Pioglitazone Hydrochloride and Metformin Hydrochloride: Package Insert and Label Information (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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/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 4 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. 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/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 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.

13.2 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).

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 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 21).

Table 21. 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 versus 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 8.7
Change 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)

14.2 Patients Previously Treated with Metformin

The efficacy and safety of pioglitazone as add-on to metformin therapy have been established in two clinical studies. Bioequivalence of pioglitazone and metformin hydrochloride with coadministered pioglitazone and metformin tablets was demonstrated for both pioglitazone and metformin hydrochloride strengths [see Clinical Pharmacology (12.3)].
The two clinical trials testing pioglitazone as add-on to metformin therapy included patients with type 2 diabetes 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 22).

Table 22. Glycemic Parameters in a 16-Week Placebo-Controlled, Add-on to Metformin Trial
Placebo +Metformin Pioglitazone30 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 9.9
Change 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 23). 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 23. Glycemic Parameters in a 24-Week Add-on to Metformin Study
Pioglitazone30 mg +Metformin Pioglitazone45 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 9.8
Change from baseline (adjusted mean*) -0.8 -1
Difference from 30 mg daily pioglitazone + metformin (adjusted mean*) (95% CI) -0.2 (-0.5, 0.1)
Fasting Plasma Glucose (mg/dL) N=398 N=399
Baseline (mean) 233 232
Change from baseline (adjusted mean*) -38 -51
Difference 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.

16 HOW SUPPLIED/STORAGE AND HANDLING


Pioglitazone and Metformin Hydrochloride Tablets USP, 15 mg/500 mg are white to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘92’ on other side.
Bottles of 60 NDC 65862-525-60
Bottles of 180 NDC 65862-525-18
Pioglitazone and Metformin Hydrochloride Tablets USP, 15 mg/850 mg are white to off-white, oblong, biconvex film-coated tablets, debossed with ‘H’ on one side and ‘93’ on other side.
Bottles of 60 NDC 65862-526-60
Bottles of 180 NDC 65862-526-18
Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Keep container tightly closed, and protect from moisture and humidity.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Medication Guide).

  • It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly.
  • Tell patients to promptly report any sign of macroscopic hematuria or other symptoms such as dysuria or urinary urgency that develop or increase during treatment as these may be due to bladder cancer.
  • 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 immediately and to promptly notify their healthcare professional if unexplained hyperventilation, myalgia, gastrointestinal symptoms, malaise, unusual somnolence, or other nonspecific symptoms occur. Instruct patients to inform their doctor that they are taking pioglitazone and metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation of pioglitazone and metformin hydrochloride may be required until renal function has been confirmed to be normal.
  • Counsel patients against excessive alcohol intake while receiving pioglitazone and metformin hydrochloride.
  • Inform patients to immediately report symptoms of an unusually rapid increase in weight or edema, shortness of breath, or other symptoms of heart failure while receiving pioglitazone and metformin hydrochloride.
  • Tell patients to promptly stop taking pioglitazone and metformin hydrochloride and seek immediate medical advice if there is unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine as these symptoms may be due to hepatotoxicity.
  • Inform patients about the importance of regular testing of renal function and hematologic parameters when receiving treatment with pioglitazone and metformin hydrochloride.
  • Inform female patients that treatment with pioglitazone and metformin hydrochloride may result in an unintended pregnancy in some premenopausal anovulatory females due to its effect on ovulation [see Use in Specific Populations (8.3)].
  • Patients should be advised to notify their health practitioner or call the Poison Control Center immediately in case of pioglitazone and metformin hydrochloride overdose.
  • Combination antihyperglycemic therapy may cause hypoglycemia. When initiating pioglitazone and metformin hydrochloride, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members.
  • Patients should be told to take pioglitazone and metformin hydrochloride as prescribed and instructed that any change in dosing should only be done if directed by their physician. If a dose is missed on one day, the dose should not be doubled the following day.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

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