% for the 30 mg dose and 1% for the 45 mg dose (see Table 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. Table 24: Glycemic Parameters in a 24 Week Add-on to Metformin Study Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin 95% CI = 95% confidence interval. * Adjusted for baseline, pooled center, and pooled center by treatment interaction. † p ≤ 0.05 vs.

30 mg daily pioglitazone + metformin. Total Population HbA1c (%) N=400 N=398 Baseline (mean) 9.9

9.8Change from baseline (adjusted mean*) -0.8 -1 Difference from 30 mg daily pioglitazone + metformin (a… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Pioglitazone and Metformin Hydrochloride No 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. Pioglitazone A 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/m 2 ).

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 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m 2 ). Urinary calculi with subsequent irritation and hyperplasia were postulated as the mechanism for bladder tumors observed in male rats.

A 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 to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m 2 ). No drug-induced tumors were observed in any organ.

Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a 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 hydrochloride daily prior to and throughout mating and gestation (approximately nine times the maximum recommended human oral dose based on mg/m 2 ).

Metformin hydrochloride Long-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 a human daily dose of 2000 mg of the metformin component of pioglitazone and metformin hydrochloride 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 with 900 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 based on body surface area comparisons.

13.2Animal 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 hydrochloride (approximately 11, one, and two times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m 2 ). In a 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 rec… [Excerpted — this section continues on DailyMed.]