Action And Clinical Pharmacology: The principal action of glyburide results in an increased insulin release from the beta cells of the pancreas. Other mechanisms leading to a reduction of blood glucose are also believed to be influenced by glyburide. The insertion of an alkylene chain on the benzene nucleus results in a product of very high potency.
Schulz and Schmidt indicated that the presence of a sulfonamide (sulfaphenazole) decreased the distribution volume of glyburide without influence on the half-life of the oral hypoglycemic agent. As a result, insulin and serum concentrations of glyburide were higher and hypoglycemic attacks could be expected.
Hirn and Konigstein have observed hypoglycemia when phenylbutazone and oxyphenbutazone were added to glyburide. Schulz and Schmidt confirmed that phenylbutazone has an enhancing effect on the blood sugar lowering effect of glyburide and found higher insulin levels. The plasma half-life of glyburide did not change with phenylbutazone administration. However, a significant decrease in the renal excretion of the main metabolite of glyburide was observed, suggesting that the elimination in the bile may compensate for the amount not excreted in the urine.
Glyburide micronized powder is well absorbed from the intestinal tract. Glyburide is highly bound to plasma proteins after absorption from the gastrointestinal tract. It is completely metabolized by hydroxylation of the cyclohexyl ring into 3-cis and 4-trans derivatives in the liver, and the kidneys play only a minor role in their biotransformation and elimination from plasma. The metabolites have no essential hypoglycemic effect and they are not stored in the body, but they are eliminated via the bile, and in approximately the same amounts in the urine conjugated to glucuronic acid and in the feces.
Maximal plasma levels of insulin, after an oral dose of 5 mg glyburide in normal subjects were reached 90 minutes after dosing.
Minimal blood levels of glucose, after an oral dose of 5 mg glyburide in normal subjects, were reached 120 minutes after dosing corresponding to a reduction of about 35%.
Raptis et al. found that the effect of an i.v. injection of 1 mg of glyburide on blood glucose and serum insulin levels of healthy subjects was slower in onset and lasted longer than that of 1 g of tolbutamide. Furthermore, when a second injection of glyburide was given 1 hour later, the effects were undiminished. When glyburide was injected at 4-hour intervals in patients with adult-onset diabetes, the effects of glyburide were not diminished.
Indications And Clinical Uses: To control hyperglycemia in glyburide-responsive diabetes mellitus of stable, mild, nonketosis-prone, maturity-onset or adult-type which cannot be controlled solely by proper dietary management, exercise and weight reduction or when insulin therapy is not appropriate.
Contra-Indications: Patients with known hypersensitivity or allergy to the active ingredient or any other component of the formulation. Glyburide should not be given to patients with: unstable and/or insulin-dependent diabetes mellitus; ketoacidosis; diabetic precoma; coma; in the presence of pre-existing complications peculiar to diabetes; during stress conditions such as severe infections, trauma or surgery; in the presence of liver disease or renal impairment; or frank jaundice.
Pregnancy: During pregnancy, no oral antidiabetic agent should be given.
Lactation: Due to the possible excretion in human milk, the patient should discontinue nursing or discontinue taking the drug depending on the importance of the drug to the mother. If glyburide is discontinued, the patient should be transferred to insulin therapy.
Manufacturers’ Warnings In Clinical States: The use of glyburide will not prevent the development of complications peculiar to diabetes mellitus.
The use of glyburide must be considered as treatment in addition to a proper dietary regimen and not as a substitute for diet.
Over a period of time, patients may become progressively less responsive to therapy with oral hypoglycemic agents because of deterioration of their diabetic state. If a loss of adequate blood glucose lowering response to glyburide is detected, the drug should be discontinued.
Precautions: Patient Selection and Followup: Careful selection of patients is important. It is imperative that there be rigid attention to diet, adherence to regular exercise, reduction of body weight in obese patients, careful adjustment of dosage, instruction of the patient on hypoglycemic reactions and their control as well as regular, thorough followup examinations.
Since the effects of oral hypoglycemic agents on the vascular changes and other long-term sequelae of diabetes mellitus are not fully known, patients receiving such drugs must be closely observed for both short and long-term complications.
Periodic assessment of cardiovascular, ophthalmic, hematologic, renal and hepatic status is advisable.
In patients stabilized on glyburide therapy, loss of blood sugar control may occur in cases of acute intercurrent disease or in stressful situations such as trauma or surgery. Under these conditions, discontinuation of glyburide and administration of insulin should be considered.
Oral hypoglycemic agents should be administered with caution to patients with Addison’s disease.
Pregnancy: The use of glyburide is not recommended for women planning a pregnancy (see Contraindications); these patients should be changed over to insulin therapy.
Hypoglycemic Reactions: Severe hypoglycemia can be induced by all sulfonylurea drugs. Particularly susceptible are elderly subjects, patients with impaired hepatic and renal function, those who are debilitated or malnourished, and patients with primary or secondary adrenal insufficiency. Hypoglycemia is more likely to occur when the caloric intake is inadequate or after strenuous or prolonged exercise.
