Glyburide and Metformin Hydrochloride (Page 6 of 8)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, 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.
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.
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 4 times the maximum
recommendation human daily dose of 2000 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 2000 mg based on body surface area comparisons.
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.
|a p<0.001 b p<0.05 c p=NS|
|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||1317 mg||2.78 mg/557 mg||4.1 mg/824 mg|
|Baseline Mean (%)||8.14||8.14||8.23||8.22||8.20|
|Mean 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% and <8%||37.4%||26.1%||29.8%||25.5%||19.1%|
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 1.25mg/250mg and 2.5mg/500mg 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 1.25mg/250mg and 2.5mg/500mg 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.
|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||1840 mg||8.8 mg/1760 mg||17 mg/1740 mg|
|Hemoglobin A 1c||N=158||N=142||N=154||N=159|
|Baseline Mean (%)||9.63||9.51||9.43||9.44|
|Difference from Glyburide||−1.69 a||−1.70 a|
|Difference from Metformin||−1.90 a||−1.91 a|
|Fasting Plasma Glucose||N=163||N=152||N=160||N=160|
|Baseline Mean (mg/dL)||218.4||213.4||212.2||210.2|
|Difference from Glyburide||−51.3 a||−59.9 a|
|Difference from Metformin||−64.2 a||−72.7 a|
|Final HbA1c Distribution (%)||N=158||N=142||N=154||N=159|
|≥7% and <8%||9.5%||11.3%||33.1%||37.1%|
Weight gain due to glyburide was comparable in all three exposed groups.
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