Pioglitazone 15 mg Tablet, 500-count — NDC 43547-426-50 (Billing 43547-0426-50)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Pioglitazone is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone tablets decrease 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. 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.

12.2Pharmacodynamics Clinical studies demonstrate that pioglitazone tablets improve insulin sensitivity in insulin-resistant patients. Pioglitazone tablets enhance cellular responsiveness to insulin, increase insulin-dependent glucose disposal and improve hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone tablets results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower HbA1c values.

In controlled clinical trials, pioglitazone tablets had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin [see Clinical Studies (14.2) ] . Patients with lipid abnormalities were included in clinical trials with pioglitazone tablets. Overall, patients treated with pioglitazone tablets 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 tablet [see Warnings and Precautions (5.8) and 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 tablets dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone tablets than in the placebo-treated patients.

There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone tablets compared to placebo (see Table 14 ) . Table 14. Lipids in a 26-Week Placebo-Controlled Monotherapy Dose-Ranging Study Placebo Pioglitazone Tablets 15 mg Once Daily Pioglitazone Tablets 30 mg Once Daily Pioglitazone Tablets 45 mg Once Daily * Adjusted for baseline, pooled center, and pooled center by treatment interaction † p<0.05 versus 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% -9.0% † -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% 6.0% 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 sulfonylurea (16 weeks and 24 weeks), metformin (16 weeks and 24 weeks) or insulin (16… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Monotherapy Three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of pioglitazone tablets as monotherapy in patients with type 2 diabetes. These trials examined pioglitazone tablets at doses up to 45 mg or placebo once daily in a total of 865 patients. In a 26-week dose-ranging monotherapy trial, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of pioglitazone tablets, or placebo once daily.

Therapy with any previous antidiabetic agent was discontinued eight weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of pioglitazone tablets produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (see Figure 1, Table 17 ) . Figure 1 shows the time course for changes in HbA1c in this 26-week study.

Figure 1. Mean Change from Baseline for HbA1c in a 26-Week Placebo-Controlled Dose-Ranging Study (Observed Values) Table 17. Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial Table 17.

Glycemic Parameters in a 26-Week Placebo-Controlled Dose-Ranging Monotherapy Trial Placebo Pioglitazone Tablets 15 mg Once Daily Pioglitazone Tablets 30 mg Once Daily Pioglitazone Tablets 45 mg Once Daily * Adjusted for baseline, pooled center, and pooled center by treatment interaction † p≤0.05 vs. placebo Total Population HbA1c (%) N=79 N=79 N=85 N=76 Baseline (mean) 10.4 10.2 10.2

10.3Change from baseline (adjusted mean * ) 0.7 -0.3 -0.3 -0.9 Difference from placebo (adjusted mean * ) -1.0 † -1.0 † -1.6 † 95% Confidence Interval (-1.6, -0.4) (-1.6, -0.4) (-2.2, -1.0) Fasting Plasma Glucose (mg/dL) N=79 N=79 N=84 N=77 Baseline (mean) 268 267 269 276 Change from baseline (adjusted mean * ) 9 -30 -32 -56 Difference from placebo (adjusted mean * ) -39 † -41 † -65 † 95% Confidence Interval (-63, -16) (-64, -18) (-89, -42) In a 24-week placebo-controlled monotherapy trial, 260 patients with type 2 diabetes were randomized to one of two forced-titration pioglitazone tablets treatment groups or a mock-titration placebo group.

Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. In one pioglitazone tablets treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the trial (16 weeks).

In the second pioglitazone tablets treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with pioglitazone tablets, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (see Table 18 ) . Table 18.

Glycemic Parameters in a 24-Week Placebo-Controlled Forced-Titration Monotherapy Trial Placebo Pioglitazone Tablets 30 mg* Once Daily Pioglitazone Tablets 45 mg * Once Daily * Final dose in forced titration † Adjusted for baseline, pooled center, and pooled center by treatment interaction ‡ p≤0.05 vs. placebo Total Population HbA1c (%) N=83 N=85 N=85 Baseline (mean) 10.8 10.3

10.8Change from baseline (adjusted mean † ) 0.9 -0.6 -0.6 Difference from placebo (adjusted mean † ) -1.5 ‡ -1.5 ‡ 95% Confidence Interval (-2.0, -1.0) (-2.0, -1.0) Fasting Plasma Glucose (mg/dL) N=78 N=82 N=85 Baseline (mean) 279 268 281 Change from baseline (adjusted mean † ) 18 -44 -50 Difference from placebo (adjusted mean † ) -62 ‡ -68 ‡ 95% Confidence Interval (-82, -0.41) (-88, -0.48) In a 16-week monotherapy trial, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of pioglitazone tablets or placebo once daily.

Therapy with any previous antidiabetic agent was discontinued six weeks prior to the double-blind period. Treatment with 30 mg of pioglit… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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 ).

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, 1, and 2 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 recommended human oral dose based on mg/m 2 ).

Heart enlargement was seen in a 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/m 2 ), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m 2 ).