Drug Interactions: Patients who receive or discontinue certain medications while undergoing treatment with glyburide may experience changes in blood glucose control.
Hypoglycemia may be potentiated when a sulfonylurea is used concurrently with agents such as: insulin and other oral antidiabetics, anabolic steroids and androgens, azapropazone, chloramphenicol, clofibrate, coumarin derivatives, cyclophosphamide, disopyramide, fenfluramine, fibrates, fluoxetine, ifosfamide, miconazole, MAO inhibitors, oxyphenbutazone, para-aminosalicylic acid, phenylbutazone, probenecid, propranolol, quinolones, salicylates, sulfinpyrazone, sulfonamides, sympatholytic agents (e.g., beta-blockers, guanethidine) tetracyclines, tuberculostatics.
Certain drugs tend to produce hyperglycemia and may lead to loss of blood sugar control; these include: acetazolamide, barbiturates, corticosteroids, diazoxide, diuretics (thiazides, furosemide), glucagon, laxatives (after protracted use), nicotinic acid (in pharmacologic doses), oral contraceptives (estrogen plus progestogen), phenothiazines, phenytoin, rifampin, sympathomimetic agents (e.g., epinephrine) and thyroid hormones.
Under the influence of sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine, the signs of adrenergic counter-regulation to hypoglycemia may be reduced or absent.
Concurrent use of H2-receptor antagonists, clonidine or reserpine with glyburide may lead to either a potentiation or an attenuation of the blood-glucose-lowering effect.
Both acute and chronic alcohol intake may potentiate or weaken the blood-glucose-lowering action of glyburide in an unpredictable fashion. Intolerance to alcohol (disulfiram-like reaction: flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia) may occur in patients treated with oral hypoglycemic drugs. These reactions can be prevented by avoiding the use of alcohol.
Barbiturates should be used cautiously in patients receiving an oral hypoglycemic agent since their action may be prolonged.
Glyburide may potentiate or weaken the effects of coumarin derivatives.
Occupational Hazards: Until optimal control has been achieved, when changing the antidiabetic preparation, or when the tablets have not been taken regularly, alertness and reaction time may be altered to such an extent that the patient cannot safely cope with road traffic or operate machinery.
Adverse Reactions: Hypoglycemia (see Precautions): Severe hypoglycemia, which may be prolonged and has occasionally been life-threatening, may occur and mimics acute CNS disorders (see Overdose: Symptoms and Treatment). Hepatic and/or renal disease, malnutrition and/or irregular meals, exercise without adequate caloric supplementation, debility, advanced age, patient noncompliance, alcoholism, certain disorders of thyroid function, adrenal or pituitary insufficiency, excessive glyburide dosage, treatment with glyburide in the absence of indication or concurrent use with other agents may be predisposing factors.
Gastrointestinal: Nausea, epigastric fullness and heartburn are common reactions. Vomiting, diarrhea, and abdominal pain have also been reported. These tend to be dose-related and may disappear when dosage is reduced.
Dermatologic and Sensitivity Reactions: Allergic and pseudoallergic skin reactions such as pruritus, erythema, urticaria, morbilliform, or maculopapular eruptions have been reported in a number of patients. These may subside on continued use of glyburide, but if they persist the drug should be discontinued. Mild reactions such as urticaria may very rarely develop into serious and life-threatening reactions including dyspnea, hypotension or shock. Porphyria cutanea tarda and photosensitivity reactions have been associated with the use of oral hypoglycemic drugs. Allergic vasculitis have been observed very rarely in patients receiving glyburide and in some circumstances may be life-threatening.
Cross-sensitivity to sulfonamides or their derivatives may occur in patients treated with oral sulfonylurea hypoglycemic agents.
Hematologic: Rare cases of mild to severe thrombocytopenia which can manifest itself as purpura have been reported. Leukopenia, agranulocytosis, pancytopenia (which may be due to myelosuppression), erythrocytopenia, granulocytopenia, hemolytic anemia and aplastic anemia have been observed very rarely with glyburide therapy. These reactions may be reversible following discontinuation of the sulfonylurea antidiabetic agent.
Metabolic: Hepatic porphyria and disulfiram-like reactions have been observed in patients treated with oral hypoglycemic drugs. Elevation of liver enzyme levels has been reported very rarely in patients treated with glyburide. In isolated cases, impairment of liver function (e.g., cholestasis and jaundice) and hepatitis have been observed which can regress after withdrawal of the drug or may lead to life-threatening liver failure.
Endocrine: Reduced radioactive iodine uptake by the thyroid gland has been reported with oral hypoglycemic therapy.
Other: Transient visual disturbances may occur at the commencement of treatment due to fluctuations in blood glucose levels.
In isolated cases, reduction of serum sodium concentrations has been observed in patients receiving glyburide.
Symptoms And Treatment Of Overdose: Symptoms: Overdosage with sulfonylureas may result in hypoglycemia, but it should be noted that the dosage which causes hypoglycemia varies widely, and may be within the accepted therapeutic range in sensitive individuals.
