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Pronunciation
(GLYE me pye ride)
Generic Available (U.S.)
Yes
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise to lower blood glucose; may be used in combination with metformin or insulin in patients whose hyperglycemia cannot be controlled by diet and exercise in conjunction with a single oral hypoglycemic agent
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have been observed in animal studies; therefore, glimepiride is classified as pregnancy category C. Severe hypoglycemia lasting 4-10 days has been noted in infants born to mothers taking a sulfonylurea at the time of delivery. The manufacturer recommends that patients be switched to insulin during pregnancy. Maternal hyperglycemia can be associated with adverse effects in the fetus, including macrosomia, neonatal hyperglycemia, and hyperbilirubinemia; the risk of congenital malformations is increased when the Hb A1c is above the normal range. Diabetes can also be associated with adverse effects in the mother. Poorly-treated diabetes may cause end-organ damage that may in turn negatively affect obstetric outcomes. Physiologic glucose levels should be maintained prior to and during pregnancy to decrease the risk of adverse events in the mother and the fetus. Until additional safety and efficacy data are obtained, the use of oral agents is generally not recommended as routine management of GDM or type 2 diabetes mellitus during pregnancy. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
It is not known if glimepiride is excreted in breast milk. Breast-feeding is not recommended by the manufacturer. Potentially, hypoglycemia may occur in a nursing infant exposed to a sulfonylurea via breast milk.
Contraindications
Hypersensitivity to glimepiride, any component of the formulation, or sulfonamides; diabetic ketoacidosis (with or without coma)
Warnings/Precautions
Concerns related to adverse effects:
• Cardiovascular mortality: 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.
• Hypoglycemia: 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. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution. Autonomic neuropathy, advanced age, and concomitant use of beta-blockers or other sympatholytic agents may impair the patient's ability to recognize the signs and symptoms of hypoglycemia; use with caution.
• Sulfonamide allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is not 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.
Disease-related concerns:
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Patients with G6PD deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.
• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
Other warnings/precautions:
• Secondary failure: Loss of efficacy may be observed following prolonged use as a result of the progression of type 2 diabetes mellitus which results in continued beta cell destruction. In patients who were previously responding to sulfonylurea therapy, consider additional factors which may be contributing to decreased efficacy (eg, inappropriate dose, nonadherence to diet and exercise regimen). If no contributing factors can be identified, consider discontinuing use of the sulfonylurea due to secondary failure of treatment. Additional antidiabetic therapy (eg, insulin) will be required.
Adverse Reactions
1% to 10%:
Central nervous system: Dizziness (2%), headache (2%)
Endocrine & metabolic: Hypoglycemia (1% to 2%)
Gastrointestinal: Nausea (1%)
Neuromuscular & skeletal: Weakness (2%)
<1% or frequency not defined: Agranulocytosis, anorexia, aplastic anemia, cholestatic jaundice, constipation, diarrhea, disulfiram-like reaction, diuretic effect, edema, epigastric fullness, gastrointestinal pain, erythema, heartburn, hemolytic anemia, hepatitis, hypoglycemia, hyponatremia, leukopenia, liver failure, liver function tests abnormal, nausea, pancytopenia, photosensitivity, porphyria cutanea tarda, pruritus, rash (morbilliform or maculopapular), SIADH, thrombocytopenia, urticaria, vasculitis (allergic), visual accommodation changes (early treatment), vomiting
Metabolism/Transport Effects
Substrate of CYP2C9 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Drug Interactions
Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy
Beta-Blockers: May enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy
Chloramphenicol: May decrease the metabolism of Sulfonylureas. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the hypoglycemic effect of Antidiabetic Agents. In some instances, corticosteroid-mediated HPA axis suppression has led to episodes of acute adrenal crisis, which may manifest as enhanced hypoglycemia, particularly in the setting of insulin or other antidiabetic agent use. Risk C: Monitor therapy
Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Risk C: Monitor therapy
CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification
Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Fluconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with GLP-1 agonists. Risk D: Consider therapy modification
Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemic Agents. Risk C: Monitor therapy
Hypoglycemic Agents: May enhance the adverse/toxic effect of other Hypoglycemic Agents. Risk C: Monitor therapy
Luteinizing Hormone-Releasing Hormone Analogs: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2C9 Substrates. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Quinolone Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. This appears to be particularly concerning early in the course of combination therapy. Quinolone Antibiotics may diminish the hypoglycemic effect of Sulfonylureas. With longer-term combination, there is a greater risk of hyperglycemia. Risk C: Monitor therapy
Ranitidine: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Rifampin: May increase the metabolism of Sulfonylureas. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Sulfonylureas. Of concern with regular, higher doses of salicylates, not sporadic, low doses. Risk C: Monitor therapy
Somatropin: May diminish the hypoglycemic effect of Antidiabetic Agents. Risk D: Consider therapy modification
Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Exceptions: Sulfacetamide. Risk C: Monitor therapy
Thiazide Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Voriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
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
Distribution: Vd: 8.8 L
Protein binding: >99.5%
Metabolism: Hepatic oxidation via CYP2C9 to M1 metabolite (~33% activity of parent compound); further oxidative metabolism to inactive M2 metabolite
Half-life elimination: 5-9 hours
Time to peak, plasma: 2-3 hours
Excretion: Urine (60%, 80% to 90% as M1 and M2); feces (40%, 70% as M1 and M2)
Dosage
Oral:
Children 10-18 years (unlabeled use): Initial: 1 mg once daily; maintenance: 1-4 mg once daily
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. If inadequate response to maximal dose, combination therapy with metformin may be considered.
