GLYBURIDE AND METFORMIN tablet film coated

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
Glyburide (UNII: SX6K58TVWC) (Glyburide - UNII:SX6K58TVWC)
Available from:
PD-Rx Pharmaceuticals, Inc.
INN (International Name):
Glyburide
Composition:
Glyburide 5 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

GLYBURIDE AND METFORMIN - glyburide and metformin tablet, film coated

PD-Rx Pharmaceuticals, Inc.

----------

GLYBURIDE and METFORMIN HYDROCHLORIDE TABLETS USP

Rx only

5710

5711

5712

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-[[p-[2-(5-chloro-o-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:

H ClN O S M.W. 494.01

Metformin hydrochloride USP is an oral antihyperglycemic drug used in the management of type 2

diabetes. Metformin hydrochloride USP ( 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.

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:

C H ClN (monohydrochloride) M.W. 165.63

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 not bioequivalent to glyburide. The metformin

component of glyburide and metformin is bioequivalent to metformin coadministered with glyburide.

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

glyburide after food is not known. The effect of food on the pharmacokinetics of the metformin

component was indeterminate.

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. 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 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

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.

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 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.

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 Table 1),

nor is there any accumulation of metformin in either group at usual clinical doses.

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 Table 1; also, see 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 Table 1).

Metformin treatment should not be initiated in patients ≥ 80 years of age unless measurement of

creatinine clearance demonstrates that renal function is not reduced.

Table 1: Select Mean (± SD) Metformin Pharmacokinetic Parameters

Following Single or Multiple Oral Doses of Metformin

Subject Groups:Metformin

Dos e

C

T

RenalClearance(mL/min)

Healthy, nondiabetic adults:

500 mg SD (24)

1.03 (± 0.33)

2.75 (±

600 (± 132)

a (number of subjects)

max

b (mcg/mL)

max

c

(hrs)

500 mg SD (24)

1.03 (± 0.33)

0.81)

600 (± 132)

850 mg SD (74)

1.60 (± 0.38)

2.64 (±

0.82)

552 (± 139)

850 mg t.i.d. for 19 doses (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 doses (9)

1.90 (± 0.62)

2.01 (±

1.22)

550 (± 160)

Elderly , healthynondiabetic

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)

1.86 (± 0.52)

3.20 (±

0.45)

384 (± 122)

Moderate (CL

31 to 60

mL/min) (4)

4.12 (± 1.83)

3.75 (±

0.50)

108 (± 57)

Severe (CL

10 to 30

mL/min) (6)

3.93 (± 0.92)

4.01 (±

1.10)

130 (± 90)

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

Peak plasma concentration

Time to peak plasma concentration

SD = single dose

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

Kinetic study done following dose 19, given fasting

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

= creatinine clearance normalized to body surface area of 1.73 m

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.

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.

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 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

Metformin500

mg

Tablets

Glyburide

and

Metformin

1.25

mg/250

mg

Tablets

Glyburide

and

Metformin

2.5

mg/500

mg

Tablets

Mean Final

Dos e

0 mg

5.3 mg

1317 mg

2.78

mg/557 mg

4.1 mg/824

Hemoglobin

A

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

-1.31

Difference

from

Glyburide

-0.24

-0.29

Difference

from

Metformin

-0.44

-0.49

Fas ting

Plas ma

N = 159

N = 158

N = 156

N = 153

N = 154

1c

Glucos e

Baseline

Mean FPG

(mg/dL)

177.2

178.9

175.1

176.6

Mean

Change from

Baseline

-35.7

-21.2

-41.5

-40.1

Difference

from

Placebo

-40.3

-25.8

-46.1

-44.7

Difference

from

Glyburide

-5.8

-4.5

Difference

from

Metformin

-20.3

-18.9

Body

Weight

Mean

Change

from

Bas eline

-0.7 kg

+1.7 kg

-0.6 kg

+1.4 kg

+1.9 kg

Final HbA

Dis tribution

(%)

N = 147

N = 142

N = 141

N = 149

N = 152

< 7%

19.7%

59.9%

50.4%

66.4%

71.7%

≥ 7% and <

37.4%

26.1%

29.8%

25.5%

19.1%

≥ 8%

42.9%

14.1%

19.9%

8.1%

9.2%

p < 0.001

p < 0.05

p = NS

Treatment with glyburide and metformin resulted in significantly greater reduction in HbA

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.

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.

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 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

Dos e

20 mg

1840 mg

8.8 mg/1760

17 mg/1740

Hemoglobin

A

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

-1.70

Difference

from

Metformin

-1.90

-1.91

Fas ting

Plas ma

Glucos e

N = 163

N = 152

N = 160

N = 160

Baseline

Mean (mg/dL)

218.4

213.4

212.2

210.2

Final Mean

233.8

169.6

161.1

Difference

from

Glyburide

-51.3

-59.9

Difference

from

Metformin

-64.2

-72.7

Body Weight

Mean

Change from

Bas eline

+0.43 kg

-2.76 kg

+0.75 kg

+0.47 kg

Final HbA

Dis tribution

(%)

N = 158

N = 142

N = 154

N = 159

1c

1c

< 7%

2.5%

2.8%

24.7%

22.6%

≥ 7% and <

9.5%

11.3%

33.1%

37.1%

≥ 8%

85.9%

42.2%

40.3%

p < 0.001

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.

