Medication Guide App

Glyburide and Metformin (Systemic)


VA CLASSIFICATION
Primary: HS509

Commonly used brand name(s): Glucovance.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antidiabetic agent—

Indications

Accepted

Diabetes, type 2 (treatment)—The combination of glyburide and metformin is indicated as an adjunct to diet in the treatment of patients with type 2 diabetes (previously referred to as non-insulin-dependent diabetes mellitus [NIDDM]) whose blood glucose cannot be controlled by diet and exercise alone.{01}The combination of glyburide and metformin also is indicated as 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.{01}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Glyburide: 494.01{01}
    Metformin hydrochloride: 165.63{01}

pKa—
    Metformin: 12.4
{01}

pH
    Metformin hydrochloride: 6.68.{01}

Mechanism of action/Effect:

Glyburide and metformin, both acting as antihyperglycemic agents, reduce blood glucose and improve glycemic control.{01}

Glyburide stimulates functioning pancreatic beta cells to produce insulin, reducing blood glucose.{01} Although the blood glucose lowering effects of glyburide continue during long-term administration despite a decline in the insulin production response, the mechanism has not been discovered.{01} It is thought that extrapancreatic effects may be involved.{01}

Metformin improves glucose tolerance by lowering basal and postprandial plasma glucose levels. Metformin has three specific actions: decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.{01}

Absorption:


Glyburide and metformin combination:

After a single tablet containing 5 mg of glyburide and 500 mg of metformin was taken with food, the time to peak concentration for glyburide was shortened from 7.5 hours to 2.75 hours. The clinical significance of the shorter time to peak concentration for the glyburide component is not known. The effect of food upon the metformin component pharmacokinetics was not determined.{01}



Glyburide:

Single-dose studies with glyburide tablets in normal subjects showed significant absorption of glyburide within 1 hour and detectable levels at 24 hours.{01}



Metformin:

Under fasting conditions, the bioavailability of a 500-mg metformin hydrochloride tablet is approximately 50–60%. Due to a lack of dose proportionality, increased doses of metformin may not result in greater bioavailability. In contrast, after administration of a single 850-mg dose of metformin with food, the absorption of metformin showed a 40% lower peak concentration, a 25% lower area under the plasma concentration–time curve (AUC), and a 35-minute longer time to peak plasma concentration. The clinical relevance of these changes is unknown.{01}


Distribution:


VolD:

Metformin: After single oral 850-mg doses, averaged 654 ± 358 L.{01}


Protein binding:

Glyburide: Very high (non-ionic binding as compared to other sulfonylurea medications which have ionic binding){01}

Metformin: Negligible.{01}

Biotransformation:

Glyburide: Metabolites are 4-transhydroxy derivative (major) and 3-cis-hydroxy derivative, but they are not thought to contribute to the hypoglycemic activity of glyburide.{01}

Metformin: Not metabolized.{01}

Half-life:


Elimination:

Glyburide: 10 hours (serum).{01}

Metformin: 6.2 hours (plasma) and 17.6 hours (blood). The longer elimination half-life in blood suggests that metformin may distribute into red blood cells.{01}


Time to peak concentration:

Glyburide: 4 hours.{01}

Metformin: Steady-state concentration is reached in 24-48 hours.{01}

Steady-state plasma concentration

Metformin: Generally less than 1 microgram per mL.{01}


Elimination:
    Glyburide (as metabolites): 50% eliminated renally and 50% eliminated via biliary pathway.{01}
    Metformin: Up to 90% of a dose is eliminated renally as unchanged drug.{01}


Precautions to Consider

Carcinogenicity

Note: No animal studies have been done that combine both glyburide and metformin. Animal data is based only on individual products.{01}


Carcinogenicity/Mutagenicity/Tumorigenicity

Glyburide: Studies with rats given doses up to 300 mg per kg of body weight (mg/kg) per day (145 times the maximum recommended human daily dose) for 18 months revealed no evidence of carcinogenic effects. In vitro mutagenic tests, specifically the Salmonella microsome test or Ames test and the DNA damage/alkaline elution assay, did not show mutagenic potential. In addition, a 2-year study in mice demonstrated no evidence of tumorigenicity. {01}

