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Pronunciation:

(GLYE me pye ride)

U.S. Brand Names:

Amaryl®

Generic Available:

Canadian Brand Names:

Amaryl®

Use:

Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise to lower blood glucose or in combination with metformin; use in combination with insulin to lower blood glucose in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent

Pregnancy Risk Factor:

Pregnancy Implications:

Abnormal blood glucose levels are associated with a higher incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.

Lactation:

Excretion in breast milk unknown/contraindicated

Contraindications:

Hypersensitivity to glimepiride, any component of the formulation, or sulfonamides; diabetic ketoacidosis (with or without coma)

Warnings/Precautions:

All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used.

Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS) have not supported an association.

Adverse Reactions:

1% to 10%: Central nervous system: Headache

<1%: Agranulocytosis, anorexia, aplastic anemia, blood dyscrasias, bone marrow suppression, cholestatic jaundice, constipation, diarrhea, diuretic effect, edema, epigastric fullness, erythema, heartburn, hemolytic anemia, hepatitis, hypoglycemia, hyponatremia, nausea, photosensitivity, pruritus, rash, thrombocytopenia, urticaria, vomiting

Other reactions reported with sulfonylureas: Porphyria, vasculitis

Overdosage/Toxicology:

Symptoms of overdose include low blood sugar, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Intoxication with sulfonylureas can cause hypoglycemia and are best managed with glucose administration (oral for milder hypoglycemia or by injection in more severe forms). Patients should be monitored for a minimum of 24-48 hours after ingestion.

Drug Interactions:

Substrate of CYP2C8/9 (major)

Beta blockers: Beta blockers may enhance the effects of sulfonylureas.

Chloramphenicol: Chloramphenicol may increase the effects of sulfonylureas.

Cimetidine: Cimetidine may increase the effects of glimepiride.

Clofibrate: Clofibrate may increase the effects of sulfonylureas.

Coumarins: Sulfonylureas may increase the effects of coumarins.

Cyclosporine: Sulfonylureas may increase the levels of cyclosporine.

CYP2C8/9 inducers: May decrease the levels/effects of glimepiride. Example inducers include carbamazepine, phenobarbital, phenytoin, rifampin, rifapentine, and secobarbital.

CYP2C8/9 inhibitors: May increase the levels/effects of glimepiride. Example inhibitors include delavirdine, fluconazole, gemfibrozil, ketoconazole, nicardipine, NSAIDs, pioglitazone, and sulfonamides.

Fluconazole: Fluconazole may increase the levels of sulfonylureas.

Gemfibrozil: Gemfibrozil may increase the effects of sulfonylureas.

Hyperglycemia-producing agents: Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid.

Pegvisomant: Pegvisomant may increase the effects of sulfonylureas.

Rifampin: Rifampin may decrease the effects of sulfonylureas.

Salicylates: Salicylates may increase the effects of sulfonylureas.

Sulfonamides: Sulfonamides may increase the effects of sulfonylureas.

Tricyclic antidepressants: TCAs may increase the effects of sulfonylureas.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Caution with ethanol (may cause hypoglycemia).

Herb/Nutraceutical: Caution with chromium, garlic, gymnema (may cause hypoglycemia).

Mechanism of Action:

Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites

Pharmacodynamics/Kinetics:

Onset of action: Peak effect: Blood glucose reductions: 2-3 hours

Duration: 24 hours

Absorption: 100%; delayed when given with food

Protein binding: >99.5%

Metabolism: Completely hepatic

Half-life elimination: 5-9 hours

Excretion: Urine and feces (as metabolites)

Dosage:

Oral (allow several days between dose titrations):

Adults: Initial: 1-2 mg once daily, administered with breakfast or the first main meal; usual maintenance dose: 1-4 mg once daily; after a dose of 2 mg once daily, increase in increments of 2 mg at 1- to 2-week intervals based upon the patient's blood glucose response to a maximum of 8 mg once daily

Combination with insulin therapy (fasting glucose level for instituting combination therapy is in the range of >150 mg/dL in plasma or serum depending on the patient): initial recommended dose: 8 mg once daily with the first main meal

After starting with low-dose insulin, upward adjustments of insulin can be done approximately weekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapy patients should monitor their capillary blood glucose on an ongoing basis, preferably daily.

Dosing adjustment/comments in renal impairment: Clcr<22 mL/minute: Initial starting dose should be 1 mg and dosage increments should be based on fasting blood glucose levels

Dosing adjustment in hepatic impairment: No data available

Elderly: Initial: 1 mg/day; dose titration and maintenance dosing should be conservative to avoid hypoglycemia

Administration:

May be administered with a meal/food. Patients who are NPO may need to have their dose held to avoid hypoglycemia.

Monitoring Parameters:

Urine for glucose and ketones; monitor for signs and symptoms of hypoglycemia (fatigue, excessive hunger, profuse sweating, numbness of extremities), fasting blood glucose, hemoglobin A1c, fructosamine

Reference Range:

Target range: Adults:

Fasting blood glucose: <120 mg/dL

Glycosylated hemoglobin: <7%

Dietary Considerations:

Administer with breakfast or the first main meal of the day. Dietary modification based on ADA recommendations is a part of therapy. Decreases blood glucose concentration. Hypoglycemia may occur. Must be able to recognize symptoms of hypoglycemia (palpitations, sweaty palms, lightheadedness).