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 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

Ros iglitazone

0 mg

7.4 mg

Hemoglobin A

N = 178

N = 177

Baseline Mean (%)

8.09

8.14

Final Mean

8.21

7.23

Difference from

Placebo

-1.02

Fasting Plasma

Glucos e

N = 181

N = 176

Baseline Mean (mg/dL)

173.1

178.4

Final Mean

181.4

136.3

Difference from

Placebo

-48.5

Body Weight Mean

Change from

Bas eline

+0.03 kg

+3.03 kg

Final HbA

Distribution (%)

N = 178

N = 177

< 7%

13.5%

42.4%

≥ 7% and < 8%

38.4%

1c

1c

≥ 8%

54.5%

19.2%

Adjusted for the baseline mean difference

p < 0.001

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.

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. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥ 1.5 mg/dL

[males], ≥ 1.4 mg/dL [females], or abnormal creatinine clearance) which may also result from

conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (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.

Glyburide and metformin should be temporarily discontinued in patients undergoing radiologic studies

involving intravascular administration of iodinated contrast materials, because use of such products may

result in acute alteration of renal function (see also PRECAUTIONS).

WARNINGS

Metformin Hydrochloride

Lactic Acidosis

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to

metformin accumulation during treatment with glyburide and metformin; when it occurs, it

is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a

number of pathophysiologic conditions, including diabetes mellitus, and whenever there is

significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated

blood lactate levels (> 5 mmol/L), decreased blood pH, electrolyte disturbances with an

increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated

as the cause of lactic acidosis, metformin plasma levels > 5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is

very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal

cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in

clinical trials, there were no reports of lactic acidosis. Reported cases have occurred

primarily in diabetic patients with significant renal insufficiency, including both intrinsic

renal disease and renal hypoperfusion, often in the setting of multiple concomitant

medical/surgical problems and multiple concomitant medications. Patients with congestive

heart failure requiring pharmacologic management, in particular those with unstable or

acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at

increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of

renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be

significantly decreased by regular monitoring of renal function in patients taking metformin

and by use of the minimum effective dose of metformin. In particular, treatment of the

elderly should be accompanied by careful monitoring of renal function. Glyburide and

metformin treatment should not be initiated in patients ≥ 80 years of age unless

measurement of creatinine clearance demonstrates that renal function is not reduced, as

these patients are more susceptible to developing lactic acidosis. In addition, glyburide and

metformin should be promptly withheld in the presence of any condition associated with

hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly

limit the ability to clear lactate, glyburide and metformin should generally be avoided in

patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned

against excessive alcohol intake, either acute or chronic, when taking glyburide and

metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate

metabolism. In addition, glyburide and metformin hydrochloride should be temporarily

discontinued prior to any intravascular radiocontrast study and for any surgical procedure

(see also PRECAUTIONS).

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms

such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific

abdominal distress. There may be associated hypothermia, hypotension, and resistant

bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must

be aware of the possible importance of such symptoms and the patient should be instructed

to notify the physician immediately if they occur (see also PRECAUTIONS). Glyburide and

metformin should be withdrawn until the situation is clarified. Serum electrolytes, ketones,

blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels

may be useful. Once a patient is stabilized on any dose level of glyburide and metformin,

gastrointestinal symptoms, which are common during initiation of therapy with metformin,

are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due

to lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5

mmol/L in patients taking glyburide and metformin do not necessarily indicate impending

lactic acidosis and may be explainable by other mechanisms, such as poorly controlled

diabetes or obesity, vigorous physical activity, or technical problems in sample handling

(see also PRECAUTIONS).

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking

evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient

with lactic acidosis who is taking glyburide and metformin, the drug should be discontinued

immediately and general supportive measures promptly instituted. Because metformin

hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good

hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis

and remove the accumulated metformin. Such management often results in prompt reversal

of symptoms and recovery (see also CONTRAINDICATIONS and 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

s tructure.

PRECAUTIONS

General

Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction

with glyburide and metformin or any other antidiabetic drug.

Glyburide and Metformin

Hypoglycemia

Glyburide and metformin is capable of producing hypoglycemia or hypoglycemic symptoms, therefore,

proper patient selection, dosing, and instructions are important to avoid potential hypoglycemic

episodes. The risk of hypoglycemia is increased when caloric intake is deficient, when strenuous

exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-

lowering agents or ethanol. Renal or hepatic insufficiency may cause elevated drug levels of both

glyburide and metformin hydrochloride, and the hepatic insufficiency may also diminish gluconeogenic

capacity, both of which increase the risk of hypoglycemic reactions. Elderly, debilitated, or

malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are

particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the

elderly, and in people who are taking beta-adrenergic blocking drugs.

Glyburide

Hemolytic Anemia

Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea

agents can lead to hemolytic anemia. Because glyburide and metformin belongs to the class of

sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea

alternative should be considered. In postmarketing reports, hemolytic anemia has also been reported in

patients who did not have known G6PD deficiency.

