glyburide and metformin hydrochloride 5 mg; 500 mg Tablet, 30-count — NDC 68382-655-06 (Billing 68382-0655-06)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Glyburide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin. Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may decrease.

12.3Pharmacokinetics Absorption Glyburide and Metformin Hydrochloride In bioavailability studies of glyburide and metformin hydrochloride 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of standard particle-size glyburide coadministered with metformin. The pharmacokinetics of metformin HCl component of glyburide and metformin hydrochloride was consistent with that of metformin HCl coadministered with glyburide.

Effect of food : Following administration of a single glyburide and metformin hydrochloride 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the C max and a relatively small effect of food on the AUC of the glyburide component. The T max for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The effect of food on the pharmacokinetics of the metformin component of glyburide and metformin hydrochloride was indeterminate.

However, food is known to decrease the extent of and slightly delay the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (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. Glyburide Single-dose studies with standard particle-size glyburide tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours.

Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between glyburide and metformin hydrochloride and single-ingredient standard particle-size glyburide products. Metformin 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 and 1,500 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. Distribution Glyburide Sulfonylurea drugs are extensively bound to serum proteins.

Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro , the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide)… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Glyburide primarily lowers blood glucose by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Sulfonylureas bind to the sulfonylurea receptor in the pancreatic beta-cell plasma membrane, leading to closure of the ATP-sensitive potassium channel, thereby stimulating the release of insulin. Metformin is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, 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. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may decrease.

12.3Pharmacokinetics Absorption Glyburide and Metformin Hydrochloride In bioavailability studies of glyburide and metformin hydrochloride 2.5 mg/500 mg and 5 mg/500 mg, the mean area under the plasma concentration versus time curve (AUC) for the glyburide component was 18% and 7%, respectively, greater than that of standard particle-size glyburide coadministered with metformin. The pharmacokinetics of metformin HCl component of glyburide and metformin hydrochloride was consistent with that of metformin HCl coadministered with glyburide.

Effect of food : Following administration of a single glyburide and metformin hydrochloride 5 mg/500 mg tablet with either a 20% glucose solution or a 20% glucose solution with food, there was no effect of food on the C max and a relatively small effect of food on the AUC of the glyburide component. The T max for the glyburide component was shortened from 7.5 hours to 2.75 hours with food compared to the same tablet strength administered fasting with a 20% glucose solution. The effect of food on the pharmacokinetics of the metformin component of glyburide and metformin hydrochloride was indeterminate.

However, food is known to decrease the extent of and slightly delay the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (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. Glyburide Single-dose studies with standard particle-size glyburide tablets in normal subjects demonstrate significant absorption of glyburide within 1 hour, peak drug levels at about 4 hours, and low but detectable levels at 24 hours.

Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Bioequivalence has not been established between glyburide and metformin hydrochloride and single-ingredient standard particle-size glyburide products. Metformin 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 and 1,500 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. Distribution Glyburide Sulfonylurea drugs are extensively bound to serum proteins.

Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro , the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs, such as phenylbutazone, warfarin, and salicylates, displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide.

It has not been shown that this difference in protein binding results in fewer drug-drug interactions with glyburide tablets in clinical use. Metformin The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins.

Metformin partitions into erythrocytes, most likely as a function of time. Metabolism and Elimination Glyburide The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. The major metabolite of glyburide is the 4-trans-hydroxy derivative.

A second metabolite, the 3-cis-hydroxy derivative, also occurs. Th… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES Patients with Inadequate Glycemic Control on Diet and Exercise Alone In a 20-week, double-blind, placebo-controlled, multicenter U.S. clinical study, involving 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] below 240 mg/dL, baseline hemoglobin A 1c [HbA1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin HCl, glyburide and metformin hydrochloride 1.25 mg/250 mg, or glyburide and metformin hydrochloride 2.5 mg/500 mg.

