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TRUPHARMA, LLC.
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52817012110

glyburide 2.5 mg tablet

Generic
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Uses

Diabetes Mellitus

Glyburide alone or in fixed combination with metformin hydrochloride is used as initial therapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone. Glyburide also may be used in combination with metformin as second-line therapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled with glyburide or metformin monotherapy, diet, and exercise. Sulfonylureas, including glyburide, also may be used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. A thiazolidinedione antidiabetic agent (e.g., rosiglitazone) has been added to therapy with the fixed combination of glyburide and metformin hydrochloride to improve glycemic control in patients not responding adequately to the fixed combination.

The American Diabetes Association (ADA) currently classifies diabetes mellitus into several subclasses including type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus was previously described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on the age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.

Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).

Oral antidiabetic agents are not effective as sole therapy for patients with type 1 diabetes mellitus; insulin is necessary in these patients. Sulfonylurea antidiabetic agents are not routinely recommended in hospitalized patients with diabetes mellitus. Because of their long duration of action (24 hours with glyburide), sulfonylureas do not allow rapid dosage adjustments to meet changing needs of hospitalized patients. In addition, the risk of hypoglycemia during sulfonylurea therapy is increased in such patients with irregular eating patterns.

Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control) nor are they prone to ketosis; however, insulin may occasionally be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis may occasionally develop during periods of severe stress (e.g., acute infections, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease, and subclassification criteria (e.g., basal and stimulated plasma insulin concentrations, insulin resistance) remain to be clearly established. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In type 2 diabetic patients, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.

Glycemic Control and Microvascular Complications

Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 or type 2 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., retinopathy, nephropathy, neuropathy) complications associated with the disease. HbA1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for development of diabetic microvascular complications. Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.

In the Diabetes Control and Complications Trial (DCCT), the reduction in risk of microvascular complications in patients with type 1 diabetes mellitus correlated continuously with the reduction in HbA1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in HbA1c. These data imply that any decrease in HbA1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic complications. Data from the largest United Kingdom Prospective Diabetes Study (UKPDS) and other smaller studies in patients with type 2 diabetes mellitus are generally consistent with the same benefits on microvascular complications as those observed with type 1 diabetes mellitus in the DCCT study.

Data from long-term follow-up (over 10 years) of UKPDS patients with type 2 diabetes mellitus who received initial therapy with conventional (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia) antidiabetic treatment or intensive (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) antidiabetic regimens indicate that intensive treatment with monotherapy generally is not capable of maintaining strict glycemic control (i.e., maintenance of blood glucose concentrations of 108 mg/dL or normal values) over time and that combination therapy eventually becomes necessary in most patients to attain target glucose concentrations in the long term; in UKPDS, intensive treatment that eventually required combination therapy in most patients resulted in median HbA1c concentrations of 7%. Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time. For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or 2 diabetes mellitus, .

Glycemic Control and Macrovascular Complications

Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials. Reduction in blood pressure to a mean of 144/82 mm Hg (''tight blood pressure control'') in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points. While intensive antidiabetic therapy titrated with the goal of reducing HbA1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes, results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus. For additional details regarding the effects of intensive antidiabetic therapy on macrovascular outcomes,

Treatment Goals

The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA1c goals recommended for patients with type 1 diabetes mellitus. Based on target values for blood glucose and HbA1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant. HbA1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal. Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA1c.

More stringent treatment goals (i.e., an HbA1c concentration less than 6%) may be considered in selected patients. An individualized HbA1c goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Achievement of HbA1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy. For additional details on individualizing treatment in patients with diabetes mellitus,

Considerations in Initiating and Maintaining Antidiabetic Therapy

When initiating therapy for type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment; caloric restriction and weight reduction are essential in obese patients. Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and maintain adequate glycemic control with dietary modification alone.

Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus. Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA1c values of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus. ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated. The manufacturer states that patients and clinicians should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that antidiabetic therapy is used only as an adjunct to, and not as a substitute for or a convenient means to avoid, proper dietary management. In addition, loss of blood glucose control on diet alone may be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity should also be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible. If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentration, initiation of monotherapy with an oral antidiabetic agent (e.g., metformin, sulfonylurea, acarbose) or insulin should be considered.

Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.(See Cautions: Precautions and Contraindications.) The ADA currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control (e.g., concomitant antihypertensive therapy) in diabetic patients to outweigh the risks overall.

Glyburide Monotherapy

Clinical studies indicate that glyburide is as effective as chlorpropamide, glipizide, tolazamide, or tolbutamide for the management of type 2 diabetes mellitus. A relative advantage compared with other sulfonylurea antidiabetic agents has not been clearly established. Some clinicians have suggested that, because of its diuretic action, glyburide may be particularly useful in patients with conditions associated with abnormal fluid retention. In some type 2 diabetic patients who are being treated with insulin, glyburide alone may be effective alternative therapy.

Clinical trial data indicate that sulfonylureas are as effective as metformin in lowering HbA1c (approximately 1.5% decrease) values, but such use is associated with hypoglycemia and weight gain. ADA generally recommends metformin as initial antidiabetic therapy because of the absence of weight gain or hypoglycemia, relatively low expense, and generally low adverse effect profile.

Glyburide may be useful in some patients with type 2 diabetes mellitus who have primary or secondary failure to other sulfonylurea antidiabetic agents; however, primary or secondary failure to glyburide may also occur.

Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Interim data from a substudy (UKPDS 26) of UKPDS in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide or chlorpropamide] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year. The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide. In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control. In another substudy (UKPDS 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control. At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.

Glyburide is not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.

Combination Therapy with Metformin or Other Oral Antidiabetic Agents

Sulfonylureas, including glyburide, may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, thiazolidinedione derivatives, α-glucosidase inhibitors) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. Combined therapy with metformin or other oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy.

ADA and other clinicians recommend initiating therapy with metformin and adding another antidiabetic agent, such as a sulfonylurea, insulin, or a thiazolidinedione if patients fail to achieve or sustain target HbA1c goals. Optimal benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin at the maximum tolerated dosage no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of therapy with metformin or at any other time when the target HbA1c goal is not achieved).

A major factor in choosing additional therapy is the degree of glycemic control obtained during metformin monotherapy. In patients with an HbA1c concentration exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When glycemic control is closer to the target HbA1c goal with metformin monotherapy (e.g., HbA1c less than 7.5%), agents with a lesser potential to lower hyperglycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin. Other antidiabetic agents such as α-glucosidase inhibitors, meglitinides, exenatide, and pramlintide generally are less effective, less well studied, and/or more expensive than recommended therapies (i.e., metformin, sulfonylurea, thiazolidinedione, insulin). However, these agents may be appropriate for treatment of type 2 diabetes mellitus in selected patients.