Metformin Hydrochloride

Monitoring of renal function

Metformin is known to be substantially excreted by the kidney, and the risk of metformin accumulation

and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum

creatinine levels above the upper limit of normal for their age should not receive glyburide and

metformin. In patients with advanced age, glyburide and metformin should be carefully titrated to

establish the minimum dose for adequate glycemic effect, because aging is associated with reduced

renal function. In elderly patients, particularly those ≥ 80 years of age, renal function should be

monitored regularly and, generally, glyburide and metformin should not be titrated to the maximum dose

(see WARNINGS and DOSAGE AND ADMINISTRATION). Before initiation of glyburide and

metformin therapy and at least annually thereafter, renal function should be assessed and verified as

normal. In patients in whom development of renal dysfunction is anticipated, renal function should be

assessed more frequently and glyburide and metformin discontinued if evidence of renal impairment is

present.

Use of concomitant medications that may affect renal function or metformin disposition

Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or

may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal

tubular secretion (see PRECAUTIONS, Drug Interactions), should be used with caution.

Radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous

urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with

intravascular contrast materials)

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and

have been associated with lactic acidosis in patients receiving metformin (see

CONTRAINDICATIONS). Therefore, in patients in whom any such study is planned, glyburide and

metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld for

48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and

found to be normal.

Hypoxic states

Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial

infarction, and other conditions characterized by hypoxemia have been associated with lactic acidosis

and may also cause prerenal azotemia. When such events occur in patients on glyburide and metformin

therapy, the drug should be promptly discontinued.

Surgical procedures

Glyburide and metformin therapy should be temporarily suspended for any surgical procedure (except

minor procedures not associated with restricted intake of food and fluids) and should not be restarted

until the patient's oral intake has resumed and renal function has been evaluated as normal.

Alcohol intake

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should

be warned against excessive alcohol intake, acute or chronic, while receiving glyburide and metformin.

Due to its effect on the gluconeogenic capacity of the liver, alcohol may also increase the risk of

hypoglycemia.

Impaired hepatic function

Since impaired hepatic function has been associated with some cases of lactic acidosis, glyburide and

metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic

disease.

Vitamin B

levels

In controlled clinical trials with metformin of 29 weeks duration, a decrease to subnormal levels of

previously normal serum Vitamin B

, without clinical manifestations, was observed in approximately

7% of patients. Such decrease, possibly due to interference with B

absorption from the B

-intrinsic

factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible

with discontinuation of metformin or Vitamin B

supplementation. Measurement of hematologic

parameters on an annual basis is advised in patients on metformin and any apparent abnormalities should

be appropriately investigated and managed (see PRECAUTIONS, Laboratory Tests).

Certain individuals (those with inadequate Vitamin B

or calcium intake or absorption) appear to be

predisposed to developing subnormal Vitamin B

levels. In these patients, routine serum Vitamin B

measurements at two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes

A patient with type 2 diabetes previously well controlled on metformin who develops laboratory

abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated

promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes

and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If

acidosis of either form occurs, glyburide and metformin must be stopped immediately and other

appropriate corrective measures initiated (see also WARNINGS).

Addition of Thiazolidinediones to Glyburide and Metformin Therapy

Hypoglycemia

Patients receiving glyburide and metformin in combination with a thiazolidinedione may be at risk for

hypoglycemia.

Weight gain

Weight gain was seen with the addition of rosiglitazone to glyburide and metformin, similar to that

reported for thiazolidinedione therapy alone.

Hepatic effects

When a thiazolidinedione is used in combination with glyburide and metformin, periodic monitoring of

liver function tests should be performed in compliance with the labeled recommendations for the

12

thiazolidinedione.

Information for Patients

Glyburide and Metformin

Patients should be informed of the potential risks and benefits of glyburide and metformin and of

alternative modes of therapy. They should also be informed about the importance of adherence to

dietary instructions, of a regular exercise program, and of regular testing of blood glucose,

glycosylated hemoglobin, renal function, and hematologic parameters.

The risks of lactic acidosis associated with metformin therapy, its symptoms, and conditions that

predispose to its development, as noted in the WARNINGS and PRECAUTIONS sections, should be

explained to patients. Patients should be advised to discontinue glyburide and metformin immediately and

to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual

somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of

glyburide and metformin, gastrointestinal symptoms, which are common during initiation of metformin

therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to

lactic acidosis or other serious disease.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its

development should be explained to patients and responsible family members.

Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving

glyburide and metformin (see PATIENT INFORMATION printed below).

Laboratory Tests

Periodic fasting blood glucose (FBG) and HbA measurements should be performed to monitor

therapeutic response.

Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood

cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis.

While megaloblastic anemia has rarely been seen with metformin therapy, if this is suspected, Vitamin

deficiency should be excluded.

Drug Interactions

Glyburide and Metformin

Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control. These

drugs include thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products,

estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking

drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide and metformin,

the patient should be closely observed for loss of blood glucose control. When such drugs are

withdrawn from a patient receiving glyburide and metformin, the patient should be observed closely for

hypoglycemia. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact

with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as

compared to sulfonylureas, which are extensively bound to serum proteins.

Glyburide

The hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidal

anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides,

chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking

agents. When such drugs are administered to a patient receiving glyburide and metformin, the patient

should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving

glyburide and metformin, the patient should be observed closely for loss of blood glucose control.

A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been

reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this

interaction is not known.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe

hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, or

vaginal preparations of miconazole is not known.