Patient Education:

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication is used to control diabetes; it is not a cure. Monitor glucose as recommended by prescriber. Other important components of treatment plan may include prescribed diet and exercise regimen (consult prescriber or diabetic educator). Always carry quick source of sugar with you. Take exactly as directed with breakfast or the first main meal of the day. Do not change dose or discontinue without consulting prescriber. Avoid alcohol while taking this medication; could cause severe reaction. Do not take other medication within 2 hours of this medication unless advised by prescriber. If you experience hypoglycemic reaction, contact prescriber immediately. You may experience side effects during first weeks of therapy (eg, headache, nausea); consult prescriber if these persist. Report severe or persistent side effects (eg, hypoglycemia: palpitations, sweaty palms, lightheadedness; extended vomiting or flu-like symptoms; skin rash; easy bruising or bleeding; or change in color of urine or stool). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Cardiovascular Considerations:

The possibility of higher doses of sulfonylureas eliciting an increase in cardiovascular events, because of their effects on blocking potassium sensitive ATP channels, has been raised. However, there are presently only limited data to support this premise, particularly with newer generation agents. An early study suggested poor cardiovascular outcomes in diabetic patients treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in diabetic patients receiving newer sulfonylureas are inconsistent. Longer-term prospective trials of sulfonylurea therapy, such as the UKPDS, do not reveal any increased cardiovascular mortality.

Dental Health: Effects on Dental Treatment:

Glimepiride-dependent diabetics (noninsulin dependent, type 2) should be appointed for dental treatment in morning in order to minimize chance of stress-induced hypoglycemia.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

None reported

Mental Health: Effects on Psychiatric Treatment:

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; phenothiazines and TCAs may antagonize glimepiride hypoglycemic effects; MAO inhibitors and TCAs may enhance hypoglycemic effects

Dosage Forms:

Tablet: 1 mg, 2 mg, 4 mg

International Brand Names:

Amarel® (FR); Amaryl® (AR, AT, AU, BR, CA, CH, CL, CO, CR, CZ, DE, DK, DO, EC, ES, FI, GB, GT, HN, HR, HU, ID, IE, IL, IN, IT, MX, NL, NO, PA, PL, PT, RO, RU, SE, SG, SI, SV, TH, TR, YU, ZA); Amarylle® (BE); Bioglic® (BR); Endial® (AR); Euglim® (IN); Glimepil® (BR); Glimepirida Gen Med® (AR); Glimepirida MK® (CO); Glimerid® (CO, DE); Glimial® (PT); Glucopirida® (AR); Islopir® (AR); Roname® (ES); Solosa® (DE, IT)

References

Alexander RW, "Prolonged Hypoglycemia Following Acetohexamide Administration,"Diabetes, 1966, 15(5):362-4.

"A Study of the Effects of Hypoglycemia Agents on Vascular Complications in Patients With Adult-onset Diabetes. VI. Supplementary Report on Nonfatal Events in Patients Treated With Tolbutamide. The University Group Diabetes Program,"Diabetes, 1976, 25(12):1129-53.

Cowen DL, Burtis B, and Youmans J, "Prolonged Coma After Acetohexamide Ingestion,"JAMA, 1967, 201(2):141-2.

"Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,"Lancet, 1998, 352(9131):854-65.

Garratt KN, Brady PA, Hassinger NL, et al, "Sulfonylurea Drugs Increase Early Mortality in Patients With Diabetes Mellitus After Direct Angioplasty for Acute Myocardial Infarction,"J Am Coll Cardiol, 1999, 33(1):119-24.

"Intensive Blood-Glucose Control With Sulphonylureas or Insulin Compared With Conventional Treatment and Risk of Complications in Patients With Type 2 Diabetes (UKPDS 33) UK Prospective Diabetes Study (UKPDS) Group,"Lancet, 1998, 352(9131):837-53.

Klamann A, Sarfert P, Launhardt V, et al, "Myocardial Infarction in Diabetic vs Nondiabetic Subjects. Survival and Infarct Size Following Therapy With Sulfonylureas (Glibenclamide),"Eur Heart J, 2000, 21(3):220-9.

Meinert CL, Knatterud GL, Prout TE, et al, "A Study of the Effects of Hypoglycemic Agents on Vascular Complications in Patients With Adult-Onset Diabetes. II. Mortality Results,"Diabetes, 1970, 19:789-830.

O'Keefe JH, Blackstone EH, Sergeant P, et al, "The Optimal Mode of Coronary Revascularization for Diabetics. A Risk-Adjusted Long-Term Study Comparing Coronary Angioplasty and Coronary Bypass Surgery,"Eur Heart J, 1998, 19(11):1696-703.

"Standards of Medical Care for Patients With Diabetes Mellitus. American Diabetes Association,"Diabetes Care, 1994, 17(6):616-23.

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