Glyburide / Metformin Hydrochloride

Pronunciation
Pronouncation: (GLYE-bure-ide/met-FOR-min HYE-droe-KLOR-ide)
Class: Antidiabetic combination

Trade Names:
Glucovance
- Tablets 1.25 mg/250 mg
- Tablets 2.5 mg/500 mg
- Tablets 5 mg/500 mg

Pharmacology

Glyburide

Decreases blood glucose by stimulating insulin release from the pancreas and may decrease hepatic glucose production or increase response to insulin.

Metformin

Decreases blood glucose by decreasing hepatic glucose production and may decrease intestinal absorption of glucose and increase response to insulin.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes whose hyperglycemia cannot be satisfactorily managed by diet and exercise alone; second-line therapy when diet, exercise, and initial treatment with a sulfonylurea or metformin do not result in adequate glycemic control in patients with type 2 diabetes.

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Contraindications

Patients with renal disease or dysfunction, which may also result from conditions such as CV collapse, acute MI, and septicemia; acute or chronic metabolic acidosis (including diabetic ketoacidosis, with or without coma); known hypersensitivity to any component of product.

Dosage and Administration

Dosage must be individualized on the basis of efficacy and tolerance, while not exceeding the maximum recommended daily dose of glyburide 20 mg/metformin 2,000 mg.

Initial Therapy
Adults

PO Starting dose 1.25 mg/250 mg every day with a meal; if glycosylated hemoglobin is more than 9% or fasting plasma glucose is more than 200 mg/dL, start with 1.25 mg/250 mg twice daily with morning and evening meals. Dosage increases may be made in increments of 1.25 mg/250 mg per day every 2 wk up to the minimum effective dose (there is no experience with daily doses more than 10 mg/2,000 mg).

Second-Line Therapy
Adults

PO Start with 2.5 mg/500 mg or 5 mg/500 mg twice daily with morning and evening meals but not exceeding the daily dose of glyburide or metformin already being taken. Titrate the daily dose in increments of no more than 5 mg/500 mg up to the minimum effective dose.

Storage/Stability

Store at controlled room temperature (up to 77°F). Protect from light.

Drug Interactions

ACE inhibitors (eg, enalapril), beta-adrenergic blocking agents, chloramphenicol, ciprofloxacin, coumarin anticoagulants, MAOIs, NSAIDs, miconazole, probenecid, salicylates, sulfonamides

May potentiate the hypoglycemic action of glyburide.

Alcohol

The effects of metformin on lactate metabolism may be potentiated. Disulfiram-like reactions have been reported rarely with glyburide.

Bosentan

Increased metabolism of glyburide and decreased plasma levels of both bosentan and glyburide. Increased risk of serious liver injury.

Calcium channel blocking agents, corticosteroids, estrogens, isoniazid, nicotinic acid, oral contraceptives, phenothiazines, phenytoin, sympathomimetics, thiazides and other diuretics, thyroid products

These agents tend to produce hyperglycemia and may lead to loss of blood glucose control.

Cationic drugs (eg, amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

May compete with metformin for renal tubular secretion, elevating metformin concentrations and increasing the pharmacologic effects.

Cyclosporine

Cyclosporine concentrations may be elevated, increasing the pharmacologic effects and adverse reactions.

Furosemide

Metformin plasma levels may be elevated while furosemide levels may be decreased.

Nifedipine

Metformin plasma levels may be increased.

Rifamycins (eg, rifampin)

Glyburide concentrations and t ½ may be decreased while Cl may be increased, increasing the risk of hyperglycemia.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Headache (9%); dizziness (6%).

GI

Diarrhea (17%); nausea/vomiting (8%); abdominal pain (7%).

Metabolic-Nutritional

Hypoglycemia (38%).

Respiratory

Upper respiratory infection (17%).

Precautions

Warnings

Lactic acidosis is a rare but serious metabolic complication that can be caused by metformin accumulation during treatment with glyburide/metformin. When it occurs, it is fatal in approximately 50% of cases.


