DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Glyburide and Metformin (Glyburide / Metformin Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Glyburide and metformin hydrochloride tablets USP contain two oral antihyperglycemic drugs used in the management of type 2 diabetes, glyburide USP and metformin hydrochloride USP.

Glyburide USP is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide USP is 1-[[ -[2-(5-chloro- -anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide USP is a white to off-white crystalline compound. The glyburide USP used in glyburide and metformin hydrochloride tablets USP has a particle size distribution of 25% undersize value not more than 6 µm, 50% undersize value not more than 7 to 10 µm, and 75% undersize value not more than 21 µm. The structural formula is represented below: p o

C H ClN O S M.W. 494.01 23 28 3 5

Metformin hydrochloride USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride USP (-dimethylimidodicarbonimidic diamide monohydrochloride) is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound. Metformin hydrochloride USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK of metformin USP is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride USP is 6.68. The structural formula is as shown: N,N a

C H ClN (monohydrochloride) M.W. 165.63 4 12 5

Each glyburide and metformin hydrochloride tablet USP, for oral administration, contains 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP, or 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each tablet contains the following inactive ingredients: copovidone, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide. The 1.25 mg/250 mg strength also contains D&C Yellow #10 aluminum lake and FD&C Red #40 aluminum lake; the 2.5 mg/500 mg strength also contains FD&C Red #40 aluminum lake and FD&C Yellow #6 aluminum lake; and the 5 mg/500 mg strength also contains D&C Yellow #10 aluminum lake and FD&C Yellow #6 aluminum lake.

CLINICAL PHARMACOLOGY

Mechanism of Action

Glyburide and metformin combines two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glyburide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in patients with type 2 diabetes, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.

Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Pharmacokinetics

Absorption and Bioavailability

Glyburide and metformin

In bioavailability studies of glyburide and metformin 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 the glyburide coadministered with metformin. The glyburide component of glyburide and metformin, therefore, is bioequivalent to glyburide. The metformin component of glyburide and metformin is bioequivalent to metformin coadministered with glyburide. not

Following administration of a single glyburide and metformin 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 and a relatively small effect of food on the AUC of the glyburide component. The T 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 clinical significance of an earlier T for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate. max max max

Glyburide

Single-dose studies with glyburide tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four 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 tablets and single ingredient glyburide products.

Metformin hydrochloride

The absolute bioavailability of a 500 mg metformin hydrochloride 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.

Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower peak concentration and a 25% lower AUC in plasma and a 35-minute prolongation of time to peak plasma concentration 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.

Distribution

Glyburide

Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. 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. In vitro,

Metformin hydrochloride

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. 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. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

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. 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. th th

Metformin hydrochloride

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) 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. Table 1

Special Populations

Patients With Type 2 Diabetes

Multiple-dose studies with glyburide in patients with type 2 diabetes demonstrate drug level concentration-time curves similar to single-dose studies, indicating no buildup of drug in tissue depots.

In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see), nor is there any accumulation of metformin in either group at usual clinical doses. Table 1

Hepatic Insufficiency

No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for either glyburide or metformin.

Renal Insufficiency

No information is available on the pharmacokinetics of glyburide in patients with renal insufficiency.

In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see; also, see). Table 1 WARNINGS

Geriatrics

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 C 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 (see). Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. max Table 1

