Pioglitazone and Metformin Hydrocholride (Page 8 of 10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Pioglitazone and Metformin Hydrochloride Tablets

No animal studies have been conducted with pioglitazone and metformin hydrochloride tablets. 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/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. 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/m2). A two-year carcinogenicity study was 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/m2). 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/m2).

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 hydrochloride 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 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 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 hydrochloride (approximately 11, one, and two times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). 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/m2). 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/m2), 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/m2).

13.3 Reproductive and Developmental Toxicology

Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2 , respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development, and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately two times the maximum recommended human oral dose based on mg/m2).

14 CLINICAL STUDIES

14.1 Patients 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 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 21).

*
Adjusted for baseline
p ≤0.05 versus pioglitazone and metformin hydrochloride tablets

Table 21. Glycemic Parameters in 24-Week Study of Pioglitazone and Metformin Hydrochloride Tablets in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise

Parameter

Treatment Group

Pioglitazone and Metformin Hydrochloride Tablets 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

8.7

Change from Baseline (adjusted mean *)

-1.8

-1.0

-1.0

Difference 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%

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 Tablets (adjusted mean *) 95% Confidence Interval

18(8, 28)

15(6, 25)

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