Glyburide may be used concomitantly with metformin as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. In a 20-week, double-blind, randomized trial in drug-naive patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (baseline HbA1c values between 7 and 11%) by diet and exercise, treatment was initiated with either placebo, glyburide 2.5 mg, metformin hydrochloride 500 mg, or the fixed combination of glyburide 1.25 mg/metformin hydrochloride 250 mg or glyburide 2.5 mg/metformin hydrochloride 500 mg daily. The dosage of each therapy was progressively increased during weeks 4-8 to achieve a target fasting plasma glucose concentration of 126 mg/dL or to a maximum of 4 tablets daily. Patients receiving the fixed combination of glyburide and metformin had greater reductions in HbA1c and fasting plasma glucose concentrations than those receiving glyburide, metformin, or placebo; at the end of the study, strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 59.9, 50.4, 66.4, or 71.7% of patients receiving mean dosages of glyburide 5.3 mg, metformin hydrochloride 1.32 g, glyburide 2.78 mg/metformin hydrochloride 557 mg, or glyburide 4.1 mg/metformin hydrochloride 824 mg, respectively.

In a comparative clinical trial in pediatric patients (9-16 years of age) with type 2 diabetes mellitus, therapy with glyburide in fixed combination with metformin hydrochloride (titrated to a final mean daily dosage of 3.1 mg of glyburide and 623 mg of metformin hydrochloride) was no more effective in improving glycemic control (as determined by reductions in HbA1c) than monotherapy with either component (titrated to a final mean daily dosage of 6.5 mg of glyburide or 1.5 g of metformin hydrochloride).

Glyburide also may be used concomitantly with metformin as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite diet, exercise, and monotherapy with either glyburide (or another sulfonylurea antidiabetic agent) or metformin. In a double-blind, randomized study, patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (mean baseline HbA1c values: 9.5%, mean baseline fasting plasma glucose: 213 mg/dL) with oral sulfonylurea therapy at a dosage at least 50% of the maximum recommended daily dosage (e.g., glyburide 10 mg daily, glipizide 20 mg daily) received therapy with glyburide 20 mg (fixed dosage), metformin hydrochloride 500 mg, or the fixed combination of glyburide 2.5 mg/metformin hydrochloride 500 mg or glyburide 5 mg/metformin hydrochloride 500 mg daily. The dosages of metformin and the fixed-combination preparations were titrated to achieve a target fasting plasma glucose concentration of less than 140 mg/dL or to a maximum of 4 tablets daily. At 16 weeks, patients receiving the fixed combination of glyburide and metformin hydrochloride in daily dosages of up to 20 mg of glyburide and 2 g of metformin hydrochloride had lower HbA1c, fasting plasma glucose, and postprandial plasma glucose concentrations than patients receiving monotherapy with glyburide or metformin, who had no appreciable change in HbA1c values.

In a 24-week double-blind, randomized study, addition of rosiglitazone to therapy in patients not adequately controlled with the fixed combination of glyburide and metformin produced additional improvement in fasting plasma glucose concentrations and HbA1c values compared with the fixed-combination regimen. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 42.4% of patients receiving the 3-drug combination regimen compared with 13.5% of those receiving the fixed combination of glyburide and metformin.

For additional information on combination therapy with sulfonylureas and other oral antidiabetic agents, see the sections on combination therapy in Uses in the individual monographs in 68:20.

When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy. In patients whose HbA1c is close to the target value (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered. However, triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.

Combination Therapy with Insulin

Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested. Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times) and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy. Oral antidiabetic therapy combined with insulin therapy may delay progression to either intensive insulin monotherapy or to a second daytime injection of insulin combined with oral antidiabetic therapy. However, combined therapy may increase the risk of hypoglycemic reactions.

ADA and other clinicians state that combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic agent. In patients with an HbA1c concentration exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When patients are not controlled with metformin with or without other oral antidiabetic agents (i.e., sulfonylurea, thiazolidinedione) and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes. Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy.

Misuse and Abuse

Dietary Supplements

Some herbal dietary supplements promoted for the treatment of diabetes mellitus and purported to contain only natural Chinese herbal ingredients have been found to contain glyburide and phenformin (a biguanide similar to metformin but no longer commercially available in the US). Adulteration of these dietary supplements was discovered after use of one of the glyburide- and phenformin-containing dietary supplements by a patient with diabetes mellitus resulted in several episodes of hypoglycemia, from which the patient fully recovered. Restrictions on the importation and sale of these dietary supplements have been initiated by FDA.

Dosage and Administration

Administration

Glyburide is administered orally. The drug is usually administered as a single daily dose given each morning with breakfast, or with the first main meal. Once-daily dosing of glyburide provides adequate control of blood glucose concentration throughout the day in most patients with usual meal patterns; however, some patients, particularly those who require more than 10 mg of the drug daily, may have a more satisfactory response when glyburide is administered in 2 divided doses daily. When a twice-daily dosing regimen is employed in patients receiving more than 10 mg of glyburide daily, the doses and schedule of administration should be individualized according to the patient's meal pattern and response. There is some evidence that, when a divided-dosing regimen is used, blood glucose concentration following breakfast may be better controlled when the morning dose is administered 30 minutes before rather than with the meal; a similar tendency has been observed following the midday meal, but not the evening meal, when the remaining portions of the equally divided daily dose were administered 30 minutes before rather than with these meals.

Dosage

Dosage of glyburide must be based on periodic fasting blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) determinations and must be carefully individualized to obtain optimum therapeutic effect. The goal of therapy should be to reduce fasting plasma glucose, postprandial plasma glucose, and HbA1c values to normal or near normal using the lowest effective dosage of glyburide-containing therapy. (Glucose concentrations in plasma generally are 10-15% higher than those in whole blood; glucose concentrations also may vary according to the method and laboratory used for these determinations.) Periodic HbA1c determinations are better indicators of long-term glycemic control than fasting plasma glucose concentrations alone. Following initiation of glyburide-containing therapy, determination of HbA1c concentrations at intervals of approximately 3 months is useful for assessing the patient's continued response to therapy. Patients must be closely monitored to determine the minimum effective glyburide dosage and to detect primary or secondary failure to the drug.If appropriate glyburide dosage regimens are not followed, hypoglycemia may be precipitated.

