GLYBURIDE Drug Interactions: What You Need to Know

Drug Interactions The hypoglycemic action of sulfonylureas may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving glyburide tablets, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving glyburide tablets, the patient should be observed closely for loss of control. An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore, concomitant administration of glyburide tablets and bosentan is contraindicated. Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving glyburide tablets, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving glyburide tablets, the patient should be observed closely for hypoglycemia. A possible interaction between glyburide and ciprofloxacin, a fluoroquinolone antibiotic, has been reported, resulting in a potentiation of the hypoglycemic action of glyburide. The mechanism for this interaction is not known. A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known. Metformin : In a single-dose interaction study in NIDDM subjects, decreases in glyburide AUC and C max were observed, but were highly variable. The single-dose nature of this study and the lack of correlation between glyburide blood levels and pharmacodynamic effects, makes the clinical significance of this interaction uncertain. Coadministration of glyburide and metformin did not result in any changes in either metformin pharmacokinetics or pharmacodynamics. Colesevelam : Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and C max of 32% and 47%, respectively. The reductions in glyburide AUC and C max were 20% and 15%, respectively when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam. Topiramate : A drug-drug interaction study conducted in patients with type 2 diabetes evaluated the steady-state pharmacokinetics of glyburide (5 mg/day) alone and concomitantly with topiramate (150 mg/day). There was a 22% decrease in C max and a 25% reduction in AUC24 for glyburide during topiramate administration. Systemic exposure (AUC) of the active metabolites, 4-trans-hydroxy-glyburide (M1) and 3-cis hydroxyglyburide (M2), was also reduced by 13% and 15%, and C max was reduced by 18% and 25%, respectively. The steady-state pharmacokinetics of topiramate were unaffected by concomitant administration of glyburide. Carcinogenesis, Mutagenesis, and Impairment of Fertility Studies in rats at doses up to 300 mg/kg/day for 18 months showed no carcinogenic effects. Glyburide is nonmutagenic when studied in the Salmonella microsome test (Ames test) and in the DNA damage/alkaline elution assay. No drug related effects were noted in any of the criteria evaluated in the two year oncogenicity study of glyburide in mice.

Pregnancy Teratogenic

Effects: Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to 500 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to glyburide. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose as close to normal as possible.

Nonteratogenic

Effects: Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If glyburide tablets is used during pregnancy, it should be discontinued at least two weeks before the expected delivery date.

Nursing Mothers

Although it is not known whether glyburide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If the drug is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Elderly patients are particularly susceptible to the hypoglycemic action of glucose lowering drugs. Hypoglycemia may be difficult to recognize in the elderly (see PRECAUTIONS ). The initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see DOSAGE AND ADMINISTRATION ). Elderly patients are prone to develop renal insufficiency, which may put them at risk of hypoglycemia. Dose selection should include assessment of renal function.

CONTRAINDICATIONS Glyburide tablets are contraindicated in patients with: 1. Known hypersensitivity or allergy to the drug. 2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin. 3. Type I diabetes mellitus. 4. Concomitant administration of bosentan.

Special Warning On Increased Risk Of Cardiovascular Mortality

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of glyburide tablets and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure .

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 )
• Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. ( 5.3 )
• Hemolytic anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. ( 5.4 )
• Vitamin B 12 Deficiency: Metformin may lower vitamin B 12 levels.
• Measure hematological parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( Error! Hyperlink reference not valid. )

5.1 Lactic 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 ( ) ]. 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 ( ) ]. 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.

5.2 Hypoglycemia All sulfonylurea drugs, including glyburide and metformin hydrochloride, are capable of producing severe hypoglycemia [ see Adverse Reactions ( ) ]. Concomitant use of glyburide and metformin hydrochloride with other antidiabetic medication can increase the risk of hypoglycemia. A lower dose of glyburide and metformin hydrochloride may be required to minimize the risk of hypoglycemia when combining it with other antidiabetic medications. Educate patients to recognize and manage hypoglycemia. When initiating and increasing glyburide and metformin hydrochloride in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications) start with a lower dose. Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of anti-diabetic medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested. The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. Early warning symptoms of hypoglycemia may be different or less pronounced in patients with autonomic neuropathy, the elderly, and in patients who are taking beta-adrenergic blocking medications or other sympatholytic agents. These situations may result in severe hypoglycemia before the patient is aware of the hypoglycemia. These impairments may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death.

5.3 Cardiovascular Mortality The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical study designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with type 2 diabetes mellitus. The study involved 823 patients who were randomly assigned to 1 of 4 treatment groups. UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and benefits of glyburide and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

5.4 Hemolytic Anemia Treatment of patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents, including glyburide and metformin hydrochloride, can lead to hemolytic anemia. Avoid use of glyburide and metformin hydrochloride in patients with G6PD deficiency. In postmarketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

5.5 Vitamin B 12 Deficiency In clinical studies of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on glyburide and metformin hydrochloride and manage any abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 ) ]</span>.

5.6 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide and metformin hydrochloride.