Metformin Hydrochloride

Furosemide

A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that

pharmacokinetic parameters of both compounds were affected by coadministration. Furosemide

increased the metformin plasma and blood C

by 22% and blood AUC by 15%, without any significant

change in metformin renal clearance. When administered with metformin, the C

and AUC of

furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal

half-life was decreased by 32%, without any significant change in furosemide renal clearance. No

information is available about the interaction of metformin and furosemide when coadministered

chronically.

Nifedipine

A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated

that coadministration of nifedipine increased plasma metformin C

and AUC by 20% and 9%,

respectively, and increased the amount excreted in the urine. T

and half-life were unaffected.

Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on

nifedipine.

Cationic drugs

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine,

triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically

have the potential for interaction with metformin by competing for common renal tubular transport

systems. Such interaction between metformin and oral cimetidine has been observed in normal healthy

volunteers in both single- and multiple-dose metformin-cimetidine drug interaction studies, with a 60%

increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and

whole blood metformin AUC. There was no change in elimination half-life in the single-dose study.

Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical

(except for cimetidine), careful patient monitoring and dose adjustment of glyburide and metformin

and/or the interfering drug is recommended in patients who are taking cationic medications that are

excreted via the proximal renal tubular secretory system.

Other

In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen

were not affected when coadministered in single-dose interaction studies.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted with the combined products in glyburide and metformin. 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 [MRHD] dose of 20 mg for the glyburide component of glyburide and

metformin based on body surface area comparisons) for 18 months revealed no carcinogenic effects. In

a two-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.

Metformin Hydrochloride

Long-term carcinogenicity studies were performed with metformin alone 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 MRHD dose of 2000 mg of

the metformin component of glyburide and metformin based on body surface area comparisons. No

evidence of carcinogenicity with metformin alone was found in either male or female mice. Similarly,

there was no tumorigenic potential observed with metformin alone in male rats. There was, however, an

increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day of

metformin alone.

There was no evidence of a mutagenic potential of metformin alone 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 alone when administered at doses as high

as 600 mg/kg/day, which is approximately 3 times the MRHD dose of the metformin component of

glyburide and metformin based on body surface area comparisons.

Pregnancy

Teratogenic Effects

Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are

associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be

used during pregnancy to maintain blood glucose as close to normal as possible. Because animal

reproduction studies are not always predictive of human response, glyburide and metformin should not

be used during pregnancy unless clearly needed (see below).

There are no adequate and well-controlled studies in pregnant women with glyburide and metformin or

its individual components. No animal studies have been conducted with the combined products in

glyburide and metformin. The following data are based on findings in studies performed with the

individual products.

Glyburide

Reproduction studies were performed in rats and rabbits at doses up to 500 times the MRHD dose of 20

mg of the glyburide component of glyburide and metformin based on body surface area comparisons and

revealed no evidence of impaired fertility or harm to the fetus due to glyburide.

Metformin hydrochloride

Metformin alone was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day. This represents an

exposure of about 2 and 6 times the MRHD dose of 2000 mg of the metformin component of glyburide

and metformin based on body surface area comparisons for rats and rabbits, respectively. Determination

of fetal concentrations demonstrated a partial placental barrier to metformin.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were

receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the

use of agents with prolonged half-lives. It is not recommended that glyburide and metformin be used

during pregnancy. However, if it is used, glyburide and metformin should be discontinued at least two

weeks before the expected delivery date (see Pregnancy, Teratogenic Effects, Pregnancy Category B ).

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are

known to be excreted in human milk. Studies in lactating rats show that metformin is excreted into milk

and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing

mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made

whether to discontinue nursing or to discontinue glyburide and metformin, taking into account the

importance of the drug to the mother. If glyburide and metformin is discontinued, and if diet alone is

inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and efficacy of glyburide and metformin were evaluated in an active-controlled, double-

blind, 26 week randomized trial involving a total of 167 pediatric patients (ranging from 9 to 16 years of

age) with type 2 diabetes. Glyburide and metformin was not shown statistically to be superior to either

metformin or glyburide with respect to reducing HbA

from baseline (see Table 5). No unexpected

safety findings were associated with glyburide and metformin in this trial.

Table 5: HbA

(Percent) Change From Baseline at 26 Weeks:

Pediatric Study

Glyburide

2.5 mg

Tablets

Metformin

500 mg

Tablets

Glyburide and

Metformin 1.25

mg/250 mg Tablets

Mean Final

Dos e

6.5 mg

1500 mg

3.1 mg/623 mg

Hemoglobin

A

N = 49

N = 54

N = 57

Baseline Mean

7.70

7.99

7.85

Mean Change

from Baseline

-0.96

-0.48

-0.80

Difference from

Metformin

-0.32

Difference from

Glyburide

+0.16

Geriatric Use

Of the 642 patients who received glyburide and metformin in double-blind clinical studies, 23.8% were

65 and older while 2.8% were 75 and older. Of the 1302 patients who received glyburide and metformin

in open-label clinical studies, 20.7% were 65 and older while 2.5% were 75 and older. No overall

differences in effectiveness or safety were observed between these patients and younger patients, and

other reported clinical experience has not identified differences in response between the elderly and

younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Metformin hydrochloride is known to be substantially excreted by the kidney and because the risk of

serious adverse reactions to the drug is greater in patients with impaired renal function, glyburide and

metformin should only be used in patients with normal renal function (see CONTRAINDICATIONS,