Formulations of micronized glyburide (Glynase® PresTab®, Pfizer, Glycron®, Zoetica, and micronized tablets available by nonproprietary name) contain smaller particles of the drug than those contained in conventional formulations (e.g., DiaBeta®, Micronase®).As a result, micronized formulations of glyburide are not bioequivalent with conventional formulations, and dosage should be retitrated when transferring patients from micronized to conventional formulations or vice versa.In general, initial dosages of micronized glyburide range from 1.5-3 mg daily, although it may be necessary to initiate micronized therapy with 0.75 mg daily in patients who are sensitive to the hypoglycemic effects of sulfonylureas (e.g., geriatric, debilitated, or malnourished patients); the manufacturer recommends that the initial dosage not exceed 3 mg daily regardless of the dosage of other sulfonylurea employed at transfer.Maintenance dosage of the micronized formulation should be individualized according to glycemic control but usually ranges from 0.75-12 mg daily.The manufacturers' labeling should be consulted for additional information on the use of micronized glyburide, including associated precautions and detailed information on dosage titration.

Glyburide therapy should be discontinued at least annually and blood glucose concentration monitored carefully to ensure that the drug continues to be effective. If adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy, the drug should be discontinued. Patients who do not adhere to their prescribed dietary and drug regimens are more likely to have an unsatisfactory response to therapy. In patients usually well controlled by dietary management alone, short-term therapy with glyburide may be sufficient during periods of transient loss of diabetic control.

Initial Dosage in Previously Untreated Patients

For the management of type 2 diabetes mellitus in patients not previously receiving insulin or sulfonylurea antidiabetic agents, the usual initial adult dosage of glyburide is 2.5-5 mg daily; in debilitated, malnourished, or geriatric patients, or other patients at increased risk of hypoglycemia (See Cautions: Precautions and Contraindications), the initial dosage of glyburide should be 1.25 mg daily. The manufacturers also recommend an initial dosage of 1.25 mg daily in patients with impaired renal or hepatic function. (See Cautions: Precautions and Contraindications.) Subsequent dosage should be adjusted according to the patient's tolerance and therapeutic response; increases in dosage should be made in increments of no more than 2.5 mg daily at weekly intervals.

Initial Dosage in Patients Transferred from Other Antidiabetic Agents

A transition period generally is not required when transferring from most other sulfonylurea antidiabetic agents to glyburide, and administration of the other agent may be abruptly discontinued. Because of the prolonged elimination half-life of chlorpropamide, an exaggerated hypoglycemic response may occur in some patients during the transition from chlorpropamide to glyburide, and patients being transferred from chlorpropamide should be closely monitored for the occurrence of hypoglycemia during the initial 2 weeks of the transition period. A drug-free interval of 2-3 days may be advisable before glyburide therapy is initiated in patients being transferred from chlorpropamide, particularly if blood glucose concentration was adequately controlled with chlorpropamide. An initial or loading dose of glyburide is not necessary when transferring from other sulfonylurea antidiabetic agents to glyburide. The transfer should be performed conservatively.

For the management of type 2 diabetes mellitus in patients previously receiving other sulfonylurea antidiabetic agents, the initial dosage of glyburide should be 2.5-5 mg daily. Although patients may be transferred from the maximum dosage of other sulfonylurea antidiabetic agents, the initial dosage of glyburide should not exceed 5 mg daily. Subsequent dosage is adjusted according to the patient's tolerance and therapeutic response. Although an exact dosage relationship between glyburide and other sulfonylurea antidiabetic agents does not exist, approximate dosage equivalencies have been estimated. (See Pharmacology: Antidiabetic Effect.)

In general, patients who were previously maintained on insulin dosages not exceeding 40 units daily may be transferred directly to glyburide, and administration of insulin may be abruptly discontinued; the initial glyburide dosage is 2.5-5 mg daily in patients whose insulin dosage was less than 20 units daily and 5 mg daily in patients whose insulin dosage was 20-40 units daily. In patients requiring insulin dosages exceeding 40 units daily, an initial glyburide dosage of 5 mg daily should be started and insulin dosage reduced by 50%. Subsequently, insulin is withdrawn gradually and dosage of glyburide is increased in increments of 1.25-2.5 mg daily every 2-10 days, according to the patient's tolerance and therapeutic response. During the period of insulin withdrawal, patients should test their blood for glucose and their urine for glucose and/or ketones at least 3 times daily, and should be instructed to report the results to their physician so that appropriate adjustments in therapy may be made, if necessary. The presence of persistent ketonuria with glycosuria, ketosis, and/or inadequate lowering or persistent elevation of blood glucose concentration indicates that the patient requires insulin therapy. During the period of insulin withdrawal, hypoglycemia may rarely occur. In some patients, hospitalization may be necessary during the transition from insulin to glyburide.

Maintenance Dosage

The adult maintenance dosage of glyburide for the management of type 2 diabetes mellitus ranges from 1.25-20 mg daily. Most patients require 2.5-10 mg daily and some may require up to 15 mg daily; only a few patients will benefit from dosages exceeding 15 mg daily. Maintenance dosage of glyburide should be conservative in debilitated, malnourished, or geriatric patients or patients with impaired renal or hepatic function because of an increased risk of hypoglycemia in these patients. (See Cautions: Precautions and Contraindications.)The maximum recommended dosage is 20 mg daily.

Concomitant Glyburide and Metformin Therapy

Combination therapy with glyburide and metformin may be used in patients who do not respond adequately to diet and exercise alone, and in those who do not respond adequately to either glyburide (or another sulfonylurea antidiabetic agent) or metformin monotherapy, diet, and exercise. When glyburide and metformin are administered concomitantly, dosage of each drug should be adjusted upward until adequate glycemic control is achieved, and patients should be monitored periodically (e.g., determination of blood glucose concentrations) to determine the minimum effective dosage of each drug. Glyburide should be added gradually to the existing dosage regimen of patients not responding adequately to 4 weeks of metformin monotherapy at maximum dosage. When glyburide is administered concomitantly with metformin, the risk of hypoglycemia may be increased. (See Cautions: Precautions and Contraindications.)

