ADVERSE REACTIONS
Glyburide and Metformin Hydrochloride
In double-blind clinical trials involving glyburide and metformin hydrochloride as initial or as second-line therapy, a total of 642 patients received glyburide and metformin hydrochloride, 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 hydrochloride (all strengths) as initial therapy and second-line therapy are listed in Table 6.
Table 6: Most Common Clinical Adverse Events (> 5 Percent) in Double-Blind Clinical Studies of Glyburide and Metformin Hydrochloride Used as Initial or Second-Line Therapy | Number (%) of Patients |
| Adverse Event | Placebo N = 161 | Glyburide N = 324 | Metformin N = 312 | Glyburide and Metformin Hydrochloride N = 642 |
| Upper respiratory infection | 22 (13.7) | 57 (17.6) | 51 (16.3) | 111 (17.3) |
| Diarrhea | 9 (5.6) | 20 (6.2) | 64 (20.5) | 109 (17.0) |
| Headache | 17 (10.6) | 37 (11.4) | 29 (9.3) | 57 (8.9) |
| Nausea/vomiting | 10 (6.2) | 17 (5.2) | 38 (12.2) | 49 (7.6) |
| Abdominal pain | 6 (3.7) | 10 (3.1) | 25 (8.0) | 44 (6.9) |
| Dizziness | 7 (4.3) | 18 (5.6) | 12 (3.8) | 35 (5.5) |
In a controlled clinical trial of rosiglitazone versus placebo in patients treated with glyburide and metformin hydrochloride (n = 365), 181 patients received glyburide and metformin hydrochloride with rosiglitazone and 184 received glyburide and metformin hydrochloride 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.
Hypoglycemia
In controlled clinical trials of glyburide and metformin hydrochloride tablets 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 hydrochloride are summarized in Table 7.
The frequency of hypoglycemic symptoms in patients treated with glyburide and metformin hydrochloride 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 of 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. When rosiglitazone was added to glyburide and metformin hydrochloride 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. (See PRECAUTIONS, General, Addition of Thiazolidinediones to Glyburide and Metformin Hydrochloride Therapy.)
Gastrointestinal Reactions
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 hydrochloride trials, GI symptoms were the most common adverse events with glyburide and metformin hydrochloride and were more frequent at higher dose levels. In controlled trials, < 2% of patients discontinued glyburide and metformin hydrochloride 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 Glyburide and Metformin Hydrochloride as Initial Therapy | Variable | Placebo N = 161 | Glyburide Tablets N = 160 | Metformin Tablets N = 159 | Glyburide and Metformin Hydrochloride Tablets 1.25 mg/250 mg N = 158 | Glyburide and Metformin Hydrochloride Tablets 2.5 mg/500 mg N = 162 |
| Mean Final Dose | 0 mg | 5.3 mg | 1317 mg | 2.78 mg/557 mg | 4.1 mg/824 mg |
| Number (%) of patients with symptoms of hypoglycemia | 5 (3.1) | 34 (21.3) | 5 (3.1) | 18 (11.4) | 61 (37.7) |
| Number (%) of patients with gastrointestinal adverse events | 39 (24.2) | 38 (23.8) | 69 (43.3) | 50 (31.6) | 62 (38.3) |
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