Metformin: Long-term studies were done using rats and mice, given doses up to 900 and 1500 mg/kg (approximately four times the recommended human daily dose based on body surface area) per day, respectively. No carcinogenicity was found in male rats and mice or in female mice. However, in female rats, the 900 mg/kg per day dose had an increased incidence of benign stromal uterine polyps. In vitro mutagenic tests, specifically the Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), and the chromosomal aberrations test (human lymphocytes), revealed no evidence of mutagenicity. The in vivo mouse micronucleus test was also negative for any mutagenic findings. {01}

Pregnancy/Reproduction
Fertility—
Glyburide: Reproduction studies were done using rats and rabbits given doses up to 500 times the maximum recommended human daily dose and did not demonstrate impaired fertility.{01}

Metformin: The fertility of male or female rats was unaffected at doses up to 600 mg/kg per day, approximately 3 times the maximum recommended human daily dose based on body surface area.{01}

Pregnancy—
Adequate and well-controlled studies with the combined glyburide and metformin have not been done in humans or animals. Glyburide and metformin were tested for their individual effects on pregnancy.

Glyburide reproduction studies were done using rats and rabbits given doses up to 500 times the maximum recommended human daily dose and did not show harm to the fetus. {01}

Like glyburide, metformin was not teratogenic in rats or rabbits at doses up to 600 mg/kg per day. For rabbits, this dosage is comparable to 6 times the maximum human daily dose of 2000 mg and in rats, the dosage compares to 2 times the maximum human daily dose. {01}

Note: Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. If sulfonylurea drugs are used to maintain proper blood glucose during pregnancy, neonates may have prolonged severe hypoglycemia that lasts from 4 to 10 days. Most experts recommend that insulin be used during pregnancy to control hyperglycemia. If the combination of glyburide and metformin must be used during pregnancy, the medications should be stopped at least 2 weeks before the expected delivery date. {01}


FDA Pregnancy Category B {01}

Breast-feeding

It is not known whether glyburide or metformin is distributed into human breast milk. However, some sulfonylurea drugs are known to be distributed into human breast milk. Metformin has been shown to be distributed into breast milk in studies with lactating rats. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of glyburide or metformin have not been performed in the pediatric population. Safety and efficacy have not been established.{01}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of glyburide or metformin in the elderly. However, elderly patients are more likely to have age-related impaired renal function, which may require normal dosage to be reduced if renal insufficiency is detected in patient. This medication should not be initiated in patients 80 years of age or older unless it can be demonstrated that renal function is not reduced.{01} Generally, elderly patients should not be titrated to the maximum dose of this medication.{01}

Surgical

Treatment with glyburide and metformin combination should be discontinued until patient's oral intake has been reestablished to pre-surgical levels and renal function is normal.{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol, acute or chronic intake of    (Alcohol consumption can potentiate the effects of metformin on lactate metabolism and can lead to lactic acidosis; alcohol, which is metabolized by the liver, also can increase the risk of hypoglycemia by impairing the liver's gluconeogenic function{01})


» Beta-adrenergic blocking agents{01}    (may blunt some of the symptoms of developing hypoglycemia making detection of this complication more difficult{01})


» Cimetidine {01} or
Other cationic medications excreted by renal tubular transport, such as:
Amiloride {01}
Calcium channel blocking agents, such as nifedipine {01}
Digoxin {01}
Morphine {01}
Procainamide {01}
Quinidine {01}
Quinine {01}
Ranitidine {01}
Triamterene {01}
Trimethoprim {01}
Vancomycin {01}    (cimetidine competes with metformin and therefore inhibits the renal tubular secretion of metformin, resulting in a 60% increase in peak plasma concentration and a 40% increase in area under the plasma concentration–time curve [AUC]; no change in elimination half-life; cimetidine pharmacokinetics were unaffected{01})

    (nifedipine increased absorption of metformin in a single-dose study with normal healthy volunteers, resulting in a 9% increase in AUC and a 20% increase in peak plasma concentration with no change in half-life and time to maximum concentration; urinary excretion of metformin also was increased; metformin had minimal effects on nifedipine{01})

    (other cationic medications excreted by renal tubular transport theoretically have the potential to increase the plasma concentration of metformin or interfere with renal clearance; careful monitoring of blood glucose would be especially appropriate when these medications are given concurrently with metformin {01})


» Furosemide {01}     (in a single-dose metformin-furosemide drug interaction study with normal healthy volunteers, furosemide increased metformin's blood AUC by 15% and increased peak plasma and blood concentration by 22%; furosemide renal clearance was not affected {01})


