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 Cmax and a relatively small effect of food on the AUC of the glyburide component. The Tmax 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 (Cmax ), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax ) 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.
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.
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 1500 mg, and 850 mg to 2550 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.
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.
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
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. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400 and 1/40 as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 4) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin [see Warnings and Precautions (8.7)].
No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (Table 4); [see Dosage and Administration (2), Contraindications (4), and Warnings and Precautions (5.1)].
There is no information on the pharmacokinetics of glyburide in elderly patients.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (Table4); [see Dosage and Administration (2.3) and Warnings and Precautions (5.1)].
Table 4: Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin HCl
|a All doses given fasting except the first 18 doses of the multiple-dose studiesb Peak plasma concentrationc Time to peak plasma concentrationd SD=single dosee Combined results (average means) of 5 studies: mean age 32 years (range 23 to 59 years)f Kinetic study done following dose 19, given fastingg Elderly subjects, mean age 71 years (range 65 to 81 years)h CLcr =creatinine clearance normalized to body surface area of 1.73 m2|
|Subject Groups: Metformin HCl Dosea (number of subjects)||Cmax b (mcg/mL)||Tmax c (hrs)||Renal Clearance (mL/min)|
|Healthy, nondiabetic adults: 500 mg SDd (24)850 mg SD (74)e 850 mg t.i.d. for 19 dosesf (9)||1.03 (±0.33)1.60 (±0.38)2.01 (±0.42)||2.75 (±0.81)2.64 (±0.82)1.79 (±0.94)||600 (±132)552 (±139)642 (±173)|
|Adults with type 2 diabetes: 850 mg SD (23)850 mg t.i.d. for 19 dosesf (9)||1.48 (±0.5)1.90 (±0.62)||3.32 (±1.08)2.01 (±1.22)||491 (±138)550 (±160)|
|Elderlyg , healthy nondiabetic adults:850 mg SD (12)||2.45 (±0.70)||2.71 (±1.05)||412 (±98)|
|Renal-impaired adults: 850 mg SD Mild (CLcr h 61 to 90 mL/min) (5)Moderate (CLcr 31 to 60 mL/min) (4)Severe (CLcr 10 to 30 mL/min) (6)||1.86 (±0.52)4.12 (±1.83)3.93 (±0.92)||3.20 (±0.45)3.75 (±0.50)4.01 (±1.10)||384 (±122)108 (±57)130 (±90)|
There is no information on the effect of gender on the pharmacokinetics of glyburide.
Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males=19, females=16).
No information is available on race differences in the pharmacokinetics of glyburide.
No studies of metformin pharmacokinetic parameters according to race have been performed.
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.
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 A1c [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<0.001b p<0.05c 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||−1.26a||−1.31a|
|Difference from Glyburide||−0.24b||−0.29b|
|Difference from Metformin||−0.44b||−0.49b|
|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||−46.1a||−44.7a|
|Difference from Glyburide||−5.8c||−4.5c|
|Difference from Metformin||−20.3c||−18.9c|
|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|
|Baseline Mean (%)||9.63||9.51||9.43||9.44|
|Difference 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|
|Difference from Glyburide||−51.3a||−59.9a|
|Difference from Metformin||−64.2a||−72.7a|
|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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