Glyburide and Metformin Hydrochloride (glyburide 5 mg metformin hydrochloride 500 mg) Dailymed

40-9179

Revised – May 2017

Rx Only

Description

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

Glyburide, USP is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide, USP is a white to off-white crystalline compound with a molecular formula of C₂₃H₂₈ClN₃O₅S and a molecular weight of 494.00. The structural formula is represented below.

Metformin hydrochloride, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-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 with a molecular formula of C₄H₁₁N₅•HCl and a molecular weight of 165.62. Metformin hydrochloride, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK_a of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is as shown:

Glyburide and metformin hydrochloride tablets, USP are available for oral administration in tablets containing 1.25 mg glyburide, USP with 250 mg metformin hydrochloride, USP, 2.5 mg glyburide, USP with 500 mg metformin hydrochloride, USP and 5 mg glyburide, USP with 500 mg metformin hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: ammonio methacrylate copolymer (type B), croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium hydroxide, sorbic acid, titanium dioxide and triacetin. The 2.5 mg/500 mg tablet also contains: black iron oxide, D&C Yellow #10 Aluminum Lake, and yellow iron oxide. The 5 mg/500 mg tablet also contains: black iron oxide, FD&C Blue #2/Indigo Carmine Aluminum Lake, and FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake.

Clinical Pharmacology

Mechanism of Action

The glyburide and metformin hydrochloride product combines glyburide and metformin hydrochloride, 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

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 the Micronase^® brand of glyburide coadministered with metformin. The glyburide component of glyburide and metformin HCl, therefore, is not bioequivalent to Micronase^®. The metformin component of glyburide and metformin is bioequivalent to metformin coadministered with glyburide.

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 clinical significance of an earlier T_max for glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin component was indeterminate.

Single-dose studies with Micronase^® (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 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 combination product and single-ingredient glyburide products.

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.

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. 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.

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^th and 1/40^th 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 1) 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.

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 build-up 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 Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.

Hepatic Impairment

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

Renal Impairment

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 (see Table 1; also, see CONTRAINDICATIONS , WARNINGS, PRECAUTIONS, and  DOSAGE AND ADMINISTRATION ).

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_max 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 Table 1; also see WARNINGS, PRECAUTIONS, and  DOSAGE AND ADMINISTRATION ).

Table 1: Select Mean (±SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin

Subject Groups: Metformin	Cmax b	Tmax c	Renal Clearance
Dosea (number of subjects)	(mcg/mL)	(hrs)	(mL/min)
aAll doses given fasting except the first 18 doses of the multiple-dose studies
bPeak plasma concentration
cTime to peak plasma concentration
dSD = single dose
eCombined results (average means) of five studies: mean age 32 years (range 23 to 59 years)
fKinetic study done following dose 19, given fasting
gElderly subjects, mean age 71 years (range 65 to 81 years)
hCLcr = creatinine clearance normalized to body surface area of 1.73 m2
Healthy, nondiabetic adults:
500 mg SDd (24)	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 dosesf (9)	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 dosesf (9)	1.90 (±0.62)	2.01 (±1.22)	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 61-90 mL/min) (5)	1.86 (±0.52)	3.20 (±0.45)	384 (±122)
Moderate (CLcr 31-60 mL/min) (4)	4.12 (±1.83)	3.75 (±0.50)	108 (±57)
Severe (CLcr 10-30 mL/min) (6)	3.93 (±0.92)	4.01 (±1.10)	130 (±90)

Pediatrics

After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C_max 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.

After administration of a single oral glyburide and metformin hydrochloride tablet with food, dose-normalized geometric mean glyburide C_max 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.

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_1c [HbA_1c] between 7% and 11%), were randomized to receive initial therapy with placebo, 2.5 mg glyburide, 500 mg metformin, glyburide and metformin hydrochloride 1.25 mg/250 mg, or glyburide and metformin hydrochloride 2.5 mg/500 mg. After four weeks, the dose was progressively increased (up to the eight-week visit) to a maximum of 4 tablets daily as needed to reach a target FPG of 126 mg/dL. Trial data at 20 weeks are summarized in Table 2.