The commercially available preparation containing glyburide in fixed combination with metformin hydrochloride may be used as initial therapy in patients with type 2 diabetes mellitus whose blood glucose is not adequately controlled with diet and exercise alone, or as second-line therapy in those in whom glycemic control with a sulfonylurea antidiabetic agent (e.g., glyburide) or metformin monotherapy is not adequate. If the fixed-combination preparation of glyburide and metformin hydrochloride is used as initial therapy, the recommended initial dosage is 1.25 mg of glyburide and 250 mg of metformin hydrochloride daily with a meal. Patients with more severe hyperglycemia (as determined by HbA1c exceeding 9% or fasting plasma glucose concentrations exceeding 200 mg/dL) may receive an initial dosage of 1.25 mg of glyburide and 250 mg of metformin hydrochloride twice daily with the morning and evening meals. Dosage may be titrated in increments of 1.25 mg of glyburide and 250 mg of metformin hydrochloride daily at 2-week intervals until the minimum effective dosage required to achieve adequate blood glucose control is reached. A total daily dosage exceeding 10 mg of glyburide and 2 g of metformin hydrochloride has not been evaluated in clinical trials in patients receiving the fixed-combination preparation as initial therapy. The manufacturer states that the fixed-combination preparation containing 5 mg of glyburide and 500 mg of metformin hydrochloride should not be used as initial therapy in treatment-naive patients because of the increased risk for hypoglycemia.

The commercially available preparation containing glyburide in fixed combination with metformin hydrochloride also may be initiated as second-line therapy in patients whose blood glucose concentrations are not adequately controlled by either glyburide (or another sulfonylurea antidiabetic agent) or metformin alone. The recommended initial dosage of the commercially available fixed-combination preparation in previously treated patients is 2.5 or 5 mg of glyburide with 500 mg of metformin hydrochloride twice daily with morning and evening meals. In order to minimize the risk of hypoglycemia, the initial dosage of glyburide and metformin hydrochloride in fixed combination should not exceed the daily dosage of glyburide or metformin given separately. The dosage of the fixed combination of glyburide and metformin should be titrated upward in increments not exceeding 5 mg of glyburide and 500 mg of metformin hydrochloride until adequate control of blood glucose is achieved or a maximum daily dosage of 20 mg of glyburide and 2 g of metformin hydrochloride is reached.

For patients being switched from combined therapy with separate preparations, the initial dosage of the fixed-combination preparation of glyburide and metformin should not exceed the daily dosage of glyburide (or equivalent dosage of another sulfonylurea antidiabetic agent) and metformin currently being taken. Such patients should be monitored for signs and symptoms of hypoglycemia following the switch. Hypoglycemia and hyperglycemia are possible in such patients, and any change in the therapy of type 2 diabetic patients should be undertaken with caution and appropriate monitoring. The safety and efficacy of switching from combined therapy with separate preparations of glyburide (or another sulfonylurea antidiabetic agent) and metformin to the fixed-combination preparation have not been established in clinical studies.

Glyburide alone or in fixed combination with metformin should be used with caution in geriatric patients, since aging is associated with reduced renal function. The initial and maintenance dosages of glyburide alone or in fixed combination with metformin should be conservative and should be titrated carefully in such patients. Renal function should be assessed with initial dosage selection and with each dosage adjustment in geriatric patients. To minimize the risk of hypoglycemia, maintenance dosage of the fixed combination of glyburide and metformin hydrochloride in geriatric, debilitated, or malnourished patients should not be titrated to the maximum dosage recommended for other patients.

Concomitant Glyburide, Metformin, and Thiazolidinedione Therapy

For patients whose hyperglycemia is not adequately controlled on therapy with the fixed combination of glyburide and metformin, a thiazolidinedione (e.g., pioglitazone, rosiglitazone) may be added at its recommended initial dosage and the dosage of the fixed combination may be continued unchanged. In patients requiring further glycemic control, the dosage of the thiazolidinedione may be titrated upward, based on the dosage regimen recommended by the manufacturer. Triple therapy with glyburide, metformin, and a thiazolidinedione may increase the potential for hypoglycemia at any time of day. If hypoglycemia develops with such triple therapy, consideration should be given to reducing the dosage of the glyburide component; adjustment of the dosage of the other components of the antidiabetic regimen also should be considered as clinically indicated.

Cautions

Hypoglycemia

Hypoglycemia, which may be severe and has occasionally been fatal, may occur in patients receiving glyburide alone or combined with other antidiabetic agents. In a controlled clinical trial in patients receiving initial therapy, symptoms of hypoglycemia (e.g., dizziness, shakiness, sweating, hunger) occurred in 21.3, 3.1, 11.4, or 37.7% of patients receiving glyburide (mean daily dosage: 5.3 mg), metformin hydrochloride (mean daily dosage: 1317 mg), glyburide in fixed combination with metformin hydrochloride (mean daily dosage: 2.78 mg of glyburide/557 mg of metformin hydrochloride), or glyburide in fixed combination with a higher dosage of metformin hydrochloride (mean daily dosage: 4.1 mg of glyburide/824 mg of metformin hydrochloride). Approximately 6.8% of patients experienced hypoglycemic symptoms while receiving the fixed combination of glyburide and metformin hydrochloride as second-line therapy following inadequate control with sulfonylurea monotherapy. Self-monitored blood glucose measurements of 50 mg/dL or less were reported by 22% of patients receiving the fixed combination of glyburide and metformin hydrochloride plus rosiglitazone compared with 3.3% of patients receiving the fixed combination of glyburide and metformin hydrochloride plus placebo. Appropriate patient selection and careful attention to dosage are important to avoid glyburide-induced hypoglycemia. (See Cautions: Precautions and Contraindications.)

Although not clearly established, it has been suggested that glyburide may be more likely than other sulfonylurea antidiabetic agents to produce severe hypoglycemia. In some clinical studies, hypoglycemia was the most frequent adverse effect of the drug. Hypoglycemia may occur as a result of excessive glyburide dosage; however, since the development of hypoglycemia is a function of many factors, including diet, or exercise without adequate caloric supplementation, this effect may occur in some patients receiving usual dosages of the drug. Severe hypoglycemia, sometimes fatal, has occurred in some patients receiving as little as 2.5-5 mg of glyburide daily. The risk of hypoglycemia is increased during concurrent use of other antidiabetic agents, certain other agents, or alcohol. (See: Drug Interactions.) In patients receiving glyburide in fixed combination with metformin, renal or hepatic insufficiency may increase the serum concentrations of both agents, and hepatic insufficiency may diminish gluconeogenic capacity; both of these conditions increase the risk of hypoglycemia. Debilitated, malnourished, or geriatric patients may be particularly susceptible to glyburide-induced hypoglycemia; this condition may be difficult to recognize in geriatric patients or in those receiving β-adrenergic blocking agents. (See Drug Interactions: β-Adrenergic Blocking Agents.) Glyburide-induced hypoglycemia may also occur in nontherapeutic situations (e.g., inadvertent or intentional ingestion).