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.
Conversion from therapy with long half-life agents: Observe patient carefully for 1-2 weeks when converting from a longer half-life agent (eg, chlorpropamide) to glimepiride due to overlapping hypoglycemic effects.
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: Oral
Administer once daily with breakfast or first main meal of the day. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.
Monitoring Parameters
Monitor for signs and symptoms of hypoglycemia (fatigue, excessive hunger, profuse sweating, numbness of extremities), fasting blood glucose, hemoglobin A1c
Reference Range
Recommendations for glycemic control in adults with diabetes:
Hb A1c: <7%
Preprandial capillary plasma glucose: 70-130 mg/dL
Peak postprandial capillary blood glucose: <180 mg/dL
Blood pressure: <130/80 mm Hg
Dietary Considerations
Administer with breakfast or the first main meal of the day. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.
Patient Education
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 with breakfast or the first main meal of the day. Avoid alcohol while taking this medication; could cause severe reaction. 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).
Geriatric Considerations
Rapid and prolonged hypoglycemia (>12 hours) despite hypertonic glucose injections have been reported with glimepiride. Age, hepatic impairment, and renal impairment are independent risk factors for hypoglycemia; dosage titration should be made at weekly intervals. Intensive glucose control (HbA1c <6.5%) has been linked to increased all-cause and cardiovascular mortality, hypoglycemia requiring assistance, and weight gain in adult type 2 diabetes. How "tightly" to control a geriatric patient's blood glucose needs to be individualized. Such a decision should be based on several factors, including the patient's functional and cognitive status, how well he/she recognizes hypoglycemic or hyperglycemic symptoms, and how to respond to them and other disease states. An HbA1c <7.5% is an acceptable endpoint for a healthy older adult, while <8% is acceptable for frail elderly patients, those with a duration of illness >10 years, or those with comorbid conditions and requiring combination diabetes medications. Patients who are unable to accurately draw up their dose will need assistance, such as prefilled syringes. Initial doses may require considerations for renal function in the elderly with dosing adjusted subsequently based on blood glucose monitoring. For elderly patients with diabetes who are relatively healthy, attaining target goals for aspirin use, blood pressure, lipids, smoking cessation, and diet and exercise may be more important than normalized glycemic control.
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 patients with diabetes treated with tolbutamide. Retrospective studies evaluating cardiovascular outcomes following angioplasty and acute myocardial infarction in patients with diabetes 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 patients with diabetes (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
Nursing: Physical Assessment/Monitoring
Assess any allergies prior to beginning therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 1 mg, 2 mg, 4 mg
Amaryl®: 1 mg, 2 mg, 4 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Amaryl)
1 mg (30): $28.07
2 mg (30): $39.99
4 mg (30): $63.99
Tablets (Glimepiride)
1 mg (30): $12.99
2 mg (90): $18.99
4 mg (30): $14.99
References
American Diabetes Association, “Standards of Medical Care in Diabetes Mellitus -- 2012,” Diabetes Care, 2012, 35(Suppl ):11-63.
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.
Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, "Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada," Can J Diabetes, 20078, 32(suppl 1):1-201.
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.
Handelsman Y, Mechanick JI, Blonde L, et al, “American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus Comprehensive Care Plan,” Endocr Pract, 2011, 17(Suppl 2):1-53.
“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.
Rodbard HW, Jellinger PS, Davidson JA, et al, “Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control,” Endocr Pract, 2009, 15(6):540-59.
International Brand Names
Lexi-Comp.com
Last full review/revision February 2012
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