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Glyburide and Metformin

Pronunciation

Pronunciation

(GLYE byoor ide & met FOR min)

Index Terms

  • Glyburide and Metformin Hydrochloride
  • Glyburide/Metformin
  • Metformin and Glyburide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, oral: 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

Glucovance: 1.25 mg/250 mg: Glyburide 1.25 mg and metformin hydrochloride 250 mg [DSC]

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

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

Brand Names: U.S.

  • Glucovance

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Sulfonylurea

Pharmacology

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)

Time to Peak

Glucovance: 2.75 hours when taken with food

Use: Labeled Indications

Type 2 diabetes mellitus: As an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes (noninsulin dependent, NIDDM)

Contraindications

Renal disease or renal impairment (eg, as suggested by serum creatinine levels of 1.5 mg/dL or more [men], 1.4 mg/dL or more [women], or abnormal creatinine clearance), which may also result from conditions such as acute myocardial infarction, cardiovascular collapse (shock), and septicemia; known hypersensitivity to metformin, glyburide, or any component of the formulation; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; concomitant administration of bosentan

Documentation of allergenic cross-reactivity for sulfonylureas is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Note: The manufacturer recommends to temporarily discontinue metformin in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.

Dosing: Adult

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

Type 2 diabetes: Oral:

Patients with inadequate glycemic control on diet and exercise alone: Initial: 1.25 mg/250 mg once daily with a meal; patients with HbA1c >9% or fasting plasma glucose (FPG) >200 mg/dL may start with 1.25 mg/250 mg twice daily with meals.

Adjustment: Dosage may be increased in increments of 1.25 mg/250 mg per day, at intervals of not less than 2 weeks; maximum daily dose: 10 mg/2000 mg (limited experience with higher doses). Note: Doses of 5 mg/500 mg should not be used as initial therapy, due to risk of hypoglycemia.

Patients with inadequate glycemic control on a sulfonylurea and/or metformin: Initial: 2.5 mg/500 mg or 5 mg/500 mg twice daily with meals.

Adjustment: Dosage may be increased in increments no greater than 5 mg/500 mg; maximum daily dose: 20 mg/2000 mg. Note: When switching patients previously on a sulfonylurea and metformin together, do not exceed the daily dose of glyburide (or glyburide equivalent) or metformin.

Combination with thiazolidinedione: May be combined with a thiazolidinedione in patients with an inadequate response to glyburide/metformin therapy; however, the risk of hypoglycemia may be increased. When adding a thiazolidinedione, continue glyburide and metformin at current dose and initiate thiazolidinedione at recommended starting dose; may increase based on the thiazolidinedione suggested titration schedule.

Dosing: Geriatric

Refer to adult dosing. Conservative doses are recommended in the elderly due to potentially decreased renal function; adjust carefully to renal function. Should not be used in patients ≥80 years of age unless renal function is verified as normal. Do not titrate to maximum dose.

Dosing: Renal Impairment

Manufacturer's labeling: Serum creatinine (SCr) ≥1.5 mg/dL (males) or ≥1.4 mg/dL (females) or abnormal CrCl (not defined): Use is contraindicated.

Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommend prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE, 2008]). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw, 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska, 2011):

eGFR ≥60 mL/minute/1.73 m2: No contraindications, monitor renal function annually

eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months

eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2

eGFR <30 mL/minute/1.73 m2: Discontinue use

Dosing: Hepatic Impairment

The manufacturer recommends avoiding metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett, 2010; Zhang, 2014). Glyburide undergoes hepatic metabolism and use of a lower initial and maintenance dose should be considered.

Administration

All doses should be administered with a meal. Twice-daily dosing should be administered with the morning and evening meals. Patients that are NPO or require decreased caloric intake may need doses held to avoid hypoglycemia.

Dietary Considerations

May cause GI upset; take with food to decrease GI upset. Dietary modification based on ADA recommendations is a part of therapy. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. Monitor for signs and symptoms of vitamin B12 and folic acid deficiency; supplementation may be required.

Storage

Store at ≤25°C (≤77°F). Protect from light.

Drug Interactions

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Antidiabetic Agents (Thiazolidinedione): May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

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. Monitor therapy

Bosentan: GlyBURIDE may enhance the hepatotoxic effect of Bosentan. GlyBURIDE may increase the metabolism of Bosentan. Bosentan may increase the metabolism of GlyBURIDE. Avoid combination

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Ceritinib: May increase the serum concentration of CYP2C9 Substrates. Management: Concurrent use of ceritinib with a CYP2C9 substrate that has a narrow therapeutic index (e.g., warfarin, phenytoin) should be avoided when possible. Monitor therapy

Chloramphenicol: May decrease the metabolism of Sulfonylureas. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Clarithromycin: May increase the serum concentration of GlyBURIDE. Monitor therapy

Colesevelam: May decrease the serum concentration of GlyBURIDE. Management: Administer glyburide at least 4 hours prior to colesevelam. Consider therapy modification

Cyclic Antidepressants: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

CycloSPORINE (Systemic): May diminish the therapeutic effect of GlyBURIDE. GlyBURIDE may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C9 Inhibitors (Moderate): May decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C9 Substrates. Management: Seek alternatives to the CYP2C9 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Fluconazole: May increase the serum concentration of Sulfonylureas. Management: Seek alternatives when possible. If used together, monitor closely for increased effects of sulfonylureas if fluconazole is initiated/dose increased, or decreased effects if fluconazole is discontinued/dose decreased. Consider therapy modification

GLP-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Lumacaftor: May decrease the serum concentration of CYP2C9 Substrates. Lumacaftor may increase the serum concentration of CYP2C9 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Avoid combination

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Probenecid: May decrease the protein binding of Sulfonylureas. Probenecid may increase the serum concentration of Sulfonylureas. Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

RaNITIdine: May increase the serum concentration of Sulfonylureas. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

RifAMPin: May decrease the serum concentration of Sulfonylureas. Management: Seek alternatives to these combinations when possible. Monitor closely for diminished therapeutic effects of sulfonylureas if rifampin is initiated/dose increased, or enhanced effects if rifampin is discontinued/dose decreased. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Sulfonamide Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Voriconazole: May increase the serum concentration of Sulfonylureas. Monitor therapy

Adverse Reactions

Also see individual agents.

