Glyburide and metformin Side Effects

Please note - some side effects for Glyburide and metformin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Glyburide and metformin Side Effects - for the Professional

Glyburide and Metformin

Glyburide and Metformin

In double-blind clinical trials involving Glyburide and Metformin as initial or as second-line therapy, a total of 642 patients received Glyburide and Metformin, 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 Glyburide and Metformin (all strengths) as initial therapy and second-line therapy are listed in Table 6.

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

In controlled clinical trials of Glyburide and Metformin 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 Glyburide and Metformin are summarized in Table 7.

The frequency of hypoglycemic symptoms in patients treated with Glyburide and Metformin 1.25 mg/250 mg was highest in patients with a baseline HbA 1c < 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 Glyburide and Metformin 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 experienced hypoglycemic symptoms. When rosiglitazone was added to Glyburide and Metformin therapy, 22% of patients reported one 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 one patient discontinued for hypoglycemia.

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

Side Effects by Body System

Metabolic

Metabolic side effects of metformin have included lactic acidosis, which is a potentially fatal metabolic complication of biguanide therapy. The incidence of lactic acidosis has been about 0.03 cases per 1,000 patient years with approximately 0.015 fatal cases per 1,000 patient-years. The risk of lactic acidosis is particularly high in patients with underlying renal insufficiency. Cases of lactic acidosis occurring in patients with normal renal function have been rarely reported. Concomitant cardiovascular or liver disease, sepsis, and hypoxia may also increase the risk of lactic acidosis.

Hypoglycemia, an extension of glyburide's pharmacologic effects, has occurred in 1.6% to 3.1% of patients. Hypoglycemia may be severe and protracted. Strenuous exercise, decreased caloric intake, general debilitation, adrenal insufficiency, pituitary insufficiency, and ethanol use may increase the risk of hypoglycemia. Fatalities are reported. In addition, hyponatremia and disulfiram-like reactions are reported.

Lactic acidosis is a medical emergency requiring immediate evaluation and treatment. The case fatality rate may be as high as 50 %. Patients taking metformin who present with even vague medical illnesses such as myalgia, malaise, somnolence, abdominal discomfort, and so forth, should be evaluated for a metabolic etiology like lactic acidosis.

Signs and symptoms of severe acidosis may include vomiting, abdominal pain, nausea, dyspnea, hypothermia, hypotension, and bradycardia.

Laboratory evaluation of metformin-induced lactic acidosis generally includes determination of the following: blood glucose concentration, lactic acid concentration, serum electrolytes, blood pH, metformin concentration, and exclusion of ketoacidosis.

If lactic acidosis is present, immediate institution of general supportive care is indicated. Prompt hemodialysis is also generally recommended in order to correct the acidosis and remove metformin. Hemodialysis often results in rapid improvement. Some investigators have suggested that dialysis with a bicarbonate-buffered dialysate may be particularly effective.

Hypoglycemia, an extension of glyburide's pharmacologic effects, may be severe, protracted, refractory to glucose infusion, and, in some cases, may require diazoxide. It most commonly presents as coma or disturbed consciousness. Other signs of hypoglycemia include tachycardia, tremor, chest pain, weakness, and increased sweating. In one review of 57 spontaneously reported cases, the mean dose of glyburide associated with hypoglycemia was 10 mg per day although there were cases with doses as low as 2.5 mg per day. The median age in these cases was 75 years. Ten patients died. In another review of 13 cases, in which renal failure, advanced age, and congestive heart failure were deemed to be predisposing factors, hypoglycemia persisted for more than 60 hours in two patients.

Patients with renal dysfunction, liver disease, adrenal or pituitary insufficiency, or congestive heart failure may be at increased risk for hypoglycemia as are those who are elderly, debilitated, or malnourished. In addition, acute illness, lack of adherence to diet, ethanol ingestion, or strenuous exercise may precipitate hypoglycemia.

Gastrointestinal

Gastrointestinal side effects of metformin have included nausea, anorexia, metallic taste, diarrhea, dyspepsia, flatulence, and abdominal pain. One study has reported a 20% incidence of diarrhea.

Hematologic

Hematologic side effects of glyburide have included rare reports of leukopenia, thrombocytopenia, eosinophilia, and hemolytic anemia.

Malabsorption of vitamin B12, due to intrinsic factor deficiency and possibly other mechanisms, has been reported in as many as 30% of patients treated with metformin. Megaloblastic anemia has occurred. Discontinuation of metformin or supplementation with vitamin B12 may be necessary.

Hepatic

Hepatic side effects of glyburide have included elevations in serum transaminase, alkaline phosphatase, and bilirubin, although jaundice has been only rarely reported. Elevations in liver function tests are usually mild and often return to normal despite continued therapy. Rare cases of acute hepatic hypersensitivity characterized by pruritus, icterus, and cholestatic jaundice have also been reported. In addition, at least two cases of granulomatous hepatitis have been associated with glyburide use.

At least two cases of hepatitis have been associated with metformin use.

A 52-year-old female with a history of type II diabetes mellitus and hypertension developed lethargy, fatigue, and diarrhea after taking metformin for more than 2 weeks. After continuing metformin for a total of four weeks, her sclera became icteric and she was hospitalized. Aside from a soft systolic ejection fracture and a moderate degree of bilateral lower extremity edema, her physical examination was unremarkable. Laboratory data showed grossly elevated total bilirubin, AST, ALT, and alkaline phosphatase. Several days after her initial presentation all of her medications were discontinued. Her signs and symptoms significantly improved over the following several days, and she was discharged within two weeks of her hospitalization. The patient's presentation was considered consistent with drug-induced toxicity attributed to metformin.

Other

A single case of leukocytoclastic vasculitis with pneumonitis has been reported in association with metformin therapy.

Renal

Renal side effects of glyburide have included include polyuria and nocturia.

Dermatologic

Dermatologic side effects have included pruritus, erythema, urticaria, morbilliform and maculopapular eruptions, and vesiculobullous rash in 1.5% of patients who received glyburide occurred in clinical trials In addition, pemphigus vulgaris, porphyria cutanea tarda, Stevens-Johnson syndrome, and photosensitivity have been reported.

Hypersensitivity

Hypersensitivity side effects of glyburide have typically included dermatological effects but have also included acute hepatic hypersensitivity, cholestatic jaundice, necrotizing angiitis, hemolytic anemia, angioedema, arthralgia, myalgia, and vasculitis.

Ocular

Ocular side effects of glyburide have included changes in accommodation and blurred vision.

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