There is no fixed dosage regimen for the management of diabetes mellitus with MICRONASE Tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, ie, inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, ie, loss of adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy. Short-term administration of MICRONASE may be sufficient during periods of transient loss of control in patients usually controlled well on diet.<br/>Usual Starting Dose: The usual starting dose of MICRONASE Tablets is 2.5 to 5 mg daily, administered with breakfast or the first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be started at 1.25 mg daily. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy.<br/>Transfer From Other Hypoglycemic Therapy Patients Receiving Other Oral Antidiabetic Therapy: Transfer of patients from other oral antidiabetic regimens to MICRONASE should be done conservatively and the initial daily dose should be 2.5 to 5 mg. When transferring patients from oral hypoglycemic agents other than chlorpropamide to MICRONASE, no transition period and no initial or priming dose are necessary. When transferring patients from chlorpropamide, particular care should be exercised during the first two weeks because the prolonged retention of chlorpropamide in the body and subsequent overlapping drug effects may provoke hypoglycemia.<br/>Patients Receiving Insulin: Some Type II diabetic patients being treated with insulin may respond satisfactorily to MICRONASE. If the insulin dose is less than 20 units daily, substitution of MICRONASE Tablets 2.5 to 5 mg as a single daily dose may be tried. If the insulin dose is between 20 and 40 units daily, the patient may be placed directly on MICRONASE Tablets 5 mg daily as a single dose. If the insulin dose is more than 40 units daily, a transition period is required for conversion to MICRONASE. In these patients, insulin dosage is decreased by 50% and MICRONASE Tablets 5 mg daily is started. Please refer to Titration to Maintenance Dose for further explanation.<br/>Titration to Maintenance Dose: The usual maintenance dose is in the range of 1.25 to 20 mg daily, which may be given as a single dose or in divided doses (See Dosage Interval section). Dosage increases should be made in increments of no more than 2.5 mg at weekly intervals based upon the patient's blood glucose response. No exact dosage relationship exists between MICRONASE and the other oral hypoglycemic agents. Although patients may be transferred from the maximum dose of other sulfonylureas, the maximum starting dose of 5 mg of MICRONASE Tablets should be observed. A maintenance dose of 5 mg of MICRONASE Tablets provides approximately the same degree of blood glucose control as 250 to 375 mg chlorpropamide, 250 to 375 mg tolazamide, 500 to 750 mg acetohexamide, or 1000 to 1500 mg tolbutamide. When transferring patients receiving more than 40 units of insulin daily, they may be started on a daily dose of MICRONASE Tablets 5 mg concomitantly with a 50% reduction in insulin dose. Progressive withdrawal of insulin and increase of MICRONASE in increments of 1.25 to 2.5 mg every 2 to 10 days is then carried out. During this conversion period when both insulin and MICRONASEare being used, hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least three times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is a Type I diabetic who requires insulin therapy.<br/>Concomitant Glyburide and Metformin Therapy: MICRONASE Tablets should be added gradually to the dosing regimen of patients who have not responded to the maximum dose of metformin monotherapy after four weeks (see Usual Starting Dose and Titration to Maintenance Dose). Refer to metformin package insert. With concomitant glyburide and metformin therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. However, attempts should be made to identify the optimal dose of each drug needed to achieve this goal. With concomitant glyburide and metformin therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken .<br/>Maximum Dose: Daily doses of more than 20 mg are not recommended.<br/>Dosage Interval: Once-a-day therapy is usually satisfactory. Some patients, particularly those receiving more than 10 mg daily, may have a more satisfactory response with twice-a-day dosage.<br/>Specific Patient Populations: MICRONASE is not recommended for use in pregnancy or for use in pediatric patients. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions.
MICRONASE Tablets contain glyburide, which is an oral blood-glucose-lowering drug of the sulfonylurea class. Glyburide is a white, crystalline compound, formulated as MICRONASE Tablets of 1.25, 2.5, and 5 mg strengths for oral administration. Inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, sodium alginate, talc. In addition, the 2.5 mg contains aluminum oxide and FD&C Red No. 40 and the 5 mg contains aluminum oxide and FD&C Blue No. 1. The chemical name for glyburide is 1-[ [p-[2-(5-chloro-o-anisamido)-ethyl]phenyl]-sulfonyl]-3-cyclohexylurea and the molecular weight is 493.99. The structural formula is represented below.
Actions: Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. Some patients who are initially responsive to oral hypoglycemic drugs, including MICRONASE, may become unresponsive or poorly responsive over time. Alternatively, MICRONASE Tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with MICRONASE Tablets.<br/>Pharmacokinetics: Single dose studies with MICRONASE Tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with MICRONASE in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-lifeis about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels.A one year study of diabetic patients treated with MICRONASE showed no reliable correlation between administered dose and serum drug level. The major metabolite of glyburide is the 4-transhydroxy derivative. A second metabolite, the 3-cishydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine. Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with MICRONASE Tablets in clinical use.
MICRONASE Tablets are contraindicated in patients with:
MICRONASE Tablets are supplied as follows: MICRONASE Tablets 1.25 mg (White, Round, Scored, imprinted MICRONASE 1.25) MICRONASE Tablets 2.5 mg (Dark Pink, Round, Scored, imprinted MICRONASE 2.5) MICRONASE Tablets 5 mg (Blue, Round, Scored imprinted MICRONASE 5)
Hypoglycemia: See Precautions and Overdosage Sections.<br/>Gastrointestinal Reactions: Cholestatic jaundice and hepatitis may occur rarely; MICRONASE Tablets should be discontinued if this occurs. Liver function abnormalities, including isolated transaminase elevations, have been reported. Gastrointestinal disturbances, eg, nausea, epigastric fullness, and heartburn are the most common reactions, having occurred in 1.8% of treated patients during clinical trials. They tend to be dose related and may disappear when dosage is reduced.<br/>Dermatologic Reactions: Allergic skin reactions, eg, pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions occurred in 1.5% of treated patients during clinical trials. These may be transient and may disappear despite continued use of MICRONASE; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.<br/>Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.<br/>Metabolic Reactions: Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas; however, hepatic porphyria has not been reported with MICRONASE and disulfiram-like reactions have been reported very rarely. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone. The syndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain other sulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral (antidiuretic) action of ADH and/or increase release of ADH.<br/>Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels. In addition to dermatologic reactions, allergic reactions such as angioedema, arthralgia, myalgia and vasculitis have been reported.
MICRONASE Tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. Glyburide may be used concomitantly with metformin when diet and glyburide or diet and metformin alone do not result in adequate glycemic control (see metformin insert). In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible. If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of MICRONASE must be viewed by both the physician and patient as a treatment in addition to diet and not as a substitution or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of MICRONASE. During maintenance programs, MICRONASE should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgment should be based on regular clinical and laboratory evaluations. In considering the use of MICRONASE in asymptomatic patients, it should be recognized that controlling blood glucose in non-insulin-dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.