Management of glyburide-induced hypoglycemia depends on the severity of the reaction; patients with severe reactions require immediate hospitalization and treatment and observation until complete recovery is assured. Hypoglycemia is usually, but not always, readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of glyburide dosage and/or the patient's meal pattern are necessary.

For further discussion of the pathogenesis, manifestations, and treatment of glyburide-induced hypoglycemia, see Acute Toxicity.

Other Endocrine and Metabolic Effects

Therapy with sulfonylureas, including glyburide, may be associated with weight gain. Weight gain observed in patients receiving rosiglitazone in addition to the fixed combination of glyburide and metformin in a controlled clinical trial was similar to that reported with rosiglitazone monotherapy. Although the exact mechanisms associated with such alterations in weight have not been established, suggested mechanisms include an increase in insulin secretion (which may increase appetite), stimulation of lipogenesis in fat tissue, or an increase in blood leptin concentrations. Data from the United Kingdom Prospective Diabetes Study (UKPDS) in patients receiving long-term (over 10 years) therapy with glyburide and other antidiabetic agents indicate that weight gain was greatest in those receiving intensive therapy (stepwise introduction of a sulfonylurea then insulin or an oral sulfonylurea and insulin, or insulin alone to achieve fasting glucose concentrations of 108 mg/dL) than conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations less than 270 mg/dL without symptoms of hyperglycemia), and weight gain was greatest in those initially receiving insulin or chlorpropamide compared with that in those receiving glyburide.

Like other sulfonylureas, hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) have occurred in patients receiving glyburide. Hyponatremia appears to occur more often in patients who concurrently are receiving other medications or have medical conditions known to cause hyponatremia or an increased release of vasopressin.

GI Effects

Adverse GI effects such as nausea, epigastric fullness, and heartburn are the most common adverse reactions to glyburide, occurring in about 1-2% of patients. Glyburide-induced adverse GI effects appear to be dose related and may subside following a reduction in dosage.

Hepatic Effects

Cholestatic jaundice may occur rarely in patients receiving glyburide and is an indication for discontinuing the drug. Glyburide-induced cholestatic jaundice has occurred rarely in conjunction with other severe systemic adverse effects (e.g., visceral arteritis, cutaneous bullae). Liver function test abnormalities, including elevations in serum aminotransferase concentrations (which may subside with continued therapy), have been reported in patients receiving glyburide. Exacerbation of hepatic porphyria has been reported with other sulfonylurea antidiabetic agents, but has not been reported to date with glyburide.

Dermatologic and Sensitivity Reactions

Allergic skin reactions including pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occur in about 1.5% of patients receiving glyburide. Glyburide-induced adverse dermatologic effects generally subside rapidly following discontinuance of the drug, but may also disappear despite continued treatment; however, if adverse dermatologic effects persist with continued glyburide therapy, the drug should be discontinued. Cutaneous bullae occurred in conjunction with cholestatic jaundice in one patient receiving glyburide. Photosensitivity reactions have also been reported with glyburide, and porphyria cutanea tarda has been reported with other sulfonylurea antidiabetic agents.

Nondermatologic allergic reactions to glyburide have included angioedema, arthralgia, myalgia, and vasculitis. A generalized hypersensitivity reaction with toxic erythema, cholestatic jaundice, eosinophilia, and visceral arteritis, resulting in death, has also been reported in one patient receiving the drug.

Hematologic Effects

Like other sulfonylurea antidiabetic agents, glyburide may rarely cause leukopenia, thrombocytopenia, pancytopenia, agranulocytosis, aplastic anemia, and hemolytic anemia. Thrombocytopenic purpura has been reported in one patient receiving glyburide.

Other Adverse Effects

Although a causal relationship has not been established, paresthesia, joint pain, and nocturia have been reported in patients receiving glyburide. Changes in accommodation and/or blurred vision have been reported in patients receiving glyburide or other sulfonylureas and are thought to be related to fluctuations in blood glucose concentrations. Edema has been reported in 2.2% of patients receiving the fixed combination of glyburide and metformin versus 7.7% of those receiving combined glyburide, metformin, and rosiglitazone therapy in a controlled clinical trial.

Precautions and Contraindications

When glyburide is used in fixed combination with metformin, the cautions, precautions, and contraindications associated with metformin must be considered in addition to those associated with glyburide.

Glyburide shares the toxic potentials of other sulfonylurea antidiabetic agents, and the usual precautions associated with their use should be observed. The diagnostic and therapeutic measures for managing diabetes mellitus that are necessary to ensure optimum control of the disease with insulin generally are necessary with glyburide. Glyburide should only be prescribed for carefully selected patients by clinicians who are familiar with the indications, limitations, and patient-selection criteria for therapy with oral sulfonylurea antidiabetic agents.

Patients receiving glyburide should be monitored with regular clinical and laboratory evaluations, including urine and/or fasting blood glucose determinations, to determine the minimum effective dosage and to detect primary failure (inadequate lowering of blood glucose concentration at the maximum recommended dosage) or secondary failure (loss of control of blood glucose concentration following an initial period of effectiveness) to the drug. Glycosylated hemoglobin (hemoglobin A1c [HbA1c]) measurements should also be performed periodically to monitor the patient's response to glyburide therapy. During the withdrawal period in patients in whom glyburide is replacing insulin, patients should be instructed to test their blood for glucose and their urine for glucose and/or ketones at least 3 times daily, and to report the results to their physician. Renal function should be evaluated prior to initiation of therapy with glyburide in fixed combination with metformin and at least annually thereafter. Care should be taken to avoid ketosis, acidosis, and coma during the withdrawal period in patients being switched from insulin to glyburide. If adequate lowering of blood glucose concentration is no longer achieved during maintenance therapy with glyburide, the drug should be discontinued. Alternatively, combined therapy with glyburide and metformin may be used in patients who do not have an adequate glycemic response to glyburide or metformin monotherapy. However, adequate adjustment of dosage and adherence to diet should be assessed before considering that secondary failure to oral antidiabetic therapy has occurred. When use of glyburide in asymptomatic type 2 diabetic patients is being considered, it should be recognized that control of blood glucose concentration in these patients has not been definitely established as effective for prevention of long-term cardiovascular or nervous system complications of the disease. There is limited evidence that sulfonylureas may reverse basement-membrane thickening of muscle capillaries in asymptomatic individuals with impaired glucose tolerance (chemical diabetes) and possibly reverse or retard the progression of microangiopathy in type 2 diabetic patients, but these findings require further evaluation.