WARNINGS, and CLINICAL PHARMACOLOGY, Pharmacokinetics). Because aging is

associated with reduced renal function, glyburide and metformin should be used with caution as age

increases. Care should be taken in dose selection and should be based on careful and regular monitoring

1c

of renal function. Generally, elderly patients should not be titrated to the maximum dose of glyburide

and metformin (see also WARNINGS and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Glyburide and Metformin

In double-blind clinical trials involving glyburide and metformin as initial therapy or as second-line

therapy, a total of 642 patients received glyburide and metformin, 312 received metformin therapy, 324

received glyburide therapy, and 161 received placebo. The percent of patients reporting events and

types of adverse events reported in clinical trials of glyburide and metformin (all strengths) as initial

therapy and second-line therapy are listed in Table 6.

Table 6: Most Common Clinical Adverse Events (> 5 Percent) in

Double-Blind Clinical Studies of Glyburide and Metformin Used

as Initial or Second-Line Therapy

Adverse Event

Number (%) of Patients

Placebo

N= 161

Glyburide

N=324

Metformin

N=312

Glyburide

andMetformin

N= 642

Upper

respiratory

infection

22 (13.7)

57 (17.6)

51 (16.3)

111 (17.3)

Diarrhea

9 (5.6)

20 (6.2)

64 (20.5)

109 (17)

Headache

17 (10.6)

37 (11.4)

29 (9.3)

57 (8.9)

Nausea/vomiting

10 (6.2)

17 (5.2)

38 (12.2)

49 (7.6)

Abdominal pain

6 (3.7)

10 (3.1)

25 (8)

44 (6.9)

Dizziness

7 (4.3)

18 (5.6)

12 (3.8)

35 (5.5)

In a controlled clinical trial of rosiglitazone versus placebo in patients treated with glyburide and

metformin (n = 365), 181 patients received glyburide and metformin with rosiglitazone and 184 received

glyburide and metformin with placebo.

Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184)

of patients treated with placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated

patients.

Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

Hypoglycemia

In controlled clinical trials of glyburide and metformin there were no hypoglycemic episodes requiring

medical intervention and/or pharmacologic therapy; all events were managed by the patients. The

incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger),

in the initial therapy trial of glyburide and metformin are summarized in Table 7.

The frequency of hypoglycemic symptoms in patients treated with glyburide and metformin 1.25 mg/250

mg was highest in patients with a baseline HbA

< 7%, lower in those with a baseline HbA

between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA

>

8%. For patients with a baseline HbA between 8% and 11% treated with glyburide and metformin 2.5

mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30 to 35%. As second-line

therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients

treated with glyburide and metformin experienced hypoglycemic symptoms. When rosiglitazone was

added to glyburide and metformin therapy, 22% of patients reported one or more fingerstick glucose

measurements ≤ 50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were

managed by the patients and only one patient discontinued for hypoglycemia (see PRECAUTIONS,

General, Addition of Thiazolidinediones to Glyburide and Metformin Therapy).

Gastrointestinal Reactions

The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the

initial therapy trial are summarized in Table 7. Across all glyburide and metformin trials, GI symptoms

were the most common adverse events with glyburide and metformin and were more frequent at higher

dose levels. In controlled trials, < 2% of patients discontinued glyburide and metformin therapy due to

GI adverse events.

Table 7: Treatment Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse

Events in a Placebo- and Active-Controlled Trial of Glyburide and Metformin as Initial

Therapy

Variable

Placebo GlyburideTablets MetforminTablets

Glyburide

andMetformin

1.25 mg/250

mgTablets

Glyburide

andMetformin

2.5 mg/500

mg Tablets

N = 161

N = 160

N = 159

N = 158

N = 162

Mean Final

Dose

0 mg

5.3 mg

1317 mg

2.78 mg/557

4.1 mg/824 mg

Number (%) of

patients with

symptoms of

hypoglycemia

5 (3.1)

34 (21.3)

5 (3.1)

18 (11.4)

61 (37.7)

Number (%) of

patients with

gastrointestinal

adverse events

(24.2)

38 (23.8)

69 (43.3)

50 (31.6)

62 (38.3)

In postmarketing reports cholestatic jaundice and hepatitis may occur rarely which may progress to liver

failure; glyburide and metformin should be discontinued if this occurs.

OVERDOSAGE

Glyburide

Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild

hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated

aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring

should continue until the physician is assured that the patient is out of danger.

Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur

infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic

coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of

concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more

dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.

Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur

after apparent clinical recovery.

Metformin Hydrochloride

Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50

grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with

metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32%

of metformin overdose cases (see WARNINGS). Metformin is dialyzable with a clearance of up to 170

mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of

accumulated drug from patients in whom metformin overdosage is suspected.

DOSAGE AND ADMINISTRATION

General Considerations

Dosage of glyburide and metformin hydrochloride tablets USP must be individualized on the

basis of both effectiveness and tolerance while not exceeding the maximum recommended daily

dose of 20 mg glyburide/2000 mg metformin. Glyburide and metformin hydrochloride tablets should

be given with meals and should be initiated at a low dose, with gradual dose escalation as described

below, in order to avoid hypoglycemia (largely due to glyburide), to reduce GI side effects (largely

due to metformin), and to permit determination of the minimum effective dose for adequate control of

blood glucose for the individual patient.

