GLIPIZIDE tablet

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

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Active ingredient:
GLIPIZIDE (UNII: X7WDT95N5C) (GLIPIZIDE - UNII:X7WDT95N5C)
Available from:
Direct_Rx
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Glipizide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Glipizide is contraindicated in patients with: 1. Known hypersensitivity to the drug. 2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
Product summary:
Glipizide Tablets, USP are supplied as white to off-white, round, scored tablets, imprinted as follows: 5 mg- “APO” on the side and “GLP” over bisect “5” on the other side; 10 mg- “APO” on one side and “GLP” over bisect “10” on the other side. 5 mg Bottles: 100’s 500’s 1,000’s 18,000’s 10 mg Bottles: 100’s 500’s 1,000’s 10,000’s
Authorization status:
Abbreviated New Drug Application
Authorization number:
61919-287-30

GLIPIZIDE- glipizide tablet

Direct_Rx

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GLIPIZIDE

Glipizide is an oral blood-glucose-lowering drug of the sulfonylurea class.

The Chemical Abstracts name of glipizide is 1-cyclohexyl-3-[[p-[2-(5-methylpyrazine-

carboxamido)ethyl]phenyl]sulfonyl]urea. The molecular formula is C21H27N5O4S; the molecular

weight is 445.55; the structural formula is shown below:

Glipizide 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. Glipizide tablets, USP for oral use

are available in 5 and 10 mg strengths.

Inert ingredients are: anhydrous lactose; colloidal silicon dioxide; magnesium stearate; sodium starch

glycolate.

Meets USP Dissolution Test 2.

Mechanism of Action

The primary mode of action of glipizide in experimental animals appears to be the stimulation of insulin

secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in

the pancreatic islets. In humans, glipizide appears to lower the 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 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. The insulinotropic response to a meal occurs within 30 minutes after an oral dose of glipizide

in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge.

Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic

drugs.

Blood sugar control persists in some patients for up to 24 hours after a single dose of glipizide, even

though plasma levels have declined to a small fraction of peak levels by that time (see Pharmacokinetics

below).

Some patients fail to respond initially, or gradually lose their responsiveness to sulfonylurea drugs,

including glipizide. Alternatively, glipizide may be effective in some patients who have not responded

or have ceased to respond to other sulfonylureas.

Other Effects

It has been shown that glipizide therapy was effective in controlling blood sugar without deleterious

changes in the plasma lipoprotein profiles of patients treated for NIDDM.

In a placebo-controlled, crossover study in normal volunteers, glipizide had no antidiuretic activity and,

in fact, led to a slight increase in free water clearance.

Pharmacokinetics

Gastrointestinal absorption of glipizide in man is uniform, rapid, and essentially complete. Peak plasma

concentrations occur 1 to 3 hours after a single oral dose. 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 two routes of administration, indicating that first-pass metabolism is not significant.

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. Thus, glipizide was more effective when administered about 30 minutes before,

rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers

who received either oral or intravenous glipizide and found to be 98 to 99% one 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.

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.

Glipizide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults

with type 2 diabetes mellitus.

Glipizide is contraindicated in patients with:

1. Known hypersensitivity to the drug.

2. Type 1 diabetes mellitus, diabetic ketoacidosis, with or without coma. This condition should be

treated with insulin.

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,

supp. 2: 747-830, 1970). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose

of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 21/2 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 advantages of glipizide 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 oral hypoglycemic drugs

in this class, in view of their close similarities in mode of action and chemical structure.

General

Macrovascular Outcomes

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

with glipizide or any other anti-diabetic drug.

Renal and Hepatic Disease

The metabolism and excretion of glipizide may be slowed in patients with impaired renal and/or hepatic

function. If hypoglycemia should occur in such patients, it may be prolonged and appropriate

management should be instituted.

Hypoglycemia

All sulfonylurea drugs are capable of producing severe hypoglycemia. Proper patient selection,

dosage, and instructions are important to avoid hypoglycemic episodes. Renal or hepatic insufficiency

may cause elevated blood levels of glipizide and the latter may also diminish gluconeogenic capacity,

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

patients, and those with adrenal or pituitary insufficiency, are particularly susceptible to the

hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the

elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to

occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or

when more than one glucose-lowering drug is used.

Loss of Control of Blood Glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection,

or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and

administer insulin.

The effectiveness of any oral hypoglycemic drug, including glipizide, in lowering blood glucose to a

desired level decreases in many patients over a period of time, which may be due to progression of the

severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as

secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual

patient when first given.

Hemolytic Anemia

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

agents can lead to hemolytic anemia. Because glipizide 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 post-marketing reports, hemolytic anemia has also been reported in patients who did not

have known G6PD deficiency.

Laboratory Tests

Blood and urine glucose should be monitored periodically. Measurement of glycosylated hemoglobin

may be useful.

Information for Patients

Patients should be informed of the potential risks and advantages of glipizide and of alternative modes

of therapy. They should also be informed about the importance of adhering to dietary instructions, of a

regular exercise program, and of regular testing of urine and/or blood glucose.