Several large, long-term studies have evaluated the cardiovascular risks associated withy the use of oral sulfonylurea antidiabetic agents. In 1970, the University Group Diabetes Program (UGDP) reported that administration of oral antidiabetic agents (i.e., tolbutamide or phenformin) was associated with increased cardiovascular mortality as compared to treatment with dietary regulation alone or with dietary regulation and insulin. The UGDP reported that type 2 diabetic patients who were treated for 5-8 years with dietary regulation and a fixed dose of tolbutamide (1.5 g daily) had a cardiovascular mortality rate approximately 2.5 times that of patients treated with dietary regulation alone; although a substantial increase in total mortality was not observed, the use of tolbutamide was discontinued because of the increase in cardiovascular mortality, thereby limiting the ability of the study to show an increase in total mortality. The results of the UGDP study have been exhaustively analyzed, and there has been general disagreement in the scientific and medical communities regarding the study's validity and clinical importance. However, recent results from the United Kingdom Prospective Diabetes Study (UKPDS), a large, long-term (over 10 years) study in newly diagnosed type 2 diabetic patients, did not confirm an increase in cardiovascular events or mortality in the group treated intensively with sulfonylureas, insulin, or combination therapy compared with that in the group treated with less intensive conventional antidiabetic therapy.

In the UKDP study, the overall aggregate rates of death from macrovascular diseases such as myocardial infarction, sudden death, stroke, or peripheral vascular disease were not appreciably different among either intensive therapies (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide] then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) or less intensive conventional therapy (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia). However, a trend in reduction in fatal and nonfatal myocardial infarction with intensive therapy was noted with sulfonylurea or insulin, and epidemiologic analysis of the data indicate that each 1% decrease in HbA1c was associated with an 18% reduction of fatal and nonfatal myocardial infarction. Among the single end points, the incidence of angina increased among patients receiving chlorpropamide, and blood pressure also was higher with chlorpropamide compared with glyburide or insulin intensive therapies. As a result of these and other findings (e.g., beneficial effects on microvascular [retinopathy, nephropathy, and possibly neuropathy] complications, confirmation of the beneficial effects of concomitant antihypertensive therapy and blood pressure lowering) of the UKDP study, the American Diabetes Association (ADA) currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control in diabetic patients to outweigh the risks overall. The ADA also recommends that clinicians continue to emphasize dietary management and weight reduction as the principal therapy for the management of type 2 diabetes mellitus, and that oral sulfonylurea antidiabetic agents or insulin be used only after these measures have failed; the decision to use sulfonylurea or insulin should be made by the clinician in consultation with the patient.

Patients should be fully and completely advised about the nature of diabetes mellitus, what they must do to prevent and detect complications, and how to control their condition. Patients should be informed of the potential risks and advantages of glyburide therapy and alternative forms of treatment. Patients should be instructed that dietary regulation is the principal consideration in the management of diabetes, and that glyburide therapy is only used as an adjunct to, and not a substitute for or a convenient means to avoid, proper dietary regulation. Patients should also be advised that they should not neglect dietary restrictions, develop a careless attitude about their condition, or disregard instructions about body-weight control, exercise, hygiene, and avoidance of infection. Primary and secondary failure to oral sulfonylurea antidiabetic agents should also be explained to patients.

Patients and responsible family members should be informed of the risks of hypoglycemia, the symptoms and treatment of hypoglycemic reactions, and conditions that predispose to the development of hypoglycemic reactions, since these reactions may occur during therapy with glyburide. Appropriate patient selection and careful attention to dosage are important to avoid glyburide-induced hypoglycemia. Debilitated, malnourished, or geriatric patients and patients with mild disease or impaired hepatic or renal function should be carefully monitored and dosage of glyburide should be carefully adjusted in these patients, since they may be predisposed to developing hypoglycemia (sometimes severe). Renal or hepatic insufficiency may cause increased serum concentrations of glyburide and hepatic insufficiency may also diminish glyconeogenic capacity, both of which increase the risk of severe hypoglycemic reactions. Some clinicians recommend that glyburide generally not be used in patients with renal or hepatic impairment. Alcohol ingestion, severe or prolonged exercise, deficient caloric intake, use of more than one antidiabetic agent (e.g., glyburide and metformin), severe endocrine disorders, and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia. Hypoglycemia may be difficult to recognize in geriatric patients or in patients receiving β-adrenergic blocking agents. Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during glyburide therapy. (See Acute Toxicity: Treatment.) Renal or hepatic insufficiency in patients receiving glyburide in fixed combination with metformin may elevate blood concentrations of both drugs and hepatic insufficiency may diminish gluconeogenic capacity, both of which increase the risk of hypoglycemic reactions.

To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary discontinuance of glyburide and administration of insulin may be required.

Although initial batches of Diaβeta 5-mg tablets contained the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals, currently distributed tablets have been reformulated and do not contain this dye. The incidence of tartrazine sensitivity is low, but tartrazine sensitivity frequently occurs in patients who are sensitive to aspirin.

If cholestatic jaundice occurs or if adverse dermatologic effects occur and persist during glyburide therapy, the drug should be discontinued. Glyburide is contraindicated as sole therapy in patients with type 1 diabetes mellitus; glyburide alone or in fixed combination with metformin is contraindicated in those with diabetes complicated by ketosis, acidosis, or diabetic coma. Diabetic ketoacidosis should be treated with insulin. Like other sulfonylureas, glyburide is generally contraindicated in patients with severe renal or hepatic impairment.

Glyburide is also contraindicated in patients with known hypersensitivity or allergy to any ingredient in the respective formulations.

Pediatric Precautions

Safety and efficacy of glyburide in children have not been established. The manufacturer states that the drug is not recommended for use in this age group. Data from a comparative trial evaluating the safety and efficacy of glyburide in fixed combination with metformin compared with monotherapy with each agent in pediatric patients (9-16 years of age) with type 2 diabetes mellitus indicate no unexpected safety concerns with such combination therapy.(See Combination Therapy with Metformin or Other Oral Antidiabetic Agents under Uses: Diabetes Mellitus.) The American Diabetes Association (ADA) states that most pediatric diabetologists use oral antidiabetic agents in children with type 2 diabetes mellitus because of greater patient compliance and convenience for the patient's family and a lack of evidence demonstrating better efficacy of insulin as initial therapy for type 2 diabetes mellitus.

Mutagenicity and Carcinogenicity

It is not known if glyburide is mutagenic or carcinogenic in humans. The drug did not exhibit mutagenic activity in the Ames microbial mutagen test or the DNA damage/alkaline elution assay. Evidence of carcinogenicity was not observed in studies in rats receiving up to 300 mg/kg of glyburide daily for 18 months or in mice receiving the drug for 2 years.

