Glyburide

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.

DOSAGE AND ADMINISTRATION Patients should be retitrated when transferred from glyburide (micronized) tablets or other oral hypoglycemic agents (see Error! Hyperlink reference not valid.). 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, 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. Usual Starting Dose The usual starting dose of glyburide tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. (See Error! Hyperlink reference not valid. section for patients at increased risk.) Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy. Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy Transfer of patients from other oral antidiabetic regimens to glyburide tablets should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to glyburide tablets, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia. Patients Receiving Insulin Some Type II diabetic patients being treated with insulin may respond satisfactorily to glyburide tablets. If the insulin dose is less than 20 units daily, substitution of glyburide tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on glyburide tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to glyburide tablets. In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started. Please refer to Error! Hyperlink reference not valid. for further explanation. Patients Receiving Colesevelam When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced. Therefore, glyburide tablets should be administered at least 4 hours prior to colesevelam. Titration to Maintenance Dose The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (see Error! Hyperlink reference not valid. section). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient’s blood glucose response. No exact dosage relationship exists between glyburide tablets and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of glyburide tablets should be observed. A maintenance dose of 5 mg of glyburide tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. When transferring patients receiving more than 40 unit …

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 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 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 .

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. To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 max were 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 max of 32% and 47%, respectively. The reductions in glyburide AUC and C max were 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 max and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis hydroxyglyburide (M2), was also reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Carcinogenesis, Mutagenesis, and Impairment of Fertility Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice. 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 stud …

Specific Patient Populations Glyburide is not recommended for use in pregnancy or for use in pediatric 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 Error! Hyperlink reference not valid. section).

Actions Glyburide 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 glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, 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. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. Some patients who are initially responsive to oral hypoglycemic drugs, including glyburide, may become unresponsive or poorly responsive over time. Alternatively, glyburide tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

DESCRIPTION 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 23 H 28 ClN 3 O 5 S 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. figure

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.

HOW SUPPLIED 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 68382-656-06 in bottles of 30 tablets NDC 68382-656-16 in bottles of 90 tablets NDC 68382-656-01 in bottles of 100 tablets NDC 68382-656-05 in bottles of 500 tablets NDC 68382-656-10 in bottles of 1000 tablets NDC 68382-656-77 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 68382-657-06 in bottles of 30 tablets NDC 68382-657-16 in bottles of 90 tablets NDC 68382-657-01 in bottles of 100 tablets NDC 68382-657-05 in bottles of 500 tablets NDC 68382-657-10 in bottles of 1000 tablets NDC 68382-657-77 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 68382-658-06 in bottles of 30 tablets NDC 68382-658-16 in bottles of 90 tablets NDC 68382-658-01 in bottles of 100 tablets NDC 68382-658-05 in bottles of 500 tablets NDC 68382-658-10 in bottles of 1000 tablets NDC 68382-658-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets Storage Store at 20° to 25°C (68° to 77°F) [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. Manufactured by: Cadila Healthcare Ltd. Baddi, India Distributed by: Zydus Pharmaceuticals USA Inc. Pennington, NJ 08534 Rev.: 05/16 Revision Date: 02/05/2016