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

development should be explained to patients and responsible family members. Primary and secondary

failure should also be explained.

Physician Counseling Information for Patients

In initiating treatment for type 2 diabetes, diet should be emphasized as the primary form of treatment.

Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary

management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia.

The importance of regular physical activity should also be stressed, and cardiovascular risk factors

should be identified and corrective measures taken where possible. Use of glipizide or other

antidiabetic medications must be viewed by both the physician and patient as a treatment in addition to

diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore,

loss of blood glucose control on diet alone may be transient, thus requiring only short-term

administration of glipizide or other antidiabetic medications. Maintenance or discontinuation of

glipizide or other antidiabetic medications should be based on clinical judgment using regular clinical

and laboratory evaluations.

Drug Interactions

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

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

sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, quinolones and

beta adrenergic blocking agents. When such drugs are administered to a patient receiving glipizide, the

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

receiving glipizide, the patient should be observed closely for loss of control. In vitro binding studies

with human serum proteins indicate that glipizide binds differently than tolbutamide and does not interact

with salicylate or dicumarol. However, caution must be exercised in extrapolating these findings to the

clinical situation and in the use of glipizide with these drugs.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the

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 glipizide, the patient should be

closely observed for loss of control. When such drugs are withdrawn from a patient receiving

glipizide, the patient should be observed closely for hypoglycemia.

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. The effect of concomitant administration of

fluconazole and glipizide has been demonstrated in a placebo-controlled crossover study in normal

volunteers. All subjects received glipizide alone and following treatment with 100 mg of fluconazole

as a single daily oral dose for 7 days. The mean percentage increase in the glipizide AUC after

fluconazole administration was 56.9% (range: 35 to 81).

In studies assessing the effect of colesevelam on the pharmacokinetics of glipizide ER in healthy

volunteers, reductions in glipizide AUC0-∞ and Cmax of 12% and 13%, respectively were observed

when colesevelam was coadministered with glipizide ER. When glipizide ER was administered 4 hours

prior to colesevelam, there was no significant change in glipizide AUC0-∞ or Cmax, -4% and 0%,

respectively. Therefore, glipizide should be administered at least 4 hours prior to colesevelam to

ensure that colesevelam does not reduce the absorption of glipizide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

A twenty month study in rats and an eighteen month study in mice at doses up to 75 times the maximum

human dose revealed no evidence of drug-related carcinogenicity. Bacterial and in vivo mutagenicity

tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose

showed no effects on fertility.

Pregnancy

Pregnancy Category C

Glipizide was found to be mildly fetotoxic in rat reproductive studies at all dose levels (5 to 50 mg/kg).

This fetotoxicity has been similarly noted with other sulfonylureas, such as tolbutamide and tolazamide.

The effect is perinatal and believed to be directly related to the pharmacologic (hypoglycemic) action

of glipizide. In studies in rats and rabbits, no teratogenic effects were found. There are no adequate and

well controlled studies in pregnant women. Glipizide should be used during pregnancy only if the

potential benefit justifies the potential risk to the fetus.

Because recent information suggests that abnormal blood glucose levels during pregnancy are

associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be

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

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. If glipizide is used during pregnancy, it should be discontinued

at least one month before the expected delivery date.

Nursing Mothers

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

known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may

exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into

account the importance of the drug to the mother. If the drug is discontinued and if diet alone is

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

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatric Use

A determination has not been made whether controlled clinical studies of glipizide included sufficient

numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other

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

younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at

the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac

function, and of concomitant disease or other drug therapy.

In U.S. and foreign controlled studies, the frequency of serious adverse reactions reported was very

low. Of 702 patients, 11.8% reported adverse reactions and in only 1.5% was glipizide discontinued.

Hypoglycemia

See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal

Gastrointestinal disturbances are the most common reactions. Gastrointestinal complaints were reported

with the following approximate incidence: nausea and diarrhea, one in seventy; constipation and

gastralgia, one in one hundred. They appear to be dose-related and may disappear on division or

reduction of dosage. Cholestatic jaundice may occur rarely with sulfonylureas: glipizide should be

discontinued if this occurs.

Dermatologic

Allergic skin reactions including erythema, morbilliform or maculopapular eruptions, urticaria, pruritus,

and eczema have been reported in about one in seventy patients. These may be transient and may

disappear despite continued use of glipizide; if skin reactions persist, the drug should be discontinued.

Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic

anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic

Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas. In the mouse,

glipizide pretreatment did not cause an accumulation of acetaldehyde after ethanol administration.

Clinical experience to date has shown that glipizide has an extremely low incidence of disulfiram-like

alcohol reactions.

Endocrine Reactions

Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have

been reported with this and other sulfonylureas.

Miscellaneous

Dizziness, drowsiness, and headache have each been reported in about one in fifty patients treated with

glipizide. They are usually transient and seldom require discontinuance of therapy.