Pregnancy, Fertility, and Lactation

Pregnancy

When a glyburide dosage 6250 times the maximum recommended human dosage was given to rats, a shortening of long bones (humerus and femur) in rat pups was noted. These effects were observed during the period of lactation and not during organogenesis. Since abnormal maternal blood glucose concentrations during pregnancy may be associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain optimum control of blood glucose concentration. Use of glyburide in pregnant women is generally not recommended, and the drug should be used during pregnancy only when clearly necessary (e.g., when insulin therapy is infeasible) or when the potential benefit justifies the possible risks to the fetus. Glyburide has been used in some pregnant women without unusual adverse effects. In a prospective, comparative clinical trial in women with gestational diabetes, treatment with glyburide (mean daily dosage 9 mg, range 2.5-20 mg) initiated in the second trimester (11-33 weeks gestation) and continued until delivery resulted in similar degrees of glycemic control and perinatal outcomes as treatment with insulin human (mean daily dosage: 85 units). The incidence of hypoglycemia in neonates whose mothers received either insulin or glyburide therapy also was similar. Additional studies in a larger number of patients are needed to establish the safety of glyburide in gestational diabetes. In a retrospective study, hypoglycemia occurred and persisted for up to 2 days or longer in a few neonates whose mothers had received glyburide up to the time of delivery. Prolonged, severe hypoglycemia lasting 4-10 days has been reported in some neonates born to women who were receiving other sulfonylurea antidiabetic agents up to the time of delivery; this effect has been reported more frequently with the use of those agents having prolonged elimination half-lives. To minimize the risk of neonatal hypoglycemia if glyburide is used during pregnancy, the manufacturers recommend that the drug be discontinued at least 2 weeks before the expected delivery date.

Fertility

Reproduction studies in rats and rabbits using glyburide doses up to 500 times the usual human dose have not revealed evidence of impaired fertility or harm to the fetus.

Lactation

Although it is not known whether glyburide is distributed into milk, some sulfonylurea antidiabetic agents are distributed into milk. Because of the potential for hypoglycemia in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman. If glyburide is discontinued, and if dietary management alone is inadequate for controlling blood glucose concentration, administration of insulin should be considered.

Drug Interactions

Protein-bound Drugs

Because glyburide is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylate and other nonsteroidal anti-inflammatory agents, and sulfonamides. However, unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide) and like that of glipizide, the protein binding of glyburide is principally nonionic; in addition, glyburide appears to bind to different but closely related sites on serum albumin and with a greater affinity than acetohexamide, chlorpropamide, or tolbutamide. Consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature. In vitro studies indicate that glyburide is less susceptible to displacement from serum albumin by acidic drugs (e.g., phenylbutazone, salicylate, warfarin) than is chlorpropamide or tolbutamide. Whether this difference in protein binding demonstrated in vitro will result in fewer clinically important drug interactions in vivo has not been established. There appears to be no clinically important interaction between tolmetin and glyburide. Patients receiving highly protein-bound drugs should be observed for adverse effects when glyburide therapy is initiated or discontinued and vice versa.

Phenylbutazone

Phenylbutazone may potentiate the hypoglycemic effects of glyburide. The exact mechanism(s) of this interaction is not known. Phenylbutazone has been shown to decrease the renal excretion of glyburide metabolites without affecting metabolism of the sulfonylurea. If phenylbutazone is administered concomitantly with glyburide, the patient should be closely monitored for signs and symptoms of hypoglycemia; dosage adjustment of glyburide may be necessary when phenylbutazone therapy is initiated or discontinued.

Thiazide Diuretics

Thiazide diuretics may exacerbate diabetes mellitus, resulting in increased requirements of sulfonylurea antidiabetic agents, temporary loss of diabetic control, or secondary failure to the antidiabetic agent. When thiazide diuretics are administered concomitantly with sulfonylurea antidiabetic agents, caution should be used.

Alcohol

Disulfiram-like reactions have occurred very rarely following the concomitant use of alcohol and glyburide.

Bosentan

An increased risk of elevated serum aminotransferase concentrations has been observed in patients receiving glyburide and bosentan concomitantly. The manufacturer of bosentan states that concomitant use of glyburide and bosentan is contraindicated.

β-Adrenergic Blocking Agents

Several potential interactions between β-adrenergic blocking agents and sulfonylurea antidiabetic agents exist. β-Adrenergic blocking agents may impair glucose tolerance; increase the frequency or severity of hypoglycemia; block hypoglycemia-induced tachycardia, but not hypoglycemic sweating which may actually be increased; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. There is some evidence that many of these effects may be minimized by use of a β1-selective adrenergic blocking agent rather than a nonselective β-adrenergic blocking agent. Acebutolol and propranolol have been shown to decrease the hypoglycemic action of glyburide in type 2 diabetic patients, presumably by decreasing insulin secretion. In another study in type 2 diabetic patients, insulin secretion during short-term atenolol therapy was reduced, but the hypoglycemic action of glyburide was not altered during short- or long-term atenolol administration. It generally is recommended that concomitant use of β-adrenergic blocking agents and sulfonylurea antidiabetic agents be avoided when possible; if concomitant therapy is necessary, use of a β1-selective adrenergic blocking agent may be preferred. When glyburide and a β-adrenergic blocking agent are used concomitantly, the patient should be monitored closely for altered antidiabetic response.

Antifungal Antibiotics

Concomitant use of certain antifungal antibiotics (i.e., miconazole, fluconazole) and oral antidiabetic agents has resulted in increased plasma concentrations of the oral antidiabetic agent and/or hypoglycemia. Clinically important hypoglycemia may be precipitated by concomitant use of oral hypoglycemic agents and fluconazole, and at least one fatality has been reported from hypoglycemia in a patient receiving glyburide and fluconazole concomitantly.

Other Drugs

Drugs that may enhance the hypoglycemic effect of sulfonylurea antidiabetic agents, including glyburide, include chloramphenicol, monoamine oxidase inhibitors, fluoroquinolone antibiotics (e.g., ciprofloxacin), and probenecid. When these drugs are administered or discontinued in patients receiving glyburide, the patient should be observed closely for hypoglycemia or loss of diabetic control, respectively.

Drugs that may decrease the hypoglycemic effect of sulfonylurea antidiabetic agents, including glyburide, include nonthiazide diuretics (e.g., furosemide), corticosteroids, phenothiazines, thyroid agents, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetic agents, calcium-channel blocking agents, rifampin, and isoniazid. When these drugs are administered or discontinued in patients receiving glyburide, the patient should be observed closely for loss of diabetic control or hypoglycemia, respectively.

