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 2½ 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.
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, 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When such drugs are withdrawn from a patient receiving glyburide, the patient should be observed closely for loss of control.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 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.
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 Cmax and a 25% reduction in AUC 24 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.
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.
Glyburide is an oral blood-glucose-lowering drug of the sulfonylurea class.
Glyburide USP is a white, crystalline compound, formulated as glyburide tablets of 1.25, 2.5, and 5 mg strengths for oral administration.
Inactive ingredients: dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline cellulose, sodium alginate, and talc.
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.
Glyburide Tablets, USP are supplied as follows: Glyburide Tablets 1.25 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘2’ & ‘9’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-028-30 (Child Resistant Closure) Bottles of 50 NDC 65862-028-50 (Child Resistant Closure) Bottles of 100 NDC 65862-028-01 (Child Resistant Closure) Glyburide Tablets 2.5 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘3’ & ‘0’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-029-30 (Child Resistant Closure) Bottles of 100 NDC 65862-029-01 (Child Resistant Closure) Bottles of 100 NDC 65862-029-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-029-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-029-99 (Non Child Resistant Closure) Glyburide Tablets 5 mg (White to off white, round, flat, beveled edge tablets with scoreline in between ‘3’ & ‘1’ on one side and ‘A’ debossed on other side.) Bottles of 30 NDC 65862-030-30 (Child Resistant Closure) Bottles of 100 NDC 65862-030-01 (Child Resistant Closure) Bottles of 100 NDC 65862-030-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-030-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-030-99 (Non Child Resistant Closure) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Dispensed in well closed containers with safety closures.
Keep container tightly closed.
Distributed by: Aurobindo Pharma USA, Inc.
279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad–500 038, India Revised: 06/2018
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.
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.
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
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 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.
INFORMATION FOR PATIENTS
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.
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 glyburide 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 glyburide or other antidiabetic medications.
Maintenance or discontinuation of glyburide or other antidiabetic medications should be based on clinical judgment using regular clinical and laboratory evaluations.
DOSAGE AND ADMINISTRATION
Patients should be retitrated when transferred from micronized glyburide tablets or other oral hypoglycemic agents.
(See PRECAUTIONS ).
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 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 PRECAUTIONS 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 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, 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.
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.
In these patients, insulin dosage is decreased by 50% and glyburide tablets 5 mg daily is started.
Please refer to Titration to Maintenance Dose for further explanation.
Patients Receiving Colesevelam: When colesevelam is coadministered with glyburide, maximum plasma concentration and total exposure to glyburide is reduced.
Therefore, glyburide 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 Dosage Interval 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 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 units of insulin daily, they may be started on a daily dose of glyburide tablets 5 mg concomitantly with a 50% reduction in insulin dose.
Progressive withdrawal of insulin and increase of glyburide in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out.
During this conversion period when both insulin and glyburide are being used, hypoglycemia may occur.
During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician.
The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.
Concomitant Glyburide and Metformin Therapy Glyburide tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose ).
Refer to metformin package insert.
With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug.
However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal.
With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased.
Appropriate precautions should be taken (see PRECAUTIONS section).
Maximum Dose Daily doses of more than 20 mg are not recommended.
Dosage Interval Once-a-day therapy is usually satisfactory.
Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage.
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 PRECAUTIONS section.)