Monitor

Check blood sugar frequently and observe for signs of hypoglycemia. Monitor hemoglobin (HbA 1c ) every 3 months. Assess Hct, Hgb, and RbCs before starting therapy and periodically thereafter.

Assess renal function and verify as healthy before starting therapy and at least annually thereafter.

Monitor patient for signs or symptoms of metabolic acidosis (eg, abdominal pain, malaise, myalgia, nausea, respiratory distress, unexplained drowsiness, vomiting).


Pregnancy

Category B . However, not recommended for use during pregnancy.

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

In general, elderly patients are not titrated to the max dose because of age-related decreases in renal function.

Renal Function

Decreased renal function results in decreased renal Cl and prolongation of the metformin t ½ . Concomitant medications that affect renal function may result in hemodynamic changes or interfere with disposition of metformin (eg, cationic drugs) and should be used with caution. Determine CrCl in patients older than 80 yr of age before initiating therapy.

Avoid use in patients whose serum creatinine levels exceed ULN for their age.

CV mortality

The administration of oral hypoglycemic drugs has been reported to be associated with increased CV mortality as compared with treatment with diet alone or diet plus insulin.

Hepatic disease

Avoid metformin in patients with clinical or laboratory evidence of hepatic disease.

Iodinated contrast material

Withhold metformin therapy at time of or prior to parenteral contrast studies with iodinated materials. Reinstitute therapy 48 h after the study and after renal function has been determined to be healthy.

Lactic acidosis

Can occur as a result of metformin accumulation (eg, renal function impairment) or in pathophysiologic conditions associated with tissue hypoperfusion and hypoxia. The risk of lactic acidosis increases with the degree of renal function impairment and the age of the patient.

Surgery

Hold therapy in patient undergoing surgical procedure until oral intake has resumed and renal function has been documented to be healthy.

Vitamin B 12

A decrease in vitamin B 12 levels to subnormal may occur. Supplementation may be necessary.

Overdosage

Symptoms

Glyburide

Hypoglycemia, coma, neurological impairment, seizures.

Metformin

Lactic acidosis.

Patient Information

  • Educate patient regarding diabetes and its management, including target ranges for blood sugar control. Instruct patient that medication is not a substitute for diet and exercise and to continue to follow prescribed regimens.
  • Educate patient or caregiver regarding potential long-term complications of diabetes and need for regular general physical and eye examinations.
  • Advise patient to read patient information leaflet before starting therapy and with each refill.
  • Advise patient to take prescribed dose once or twice daily and to take with food to decrease GI distress.
  • Advise patient that dose may be gradually increased every 2 wk until max benefit is obtained.
  • Advise patient to take as prescribed and not to stop taking or change the dose unless advised by health care provider.
  • Ensure that patient understands how to use home glucose monitor and has a plan for monitoring and recording blood sugar measurements (eg, log). Advise patient to take log to each visit with health care provider.
  • Educate patient regarding value of periodic HbA 1c testing to confirm level of glucose control.
  • Advise patient to carry medical identification indicating diabetes (eg, card, bracelet).
  • Caution patient to avoid excessive alcohol intake to reduce risk of lactic acidosis.
  • Instruct patient to report any of the following to health care provider immediately: general body discomfort, muscle aches, unexplained rapid breathing or shortness of breath, unexplained drowsiness, nausea, vomiting, abdominal pain.
  • Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake in the event either occur.
  • Advise patient to discuss with health care provider a plan for managing each of the following situations: medication dosing during intercurrent conditions (eg, infection, sick days, stress, trauma, vomiting); accidental administration of too little or too much medication; missed dose; inadequate food intake or a skipped meal; travel across time zones; change in physical activity.
  • Instruct patient to notify health care provider if experiencing hypoglycemic episodes or if measured blood sugars are outside target range.
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