Glyburide and Metformin

Pronunciation

(GLYE byoor ide & met FOR min)

U.S. Brand Names

Glucovance®

Synonyms

Glyburide and Metformin Hydrochloride; Metformin and Glyburide

Generic Available

Yes

Use

Initial therapy for management of type 2 diabetes mellitus (noninsulin dependent, NIDDM). Second-line therapy for management of type 2 diabetes (NIDDM) when hyperglycemia cannot be managed with a sulfonylurea or metformin; combination therapy with a thiazolidinedione may be required to achieve additional control.

Pregnancy Risk Factor

B (manufacturer); C (expert analysis)

Pregnancy Implications

Abnormal blood glucose levels during pregnancy may be associated with an increased incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. Use glyburide/metformin during pregnancy only if clearly needed.

Glyburide: Crosses the placenta. Hypoglycemia, ear defects reported; other malformations reported but may have been secondary to poor maternal glucose control/diabetes.

Metformin: May partially cross the placenta.

Severe prolonged hypoglycemia has been reported in neonates whose mothers were taking sulfonylureas at the time of delivery. If the decision has been made to use glyburide/metformin during pregnancy, it should be discontinued at least 2 weeks prior to delivery.

Lactation

No data available/use caution

Contraindications

Hypersensitivity to glyburide or other sulfonamides, metformin, or any component of the formulation; renal disease or renal dysfunction (serum creatinine

1.5 mg/dL in males or

1.4 mg/dL in females, or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia); acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis); congestive heart failure requiring pharmacologic treatment

Note: Temporarily discontinue in patients undergoing radiologic studies in which intravascular iodinated contrast materials are utilized.

Warnings/Precautions

Age, hepatic and renal impairment are independent risk factors for hypoglycemia. Use with caution in patients with hepatic impairment, malnourished or debilitated conditions, or adrenal or pituitary insufficiency. Use caution in patients with renal impairment. Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin. Withhold therapy in hypoxemia, dehydration, or sepsis. The risk of lactic acidosis is increased in any patient with CHF requiring pharmacologic management. This risk is particularly high during acute or unstable CHF because of the risk of hypoperfusion and hypoxemia.

Metformin is substantially excreted by the kidney. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Patients with renal function below the limit of normal for their age should not receive metformin. In elderly patients, renal function should be monitored regularly; should not be used in any patient 80 years of age unless measurement of creatinine clearance verifies normal renal function. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be suspended in patients with dehydration and/or prerenal azotemia. Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified).Intravascular iodinated contrast materials used for radiologic studies are associated with alteration of renal function and may increase risk of lactic acidosis. Discontinue Glucovance® at the time of or prior to the procedure and withhold for 48 hours subsequent to the procedure; reinstitute only after renal function has been re-evaluated and found to be normal.

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

Also see individual agents.

>10%:

Endocrine & metabolic: Hypoglycemia (11% to 38%, effects higher when increased doses were used as initial therapy)

Gastrointestinal: Diarrhea (17%)

Respiratory: Upper respiratory infection (17%)

1% to 10%:

Central nervous system: Headache (9%), dizziness (6%)

Gastrointestinal: Nausea (8%), vomiting (8%), abdominal pain (7%) (combined GI effects increased to 38% in patients taking high doses as initial therapy)

<1%: Disulfuram-like reactions (rare) reported in patients taking glyburide

Overdosage/Toxicology

Glyburide: Symptoms of overdose include severe hypoglycemia, seizures, cerebral damage, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Intoxications with sulfonylureas can cause hypoglycemia and are best managed with glucose administration (orally for milder hypoglycemia or by injection in more severe forms).

Metformin: Hypoglycemia (10% of cases) or lactic acidosis (~32% of cases) may occur. Hemodialysis may be used in suspected cases of overdose.

Drug Interactions

Also see individual agents.

Decreased effect: Drugs that tend to produce hyperglycemia (eg, diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) may lead to a loss of glycemic control

Ethanol/Nutrition/Herb Interactions

Ethanol: May cause hypoglycemia; incidence of lactic acidosis may be increased; a disulfiram-like reaction characterized by flushing, headache, nausea, vomiting, sweating, or tachycardia has been reported with sulfonylureas; avoid or limit use.