Table 1: Select Mean (± SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
Subject Groups: Metformin Dose a   (number of subjects) C max  b  (mcg/mL) T max  c (hrs) Renal Clearance (mL/min)
Healthy, nondiabetic adults:
500 mg SD (24) d 1.03 (± 0.33) 2.75 (± 0.81) 600 (± 132)
850 mg SD (74) e 1.60 (± 0.38) 2.64 (± 0.82) 552 (± 139)
850 mg t.i.d. for 19 doses (9) f 2.01 (± 0.42) 1.79 (± 0.94) 642 (± 173)
Adults with type 2 diabetes:
850 mg SD (23) 1.48 (± 0.5) 3.32 (± 1.08) 491 (± 138)
850 mg t.i.d. for 19 doses (9) f 1.90 (± 0.62) 2.01 (± 1.22) 550 (± 160)
  Elderly g , healthy nondiabetic adults:
850 mg SD (12) 2.45 (± 0.70) 2.71 (± 1.05) 412 (± 98)
Renal-impaired adults: 850 mg SD
Mild (CL 61 to 90 mL/min)  (5) cr h 1.86 (± 0.52) 3.20 (± 0.45) 384 (± 122)
Moderate (CL 31 to 60 mL/min) (4) cr 4.12 (± 1.83) 3.75 (± 0.50) 108 (± 57)
Severe (CL 10 to 30 mL/min) (6) cr 3.93 (± 0.92) 4.01 (± 1.10) 130 (± 90)

All doses given fasting except the first 18 doses of the multiple-dose studies a

Peak plasma concentration b

Time to peak plasma concentration c

SD = single dose d

Combined results (average means) of five studies: mean age 32 years (range 23 to 59 years) e

Kinetic study done following dose 19, given fasting f

Elderly subjects, mean age 71 years (range 65 to 81 years) g

CL = creatinine clearance normalized to body surface area of 1.73 m h cr 2

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C and AUC differed < 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. max

After administration of a single oral glyburide and metformin tablet with food, dose-normalized geometric mean glyburide C and AUC in pediatric patients with type 2 diabetes (11 to 16 years of age, n = 28, mean body weight of 97 kg) differed < 6% from historical values in healthy adults. max

Gender

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). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.

Race

No information is available on race differences in the pharmacokinetics of glyburide.

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).

Clinical Studies

Patients with Inadequate Glycemic Control on Diet and Exercise Alone

In a 20 week, double-blind, multicenter U.S. clinical trial, a total of 806 drug-naive patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (baseline fasting plasma glucose [FPG] < 240 mg/dL, baseline hemoglobin A [HbA ] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin, glyburide and metformin 1.25 mg/250 mg, or glyburide and metformin 2.5 mg/500 mg. After four weeks, the dose was progressively increased (up to the eight-week visit) to a maximum of four tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in. 1c 1c Table 2

Table 2: Placebo- and Active-Controlled Trial of Glyburide and Metformin in Patients with Inadequate Glycemic Control on Diet and Exercise Alone: Summary of Trial Data at 20 Weeks
Placebo

Glyburide

2.5 mg Tablets

Metformin 500 mg

Tablets

Glyburide and Metformin 1.25 mg/250 mg Tablets Glyburide and Metformin 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
Hemoglobin A 1c N = 147 N = 142 N = 141 N = 149 N = 152
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
Body Weight Mean Change from Baseline -0.7 kg +1.7 kg -0.6 kg +1.4 kg +1.9 kg
Final HbA Distribution (%) 1c 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%

p < 0.001 a

p < 0.05 b

p = NS c

Treatment with glyburide and metformin resulted in significantly greater reduction in HbA and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, glyburide and metformin therapy resulted in greater reduction in FPG compared to glyburide, metformin, or placebo, but the differences from glyburide and metformin did not reach statistical significance. 1c

Changes in the lipid profile associated with glyburide and metformin treatment were similar to those seen with glyburide, metformin, and placebo.

The double-blind, placebo-controlled trial described above restricted enrollment to patients with HbA < 11% or FPG < 240 mg/dL. Screened patients ineligible for the first trial because of HbA and/or FPG exceeding these limits were treated directly with glyburide and metformin 2.5 mg/500 mg in an open-label, uncontrolled protocol. In this study, three out of 173 patients (1.7%) discontinued because of inadequate therapeutic response. 1c 1c

Across the group of 144 patients who completed 26 weeks of treatment, mean HbA was reduced from a baseline of 10.6% to 7.1%. The mean baseline FPG was 283 mg/dL and was reduced to 164 and 161 mg/dL after 2 and 26 weeks, respectively. The mean final titrated dose of glyburide and metformin was 7.85 mg/1569 mg (equivalent to approximately three glyburide and metformin 2.5 mg/500 mg tablets per day). 1c

