Glyburide tablet

Description

Glyburide tablets, USP contain a smaller particle size glyburide, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound, formulated as glyburide tablets, USP of 1.25, 2.5, and 5 mg strengths for oral administration. Inactive ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate. In addition, the 2.5 mgcontains FD&C Red No.40 and the 5 mgcontains FD&C Blue No.1. The chemical name for glyburide is 1-[[p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 493.99. The structural formula is represented below.

structure

Clinical pharmacology

Pharmacokinetics

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. Multiple dose studies with glyburide tablets in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-life is about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels. A one year study of diabetic patients treated with glyburide tablets showed no reliable correlation between administered dose and serum drug level.

The major metabolite of glyburide is the 4-transhydroxy derivative. A second metabolite, the 3-cishydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits.

Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine.

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 will result in fewer drug-drug interactions with glyburide tablets in clinical use.

Indications and usage

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

Contraindications

Glyburide tablets are contraindicated in patients with:

  1. Known hypersensitivity or allergy to the drug.
  2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
  3. Type I diabetes mellitus.
  4. Concomitant administration of bosentan.

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.

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 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 glyburide tablets 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.

Precautions

Laboratory tests

Therapeutic response to glyburide tablets should be monitored by frequent urine glucose tests and periodic blood glucose tests. Measurement of glycosylated hemoglobin levels may be helpful in some patients.

Drug interactions

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 tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide tablets, the patient should be observed closely for loss of control.

An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of glyburide tablets and bosentan is contraindicated.

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 glyburide tablets, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide tablets, the patient should be observed closely for hypoglycemia.

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:In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and C maxwere observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics.

Colesevelam:Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and C maxof 32% and 47%, respectively. The reductions in glyburide AUC and C maxwere 20% and 15%, respectively when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam.

Topiramate:A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C maxand a 25% reduction in AUC 24for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cishydroxyglyburide (M2), was also reduced by 13% and 15%, and C maxwas reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide.

Pregnancy

Teratogenic Effects: Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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 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 glyburide tablets is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

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. 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 pediatric patients have not been established.

Geriatric use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION).

Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

Adverse reactions

Hypoglycemia:See Precautions and Overdosage Sections.

Gastrointestinal Reactions:Cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; glyburide tablets should be discontinued if this occurs.

Liver function abnormalities, including isolated transaminase elevations, have been reported.

Gastrointestinal disturbances, eg, nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.

Dermatologic Reactions:Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of glyburide tablets; if skin reactions persist, the drug should be discontinued.

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

Hematologic Reactions:Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia (see PRECAUTIONS), aplastic anemia, and pancytopenia have been reported with sulfonylureas.

Metabolic Reactions:Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with Glyburide tablets and disulfiram-like reactions have been reported very rarely.

Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.

Other Reactions:Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.

Overdosage

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 which 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.

Dosage and administration

Patients should be retitrated when transferred from glyburide tablets or other oral hypoglycemic agents.

There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets. 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, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of 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 glyburide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

How supplied

Glyburide tablets, USP are supplied as follows:

Glyburide tablets, USP 2.5 mg(Pink colored, slightly mottled, capsule shaped, biconvex tablets de-bossed with 'I36' on one side and scored on the other side)

Bottles of 30 NDC 66267-102-30

Bottles of 60 NDC 66267-102-60

Bottles of 90 NDC 66267-102-90

Rx only

Store at 20 to 25C (68 to 77F) [see USP controlled room temperature ]. Dispensed in well closed containers with safety closures. Keep container tightly closed.

Manufactured for:

Heritage Pharmaceuticals Inc.

Eatontown, NJ 07724

1.866.901.DRUG (3784)

Made in India

Revised: 06/15

Ingredients and appearance - Product information

Glyburide tablet- Glyburide

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 66267-102
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Glyburide ( UNII: SX6K58TVWC)( Glyburide - UNII: SX6K58TVWC ) 2.5 mgin 1

Inactive Ingredients

Ingredient Name Code
Lactose monohydrate ( UNII: EWQ57Q8I5X)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Magnesium stearate ( UNII: 70097M6I30)
Fd&c red no. 40 ( UNII: WZB9127XOA)

Product Characteristics

Color pink Shape CAPSULE
Size 9 mm Score 2
Imprint Code I36

Packaging

# Item Code Package Description Marketing Start Date
1 NDC: 66267-102-30 30 in 1 BOTTLE 2016/10/06
2 NDC: 66267-102-60 60 in 1 BOTTLE 2016/10/06
3 NDC: 66267-102-90 90 in 1 BOTTLE 2016/10/06

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA090937 USA 2016/10/06

Labeler - NuCare Pharmaceuticals, Inc.( 010632300)

Establishment

Name ID/FEI Business Operations
NuCare Pharmaceuticals, Inc. 010632300 repack( 66267-102)

Package label.principal display panel 2.5 mg