Food: Metformin decreases absorption of vitamin B12. Metformin decreases absorption of folic acid.

Stability

Store at 25°C (77°F).

Mechanism of Action

The combination of glyburide and metformin is used to improve glycemic control in patients with type 2 diabetes mellitus by using two different, but complementary, mechanisms of action:

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

Metformin: Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Pharmacodynamics/Kinetics

Glucovance®:

Bioavailability: 18% with 2.5 mg glyburide/500 mg metformin dose; 7% with 5 mg glyburide/500 mg metformin dose; bioavailability is greater than that of Micronase® brand of glyburide and therefore not bioequivalent

Time to peak: 2.75 hours when taken with food

Glyburide: See Glyburide monograph.

Metformin: This component of Glucovance® is bioequivalent to metformin coadministration with glyburide.

Dosage

Note: Dose must be individualized. Dosages expressed as glyburide/metformin components.

Adults: Oral:

Initial therapy (no prior treatment with sulfonylurea or metformin): 1.25 mg/250 mg once daily with a meal; patients with Hb A1c >9% or fasting plasma glucose (FPG) >200 mg/dL may start with 1.25 mg/250 mg twice daily

Dosage may be increased in increments of 1.25 mg/250 mg, at intervals of not less than 2 weeks; maximum daily dose: 10 mg/2000 mg (limited experience with higher doses)

Previously treated with a sulfonylurea or metformin alone: Initial: 2.5 mg/500 mg or 5 mg/500 mg twice daily; increase in increments no greater than 5 mg/500 mg; maximum daily dose: 20 mg/2000 mg

When switching patients previously on a sulfonylurea and metformin together, do not exceed the daily dose of glyburide (or glyburide equivalent) or metformin.

Note: May combine with a thiazolidinedione in patients with an inadequate response to glyburide/metformin therapy (risk of hypoglycemia may be increased).

Elderly: Oral: Conservative doses are recommended in the elderly due to potentially decreased renal function; do not titrate to maximum dose ; should not be used in patients 80 years of age unless renal function is verified as normal

Dosage adjustment in renal impairment: Risk of lactic acidosis increases with degree of renal impairment; contraindicated in renal disease or renal dysfunction (see Contraindications)

Dosage adjustment in hepatic impairment: Use conservative initial and maintenance doses and avoid use in severe hepatic disease

Administration

All doses should be administered with a meal. Twice-daily dosing should be administered with the morning and evening meals. Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia.

Monitoring Parameters

Signs and symptoms of hypoglycemia, urine for glucose and ketones, FPG, Hb A1c, and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed. Monitor at least annually once patient is on maintenance therapy. While megaloblastic anemia has been rarely seen with metformin, if suspected, vitamin B12 deficiency should be excluded.

Reference Range

Target range: Adults: Fasting blood glucose: <120 mg/dL; glycosylated hemoglobin: <7%

Dietary Considerations

May cause GI upset; take with food to decrease GI upset. 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). Monitor for signs and symptoms of vitamin B12 deficiency. Monitor for signs and symptoms of folic acid deficiency.

Patient Education

See individual agents. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Cardiovascular Considerations

Combination therapy for the treatment of diabetes should be individualized for each patient.

Glyburide: 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.

Metformin: Metformin, alone or in combination with other agents (sulfonylurea), is effective in the management of diabetes. Lactic acidosis is an uncommon side effect in patients without renal or respiratory insufficiency, hepatic failure, or conditions that predispose to hypoxemia. As heart failure may affect renal and pulmonary function, metformin should be avoided or used with caution in diabetic patients with heart failure.

Dental Health: Effects on Dental Treatment

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

Dizziness is common; may cause sedation

Mental Health: Effects on Psychiatric Treatment

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; phenothiazines and TCAs may antagonize glyburide's hypoglycemic effects; MAO inhibitors and TCAs may enhance hypoglycemic effects; concurrent use with psychotropics may produce additive sedation

Dosage Forms

Tablet [film coated]:

1.25 mg/250 mg: Glyburide 1.25 mg and metformin hydrochloride 250 mg

2.5 mg/500 mg: Glyburide 2.5 mg and metformin hydrochloride 500 mg

5 mg/500 mg: Glyburide 5 mg and metformin hydrochloride 500 mg

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