Spl product data elements section
Spl product data elements section
Glyburide tablets USP contain glyburide, USP, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide, USP is a white or almost white, crystalline powder. The chemical name for Glyburide, USP is 1-[[p-[2-(5-chloro-o-anisamido)ethyl]phenyl]-sulfonyl]-3-cyclohexylurea. It has the following structural formula:
C 23H 28ClN 3O 5S M.W. 494.0
Each glyburide tablet, USP intended for oral administration contains 1.25 mg or 2.5 mg or 5 mg of Glyburide, USP. In addition, each tablet contains the following inactive ingredients: calcium carbonate, dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch and sodium starch glycolate. Additionally each 2.5 mg tablet contains D&C yellow # 10 aluminum lake and FD & C yellow # 6 aluminum lake; each 5 mg tablet contains D&C yellow # 10 aluminum lake and FD & C blue # 1 aluminum lake.
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 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 showed no reliable correlation between administered dose and serum drug level.
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 thand 1/40 thas 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 are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Glyburide tablets are contraindicated in patients with:
- Known hypersensitivity or allergy to the drug.
- Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
- Type I diabetes mellitus.
- Concomitant administration of bosentan.
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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 as signed 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 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.
Bioavailability studies have demonstrated that micronized glyburide tablets 3 mg provide serum glyburide concentrations that are not bioequivalent to those from nonmicronized glyburide tablets 5 mg. Therefore, patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents.
Information for patients
Patients should be informed of the potential risks and advantages of glyburide and of alternative modes of therapy. They also should be informed about the importance of adherence 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 also should be explained.
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.
The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including non-steroidal 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, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide, 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, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide, 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.
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.
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.
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 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.
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 is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.
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.
Safety and effectiveness in pediatric patients have not been established.
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.
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, e.g., 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, e.g., 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; 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 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 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 (micronized) tablets or other oral hypoglycemic agents (see PRECAUTIONS).
There is no fixed dosage regimen for the management of diabetes mellitus with glyburide tablets 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 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.
Glyburide Tablets USP, 1.25 mg are white to off-white colored, round shaped, biconvex, uncoated tablets debossed with '656' on one side and breakline on the other side and are supplied as follows:
NDC 65841-832-06 in bottles of 30 tablets
NDC 65841-832-16 in bottles of 90 tablets
NDC 65841-832-01 in bottles of 100 tablets
NDC 65841-832-05 in bottles of 500 tablets
NDC 65841-832-10 in bottles of 1000 tablets
NDC 65841-832-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Glyburide Tablets USP, 2.5 mg are light yellow to yellow colored, may be spotted, round shaped, biconvex, uncoated tablets, debossed with "657" on one side and breakline on the other side and are supplied as follows:
NDC 65841-833-06 in bottles of 30 tablets
NDC 65841-833-16 in bottles of 90 tablets
NDC 65841-833-01 in bottles of 100 tablets
NDC 65841-833-05 in bottles of 500 tablets
NDC 65841-833-10 in bottles of 1000 tablets
NDC 65841-833-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Glyburide Tablets USP, 5 mg are light green colored, may be spotted, round shaped, biconvex, uncoated tablets, debossed with "658" on one side and breakline on the other side and are supplied as follows:
NDC 65841-834-06 in bottles of 30 tablets
NDC 65841-834-16 in bottles of 90 tablets
NDC 65841-834-01 in bottles of 100 tablets
NDC 65841-834-05 in bottles of 500 tablets
NDC 65841-834-10 in bottles of 1000 tablets
NDC 65841-834-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature] .
Dispense in a tight container (USP).
KEEP THIS AND ALL DRUGS OUT OF THE REACH OF CHILDREN.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
Cadila Healthcare Ltd.
Ingredients and appearance - Product information
Glyburide tablet- Glyburide
|Product Type||HUMAN PRESCRIPTION DRUG LABEL||Item Code (Source)||NDC: 65841-832|
|Route of Administration||Oral|
|Glyburide ( UNII: SX6K58TVWC)( Glyburide - UNII: SX6K58TVWC )||1.25 mgin 1|
|Calcium carbonate||( UNII: H0G9379FGK)|
|Cellulose, microcrystalline||( UNII: OP1R32D61U)|
|Dibasic calcium phosphate dihydrate||( UNII: O7TSZ97GEP)|
|Magnesium stearate||( UNII: 70097M6I30)|
|Povidone k29/32||( UNII: 390RMW2PEQ)|
|Sodium starch glycolate type a potato||( UNII: 5856J3G2A2)|
|Starch, pregelatinized corn||( UNII: O8232NY3SJ)|
|Color||WHITE (white to off-white)||Shape||ROUND|
|Marketing Category||Application Number or Monograph Citation||Territorial Authority||Marketing Start Date|
Labeler - Cadila Healthcare Limited( 918596198)
|Cadila Healthcare Limited||918596198||analysis( 65841-832, 65841-833, 65841-834), manufacture( 65841-832, 65841-833, 65841-834)|
Package label.principal display panel
NDC 65841-832-01 in bottles of 100 tablets
Glyburide Tablets USP, 1.25 mg
NDC 65841-833-01 in bottles of 100 tablets
Glyburide Tablets USP, 2.5 mg
NDC 65841-834-01 in bottles of 100 tablets
Glyburide Tablets USP, 5 mg