>10%:

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

Gastrointestinal: Gastrointestinal symptoms (38%; combined GI effects increased to 38% in patients taking high doses as initial therapy), 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%)

<1% (Limited to important or life-threatening): Cholestatic jaundice, hepatitis

ALERT: U.S. Boxed Warning

Lactic acidosis:

Lactic acidosis is a rare, but serious, metabolic complication that can occur because of metformin accumulation during treatment; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (more than 5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of more than 5 mcg/mL are generally found.

The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1,000 patient-years, with approximately 0.015 fatal cases per 1,000 patient-years). In more than 20,000 patient-years' exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure (CHF) requiring pharmacologic management, in particular those with unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin and use of the minimum effective dose of metformin. In particular, accompany the treatment of elderly patients with careful monitoring of renal function. Do not initiate treatment in patients 80 years and older unless measurement of creatinine clearance (CrCl) demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis. In addition, promptly withhold glyburide/metformin in the presence of any condition associated with dehydration, hypoxemia, or sepsis. Because hepatic impairment may significantly limit the ability to clear lactate, generally avoid glyburide/metformin in patients with clinical or laboratory evidence of hepatic disease. Caution patients against excessive alcohol intake, acute or chronic, when taking glyburide/metformin because alcohol potentiates the effects of metformin on lactate metabolism. In addition, temporarily discontinue glyburide/metformin prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms, such as increasing somnolence, malaise, myalgias, nonspecific abdominal distress, and respiratory distress. There may be associated hypotension, hypothermia, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's health care provider must be aware of the possible importance of such symptoms. Instruct the patient to notify their health care provider immediately if symptoms occur. Withdraw glyburide/metformin until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of glyburide/metformin, GI symptoms, which are common during initiation of therapy with metformin, are unlikely to be drug related. Later occurrence of GI symptoms could be caused by lactic acidosis or other serious disease.

Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking glyburide/metformin do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.

Suspect lactic acidosis in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (eg, ketonemia, ketonuria).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking glyburide/metformin, immediately discontinue the drug and institute general supportive measures promptly. Because metformin is dialyzable (with a clearance of up to 170 mL/minute under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.

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. Metformin does not appear to share this risk.

• 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 or debilitated patients, and in patients with impaired renal, hepatic, adrenal, and/or pituitary function; use with caution.

• Lactic acidosis: [U.S. Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization. The risk is increased in patients with acute congestive heart failure, dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate may be observed. Discontinue immediately if acidosis is suspected. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function and the patient’s age.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

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.

• Heart failure: Use metformin with caution in patients with heart failure requiring pharmacologic management, particularly in patients with unstable or acutely decompensated heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.

• Hepatic impairment: The metabolism and excretion of glyburide may be slowed in patients with hepatic impairment; if hypoglycemia should occur in such patients, it may be prolonged. Use metformin with caution in patients with impaired liver function due to potential for lactic acidosis.

• Renal impairment: The metabolism and excretion of glyburide may be slowed in patients with renal impairment; if hypoglycemia should occur in such patients, it may be prolonged. Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment (use is contraindicated in some patients). Monitor renal function; may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia. Use in patients with renal disease or renal dysfunction is contraindicated.

• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Thiazolidinediones: Concurrent use with a thiazolidinedione may increase risk of hypoglycemia and/or weight gain. Liver function tests should be monitored periodically with concurrent use.

Special populations:

• Elderly: Rapid and prolonged hypoglycemia (>12 hours) despite hypertonic glucose injections have been reported; age and hepatic and renal impairment are independent risk factors for hypoglycemia. Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed.

Other warnings/precautions:

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: The FDA recommends temporary discontinuation of metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015). Temporary discontinuation of metformin should occur at the time of or prior to the procedure, withheld for 48 hours following the procedure, and then resumed only when normal renal function is confirmed.

• 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.

• Surgical procedures: Metformin therapy should be suspended for any surgical procedures requiring food or fluid restriction (resume only after normal intake returns and normal renal function is verified).

• Vitamin B12 concentrations: Metformin may impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with supplementation or discontinuation of metformin therapy. Monitor vitamin B12 serum concentrations and hematologic parameters periodically with long-term therapy.

Monitoring Parameters

Signs and symptoms of hypoglycemia, urine for glucose and ketones, FPG, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal and hepatic function should be performed; monitor at least annually once patient is on maintenance therapy. Monitor vitamin B12 concentrations (periodically with long-term treatment) and folate (if megaloblastic anemia is suspected).

Pregnancy Risk Factor

B

Pregnancy Considerations

Animal reproduction studies were not conducted with this combination. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, abdominal pain, nausea, vomiting, diarrhea, or dizziness. Have patient report immediately to prescriber signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or vision changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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