Hyperglycemia-causing medications, such as:
Calcium channel blocking agents{01}
Contraceptives, estrogen-containing, oral {01}
Corticosteroids {01}
Diuretics, thiazide {01}
Estrogens {01}
Isoniazid {01}
Niacin{01}
Phenothiazines{01}such as chlorpromazine
Phenytoin {01}
Sympathomimetic agents {01}
Thyroid hormones {01}    (these medications may contribute to hyperglycemia; an increased dose of glyburide and metformin combination or a change to another antidiabetic agent may be needed {01})


Hypoglycemia-causing medications, such as:
Beta-adrenergic blocking agents{01}
Ciprofloxacin{01}
Chloramphenicol{01}
Coumarin derivatives{01}
Miconazole, oral{01}
Monoamine oxidase (MAO) inhibitors {01}
Nonsteroidal anti-inflammatory drugs (NSAIDs){01}
Probenecid {01}
Salicylates {01}
Sulfonamides {01}
Sulfonylureas {01}    (these medications may cause hypoglycemia; however, highly protein-bound medications such as salicylates, sulfonamides, chloramphenicol, and probenecid are less likely to interact with metformin, which is negligibly bound to plasma proteins; glyburide is highly protein-bound and is therefore more likely to interact with other protein-bound drugs; monitoring of patient's blood glucose levels is very important when administering sulfonylurea medications{01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Any condition needing stringent blood glucose control, such as:
Diabetic coma{01}
Diabetic ketoacidosis{01}
Metabolic acidosis, acute or chronic{01}
Surgery, major{01}    (metformin should be discontinued because of increased risk of side effects due to uncontrolled blood glucose or lactic acidosis; insulin controls blood glucose best in patients with these conditions)

{01}
» Conditions associated with hypoxemia, such as:{01}
Cardiovascular collapse{01}
Congestive heart failure{01}
Myocardial infarction, acute{01} or
» Dehydration, severe{01} or
» Septicemia{01}
» Diagnostic radiologic studies using intravascular iodinated contrast media, such as:{01}
Angiography{01}
Cholangiography, intravenous{01}
Computed tomography (CT) scan{01}
Urography, intravenous{01}    (increased risk of lactic acidosis due to acute renal function change, glyburide and metformin combination should be discontinued at the time of or prior to medical or diagnostic examinations requiring use of contrast media that can cause functional oliguria; therapy should be withheld for 48 hours after the procedure and should not be restarted until after renal function returns to normal{01})


» Renal function impairment, severe (creatinine clearance ³ 1.4 mg/dL in females or ³ 1.5 mg/dL in males){01}
Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment{01} or
» Renal function impairment{01}    (risk of developing lactic acidosis may be increased{01})


Hypersensitivity to glyburide or metformin{01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Anion gap{01} and
Electrolyte concentrations{01} and
Lactic acid, blood{01} and
Lactic acid/pyruvate ratio{01} and
Metformin concentration, plasma{01} and
pH, blood{01}    (may be useful in confirming diagnosis of lactic acidosis, which is characterized by an increased anion gap, electrolyte disturbances, blood lactic acid concentration greater than 5 millimoles/L, an increased lactic acid/pyruvate ratio, plasma metformin concentration greater than 5 mcg/mL, and a decreased blood pH{01})


» Glucose concentration, in blood, serum, or urine{01}    (glucose concentrations should be routinely monitored{01})


» Glycosylated hemoglobin (HbA1c measurements){01}    (monitoring is recommended every 3 months to assess the efficacy of therapy{01})


Hematocrit{01}and
Hemoglobin concentrations{01}and
Red blood cell indices{01}    (initial and periodic monitoring of hematologic factors should be done, at least once annually)

{01}
» Ketone bodies, urine{01}    (if ketone bodies reach a high level, patient could develop ketoacidotic shock)


» Renal function assessment{01}    (recommended prior to initiation of therapy and thereafter annually or more often in patients in whom the risk of developing lactic acidosis is increased{01})


Vitamin B12 concentrations{01}    (although megaloblastic anemia is a rare finding, check for possible vitamin B12 deficiency to exclude diagnosis; recommended every 1 or 2 years)