The manifestations of hypoglycemia include: flushing or pallor, chilliness, excessive hunger, trembling, headache, dizziness, nausea, vomiting, restlessness, aggressiveness, depression, speech disorders, sensory and/or visual disturbances, helplessness, lassitude, shallow respiration or bradycardia. In more severe cases, the clinical symptoms of a stroke or coma appear. However, symptoms of hypoglycemia are not necessarily as typical as described above and sulfonylureas may cause insidious development of symptoms mimicking cerebrovascular insufficiency (e.g., disordered sleep, somnolence, impaired alertness and reactions, confusion, delirium, cerebral convulsions, paralytic symptoms or loss of consciousness).
Signs of adrenergic counter-regulation to hypoglycemia include: sweating, damp skin, anxiety, tachycardia, hypertension, palpitations, angina pectoris and cardiac arrhythmias. However, these symptoms may be milder or absent in patients who develop hypoglycemia gradually, patients with autonomic neuropathy, or patients who receive concurrent treatment with sympatholytic agents (e.g., beta-blockers, clonidine, reserpine, guanethidine).
Treatment: Discontinue medication and treat hypoglycemia by giving dextrose promptly and in sufficient quantity.
The symptoms of hypoglycemia nearly always subside when blood glucose control is attained. However, some sulfonylurea-induced hypoglycemias may be refractory to treatment and susceptible to relapse, especially in elderly or malnourished patients. Continuous dextrose infusions for hours to days have been necessary.
Dosage And Administration: In diabetic subjects, there is no fixed dosage regimen for management of blood glucose levels. Individual determination of the minimum dose that will lower the blood glucose adequately should be made.
If the maximal recommended dose fails to lower blood glucose adequately in patients on initial trial, glyburide should be discontinued. During the course of therapy a loss of effectiveness may occur. It is advisable to ascertain the contribution of the drug in the control of blood glucose by discontinuing the medication semi-annually or at least annually with careful monitoring of the patient. If the need for the drug is not evident, the drug should not be resumed. In some diabetic subjects, short-term administration of the drug may be sufficient during periods of transient loss of blood sugar control.
Adjustment of glyburide dosage should be considered whenever factors predisposing the patient to the development of hypo- or hyperglycemia, such as weight or life-style changes, are present (see Contraindications, Warnings, Precautions and Adverse Effects).
Newly-Diagnosed Diabetics: The initial dose is 5 mg daily (2.5 mg in patients over 60 years of age) and it should be continued for 5 to 7 days. Depending on the response, the dosage should then be either increased or decreased by steps of 2.5 mg. The maximum daily dose of glyburide is 20 mg (because higher doses normally have no additional effect on control of metabolic state). Occasionally, control is maintained with 2.5 mg daily. The majority of cases can be controlled by 5 to 10 mg (1 to 2 tablets) daily given as a single dose during or immediately after breakfast. Patients who eat only a light breakfast should defer the first dose of the day until lunchtime. If more than 10 mg (2 tablets) daily is required, the excess should be taken with the evening meal.
Changeover From Other Oral Hypoglycemic Agents: There is no exact dosage relationship between glyburide and other oral antidiabetic agents. Discontinue previous oral medication and start glyburide 5 mg daily (2.5 mg in patients over 60 years of age). This also applies to patients changed over from the maximum dose of other oral antidiabetic medication. Determine maintenance dosage as in newly diagnosed diabetics.
Consideration must be given to the potency and duration of action of the previous antidiabetic agent. A break from medication may be required to avoid any summation of effects entailing a risk of hypoglycemia.
Changeover From Insulin: If a change from insulin to glyburide is contemplated in a patient with stable, mild, maturity-onset diabetes, treatment with insulin should be discontinued for a period of 2 or 3 days to determine whether any therapy other than dietary regulation and exercise is needed. During this insulin-free interval, the patient’s urine should be tested at least 3 times daily for glucose and ketone-bodies, and the results monitored carefully by a physician. The appearance of significant ketonuria accompanied by glucosuria within 12 to 24 hours after the withdrawal of insulin strongly suggests that the patient is ketosis-prone and precludes the change from insulin to glyburide.
Availability And Storage: 2.5 mg: Each white, round, uncoated, beveled tablet, with score-break and code letters GLY (imprinted both above and below the score-break) on obverse and Albert logo trademark on reverse, contains: glyburide 2.5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose hydrous, magnesium stearate, purified water and talc. Tartrazine-free. Cartons of 30 (3´10) and 300 (10´30) in blister packs. Plastic bottles of 300.
5 mg: Each white, oblong, uncoated, beveled tablet, with score-break, number 5 and Albert logo trademark on obverse, contains: glyburide 5 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose hydrous, magnesium stearate, purified water and talc. Tartrazine-free. Cartons of 30 (3´10) and 300 (10´30) in blister packs. Plastic bottles of 300.
Store at room temperature, below 25°C, and not beyond the expiry date indicated on the package.
ALBERT® GLYBURIDE Albert Pharma Glyburide Oral Hypoglycemic