With initial treatment and during dose titration, appropriate blood glucose monitoring should be used to

determine the therapeutic response to glyburide and metformin hydrochloride tablets USP and to

identify the minimum effective dose for the patient. Thereafter, HbA

should be measured at intervals

of approximately 3 months to assess the effectiveness of therapy. The therapeutic goal in all patients

with type 2 diabetes is to decrease FPG, PPG, and HbA

to normal or as near normal as possible.

Ideally, the response to therapy should be evaluated using HbA

(glycosylated hemoglobin), which is a

better indicator of long-term glycemic control than FPG alone.

No studies have been performed specifically examining the safety and efficacy of switching to

glyburide and metformin hydrochloride tablets USP therapy in patients taking concomitant glyburide (or

other sulfonylurea) plus metformin. Changes in glycemic control may occur in such patients, with either

hyperglycemia or hypoglycemia possible. Any change in therapy of type 2 diabetes should be

undertaken with care and appropriate monitoring.

Glyburide and Metformin Hydrochloride Tablets USP Use in Patients with Inadequate Glycemic

Control on Diet and Exercise

Recommended starting dose: 1.25 mg/250 mg once or twice daily with meals

For patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed with diet and

exercise alone, the recommended starting dose of glyburide and metformin hydrochloride tablets USP

is 1.25 mg/250 mg once a day with a meal. As initial therapy in patients with baseline HbA

> 9% or an

FPG > 200 mg/dL, a starting dose of glyburide and metformin hydrochloride tablets USP 1.25 mg/250

mg twice daily with the morning and evening meals may be used. Dosage increases should be made in

increments of 1.25 mg/250 mg per day every two weeks up to the minimum effective dose necessary to

achieve adequate control of blood glucose. In clinical trials of glyburide and metformin hydrochloride

tablets USP as initial therapy, there was no experience with total daily doses greater than 10 mg/2000

mg per day. Glyburide and metformin hydrochloride tablets USP 5 mg/500 mg should not be used

as initial therapy due to an increased risk of hypoglycemia.

Glyburide and Metformin Hydrochloride Tablets USP Use in Patients with Inadequate Glycemic

Control on a Sulfonylurea and/or Metformin

Recommended starting dose: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals

For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin alone,

the recommended starting dose of glyburide and metformin hydrochloride tablets USP is 2.5 mg/500 mg

or 5 mg/500 mg twice daily with the morning and evening meals. In order to avoid hypoglycemia, the

starting dose of glyburide and metformin hydrochloride tablets USP should not exceed the daily doses

of glyburide or metformin already being taken. The daily dose should be titrated in increments of no

more than 5 mg/500 mg up to the minimum effective dose to achieve adequate control of blood glucose

or to a maximum dose of 20 mg/2000 mg per day.

For patients previously treated with combination therapy of glyburide (or another sulfonylurea) plus

metformin, if switched to glyburide and metformin hydrochloride tablets USP, the starting dose should

not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin

already being taken. Patients should be monitored closely for signs and symptoms of hypoglycemia

following such a switch and the dose of glyburide and metformin hydrochloride tablets USP should be

titrated as described above to achieve adequate control of blood glucose.

Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Tablets USP Therapy

For patients not adequately controlled on glyburide and metformin hydrochloride tablets USP, a

thiazolidinedione can be added to glyburide and metformin hydrochloride tablets USP therapy. When a

thiazolidinedione is added to glyburide and metformin hydrochloride tablets USP therapy, the current

dose of glyburide and metformin hydrochloride tablets USP can be continued and the thiazolidinedione

initiated at its recommended starting dose. For patients needing additional glycemic control, the dose of

the thiazolidinedione can be increased based on its recommended titration schedule. The increased

glycemic control attainable with glyburide and metformin hydrochloride tablets USP plus a

thiazolidinedione may increase the potential for hypoglycemia at any time of day. In patients who

develop hypoglycemia when receiving glyburide and metformin hydrochloride tablets USP and a

thiazolidinedione, consideration should be given to reducing the dose of the glyburide component of

glyburide and metformin hydrochloride tablets USP. As clinically warranted, adjustment of the dosages

of the other components of the antidiabetic regimen should also be considered.

Specific Patient Populations

Glyburide and metformin hydrochloride tablets USP are not recommended for use during pregnancy.

The initial and maintenance dosing of glyburide and metformin hydrochloride tablets USP should be

conservative in patients with advanced age, due to the potential for decreased renal function in this

population. Any dosage adjustment requires a careful assessment of renal function. Generally, elderly,

debilitated, and malnourished patients should not be titrated to the maximum dose of glyburide and

metformin hydrochloride tablets USP to avoid the risk of hypoglycemia. Monitoring of renal function is

necessary to aid in prevention of metformin-associated lactic acidosis, particularly in the elderly (see

WARNINGS).

HOW SUPPLIED

Glyburide and Metformin Hydrochloride Tablets USP, 1.25/250 mg are available as light yellow, oval-

shaped, beveled-edged, film-coated tablets, debossed

and "5710" on one side and "1.25/250" on the other side containing 1.25 mg glyburide USP and 250 mg

metformin hydrochloride USP packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100

tablets.