{01}


Side/Adverse Effects

Note: Although no hypoglycemic episodes requiring medical or pharmacologic therapy were seen in controlled clinical trials, the combination medication of glyburide and metformin can induce hypoglycemia as shown in the initial therapy trials.{01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Hypoglycemia {01}(anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; coma; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat ; headache, continuing; nausea; nervousness; nightmares; restless sleep; seizures; shakiness; slurred speech; unusual tiredness or weakness)
    
upper respiratory infection{01} ( cough; fever; sneezing; sore throat)

Incidence rare
    
Lactic acidosis {01}(abdominal discomfort; decreased appetite; diarrhea; fast, shallow breathing; general feeling of discomfort; muscle pain or cramping; unusual sleepiness; unusual tiredness or weakness)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal pain{01} (stomach or abdomen pain)
    
diarrhea{01} (increase in bowel movements; loose stools; soft stools)
    
dizziness{01}
    
headache{01}
    
nausea or vomiting{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Note: An overdose of glyburide may induce a mild to severe hypoglycemic state and a metformin overdose (over 85 grams) may cause lactic acidosis.{01}


Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Hypoglycemia {01}(anxiety; behavior change, similar to drunkenness ; blurred vision; cold sweats; coma; confusion; cool, pale skin ; difficulty in concentrating; drowsiness ; excessive hunger; fast heartbeat; headache, continuing; nausea; nervousness; nightmares; restless sleep ; seizures; shakiness; slurred speech; unusual tiredness or weakness)
    
lactic acidosis {01}(abdominal discomfort; decreased appetite; diarrhea; fast, shallow breathing; general feeling of discomfort; muscle pain or cramping; unusual sleepiness; unusual tiredness or weakness)

Note: The following signs also may be indicative of lactic acidosis: increased anion gap, electrolyte disturbances, blood lactic acid concentration greater than 5 millimoles/L, increased lactic acid/pyruvate ratio, plasma metformin concentration greater than 5 mcg/mL, and decreased blood pH.{01}



Treatment of overdose


Specific treatment:
Hypoglycemia, due to a sulfonylurea medication (glyburide) overdose, is treated by replacing glucose via an oral or intravenous route, depending on severity of the hypoglycemia. For mild hypoglycemia, without loss of consciousness or neurological findings, treat aggressively with oral glucose, adjust drug dosage and/or meal patterns, and monitor patient until out of danger. For severe hypoglycemia, a medical emergency, such as hypoglycemic coma, seizure, or other neurological impairment (infrequent), transport patient to hospital immediately. If hypoglycemic coma is suspected, give patient a rapid intravenous (IV) injection of concentrated (50%) glucose solution and follow with a continuous IV of 10% glucose solution. Use an infusion rate that will maintain blood glucose level at greater than 100 mg per dL. Monitor patient closely for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.{01} Hypoglycemia has not been seen with metformin even at doses as high as 85 grams.{01}

Accumulation of metformin may lead to lactic acidosis, which is a medical emergency that must be treated in a hospital.{01} Glyburide and metformin combination should be discontinued immediately.{01} Hemodialysis at a rate of up to 170 mL per minute is recommended to correct the acidosis and remove the accumulated metformin.{01} General supportive measures also should be instituted.{01}

Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Glyburide and Metformin (Systemic)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to glyburide or metformin

Pregnancy—Diet or diet/insulin is recommended to prevent maternal and fetal problems; importance of controlling and monitoring blood glucose during pregnancy; alerting physician if planning to become pregnant





Breast-feeding—It is not known whether glyburide or metformin passes into human breast milk.{01}
Other medications, especially alcohol, beta adrenergic blockers, cimetidine, or furosemide
Other medical problems, especially acute or chronic metabolic acidosis, acute myocardial infarction, cardiovascular collapse, congestive heart failure, diabetic coma or ketoacidosis, diagnostic radiologic exams using intravascular iodinated contrast media, hepatic function impairment, major surgery, renal function impairment, septicemia, or severe dehydration

Proper use of this medication
» Importance of adherence to recommended regimens for diet, exercise, and glucose monitoring

Taking medication with meals to reduce gastrointestinal symptoms

» Proper dosing

Proper storage

Precautions while using this medication
» Regular visits to physician to check progress

» Recognizing symptoms of lactic acidosis, such as abdominal discomfort; decreased appetite; diarrhea; fast, shallow breathing; general feeling of discomfort; muscle pain or cramping; or unusual sleepiness, tiredness, or weakness