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

				Glyburide and	Glyburide and
				Metformin	Metformin
		Glyburide	Metformin	Hydrochloride	Hydrochloride
		2.5 mg	500 mg	1.25 mg/250 mg	2.5 mg/500 mg
	Placebo	Tablets	Tablets	Tablets	Tablets
ap<0.001
bp<0.05
cp=NS
Mean Final Dose	0 mg	5.3 mg	1317 mg	2.78 mg/557 mg	4.1 mg/824 mg
Hemoglobin A1c	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	-1.26a	-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
Body Weight Mean Change from Baseline	-0.7 kg	+1.7 kg	-0.6 kg	+1.4 kg	+1.9 kg
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%

Treatment with glyburide and metformin hydrochloride resulted in significantly greater reduction in HbA_1c and postprandial plasma glucose (PPG) compared to glyburide, metformin, or placebo. Also, glyburide and metformin hydrochloride 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.

Changes in the lipid profile associated with glyburide and metformin hydrochloride 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_1c <11% or FPG <240 mg/dL. Screened patients ineligible for the first trial because of HbA_1c and/or FPG exceeding these limits were treated directly with glyburide and metformin hydrochloride 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. Across the group of 144 patients who completed 26 weeks of treatment, mean HbA_1c 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 hydrochloride was 7.85 mg/1569 mg (equivalent to approximately three glyburide and metformin hydrochloride 2.5 mg/500 mg tablets per day).

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_1c 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 hydrochloride 2.5 mg/500 mg, or glyburide and metformin hydrochloride 5 mg/500 mg. The doses of metformin and glyburide and metformin hydrochloride 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 Table 3.

Table 3: Glyburide and Metformin Hydrochloride in Patients with Inadequate Glycemic Control on Sulfonylurea Alone: Summary of Trial Data at 16 Weeks

			Glyburide and	Glyburide and
			Metformin	Metformin
	Glyburide	Metformin	Hydrochloride	Hydrochloride
	5 mg	500 mg	2.5 mg/500 mg	5 mg/500 mg
	Tablets	Tablets	Tablets	Tablets
ap<0.001
Mean Final Dose	20 mg	1840 mg	8.8 mg/1760 mg	17 mg/1740 mg
Hemoglobin A1c	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			-1.69a	-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
Body Weight Mean Change from Baseline	+0.43 kg	-2.76 kg	+0.75 kg	+0.47 kg
Final HbA1c Distribution (%)	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%

After 16 weeks, there was no significant change in the mean HbA_1c in patients randomized to glyburide or to metformin therapy. Treatment with glyburide and metformin hydrochloride at doses up to 20 mg/2000 mg per day resulted in significant lowering of HbA_1c, FPG, and PPG from baseline compared to glyburide or metformin alone.

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_1c >7.0% 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_1c <7%. Trial data at 24 weeks or the last prior visit are summarized in Table 4.

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

	Placebo	Rosiglitazone
	+	+
	Glyburide and Metformin	Glyburide and Metformin
	Hydrochloride	Hydrochloride
a Adjusted for the baseline mean difference
b p<0.001
Mean Final Dose
Glyburide and Metformin	10 mg/1992 mg	9.6 mg/1914 mg
Hydrochloride
Rosiglitazone	0 mg	7.4 mg
Hemoglobin A1c	N=178	N=177
Baseline Mean (%)	8.09	8.14
Final Mean	8.21	7.23
Difference from Placeboa		-1.02b
Fasting Plasma Glucose	N=181	N=176
Baseline Mean (mg/dL)	173.1	178.4
Final Mean	181.4	136.3
Difference from Placeboa		-48.5b
Body Weight Mean Change from Baseline	+0.03 kg	+3.03 kg
Final HbA1c Distribution (%)	N=178	N=177
<7%	13.5%	42.4%
≥7% and <8%	32.0%	38.4%
≥8%	54.5%	19.2%

For patients who did not achieve adequate glycemic control on glyburide and metformin hydrochloride, the addition of rosiglitazone, compared to placebo, resulted in significant lowering of HbA_1c and FPG.

Indications And Usage

Glyburide and metformin hydrochloride tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Contraindications

Glyburide and metformin hydrochloride tablets are contraindicated in patients with:

• 1.Severe renal impairment (eGFR below 30 mL/min/1.73m²) (see WARNINGS and PRECAUTIONS).
• 2.Known hypersensitivity to metformin hydrochloride or glyburide.
• 3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
• 4.Concomitant administration of bosentan. 

Warnings

Metformin Hydrochloride

 

WARNING: LACTIC ACIDOSIS

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see PRECAUTIONS).

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g. acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided (see  DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and PRECAUTIONS ).

If metformin-associated lactic acidosis is suspected, immediately discontinue glyburide and metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended (see PRECAUTIONS).

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes 19 (Suppl. 2):747-830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 g per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.