Glyburide and Metformin Hydrochloride Tablets USP, 2.5/500 mg are available as light orange, oval-

shaped, beveled-edged, film-coated tablets, debossed

and "5711" on one side and "2.5/500" on the other side containing 2.5 mg glyburide USP and 500 mg

metformin hydrochloride USP packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100

tablets.

Glyburide and Metformin Hydrochloride Tablets USP, 5/500 mg are available as yellow, oval-shaped,

beveled-edged, film-coated tablets, debossed

and "5712" on one side and "5/500" on the other side containing 5 mg glyburide USP and 500 mg

metformin hydrochloride USP packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100

tablets.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured In India By:

EMCURE PHARMACEUTICALS LTD.

Hinjwadi, Pune, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. H 12/2010

PATIENT INFORMATION ABOUT GLYBURIDE AND METFORMIN HYDROCHLORIDE

TABLETS USP

Rx only

WARNING

A small number of people who have taken metformin hydrochloride have developed a

serious condition called lactic acidosis. Properly functioning kidneys are needed to help

prevent lactic acidosis. Most people with kidney problems should not take glyburide and

metformin (see questions 9 through 13).

1. Why do I need to take glyburide and metformin?

Your doctor has prescribed glyburide and metformin to treat your type 2 diabetes. This is also known as

non-insulin-dependent diabetes mellitus.

2. What is type 2 diabetes?

People with diabetes are not able to make enough insulin and/or respond normally to the insulin their

body does make. When this happens, sugar (glucose) builds up in the blood. This can lead to serious

medical problems including kidney damage, amputations, and blindness. Diabetes is also closely linked

to heart disease. The main goal of treating diabetes is to lower your blood sugar to a normal level.

3. Why is it important to control type 2 diabetes?

The main goal of treating diabetes is to lower your blood sugar to a normal level. Studies have shown

that good control of blood sugar may prevent or delay complications such as heart disease, kidney

disease, or blindness.

4. How is type 2 diabetes usually controlled?

High blood sugar can be lowered by diet and exercise, a number of oral medications, and insulin

injections. Before taking glyburide and metformin you should first try to control your diabetes by

exercise and weight loss. Even if you are taking glyburide and metformin, you should still exercise and

follow the diet recommended for your diabetes.

5. Does glyburide and metformin work differently from other glucose-control medications?

Yes it does. Glyburide and metformin combines two glucose-lowering drugs, glyburide and metformin.

These two drugs work together to improve the different metabolic defects found in type 2 diabetes.

Glyburide lowers blood sugar primarily by causing more of the body’s own insulin to be released, and

metformin lowers blood sugar, in part, by helping your body use your own insulin more effectively.

Together, they are efficient in helping you achieve better glucose control.

6. What happens if my blood sugar is still too high?

When blood sugar cannot be lowered enough by glyburide and metformin your doctor may prescribe

injectable insulin or take other measures to control your diabetes.

7. Can glyburide and metformin cause side effects?

Glyburide and metformin, like all blood sugar-lowering medications, can cause side effects in some

patients. Most of these side effects are minor. However, there are also serious, but rare, side effects

related to glyburide and metformin (see questions 9 through 13).

8. What are the most common side effects of glyburide and metformin?

The most common side effects of glyburide and metformin are normally minor ones such as diarrhea,

nausea, and upset stomach. If these side effects occur, they usually occur during the first few weeks of

therapy. Taking your glyburide and metformin with meals can help reduce these side effects.

Less frequently, symptoms of hypoglycemia (low blood sugar), such as lightheadedness, dizziness,

shakiness, or hunger may occur. The risk of hypoglycemic symptoms increases when meals are

skipped, too much alcohol is consumed, or heavy exercise occurs without enough food. Following the

advice of your doctor can help you to avoid these symptoms.

9. Are there any serious side effects that glyburide and metformin can cause?

People who have a condition known as glucose-6-phosphate dehydrogenase (G6PD) deficiency and

who take glyburide and metformin may develop hemolytic anemia (fast breakdown of red blood cells).

G6PD deficiency usually runs in families. Tell your doctor if you or any members of your family have

been diagnosed with G6PD deficiency before you start taking glyburide and metformin.

Glyburide and metformin rarely cause serious side effects. The most serious side effect that glyburide

and metformin can cause is called lactic acidosis.

10. What is lactic acidosis and can it happen to me?

Lactic acidosis is caused by a buildup of lactic acid in the blood. Lactic acidosis associated with

metformin is rare and has occurred mostly in people whose kidneys were not working normally. Lactic

acidosis has been reported in about one in 33,000 patients taking metformin over the course of a year.

Although rare, if lactic acidosis does occur, it can be fatal in up to half the cases.

It’s also important for your liver to be working normally when you take glyburide and metformin. Your

liver helps remove lactic acid from your bloodstream.

Your doctor will monitor your diabetes and may perform blood tests on you from time to time to make

sure your kidneys and your liver are functioning normally.

There is no evidence that glyburide and metformin causes harm to the kidneys or liver.

11. Are there other risk factors for lactic acidosis?

Your risk of developing lactic acidosis from taking glyburide and metformin is very low as long as

your kidneys and liver are healthy. However, some factors can increase your risk because they can

affect kidney and liver function. You should discuss your risk with your physician.