Laboratory Tests

The pattern of laboratory test abnormalities observed with glipizide was similar to that for other

sulfonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN, and

creatinine were noted. One case of jaundice was reported. The relationship of these abnormalities to

glipizide is uncertain, and they have rarely been associated with clinical symptoms.

Post-Marketing Experience

The following adverse events have been reported in post-marketing surveillance:

Hepatobiliary

Cholestatic and hepatocellular forms of liver injury accompanied by jaundice have been reported rarely

in association with glipizide; glipizide should be discontinued if this occurs.

There is no well documented experience with glipizide overdosage. The acute oral toxicity was

extremely low in all species tested (LD50 greater than 4 g/kg).

Overdosage of sulfonylureas, including glipizide, can produce hypoglycemia. Mild hypoglycemic

symptoms without loss of consciousness or neurologic 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. Clearance of glipizide

from plasma would be prolonged in persons with liver disease. Because of the extensive protein

binding of glipizide, dialysis is unlikely to be of benefit.

There is no fixed dosage regimen for the management of diabetes mellitus with glipizide or any other

hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose

must also be monitored periodically to determine the minimum effective dose for the patient; to detect

primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of

medication; and to detect secondary failure, i.e., loss of an adequate blood-glucose-lowering response

after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in

monitoring the patient's response to therapy.

Short-term administration of glipizide may be sufficient during periods of transient loss of control in

patients usually controlled well on diet.

In general, glipizide tablets should be given approximately 30 minutes before a meal to achieve the

greatest reduction in postprandial hyperglycemia.

Initial Dose

The recommended starting dose is 5 mg, given before breakfast. Geriatric patients or those with liver

disease may be started on 2.5 mg.

T itration

Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose

response. At least several days should elapse between titration steps. If response to a single dose is not

satisfactory, dividing that dose may prove effective. The maximum recommended once daily dose is 15

mg. Doses above 15 mg should ordinarily be divided and given before meals of adequate caloric

content. The maximum recommended total daily dose is 40 mg.

Maintenance

Some patients may be effectively controlled on a once-a-day regimen, while others show better

response with divided dosing. Total daily doses above 15 mg should ordinarily be divided. Total daily

doses above 30 mg have been safely given on a b.i.d. basis to long-term patients.

In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic

function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions

(see PRECAUTIONS section).

Patients Receiving Insulin

As with other sulfonylurea-class hypoglycemics, many stable non-insulin-dependent diabetic patients

receiving insulin may be safely placed on glipizide. When transferring patients from insulin to glipizide,

the following general guidelines should be considered:

For patients whose daily insulin requirement is 20 units or less, insulin may be discontinued and

glipizide therapy may begin at usual dosages. Several days should elapse between glipizide titration

steps.

For patients whose daily insulin requirement is greater than 20 units, the insulin dose should be reduced

by 50% and glipizide therapy may begin at usual dosages. Subsequent reductions in insulin dosage

should depend on individual patient response. Several days should elapse between glipizide titration

steps.

During the insulin withdrawal period, the patient should test urine samples for sugar and ketone bodies

at least three times daily. Patients should be instructed to contact the prescriber immediately if these

tests are abnormal. In some cases, especially when patient has been receiving greater than 40 units of

insulin daily, it may be advisable to consider hospitalization during the transition period.

Patients Receiving Other Oral Hypoglycemic Agents

As with other sulfonylurea-class hypoglycemics, no transition period is necessary when transferring

patients to glipizide. Patients should be observed carefully (1 to 2 weeks) for hypoglycemia when being

transferred from longer half-life sulfonylureas (e.g., chlorpropamide) to glipizide due to potential

overlapping of drug effect.

When colesevelam is coadministered with glipizide ER, maximum plasma concentration and total

exposure to glipizide is reduced. Therefore, glipizide should be administered at least 4 hours prior to

colesevelam.

Glipizide Tablets, USP are supplied as white to off-white, round, scored tablets, imprinted as follows:

5 mg- “APO” on the side and “GLP” over bisect “5” on the other side; 10 mg- “APO” on one side and

“GLP” over bisect “10” on the other side.

5 mg Bottles:

100’s

500’s

1,000’s

18,000’s

10 mg Bottles:

100’s

500’s

1,000’s

10,000’s

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

Dispense in a tight, light-resistant container [see USP].

APOTEX INC.

GLIPIZIDE TABLETS, USP

5 mg and 10 mg

Manufactured by Manufactured for

Apotex Inc. Apotex Corp.

Toronto, Ontario Weston, Florida

Canada M9L 1T9 USA 33326

Revised: May 2017

Rev. 8

GLIPIZIDE

glipizide tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 19 19 -28 7(NDC:6 0 50 5-0 142)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

GLIPIZIDE (UNII: X7WDT9 5N5C) (GLIPIZIDE - UNII:X7WDT9 5N5C)

GLIPIZIDE

10 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

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

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

Product Characteristics

Color

white

S core

2 pieces

Dire ct_Rx

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

APO;GLP;10

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 19 19 -28 7-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /20 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7579 5

0 8 /20 /20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(6 19 19 -28 7)

Revised: 1/2020

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