Glimepiride: uses, appearance and warnings

Glimepiride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14.1)] . Limitations of Use Glimepiride tablets should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings. Glimepiride is a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) . Limitations of Use: Not for treating type 1 diabetes mellitus or diabetic ketoacidosis ( 1 ).

Glimepiride is formulated as tablets of: 1 mg (pink colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “X” and “76” on either side of the bisect on one face and plain on the other face) 2 mg (light green to green colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “Y” and “32” on either side of the bisect on one face and plain on the other face) 4 mg (light blue to blue colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “Y” and “34” on either side of the bisect on one face and plain on the other face) Tablets (scored): 1 mg, 2 mg, and 4 mg (3)

Glimepiride tablets, USP are available in the following strengths and package sizes: Glimepiride Tablets USP, 1 mg are pink colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “X” and “76” on either side of the bisect on one face and plain on the other face. Bottles of 100 NDC 65862-579-01 Bottles of 500 NDC 65862-579-05 Bottles of 1,000 NDC 65862-579-99 Glimepiride Tablets USP, 2 mg are light green to green colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “Y” and “32” on either side of the bisect on one face and plain on the other face. Bottles of 100 NDC 65862-580-01 Bottles of 500 NDC 65862-580-05 Bottles of 1,000 NDC 65862-580-99 Glimepiride Tablets USP, 4 mg are light blue to blue colored, flat-faced, oblong uncoated tablets with notched sides at double bisect, debossed with “Y” and “34” on either side of the bisect on one face and plain on the other face. Bottles of 100 NDC 65862-581-01 Bottles of 250 NDC 65862-581-25 Bottles of 500 NDC 65862-581-05 Bottles of 1,000 NDC 65862-581-99 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in well-closed containers with safety closures.

Glimepiride tablets are contraindicated in patients with a history of a hypersensitivity reaction to: Glimepiride or any of the product’s ingredients [see Warnings and Precautions (5.2) ]. Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to glimepiride tablets. Do not use glimepiride tablets in patients who have a history of an allergic reaction to sulfonamide derivatives. Hypersensitivity to glimepiride or any of the product’s ingredients (4) Hypersensitivity to sulfonamide derivatives (4)

Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications. (5.1) Hypersensitivity Reactions: Postmarketing reports include anaphylaxis, angioedema and Stevens-Johnson syndrome. If a reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. (5.2) Hemolytic Anemia: Can occur if glucose 6-phosphate dehydrogenase (G6PD) deficient. Consider a non-sulfonylurea alternative. (5.3) Potential Increased Risk of Cardiovascular Mortality with Sulfonylureas: Inform patient of risks, benefits and treatment alternatives. (5.4) Macrovascular Outcomes: No clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug. (5.5) 5.1 Hypoglycemia All sulfonylureas, including glimepiride, can cause severe hypoglycemia [see Adverse Reactions (6.1) ] . The patient’s ability to concentrate and react may be impaired as a result of 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. Patients must be educated to recognize and manage hypoglycemia. Use caution when initiating and increasing glimepiride doses in patients who may be predisposed to hypoglycemia (e.g., the elderly, patients with renal impairment, patients on other anti-diabetic medications). Debilitated or malnourished patients, and those with adrenal, pituitary, or hepatic impairment are particularly susceptible to the hypoglycemic action of glucose-lowering medications. Hypoglycemia is also more likely to occur when caloric intake is deficient, after severe or prolonged exercise, or when alcohol is ingested. 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. 5.2 Hypersensitivity Reactions There have been postmarketing reports of hypersensitivity reactions in patients treated with glimepiride, including serious reactions such as anaphylaxis, angioedema, and Stevens-Johnson syndrome [see Adverse Reactions (6.2) ] . If a hypersensitivity reaction is suspected, promptly discontinue glimepiride, assess for other potential causes for the reaction, and institute alternative treatment for diabetes. 5.3 Hemolytic Anemia Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Because glimepiride is a sulfonylurea, use caution in patients with G6PD deficiency and consider the use of a non-sulfonylurea alternative. There are also postmarketing reports of hemolytic anemia in patients receiving glimepiride who did not have known G6PD deficiency [see Adverse Reactions (6.2) ] . 5.4 Increased Risk of Cardiovascular Mortality with Sulfonylureas 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 trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four 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 2 and a half 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 advantages of glimepiride 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 oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. 5.5 Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with glimepiride or any other anti-diabetic drug.

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions (5.1) ] Hemolytic anemia [see Warnings and Precautions (5.3) ] Common adverse reactions in clinical trials (≥5% and more common than with placebo) include hypoglycemia, headache, nausea, and dizziness (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. …

Certain medications may affect glucose metabolism, requiring glimepiride dose adjustment and close monitoring of blood glucose. (7.1) Miconazole: Severe hypoglycemia can occur when glimepiride and oral miconazole are used concomitantly. (7.2) Cytochrome P450 2C9 interactions: Inhibitors and inducers of cytochrome P450 2C9 may affect glycemic control by altering glimepiride plasma concentrations. (7.3) Colesevelam: Coadministration may reduce glimepiride absorption. Glimepiride should be administered at least 4 hours prior to colesevelam. (2.1, 7.4) 7.1 Drugs Affecting Glucose Metabolism A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control. …