Patients with Inadequate Glycemic Control on Sulfonylurea Alone

In a 16 week, double-blind, active-controlled U.S. clinical trial, a total of 639 patients with type 2 diabetes not adequately controlled (mean baseline HbA 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 (500 mg), glyburide and metformin 2.5 mg/500 mg, or glyburide and metformin 5 mg/500 mg. The doses of metformin and glyburide and metformin were titrated to a maximum of four tablets daily as needed to achieve FPG < 140 mg/dL. Trial data at 16 weeks are summarized in. 1c Table 3

Table 3: Glyburide and Metformin in Patients with Inadequate Glycemic Control on Sulfonylurea Alone: Summary of Trial Data at 16 Weeks
Glyburide 5 mg Tablets Metformin 500 mg Tablets Glyburide and Metformin 2.5 mg/500 mg Tablets Glyburide and Metformin 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
Final Mean 9.61 9.82 7.92 7.91
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
Final Mean 221 233.8 169.6 161.1
Difference from Glyburide -51.3 a -59.9 a
Difference from Metformin -64.2 a -72.7 a
Body Weight Mean Change from Baseline +0.43 kg -2.76 kg +0.75 kg +0.47 kg
Final HbA Distribution (%) 1c N = 158 N = 142 N = 154 N = 159
< 7% 2.5% 2.8% 24.7% 22.6%
≥ 7% and < 8% 9.5% 11.3% 33.1% 37.1%
≥ 8% 88% 85.9% 42.2% 40.3%

p < 0.001 a

After 16 weeks, there was no significant change in the mean HbA in patients randomized to glyburide or metformin therapy. Treatment with glyburide and metformin at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA, FPG, and PPG from baseline compared to glyburide or metformin alone. 1c 1c

Addition of Thiazolidinediones to Glyburide and Metformin Therapy

In a 24 week, double-blind, multicenter U.S. clinical trial, patients with type 2 diabetes not adequately controlled on current oral antihyperglycemic therapy (either monotherapy or combination therapy) were first switched to open label glyburide and metformin hydrochloride 2.5 mg/500 mg tablets and titrated to a maximum daily dose of 10 mg/2000 mg. A total of 365 patients inadequately controlled (HbA > 7% and ≤ 10%) after 10 to 12 weeks of a daily glyburide and metformin hydrochloride dose of at least 7.5 mg/1500 mg were randomized to receive add-on therapy with rosiglitazone 4 mg or placebo once daily. After eight weeks, the rosiglitazone dose was increased to a maximum of 8 mg daily as needed to reach a target mean daily glucose of 126 mg/dL or HbA < 7%. Trial data at 24 weeks or the last prior visit are summarized in. 1c 1c Table 4

Table 4: Effects of Adding Rosiglitazone or Placebo in Patients Treated with Glyburide and Metformin in a 24 Week Trial
Placebo + Glyburide and Metformin Rosiglitazone + Glyburide and Metformin

Mean Final Dose

Glyburide and Metformin

10 mg/1992 mg 9.6 mg/1914 mg
Rosiglitazone 0 mg 7.4 mg
Hemoglobin A 1c N = 178 N = 177
Baseline Mean (%) 8.09 8.14
Final Mean 8.21 7.23
Difference from Placebo a -1.02 b
Fasting Plasma Glucose N = 181 N = 176
Baseline Mean (mg/dL) 173.1 178.4
Final Mean 181.4 136.3
Difference from Placebo a -48.5 b

Body Weight Mean Change from Baseline

+0.03 kg +3.03 kg
Final HbA Distribution (%) 1c N = 178 N = 177
< 7% 13.5% 42.4%
≥ 7% and < 8% 32% 38.4%
≥ 8% 54.5% 19.2%

Adjusted for the baseline mean difference a

p < 0.001 b

For patients who did not achieve adequate glycemic control on glyburide and metformin, the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA and FPG. 1c

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017