You should not take glyburide and metformin if:

You have chronic kidney or liver problems

You have congestive heart failure which is treated with medications, e.g., digoxin (Lanoxin ) or

furosemide (Lasix

You drink alcohol excessively (all the time or short-term "binge" drinking)

You are seriously dehydrated (have lost a large amount of body fluids)

You are going to have certain x-ray procedures with injectable contrast agents

You are going to have surgery

You develop a serious condition such as a heart attack, severe infection, or a stroke

You are ≥ 80 years of age and have NOT had your kidney function tested

12. What are the symptoms of lactic acidosis?

Some of the symptoms include: feeling very weak, tired or uncomfortable; unusual muscle pain, trouble

breathing, unusual or unexpected stomach discomfort, feeling cold, feeling dizzy or lightheaded, or

suddenly developing a slow or irregular heartbeat.

If you notice these symptoms, or if your medical condition has suddenly changed, stop taking glyburide

and metformin tablets and call your doctor right away. Lactic acidosis is a medical emergency that must

be treated in a hospital.

13. What does my doctor need to know to decrease my risk of lactic acidosis?

Tell your doctor if you have an illness that results in severe vomiting, diarrhea, and/or fever, or if your

intake of fluids is significantly reduced. These situations can lead to severe dehydration, and it may be

necessary to stop taking glyburide and metformin temporarily.

You should let your doctor know if you are going to have any surgery or specialized x-ray procedures

that require injection of contrast agents. Glyburide and metformin therapy will need to be stopped

temporarily in such instances.

14. Can I take glyburide and metformin with other medications?

Remind your doctor that you are taking glyburide and metformin when any new drug is prescribed or a

change is made in how you take a drug already prescribed. Glyburide and metformin may interfere with

the way some drugs work and some drugs may interfere with the action of glyburide and metformin.

15. What if I become pregnant while taking glyburide and metformin?

Tell your doctor if you plan to become pregnant or have become pregnant. As with other oral glucose-

control medications, you should not take glyburide and metformin during pregnancy.

Usually your doctor will prescribe insulin while you are pregnant. As with all medications, you and

your doctor should discuss the use of glyburide and metformin if you are nursing a child.

16. How do I take glyburide and metformin?

Your doctor will tell you how many glyburide and metformin tablets to take and how often. This should

also be printed on the label of your prescription. You will probably be started on a low dose of

glyburide and metformin and your dosage will be increased gradually until your blood sugar is

controlled.

17. Where can I get more information about glyburide and metformin?

This leaflet is a summary of the most important information about glyburide and metformin. If you have

any questions or problems, you should talk to your doctor or other healthcare provider about type 2

diabetes as well as glyburide and metformin and its side effects. There is also a leaflet (package insert)

written for health professionals that your pharmacist can let you read.

Lanoxin is a registered trademark of GlaxoSmithKline.

Lasix

is a registered trademark of Aventis Pharmaceuticals Inc.

Manufactured In India By:

EMCURE PHARMACEUTICALS LTD.

Hinjwadi, Pune, India

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. B 12/2009

PRINCIPAL DISPLAY PANEL

PDRx Label

GLYBURIDE and METFORMIN HYDROCHLORIDE Tablets USP

5 mg/500 mg

PHARMACIST: PLEASE DISPENSE WITH PATIENT INFORMATION LEAFLET PROVIDED

SEPARATELY

Rx only

Each tablet contains 5 mg glyburide, USP and 500 mg metformin hydrochloride, USP.

Usual Dosage: See package insert for full prescribing information.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

GLYBURIDE AND METFORMIN

glyburide and metformin tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:5528 9 -28 1(NDC:0 0 9 3-5712)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

Glyburide (UNII: SX6 K58 TVWC) (Glyburide - UNII:SX6 K58 TVWC)

Glyburide

5 mg

Metfo rmin Hydro chlo ride (UNII: 78 6 Z46 38 9 E) (METFORMIN - UNII:9 10 0 L32L2N)

Metfo rmin Hydro chlo ride

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CO PO VIDO NE (UNII: D9 C330 MD8 B)

CRO SPO VIDO NE (UNII: 6 8 40 19 6 0 MK)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

Product Characteristics

Color

YELLOW

S core

no sco re

PD-Rx Pharmaceuticals, Inc.

S hap e

OVAL

S iz e

16 mm

Flavor

Imprint Code

5712;5;50 0

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:5528 9 -28 1-30

30 in 1 BOTTLE, PLASTIC

2

NDC:5528 9 -28 1-6 0

6 0 in 1 BOTTLE, PLASTIC

3

NDC:5528 9 -28 1-8 6

36 0 in 1 BOTTLE, PLASTIC

4

NDC:5528 9 -28 1-9 0

9 0 in 1 BOTTLE, PLASTIC

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 345

0 1/0 3/20 11

Labeler -

PD-Rx Pharmaceuticals, Inc. (156893695)

Registrant -

PD-Rx Pharmaceuticals, Inc. (156893695)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

PD-Rx Pharmaceuticals, Inc.

156 8 9 36 9 5

re pa c k

Revised: 1/2011

Similar products

Search alerts related to this product

Share this information