NORMALLIANCE

Repaglinide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM).

It belongs to the meglitinide class of short-acting insulin secretagogues, which act by binding to β cells of the pancreas to stimulate insulin release.

Repaglinide induces an early insulin response to meals decreasing postprandial blood glucose levels.

It should only be taken with meals and meal-time doses should be skipped with any skipped meal.

Approximately one month of therapy is required before a decrease in fasting blood glucose is seen.

Meglitnides may have a neutral effect on weight or cause a slight increase in weight.

The average weight gain caused by meglitinides appears to be lower than that caused by sulfonylureas and insulin and appears to occur only in those naïve to oral antidiabetic agents.

Due to their mechanism of action, meglitinides may cause hypoglycemia although the risk is thought to be lower than that of sulfonylureas since their action is dependent on the presence of glucose.

In addition to reducing postprandial and fasting blood glucose, meglitnides have been shown to decrease glycosylated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control.

Meglitinides appear to be more effective at lowering postprandial blood glucose than metformin, sulfonylureas and thiazolidinediones.

Repaglinide is extensively metabolized in the liver and excreted in bile.

Repaglinide metabolites do not possess appreciable hypoglycemic activity.

Approximately 90% of a single Oral administered dose is eliminated in feces and 8% in urine.

As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential.

Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations.

Extracellular glucose enters the cell via

GLUT2 (SLC2A2) transporters.

Once inside the cell, glucose is metabolized to produce ATP.

High concentrations of ATP inhibit

ATP-sensitive potassium channels causing membrane depolarization.

When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization.

High glucose concentrations cause

ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels.

The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules.

Repaglinide increases insulin release by inhibiting

ATP-sensitive potassium channels in a glucose-dependent manner.

ATP-binding cassette sub-family

C member 8 Inhibitor Histamine H1 receptor Antagonist.

Rapidly and completely absorbed following oral administration.

Peak plasma concentrations are observed within 1 hour (range 0.5-1.4 hours).

The absolute bioavailability is approximately 56%.

Maximal biological effect is observed within 3-3.5 hours and plasma insulin levels remain elevated for 4-6 hours.

When a single 2 mg dose of repaglinide is given to healthy subjects, the area under the curve (AUC) is 18.0-18.7 (ng/mL/h)^3.

L following

Intravenous administration in healthy individuals.

Repaglinide is rapidly metabolized via oxidation and dealkylation by cytochrome P450 3A4 and 2C9 to form the major dicarboxylic acid derivative (M2).

Further oxidation produces the aromatic amine derivative (M1).

Glucuronidation of the carboxylic acid group of repaglinide yields an acyl glucuronide (M7).

Several other unidentified metabolites have been detected.

Repaglinide metabolites to not possess appreciable hypoglycemic activity.

Hover over products below to view reaction partners Repaglinide hydroxyrepaglinide repaglinide aromatic amine.

90% eliminated in feces (<2% as unchanged drug), 8% in urine (0.1% as unchanged drug).

33-38 L/hour following Intravenous administration.

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Severe hypoglycemic reactions with coma, seizure, or other neurological impairment may occur and constitute medical emergencies requiring immediate hospitalization.

Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns.

Close monitoring may continue until the physician is assured that the patient is out of danger.

Patients should be closely monitored for a minimum of to 48 hours, since hypoglycemia may recur after apparent clinical recovery.

There is no evidence that repaglinide is dialyzable using hemodialysis.

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.

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 to 40 mL/min), recommended starting dose is 0.5 mg orally before each meal.

Dose modifications are required when used concominantly with some medications. 2.1 Recommended Dosage and Administration The recommended starting dose for patients whose HbA 1c is less than 8% is 0.5 mg orally before each meal.

For patients whose

HbA 1c is 8% or greater the starting dose is 1 mg or 2 mg orally before each meal.

Instruct patients to take repaglinide tablets within 30 minutes before meals.

Repaglinide tablets may be dosed 2, 3, or 4 times a day in response to changes in the patient’s meal pattern.

In patients who skip meals, instruct patients to skip the scheduled dose of repaglinide tablets to reduce the risk of hypoglycemia.

In patients who experience hypoglycemia, the dose of repaglinide tablets should be reduced. 2.2 Patients with Severe Renal Impairment In patients with severe renal impairment (CrCl = 20 to 40 mL/min) initiate repaglinide tablets 0.5 mg orally before each meal.

Gradually titrate the dose, if needed to achieve glycemic control. 2.3 Dose Modifications for Drug Interactions Dosage adjustments are recommended in patients taking concomitant strong CYP3A4 or CYP2C8 inhibitors or strong CYP3A4 or CYP2C8 inducers.

Concomitant use with gemfibrozil is contraindicated.

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.

Do not exceed a total daily dose of 6 mg of repaglinide tablets in patients receiving cyclosporine.

USP, 0.5 mg are white to off white, round, biconvex uncoated tablets, debossed with ‘H’ on one side and ‘10’ on other side.

NDC: 63629-4866-1: 30 Tablets in a BOTTLE NDC: 63629-4866-2: 90 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F) .

Protect from moisture.

Keep bottles tightly closed.

Dispense in tight containers with safety closures.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

Limited available data from case reports and case series with repaglinide use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Teratogenicity was not observed in rats and rabbits administered repaglinide during organogenesis at approximately and 1 times the maximum daily clinical dose, based on body surface area.

No adverse developmental effects were observed in offspring of rats administered repaglinide during late gestation and lactation at approximately 4 times the maximum daily clinical dose.

The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as to 25% in women with a HbA1c>10.

The estimated background risk of miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth and macrosomia related morbidity.

Repaglinide was not teratogenic in rats or rabbits at doses 60 times (rats) and approximately 1 times (rabbit) clinical exposure (on a mg/m 2 basis) when administered during the period of organogenesis.

Offspring of rat dams exposed to repaglinide at ≥22 times clinical exposure on a mg/m 2 basis during days to 22 of gestation and during lactation were less viable and developed skeletal deformations consisting of shortening, thickening, and bending of the humerus during the postnatal period.

This effect was not seen at doses up to 4 times clinical exposure (on a mg/m 2 basis).

Safety and effectiveness have not been established in pediatric patients.

In clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age and no patients were greater than 75 years of age.

In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65.

There was no increase in frequency or severity of hypoglycemia in older subjects, but greater sensitivity of some older individuals to repaglinide therapy cannot be ruled out.