» Getting immediate emergency medical help if symptoms of lactic acidosis occur
»
Carefully following special instructions of health care team:
Discussing use of alcohol and tobacco

Not taking other medications unless discussed with physician

Getting counseling for family members to help the patient with diabetes; also, special counseling for pregnancy planning and contraception

Making travel plans that include readiness for diabetic emergencies and eating meals at the usual times, even with changing time zones
» Preparing for and understanding what to do in case of diabetic emergency; carrying medical history and current medication list and wearing medical identification

» Recognizing symptoms of hypoglycemia: anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; coma; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache (continuing); nausea; nervousness; nightmares; restless sleep; seizures; shakiness; slurred speech; and unusual tiredness or weakness

» Recognizing what brings on symptoms of hypoglycemia, such as delaying or missing a meal or snack; drinking significant amounts of alcohol; exercising more than usual; having an illness, including vomiting or diarrhea; taking certain medications; or using other antidiabetic medication

» Knowing what to do if symptoms of hypoglycemia occur, such as eating glucose tablets or gel, corn syrup, honey, or sugar cubes; drinking fruit juice, nondiet soft drink, or sugar dissolved in water; or injecting glucagon if symptoms are severe

» Recognizing symptoms of hyperglycemia and ketoacidosis: blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased urination (frequency and volume); ketones in urine; loss of appetite; somnolence (sleepiness); stomachache, nausea, or vomiting; tiredness; troubled breathing (rapid and deep); unconsciousness; and unusual thirst

» Recognizing what brings on symptoms of hyperglycemia, such as exercising less than usual, having a fever or infection, not taking enough or skipping a dose of antidiabetic medication, or overeating or not following meal plan

» Knowing what to do if symptoms of hyperglycemia occur, such as checking blood glucose and contacting a member of the health care team


Side/adverse effects
Signs of potential side effects, especially hypoglycemia, upper respiratory infection, and lactic acidosis


General Dosing Information

Diet/Nutrition
Glyburide and metformin combination should be taken with food to reduce gastrointestinal symptoms.{01}


Oral Dosage Forms

GLYBURIDE AND METFORMIN HYDROCHLORIDE TABLETS

Usual Adult Dose
Type 2 diabetes
As initial therapy: Oral, 1.25 mg of glyburide and 250 mg of metformin one or two times a day with meals.{01} Dosage may be increased in increments of 1.25 mg of glyburide and 250 mg of metformin per day every two weeks until the minimum dose necessary to achieve glycemic control is attained.{01}

As second-line therapy: Oral, 2.5 mg of glyburide and 500 mg of metformin or 5 mg of glyburide and 500 mg of metformin two times a day, with the morning and evening meals. Dosage may be increased in increments of no more than 5 mg of glyburide and 500 mg of metformin until the minimum dose necessary to achieve glycemic control is attained.{01}

Note: When switching patients from a sulfonylurea plus metformin to the glyburide and metformin combination, the initial dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin that was being taken.{01}



Usual adult prescribing limits
20 mg glyburide and 2000 mg metformin daily.{01}

Usual Pediatric Dose
Safety and efficacy have not been established.{01}

Usual Geriatric Dose
See Usual adult dose.

Note: This medication should not be initiated in patients 80 years of age or older unless it can be demonstrated that renal function is not reduced.{01} Maximum doses are not advised for use in elderly patients.{01}


Strength(s) usually available
U.S.—


1.25 mg of glyburide and 250 mg of metformin hydrochloride (Rx) [Glucovance (microcrystalline cellulose) (povidone) (croscarmellose sodium) (magnesium stearate)]{01}


2.5 mg of glyburide and 500 mg of metformin hydrochloride (Rx) [Glucovance (microcrystalline cellulose) (povidone) (croscarmellose sodium) (magnesium stearate)]{01}


5 mg of glyburide and 500 mg of metformin hydrochloride (Rx) [Glucovance (microcrystalline cellulose) (povidone) (croscarmellose sodium) (magnesium stearate)]{01}

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a light-resistant container.{01}

Auxiliary labeling:
   • Take with food.
   • Keep out of reach of children.



Developed: 12/07/2000



References
  1. Product Information: Glucovance™, glyburide and metformin. Bristol-Myers Squibb Company, Princeton, NJ, (PI issued 07/2000) reviewed 11/2000.
Hide
(web2)