Side Effects of Glucovance (glyburide/metformin)

Glucovance (glyburide/metformin) is a combination of antidiabetic medication used as an adjunct to diet and exercise to improve blood glucose (sugar) control in adults with type 2 diabetes mellitus.

Glyburide is a second-generation oral sulfonylurea. It helps lower blood glucose by stimulating the release of insulin, the hormone responsible for regulating blood glucose.

Metformin is an oral biguanide antidiabetic agent. It decreases the production of glucose in the liver, decreases the absorption of glucose by the intestines, and increases the uptake and use of blood glucose by cells throughout the body. In clinical studies, Glucovance therapy was observed to be superior in improving fasting plasma glucose, post-meal blood glucose, and HbA1c levels versus treatment with glyburide or metformin alone.

Common side effects of Glucovance include:

• stomach pain,
• diarrhea,
• upset stomach,
• nausea,
• vomiting,
• headache,
• dizziness,
• decreased appetite,
• metallic taste,
• gas,
• heartburn, and
• weight loss.

Serious side effects of Glucovance include:

• hypoglycemia (low blood glucose),
• blood disorders,
• decreased blood sodium levels,
• rash,
• sensitivity to the sunlight,
• itching,
• liver disease,
• SIADH,
• hives,
• hypersensitivity-type reactions, and
• lactic acidosis
  • Symptoms include:
    • tiredness,
    • weakness,
    • unusual muscle pain,
    • stomach pain,
    • difficulty breathing,
    • dizziness, and
    • slow or irregular heartbeat.

Drug interactions of Glucovance include drugs that cause blood glucose levels to increase such as thiazides and other diuretics, corticosteroids, phenothiazines, thyroid medications, estrogens, birth control pills, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid, because these may diminish the effectiveness of Glucovance therapy. When these drugs are stopped, patients should be closely observed for signs of low blood glucose.

• Cimetidine, by decreasing the elimination of metformin from the body, can increase the amount of metformin in the blood by 40%. This may increase the frequency of side effects from metformin.
• Contrast media used for radiological procedures may reduce kidney function which reduces the elimination of metformin, leading to increased concentrations of metformin in the blood.
• Metformin should be stopped 48 hours before and after the use of contrast media. Alcohol consumption increases the effect of metformin on lactate production, increasing the risk of lactic acidosis.
• Certain drugs such as nonsteroidal anti-inflammatory medications (NSAIDs), salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, ciprofloxacin, monoamine oxidase inhibitors (MAOIs), oral miconazole, and beta-blockers may increase the blood glucose lowering actions of glyburide.
• Hypoglycemia (low blood glucose) and symptoms from hypoglycemia may result.
• Coadministration of glyburide with bosentan may cause an abnormal increase in liver enzymes. Concomitant use of these agents is not recommended.
• Colesevelam may reduce blood levels of glyburide. Patients are advised to take glyburide 1 hour before or 4 hours after colesevelam administration to minimize the risk of their interaction.

Glucovance has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, Glucovance should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Glucovance is excreted in breast milk. Due to the lack of safety data and the potential risk for hypoglycemia (low blood glucose) in nursing infants, the use of Glucovance in breastfeeding mothers is not recommended.

The most common side effects include:

• stomach pain,
• diarrhea,
• upset stomach,
• nausea,
• vomiting,
• headache, and
• dizziness.

Other commonly reported side effects with Glucovance therapy include:

• decreased appetite,
• metallic taste,
• gas,
• heartburn, and
• weight loss.

Other side effects include:

• hypoglycemia (low blood glucose),
• blood disorders,
• decrease blood sodium levels,
• rash,
• sensitivity to the sunlight,
• itching,
• liver disease,
• SIADH,
• hives, and
• hypersensitivity-type reactions.

Metformin can cause a rare but serious condition known as lactic acidosis, a build-up of acid in the blood. Lactic acidosis can cause death and requires immediate treatment.

Symptoms of lactic acidosis include:

• tiredness,
• weakness,
• unusual
• muscle pain,
• pain in the stomach,
• difficulty breathing,
• dizziness, and
• slow or irregular heartbeat.

Patients suspected of having signs or symptoms of lactic acidosis must seek emergency medical help.

Glucovance

In double-blind clinical trials involving Glucovance as initial therapy or as second-line therapy, a total of 642 patients received Glucovance, 312 received metformin therapy, 324 received glyburide therapy, and 161 received placebo. The percent of patients reporting events and types of adverse events reported in clinical trials of Glucovance (all strengths) as initial therapy and second-line therapy are listed in Table 6.

