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.
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.
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)].
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glyburide and metformin hydrochloride.
The following adverse reactions are also discussed elsewhere in the labeling:
- Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
- Hypoglycemia [see Warnings and Precautions (5.2)]
- Cardiovascular mortality [see Warnings and Precautions (5.3)]
- Hemolytic anemia [see Warnings and Precautions (5.4)]
- Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
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.
|Adverse Reaction||Number (%) of Patients|
|Placebo N=161||Glyburide N=324||Metformin HCl N=312||Glyburide and Metformin Hydrochloride N=642|
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.
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.
|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%|
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.
The following adverse reactions have been identified during post-approval use of glyburide and metformin hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Allergic: Angioedema, arthralgia, myalgia, and vasculitis have been reported.
Dermatologic: Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
Hematologic: Leukopenia, agranulocytosis, thrombocytopenia, which occasionally may present as purpura, hemolytic anemia, aplastic anemia, and pancytopenia, have been reported with sulfonylureas.
Hepatic: Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin. Cholestatic jaundice and hepatitis may occur rarely with glyburide, which may progress to liver failure. Liver function abnormalities, including isolated transaminase elevations, have been reported.
Metabolic: Hepatic porphyria reactions have been reported with sulfonylureas; however, these have not been reported with glyburide. Disulfiram-like reactions have been reported very rarely with glyburide. Cases of hyponatremia have been reported with glyburide and all other sulfonylureas, most often in patients who are on other medications or have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone.
Other Reactions: Changes in accommodation and/or blurred vision have been reported with glyburide and other sulfonylureas. These are thought to be related to fluctuation in glucose levels.
Table 3 presents clinically significant drug interactions with glyburide and metformin hydrochloride.
Table 3: Clinically Significant Drug Interactions with Glyburide and Metformin Hydrochloride
|Carbonic Anhydrase Inhibitors|
|Clinical Impact:||Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with glyburide and metformin hydrochloride may increase the risk for lactic acidosis.|
|Intervention:||Consider more frequent monitoring of these patients.|
|Examples:||Topiramate, zonisamide, acetazolamide and dichlorphenamide.|
|Drugs that Reduce Metformin Clearance|
|Clinical Impact:||Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3) ].|
|Intervention:||Consider the benefits and risks of concomitant use with glyburide and metformin hydrochloride.|
|Examples:||Ranolazine, vandetanib, dolutegravir, and cimetidine.|
|Clinical Impact:||Alcohol is known to potentiate the effect of metformin on lactate metabolism.|
|Intervention:||Warn patients against excessive alcohol intake while receiving glyburide and metformin hydrochloride.|
|Drugs that potentiate the hypoglycemic action of glyburide and metformin hydrochloride|
|Clinical Impact:||Certain drugs may potentiate the hypoglycemic action of sulfonylureas, one of the components of glyburide and metformin hydrochloride.|
|Intervention:||Closely observe patient for hypoglycemia during co-administration and for loss of glycemic control when withdrawing these agents.|
|Examples:||Nonsteroidal anti-inflammatory agents and other highly protein-boind drugs, salicylcates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, beta-adrenergic blocking agents; potentially with ciprofloxacin, micronazole.|
|Clinical Impact:||Increased risk of liver enzyme elevations was observed.|
|Intervention:||Concomitant administration is contraindicated.|
|Clinical Impact:||Concomitant administration may led to reduced glyburide absorption (AUC and Cmax: -32% and -47%, respectively).|
|Intervention:||Glyburide and metformin hydrochloride should be administered at least 4 hours prior to colesevelam.|
|Drugs Reducing Glycemic Control|
|Clinical Impact:||Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.|
|Intervention:||When such drugs are administered to a patient receiving glyburide and metformin hydrochloride observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving glyburide and metformin hydrochloride, observe the patient closely for hypoglycemia.|
|Examples:||Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.|
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