Prescription Drug Information: Glipizide and Metformin Hydrochloride

GLIPIZIDE AND METFORMIN HYDROCHLORIDE- glipizide and metformin hydrochloride tablet, film coated
Teva Pharmaceuticals USA, Inc.

Glipizide and Metformin Hydrochloride Tablets, USP Rx only


Glipizide and metformin hydrochloride tablets, USP contain 2 oral antihyperglycemic drugs used in the management of type 2 diabetes, glipizide, USP and metformin hydrochloride, USP.

Glipizide, USP is an oral antihyperglycemic drug of the sulfonylurea class. The chemical name for glipizide, USP is 1-cyclohexyl-3-[[p -[2-(5-methylpyrazinecarboxamido)ethyl]phenyl]sulfonyl]urea. Glipizide, USP is a whitish, odorless powder with a pKa of 5.9. It is insoluble in water and alcohols, but soluble in 0.1 N NaOH; it is freely soluble in dimethylformamide. The structural formula is represented below.

Structural formula for glipizide

C21 H27 N5 O4 S M.W. 445.55

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 pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride, USP is 6.68. The structural formula is as shown:

structural formula for metformin hydrochloride

C4 H12 ClN5 M.W. 165.63

Glipizide and metformin hydrochloride tablets, USP for oral administration contain 2.5 mg glipizide, USP with 250 mg metformin hydrochloride, USP, 2.5 mg glipizide, USP with 500 mg metformin hydrochloride, USP, and 5 mg glipizide, USP with 500 mg metformin hydrochloride, USP. In addition, each tablet contains the following inactive ingredients: corn starch, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol-part. hydrolyzed, povidone, talc, and titanium dioxide. Additionally, 2.5 mg/250 mg and 5 mg/500 mg tablets contain iron oxide black, iron oxide red, and iron oxide yellow. The tablets are film-coated, which provides color differentiation.


Mechanism of Action

Glipizide and metformin hydrochloride tablets combine glipizide and metformin hydrochloride, 2 antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes.

Glipizide 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. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the postprandial insulin response continues to be enhanced after at least 6 months of treatment.

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.


Absorption and Bioavailability

Glipizide and metformin hydrochloride tablets

In a single-dose study in healthy subjects, the glipizide and metformin components of glipizide and metformin hydrochloride tablets, 5 mg/500 mg were bioequivalent to coadministered glipizide tablets and metformin hydrochloride tablets. Following administration of a single glipizide and metformin hydrochloride 5 mg/500 mg tablet in healthy subjects with either a 20% glucose solution or a 20% glucose solution with food, there was a small effect of food on peak plasma concentration (Cmax ) and no effect of food on area under the curve (AUC) of the glipizide component. Time to peak plasma concentration (Tmax ) for the glipizide component was delayed 1 hour with food relative to the same tablet strength administered fasting with a 20% glucose solution. Cmax for the metformin component was reduced approximately 14% by food whereas AUC was not affected. Tmax for the metformin component was delayed 1 hour after food.


Gastrointestinal absorption of glipizide is uniform, rapid, and essentially complete. Peak plasma concentrations occur 1 to 3 hours after a single oral dose. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes.

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.



Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98% to 99% 1 hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 liters, indicative of localization within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the fetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the fetuses of rats given labeled drug.

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


The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates, and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in the urine. The half-life of elimination ranges from 2 to 4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the 2 routes of administration, indicating that first-pass metabolism is not significant.

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.

Specific Populations

Patients With Type 2 Diabetes

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.

Renal Impairment

The metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

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 WARNINGS).

Hepatic Impairment

The metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see PRECAUTIONS).

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


There is no information on the pharmacokinetics of glipizide in elderly patients.

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax is increased, when compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1).

Table 1: Select Mean (± SD) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin
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 5 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)
CLcr = creatinine clearance normalized to body surface area of 1.73 m2

Subject Groups: Metformin Dose *

(Number of Subjects)





Renal Clearance


Healthy, Nondiabetic Adults:

500 mg SD § (24)

1.03 (± 0.33)

2.75 (± 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 Þ , 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 ß 61 to 90 mL/min) (5)

1.86 (± 0.52)

3.20 (± 0.45)

384 (± 122)

Moderate (CLcr 31 to 60 mL/min) (4)

4.12 (± 1.83)

3.75 (± 0.50)

108 (± 57)

Severe (CLcr 10 to 30 mL/min) (6)

3.93 (± 0.92)

4.01 (± 1.10)

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