Table 6: Most Common Clinical Adverse Events ( > 5%) in Double-Blind Clinical Studies of Glucovance Used as Initial or Second-Line Therapy

In a controlled clinical trial of rosiglitazone versus placebo in patients treated with Glucovance (n=365), 181 patients received Glucovance with rosiglitazone and 184 received Glucovance with placebo.

Edema was reported in 7.7% (14/181) of patients treated with rosiglitazone compared to 2.2% (4/184) of patients treated with a placebo. A mean weight gain of 3 kg was observed in rosiglitazone-treated patients.

Disulfiram-like reactions have very rarely been reported in patients treated with glyburide tablets.

Hypoglycemia

• In controlled clinical trials of Glucovance, there were no hypoglycemic episodes requiring medical intervention and/or pharmacologic therapy; all events were managed by the patients.
• The incidence of reported symptoms of hypoglycemia (such as dizziness, shakiness, sweating, and hunger), in the initial therapy trial of Glucovance, are summarized in Table 7.
• The frequency of hypoglycemic symptoms in patients treated with Glucovance 1.25 mg/250 mg was highest in patients with a baseline HbA1c < 7%, lower in those with a baseline HbA1c of between 7% and 8%, and was comparable to placebo and metformin in those with a baseline HbA1c > 8%.
• For patients with a baseline HbA1c between 8% and 11% treated with Glucovance 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 Glucovance experienced hypoglycemic symptoms.
• When rosiglitazone was added to Glucovance therapy, 22% of patients reported 1 or more fingerstick glucose measurements = 50 mg/dL compared to 3.3% of placebo-treated patients. All hypoglycemic events were managed by the patients and only 1 patient discontinued for hypoglycemia.

• The incidence of gastrointestinal (GI) side effects (diarrhea, nausea/vomiting, and abdominal pain) in the initial therapy trial are summarized in Table 7.
• Across all Glucovance trials, GI symptoms were the most common adverse events with Glucovance and were more frequent at higher dose levels.
• In controlled trials, < 2% of patients discontinued Glucovance therapy due to GI adverse events.

Table 7: Treatment-Emergent Symptoms of Hypoglycemia or Gastrointestinal Adverse Events in a Placebo- and Active-Controlled Trial of Glucovance as Initial Therapy

• In postmarketing reports cholestatic jaundice and hepatitis may occur rarely which may progress to liver failure; Glucovance should be discontinued if this occurs.

Glucovance

• Certain drugs tend to produce hyperglycemia and may lead to loss of blood glucose control.
• These drugs include 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 Glucovance, the patient should be closely observed for loss of blood glucose control.
• When such drugs are withdrawn from a patient receiving Glucovance, the patient should be observed closely for hypoglycemia.
• Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid as compared to sulfonylureas, which are extensively bound to serum proteins.

Glyburide

• 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 Glucovance, the patient should be observed closely for hypoglycemia.
• When such drugs are withdrawn from a patient receiving Glucovance, the patient should be observed closely for loss of blood glucose control.
• An increased risk of liver enzyme elevations was observed in patients receiving glyburide concomitantly with bosentan. Therefore concomitant administration of Glucovance and bosentan is contraindicated.
• 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.
• Colesevelam: Concomitant administration of colesevelam and glyburide resulted in reductions in glyburide AUC and Cmax of 32% and 47%, respectively. The reductions in glyburide AUC and Cmax were 20% and 15%, respectively, when administered 1 hour before, and not significantly changed (-7% and 4%, respectively) when administered 4 hours before colesevelam.

Metformin Hydrochloride

• A single-dose, metformin-furosemide drug interaction study in healthy subjects demonstrated that the pharmacokinetic parameters of both compounds were affected by coadministration.
• Furosemide increased the metformin plasma and blood Cmax by 22% and blood AUC by 15%, without any significant change in metformin renal clearance.
• When administered with metformin, the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance.
• No information is available about the interaction of metformin and furosemide when coadministered chronically.

• A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount excreted in the urine.
• Tmax and half-life were unaffected.
• Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on nifedipine.

• Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems.
• Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC.
• There was no change in the elimination half-life in the single-dose study. Metformin did not affect cimetidine pharmacokinetics.
• Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Glucovance and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

• In healthy volunteers, the pharmacokinetics of metformin and propranolol and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies.