Repaglinide

Repaglinide tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: Repaglinide tablets should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Repaglinide tablets are glinide indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis

Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations. Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.

• The recommended starting dose is 0.5 mg orally before each meal if HbA1c is less than 8%, and 1 or 2 mg orally before each meal if HbA1c is 8% or greater. • The recommended dose range is 0.5 mg to 4 mg before meals, with a maximum daily dose of 16 mg. • The patient’s dose should be doubled up to 4 mg with each meal until satisfactory glycemic control is achieved. At least one week should elapse to assess response after each dose adjustment. • Instruct patients to skip the dose of repaglinide tablets if a meal is skipped. In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced. ( 2.1, 5.1 ) • Instruct patients to take repaglinide tablets within 30 minutes before meals. • In patients with severe renal impairment (CrCl = 20 – 40 mL/min), recommended starting dose is 0.5 mg orally before each meal.

Repaglinide tablets are contraindicated in patients with: • Concomitant use of gemfibrozil • Known hypersensitivity to repaglinide or any inactive ingredients • Concomitant use with gemfibrozil. • Known hypersensitivity to repaglinide or any inactive ingredients

• Hypoglycemia: repaglinide tablets may cause hypoglycemia. Skip the scheduled dose of repaglinide tablets if a meal is skipped to reduce the risk of hypoglycemia. Reduce the dose of repaglinide tablets if hypoglycemia occurs. • Serious Cardiovascular Adverse Reactions with Concomitant NPH-insulin: repaglinide tablets are not indicated for use in combination with NPH-insulin. • Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with repaglinide tablets.

The following serious adverse reaction is also described elsewhere in the labeling: Hypoglycemia The most common adverse reactions (5% or greater incidence) among patients treated with repaglinide tablets were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain.

Clinically Important Drug Interactions with Repaglinide Tablets Table 3 includes a list of drugs with clinically important drug interactions when administered concomitantly with repaglinide tablets and instructions for preventing or managing them. Table 3: Clinically Important Drug Interactions with Repaglinide Tablets Gemfibrozil Clinical Impact: Gemfibrozil significantly increased repaglinide exposures by 8.1 fold Intervention: Do not administer repaglinide tablets to patients receiving gemfibrozil. Clopidogrel Clinical Impact: Clopidogrel increased repaglinide exposures by 3.9-5.1 fold Intervention: Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.

Store at 20º to 25º C (68º to 77º F), excursions permitted to 15º to 30ºC (59º to 86º F). Protect from moisture.