After 4 weeks, the dose was progressively increased to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Study data at 20 weeks are summarized in Table 5 . Table 5: Mean Change in Hemoglobin A1c and Fasting Plasma Glucose in Patients Receiving Placebo, Glyburide, Metformin HCl or Glyburide and Metformin Hydrochloride at 20 Weeks Placebo Glyburide 2.5 mg tablets Metformin HCl 500 mg tablets Glyburide and Metformin Hydrochloride 1.25 mg/250 mg tablets Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets Mean Final Dose 0 mg 5.3 mg 1,317 mg 2.78 mg/557 mg 4.1 mg/824 mg Hemoglobin A 1c N=147 N=142 N=141 N=149 N=152 Baseline Mean (%) 8.14 8.14 8.23 8.22

8.20Mean Change from Baseline −0.21 −1.24 −1.03 −1.48 −1.53 Difference from Placebo −1.02 −0.82 −1.26 a −1.31 a Difference from Glyburide −0.24 b −0.29 b Difference from Metformin −0.44 b −0.49 b Fasting Plasma Glucose N=159 N=158 N=156 N=153 N=154 Baseline Mean FPG (mg/dL) 177.2 178.9 175.1 178 176.6 Mean Change from Baseline 4.6 −35.7 −21.2 −41.5 −40.1 Difference from Placebo −40.3 −25.8 −46.1 a −44.7 a Difference from Glyburide −5.8 c −4.5 c Difference from Metformin −20.3 c −18.9 c Final HbA1c Distribution (%) N=147 N=142 N=141 N=149 N=152 <7% 19.7% 59.9% 50.4% 66.4% 71.7% ≥7% and <8% 37.4% 26.1% 29.8% 25.5% 19.1% ≥8% 42.9% 14.1% 19.9% 8.1% 9.2% a p<0.001 b p<0.05 c p=NS Mean baseline body weight was 87 kg, 87 kg, 89 kg, 89 kg and 87 kg in the placebo, glyburide 2.5mg, metformin 500mg, glyburide and metformin hydrochloride 1.25 mg/250 mg and 2.5 mg/500 mg arms, respectively.

Mean change in body weight from baseline to week 20 was -0.7 kg, +1.7 kg, -0.6 kg, +1.4 kg and +1.9 in the placebo, glyburide, metformin, glyburide and metformin hydrochloride 1.25 mg/250 mg and 2.5 mg/500 mg arms, respectively. Patients with Inadequate Glycemic Control on Sulfonylurea Alone In a 16-week, double-blind, active-controlled U.S. clinical study, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA1c 9.5%, mean baseline FPG 213 mg/dL) while being treated with at least one-half the maximum dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glyburide (fixed dose, 20 mg), metformin HCl (500 mg), glyburide and metformin hydrochloride 2.5 mg/500 mg, or glyburide and metformin hydrochloride 5 mg/500 mg.

The doses of metformin HCl and glyburide and metformin hydrochloride were titrated to a maximum of 4 tablets daily as needed to achieve FPG <140 mg/dL. Study data at 16 weeks are summarized in Table 6. Table 6: Mean Change in Hemoglobin A1c and Fasting Plasma Glucose in Patients Receiving Glyburide, Metformin HCl or Glyburide and Metformin Hydrochloride at 16 Weeks Glyburide 5 mg tablets Metformin HCl 500 mg tablets Glyburide and Metformin Hydrochloride 2.5 mg/500 mg tablets Glyburide and Metformin Hydrochloride 5 mg/500 mg tablets Mean Final Dose 20 mg 1,840 mg 8.8 mg/1,760 mg 17 mg/1,740 mg Hemoglobin A 1c N=158 N=142 N=154 N=159 Baseline Mean (%) 9.63 9.51 9.43

9.44Final Mean 9.61 9.82 7.92

7.91Difference from Glyburide −1.69a −1.70a Difference from Metformin −1.90a −1.91a Fasting Plasma Glucose N=163 N=152 N=160 N=160 Baseline Mean (mg/dL) 218.4 213.4 212.2 210.2 Final Mean 221.0 233.8 169.6 161.1 Difference from Glyburide −51.3a −59.9a Difference from Metformin −64.2a −72.7a Fin… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted with the combined products in glyburide and metformin hydrochloride. The following data are based on findings in studies performed with the individual products. Glyburide Studies in rats with glyburide alone at doses up to 300 mg/kg/day (approximately 145 times the maximum recommended human daily dose of 20 mg for the glyburide component of glyburide and metformin hydrochloride based on body surface area comparisons) for 18 months revealed no carcinogenic effects.

In a 2-year oncogenicity study of glyburide in mice, there was no evidence of treatment-related tumors. There was no evidence of mutagenic potential of glyburide alone in the following in vitro tests: Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No evidence of impaired fertility was observed when doses up to 500 times the maximum recommended human dose of 20 mg of glyburide, based on body surface area comparisons, were administered to rats in reproduction studies.

Metformin 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 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommendation human daily dose of 2,000 mg 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 a 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 3 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons.