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Sulfonylurea

Glyburide and Metformin Hydrochloride

Approved 3 Jun 2009OralTablet

The FDA lists this product in 21 strengths and forms.

Boxed warningThe FDA label of this medicine carries a boxed warning, the strongest warning the FDA gives. Read it under warnings and precautions.

Indications

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 )

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 )

Warnings and precautions

Lactic Acidosis: See boxed warning. ( 5.1 )
Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. ( 5.2 )

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5.1Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL.

Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of glyburide and metformin hydrochloride. In Glyburide and metformin hydrochloride treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions).

Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue Glyburide and metformin hydrochloride and report these symptoms to their healthcare provider. For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment —The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [ see Dosage and Administration ( 2.1 ) , Clinical Pharmacology ( 12.3 ) ] : o Before initiating glyburide and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR). o Glyburide and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [ see CONTRAINDICATIONS ( 4 )]. o Initiation of glyburide and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 . o Obtain an eGFR at least annually in all patient taking glyburide and metformin hydrochloride. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking glyburide and metformin hydrochloride whose eGFR falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy.
Drug interactions —The concomitant use of glyburide and metformin hydrochloride with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation [ see Drug Interactions ( 7 ) ]. Consider more frequent monitoring of patients.
Age 65 or Greater —The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
Radiologic studies with contrast —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop glyburide and metformin hydrochloride at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism or heart failure, or in patients who will be administered intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after the imaging procedure, and restart glyburide and metformin hydrochloride if renal function is stable.
Surgery and other procedures —Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Glyburide and metformin hydrochloride should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic states —Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue glyburide and metformin hydrochloride.
Excessive Alcohol intake —Alcohol potentiates the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake, acute or chronic, while receiving glyburide and metformin hydrochloride.
Hepatic impairment —Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of glyburide and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

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, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.

Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 )
Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. ( 7 )
Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 )
The hypoglycemic action of glyburide and metformin hydrochloride tablets may be potentiated by certain drugs. ( 7 )
Concomitant administration of colesevalam may led to reduced glyburide absorption. ( 7 )

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 .

6.1Clinical 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.

6.2Postmarketing 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 always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Allergic : Angioedema, arthralgia, myalgia, and vasculitis have been reported. Dermatologic : Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.

Hematologic : Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas. Hepatic : Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure.

Liver function abnormalities, including isolated transaminase elevations, have been reported. Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.

Other Reactions : Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.

Glyburide and Metformin Hydrochloride

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Lactic Acidosis

5.2Hypoglycemia

Interactions

Adverse reactions

6.1Clinical Studies Experience

6.2Postmarketing Adverse Reactions

Composition

Strengths and forms

Official product information

At a glance

Guidelines