Home › Drugs › Glyburide-Metformin Hydrochloride

Glyburide-Metformin Hydrochloride

FDA Drug Information • Also known as: Glyburide-Metformin Hydrochloride

Brand Names
Glyburide-Metformin Hydrochloride
Drug Class
Sulfonylurea [EPC]
Route
ORAL
Dosage Form
TABLET
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: LACTIC ACIDOSIS WARNING: LACTIC ACIDOSIS Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metforminassociated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [ see Warnings and Precautions ( 5.1 ) ]. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [ see Dosage and Administration ( 2.3 ), Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. If metformin-associated lactic acidosis is suspected, immediately discontinue glyburide and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [ see Warnings and Precautions ( 5.1 ) ]. See full prescribing information for complete boxed warning.

  • Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms include malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. ( 5.1 )
  • Risk factors include renal impairment, concomitant use of certain drugs, age > 65 years old, radiological study with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 )
  • If lactic acidosis is suspected, discontinue glyburide and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. ( 5.1 )

    • Description

    11 DESCRIPTION Glyburide and metformin hydrochloride tablets, USP contain 2 oral 2 oral antihyperglycemic drugs used in the management of type 2 diabetis, glyburide USP and metformin hydrochloride USP. Glyburide, USP is an oral antihyperglycemia sulfonylurea class. The chemical name for glyburide USP is 1-[[p-[2-(5-chloro-o-anisamido) ethyl]phenyl]sulfonyl]-3-cyclo-hexylurea. Glyburide USP is a white to off-white crystalline compound with a molecular formula of C 23 H 28 ClN 3 O 5 S and a molecular weight of 494.01. Micronised glyburide is used in glyburide and metformin hydrochloride tablets, USP. The structural formula is represented below. Metformin hydrochloride, USP is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide monohydrochloride) Is not chemically or pharmacologically related to sulfonylureas, thiazolidinediones, or α-glucosidase inhibitors. It is a white to off-white crystalline compound with a molecular formula of C 4 H 12 CIN 5 (monohydrochloride) and a molecular weight of 165.63. Metformin is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin is 6.68. The structural formula is as shown: Glyburide and metformin hydrochloride tablets, USP are available for oral administration in tablets containing 1.25 mg glyburide USP with 250 mg metformin hydrochloride USP, 2.5 mg glyburide USP with 500 mg metformin hydrochloride USP, and 5 mg glyburide USP with 500 mg metformin hydrochloride USP. In addition, each tablet contains the following inactive ingredients: Sodium Starch Glycolate, Povidone, Colloidal Silicon Dioxide, Magnesium Stearate. The tablets are film coated, which provides color differentiation. Additionally 1.25 mg/250 mg tablet contains Opadry Yellow which contains Hypromellose, Talc, Titanium Dioxide, Macrogol/PEG 6000, Propylene Glycol and Iron...

    What Is Glyburide-Metformin Hydrochloride Used For?

    1 INDICATIONS AND USAGE Glyburide and metformin hydrochloride tablets is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Glyburide and metformin hydrochloride tablets are a combination of glyburide, a sulfonylurea, and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 )

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION Adult Dosage:

  • Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals. ( 2.1 )
  • For patients not treated with either glyburide (or another sulfonylurea) or metformin HCl, initiate treatment with another formulation with a dose of 1.25 mg glyburide and 250mg metformin HCl orally, once or twice daily with meals. ( 2.1 )
  • For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose is 2.5 mg/500 mg or 5 mg/500 mg orally twice daily with meals. ( 2.1 )
  • For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin HCl, the starting dose should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin HCl already being taken. ( 2.1 )
  • Increase the dose gradually on the basis of glycemic control and tolerability, up to a maximum to a maximum dose of 20 mg glyburide/2,000 mg metformin HCl daily. ( 2.1 ) Renal Impairment: Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.4 ) o Do not use in patients with eGFR below 30 mL/minute/1.73 m 2 ( 2.4 ) o Initiation is not recommended in patients with eGFR between 30 to 45 mL/minute/1.73 m 2 ( 2.4 ) o Assess risk/benefit if eGFR falls below 45 mL/minute/1.73 m 2 ( 2.4 ) o Discontinue if eGFR falls below 30 mL/minute/1.73 m 2 ( 2.4 ) Discontinuation for Iodinated Contrast Imaging Procedures: o Glyburide and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.5 ) 2.1 Dosage
  • Give glyburide and metformin hydrochloride tablets in divided doses, twice daily, with meals.
  • For patients not treated with either glyburide (or another sulfonylurea) or metformin hydrochloride (HCl), initiate treatment with another formulation of glyburide and metformin HCl at a starting dose of 1.25 mg glyburide and 250mg metformin HCl orally, once or twice daily with meals.
  • For patients not adequately controlled on either glyburide (or another sulfonylurea) or metformin HCl alone, the recommended starting dose of glyburide and metformin hydrochloride tablets is 2.5 mg/500 mg or 5 mg/500 mg orally twice daily with meals.
  • For patients previously treated with a combination therapy of glyburide (or another sulfonylurea) and metformin HCl, the starting dose of glyburide and metformin hydrochloride tablets should not exceed the daily dose of glyburide (or equivalent dose of another sulfonylurea) and metformin HCl already being taken.
  • Increase the dose gradually on the basis of glycemic control and tolerability, up to a maximum to a maximum dose of 20 mg glyburide/2,000 mg metformin HCl daily. 2.2 Patients Receiving Colesevelam
  • Administer glyburide and metformin hydrochloride tablets at least 4 hours prior to colesevelam for patients taking both drugs concomitantly [ see Drug...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere in the labeling:

  • Lactic Acidosis [see Boxed Warning and Warnings and Precautions ( 5.1 ) ]
  • Hypoglycemia [see Warnings and Precautions ( 5.2 ) ]
  • Cardiovascular mortality [see Warnings and Precautions ( 5.3 ) ]
  • Hemolytic anemia [see Warnings and Precautions ( 5.4 ) ]
  • Vitamin B 12 Deficiency [see Warnings and Precautions ( 5.5 ) ] Most common (>5%) adverse reactions to glyburide and metformin hydrochloride tablets diarrhea, headache, nausea/vomiting, abdominal pain, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In double-blind clinical studies with glyburide and metformin hydrochloride as initial therapy or as second-line therapy of 20 and 14 weeks, respectively (see section 14), a total of 642 patients received glyburide and metformin hydrochloride, 312 received metformin HCl, 324 received glyburide, and 161 received placebo. Adverse reactions are listed in Table 1. Table 1: Adverse Reactions Occurring >5% in Double-Blind Clinical Studies of Glyburide and Metformin Hydrochloride Used as Initial (20 Weeks) or Second-Line (14 Weeks) Therapy Number (%) of Patients Adverse Reaction Placebo N=161 Glyburide N=324 Metformin HCl N=312 Glyburide and Metformin Hydrochloride N=642 Diarrhea 6% 6% 21% 17% Headache 11% 11% 9% 9% Nausea/vomiting 6% 5% 12% 8% Abdominal pain 4% 3% 8% 7% Dizziness 4% 6% 4% 6% Hypoglycemia The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy study of glyburide and metformin hydrochloride are summarized in Table 2. For patients with a baseline HbA1c between 8% and 11% treated with glyburide and metformin hydrochloride 2.5 mg/500 mg as initial therapy, the frequency of hypoglycemic symptoms was 30% to 35%. As second-line therapy in patients inadequately controlled on sulfonylurea alone, approximately 6.8% of all patients treated with glyburide and metformin hydrochloride experienced hypoglycemic symptoms. Gastrointestinal Reactions The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the glyburide and metformin hydrochloride initial therapy study are summarized in Table 2. Across all glyburide and metformin hydrochloride studies, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels. In controlled studies, <2% of patients discontinued glyburide and metformin hydrochloride therapy due to GI adverse events. Table 2: Hypoglycemia or Gastrointestinal Adverse Reactions in a Placebo and Active-Controlled Study of Glyburide and Metformin Hydrochloride as Initial Therapy (20 Weeks) Variable Placebo N=161 Glyburide Tablets N=160 Metformin HCl Tablets N=159 Glyburide and Metformin Hydrochloride 1.25 mg/250 mg Tablets N=158 Glyburide and Metformin Hydrochloride 2.5 mg/500 mg Tablets N=162 Number (%) of patients with symptoms of hypoglycemia 3% 21% 3% 11% 38% Number (%) of patients with gastrointestinal adverse events 24% 24% 43% 32% 38% Dermatologic Reactions Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.5% of glyburide-treated patients. These may be transient and may disappear despite continued use. 6.2 Postmarketing Adverse Reactions The following adverse reactions have been identified during post-approval use of glyburide and metformin hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 3 presents clinically significant drug interactions with glyburide and metformin hydrochloride. Table 3: Clinically Significant Drug Interactions with Glyburide and Metformin Hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with glyburide and metformin hydrochloride may increase the risk for lactic acidosis. Intervention: Consider more frequent monitoring of these patients. Examples: Topiramate, zonisamide, acetazolamide and dichlorphenamide. Drugs that Reduce Metformin Clearance Clinical Impact: Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [ see Clinical Pharmacology ( 12.3 ) ]. Intervention: Consider the benefits and risks of concomitant use with glyburide and metformin hydrochloride. Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine. Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention: Warn patients against excessive alcohol intake while receiving glyburide and metformin hydrochloride. Drugs that potentiate the hypoglycemic action of glyburide and metformin hydrochloride Clinical Impact: Certain drugs may potentiate the hypoglycemic action of sulfonylureas, one of the components of glyburide and metformin hydrochloride. Intervention: Closely observe patient for hypoglycemia during co-administration and for loss of glycemic control when withdrawing these agents. Examples: Nonsteroidal anti-inflammatory agents and other highly protein-boind drugs, salicylcates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, beta-adrenergic blocking agents; potentially with ciprofloxacin, micronazole. Bosentan Clinical Impact: Increased risk of liver enzyme elevations was observed. Intervention: Concomitant administration is contraindicated. Colesevalam Clinical Impact: Concomitant administration may led to reduced glyburide absorption (AUC and Cmax: -32% and -47%, respectively). Intervention: Glyburide and metformin hydrochloride should be administered at least 4 hours prior to colesevelam. Drugs Reducing Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. Intervention: When such drugs are administered to a patient receiving glyburide and metformin hydrochloride observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, observe the patient closely for hypoglycemia. Examples: Thiazides and other diuretics,...

    Contraindications

    4 CONTRAINDICATIONS Glyburide and metformin hydrochloride tablets is contraindicated in patients with:

  • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [ see Warnings and Precautions ( 5.1 ) ].
  • Hypersensitivity to metformin or glyburide.
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
  • Concomitant administration of bosentan [ see Drug Interactions ( 7 ) ].
  • Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 , 5.1 )
  • Hypersensitivity to metformin or glyburide. ( 4 )
  • Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. ( 4 )
  • Concomitant administration of bosentan. ( 4 , 7 )

    • Overdosage

    10 OVERDOSAGE Glyburide Overdosage of sulfonylureas, including glyburide tablets, can produce hypoglycemia. Mild hypoglycemic symptoms, without loss of consciousness or neurological findings, should be treated with oral glucose. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment are medical emergencies requiring immediate treatment. The patient should be treated with glucagon or intravenous glucose. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery. Clearance of glyburide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glyburide, dialysis is unlikely to be of benefit. Metformin Overdose of metformin has occurred, including ingestion of amounts greater than 50 g. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1 ) ]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Glyburide-metformin hydrochloride tablet 5mg/500 mg: color yellow, oval (biconvex), size 15mm and imprint code 124. NDC: 71335-2508-1: 30 Tablets in a BOTTLE NDC: 71335-2508-3: 60 Tablets in a BOTTLE NDC: 71335-2508-4: 90 Tablets in a BOTTLE NDC: 71335-2508-5: 120 Tablets in a BOTTLE NDC: 71335-2508-6: 100 Tablets in a BOTTLE NDC: 71335-2508-7: 180 Tablets in a BOTTLE NDC: 71335-2508-8: 25 Tablets in a BOTTLE Store at temperatures up to 25°C (77°F). [See USP Controlled Room Temperature.] Dispense in light-resistant containers. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.