Pharmacokinetics

Absorption

Currently available tablet formulations of glyburide appear to be reliably and almost completely absorbed following oral administration; however, studies to determine the absolute bioavailability are generally lacking. Initial pharmacokinetic studies using other tablet formulations suggested that the drug was variably and incompletely absorbed. Food apparently does not affect the rate or extent of absorption of glyburide.

Following oral administration of a single 5-mg dose of glyburide, the drug appears in plasma or serum within 15-60 minutes and average peak plasma or serum concentrations of approximately 140-350 ng/mL usually are attained within 2-4 hours (range: 2-8 hours). The area under the serum concentration-time curve (AUC) for glyburide increases in proportion to increasing doses. Substantial interindividual variations in steady-state serum concentration have been reported in diabetic patients receiving the same dosage of glyburide.

Following single oral doses of glyburide in nonfasting diabetic or healthy individuals, plasma insulin concentration generally begins to increase within 15-60 minutes and is maximal within 1-2 hours; in diabetic patients, increases in plasma insulin concentration may persist for up to 24 hours. Following single oral doses of the drug in fasting healthy individuals, the degree and duration of lowering of blood glucose concentration are proportional to the dose administered and the AUC; the hypoglycemic action generally begins within 45-60 minutes and is maximal within 1.5-3 hours. In nonfasting diabetic patients, the hypoglycemic action of a single morning dose of glyburide may persist for up to 24 hours. There is some evidence that a serum glyburide concentration of approximately 30-50 ng/mL is required to lower blood glucose concentration. A correlation between blood concentrations of the drug and fasting blood glucose concentration in diabetic patients receiving long-term glyburide therapy has not been established.

Distribution

Distribution of glyburide into human body tissues and fluids has not been fully characterized. Following oral or IV administration in animals, highest concentrations of the drug are attained in the liver, kidneys, and small and large intestines, with lower concentrations in the stomach, pancreas, spleen, mesenteric lymph nodes, mesenteric and retroperitoneal fat, heart, lungs, gonads, skeletal muscle, and brain. In humans, glyburide is distributed in substantial amounts into bile. Glyburide appears to cross the placenta, since prolonged hypoglycemia has occurred in neonates born to women who received the drug up to the time of delivery. It is not known if the drug is distributed into milk.

In healthy adults, the volume of distribution of glyburide during the elimination phase averages 0.155 L/kg and the apparent steady-state volume of distribution averages 0.125 L/kg. Serum glyburide concentration-time curves in diabetic individuals receiving multiple doses of the drug have been shown to be similar to those following single doses, suggesting that glyburide does not accumulate in tissue depots; however, other pharmacokinetic data have suggested that the drug may accumulate in a deep tissue compartment following continuous administration.

At a concentration of 0.05-10 mcg/mL in vitro, glyburide is more than 99% bound to serum proteins and its major metabolite, 4-trans-hydroxyglyburide, is more than 97% bound to serum proteins. Glyburide has a higher affinity for binding to serum albumin than does acetohexamide, chlorpropamide, glipizide, or tolbutamide. Unlike the protein binding of some other sulfonylurea antidiabetic agents (e.g., acetohexamide, chlorpropamide, tolazamide, tolbutamide) and like that of glipizide, the protein binding of glyburide is principally nonionic; consequently, glyburide may be less likely to be displaced from binding sites by, or displace from binding sites, other highly protein-bound drugs whose protein binding is ionic in nature. (See Drug Interactions: Protein-Bound Drugs.)

Elimination

Serum concentrations of glyburide appear to decline in a biphasic manner. In studies in healthy adults using assays relatively specific for unchanged glyburide, the terminal elimination half-life has reportedly averaged 1.4-1.8 hours (range: 0.7-3 hours); when assays that also measured metabolites of the drug were used, the terminal elimination half-life has averaged about 10 hours (range: 5-26 hours). Serum glyburide concentrations may be increased in patients with renal or hepatic insufficiency. Data are limited, but the half-life may be prolonged in patients with severe renal impairment. In one study in patients with normal hepatic function and impaired renal function given a single oral dose of radiolabeled glyburide, the plasma half-life of total radioactivity was 2-5 hours in those with creatinine clearances of 29-131 mL/minute per 1.73 m and 11 hours in one patient with a creatinine clearance of 5 mL/minute per 1.73 m; in those patients with creatinine clearances of 29-131 mL/minute per 1.73 m, no relationship between plasma half-life and creatinine clearance was observed.

Glyburide appears to be completely metabolized, probably in the liver. The drug is metabolized at the cyclohexyl ring principally to 4-trans-hydroxyglyburide; the 4-trans-hydroxy metabolite has only 0.25% of the hypoglycemic activity of glyburide following oral administration in rabbits, but has about 15% of the hypoglycemic activity of the parent compound following intraperitoneal administration in rats. Glyburide is also metabolized to the 3-cis-hydroxy derivative and to another unidentified metabolite; the 3-cis-hydroxy metabolite has 2.5% of the hypoglycemic activity of glyburide following oral administration in rabbits. The hypoglycemic activity of glyburide metabolites is generally considered clinically unimportant; however, results of studies in rats indicate that retention of the 4-trans-hydroxy metabolite in the presence of renal insufficiency may enhance and prolong the hypoglycemic effect of the drug.

Unlike other currently available sulfonylurea antidiabetic agents which are excreted principally in urine, glyburide is excreted as metabolites in urine and feces in approximately equal proportions. Fecal excretion appears to occur almost completely via biliary elimination; only small amounts may be excreted in feces as unabsorbed drug following oral administration. Most urinary excretion occurs within the first 6-24 hours after oral administration of the drug. Following oral administration of a single 5-mg dose of glyburide in healthy individuals, approximately 30-50% of the dose is excreted in urine as metabolites within 24 hours; about 80% of the urinary excretion occurs as the 4-trans-hydroxy metabolite, 15% as the 3-cis-hydroxy metabolite, and 5% as an unidentified metabolite. Fecal excretion occurs more slowly, but a single oral dose of the drug is completely excreted in urine and feces within 3-5 days in healthy individuals.

Total plasma clearance of glyburide reportedly averages 78 mL/hour per kg in healthy adults. The effects of renal impairment on the elimination of glyburide and its metabolites have not been fully evaluated. Limited data indicate that renal excretion of glyburide metabolites and plasma clearance of glyburide may be substantially decreased in patients with severe renal impairment.

Glyburide appears to be only minimally removed by hemodialysis.

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