Glyburide and Metformin Hydrochloride (Page 2 of 7)

5.2 Hypoglycemia

All sulfonylurea drugs, including glyburide and metformin hydrochloride, are capable of producing severe hypoglycemia [see Adverse Reactions (6)]. Concomitant use of glyburide and metformin hydrochloride with other anti-diabetic 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 anti-diabetic 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 B₁₂ Deficiency

In clinical studies of 29-week duration with metformin HCl tablets, a decrease to subnormal levels of previously normal serum vitamin B₁₂ levels, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B₁₂ absorption from the B₁₂ -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B₁₂ supplementation. Certain individuals (those with inadequate vitamin B₁₂ or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B₁₂ levels. Measure hematologic parameters on an annual basis and vitamin B₁₂ at 2 to 3 year intervals in patients on glyburide and metformin hydrochloride and manage any abnormalities [see Adverse Reactions (6.1)].

5.6 Macrovascular Outcomes

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

6 ADVERSE REACTIONS

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

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Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]

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Hypoglycemia [see Warnings and Precautions (5.2)]

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Cardiovascular mortality [see Warnings and Precautions (5.3)]

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Hemolytic anemia [see Warnings and Precautions (5.4)]

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Vitamin B₁₂ Deficiency [see Warnings and Precautions (5.5) ]

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

Adverse Reaction	Number (%) of Patients
	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.