Repaglinide - Indications, Dosage Forms, and Mechanism of Action

Overview:

Repaglinide is a drug used in the treatment of type 2 diabetes mellitus that belongs to a class of antihyperglycemic agents known as meglitinides. Meglitinides reduce blood glucose levels by stimulating endogenous insulin production. The present recommended starting dose is dependent on hemoglobin A1c levels, with those below 8 percent urged to start with 0.5 mg pre-prandially and those above 8 percent to start with 1 to 2 mg. Repaglinide is Food and Drug Administration class C during pregnancy, meaning its use requires caution. There has been no evidence to support its safe use during breastfeeding, and thus, an alternative is recommended.

For Patients:

What Is Type 2 Diabetes?

Type 2 diabetes mellitus is a common type of diabetes. It is a disease that occurs when the blood glucose is too high. Blood glucose is the main source of energy and comes mainly from food. Insulin is secreted by the pancreas, which helps glucose get into the cells to be used for energy. In type 2 diabetes, the body does not make enough insulin. Too much glucose then stays in the blood, and not enough reaches the cells.

What Is the Mechanism of Action?

• Repaglinide binds to receptors on pancreatic beta cells and stimulates insulin release. Repaglinide then binds to an adenosine triphosphate (ATP)-dependent potassium channel on beta cells, known as sulfonylurea receptor 1, and brings about its closure.

• It is found that Repaglinide reduces postprandial glucose to around 5.8 mmol/L and fasting glucose to around 3.1 to 3.4 mmol/L.

Absorption:

• Repaglinide is rapidly absorbed within 60 minutes.

• Repaglinide binds to 98 percent of albumin and is associated with a reduction in glycated albumin than sulfonylureas.

Excretion:

• Repaglinide is inactivated and eliminated through the liver.

How to Take Repaglinide?

• Repaglinide should be taken orally.

• A dose of 0.5 to 4 mg is recommended to be taken twice to three times daily, to a maximum of 16 mg.

• Repaglinide should be taken 30 minutes before an intended meal, and in case the scheduled meal is skipped, the dose should also be skipped.

• A week later, the review is mandatory for dose adjustments.

What Are the Adverse Effects of Repaglinide?

• Hypoglycemia (reduced blood glucose level).

• Upper respiratory tract infection.

• Sinus infections (infection of the fluid present in sinus spaces).

• Weight gain.

• Diarrhea.

• Joint pain.

What Are the Contraindications?

• Hypersensitivity (developing allergic reactions such as skin redness or breathing difficulty).

• Type 1 diabetes mellitus (little or no insulin production due to defects in insulin-producing cells).

• Severe liver dysfunction (hepatic failure or cirrhosis).

For Doctors:

Indications

Repaglinide is used to control type 2 diabetes mellitus as an adjunct to exercise and diet to improve glycemic control in adults.

• Repaglinide is used to improve glycemic control in adults with type 2 diabetes mellitus.

• It is used as a supplement to exercise and diet.

Limitations

Repaglinide should not be used in patients with type 1 diabetes mellitus and also for the treatment of diabetic ketoacidosis.

Dosage

• The recommended starting dose of Repaglinide for patients with HbA1c less than 8 % is 0.5 mg and should be taken orally before every meal.

• Whereas for patients with HbA1c 8 % or greater, the starting dose should be 1 or 2 mg.

• The recommended daily dose range is 0.5 mg to 4 mg before meals, with a maximum of up to 16 mg.

• In order to achieve satisfactory glycemic control, the dose should be doubled up to 4 mg with each meal.

• At least one week is required to assess response after each dose adjustment.

• Instruct patients to take Repaglinide within 30 minutes before meals.

• Repaglinide may be dosed in response to changes in the patient’s meal pattern two, three, or even four times a day.

• Patients should skip the scheduled dose of Repaglinide to reduce the risk of hypoglycemia, especially those who skip their meals.

• The dose of Repaglinide should be reduced for those who experience hypoglycemia.

Considerations for Administration

Severe Renal Impairment:

• For severe renal impairment patients with CrCl = 20 to 40 mL/min, initiate Repaglinide 0.5 mg orally before each meal.

Gradually titrate the dose in order to achieve glycemic control.

Dose Modifications for Drug Interactions

• Dosage adjustments are required in patients taking concomitant strong CYP3A4 or CYP2C8 inducers or strong CYP3A4 or CYP2C8 inhibitors.

• Concomitant use with Gemfibrozil is contraindicated.

• Avoid concomitant use of Repaglinide with clopidogrel. If concomitant use cannot be avoided, then initiate Repaglinide at 0.5 mg before each meal, and the dose should not exceed the daily dose of 4 mg.

• For patients receiving Cyclosporine, the dose of Repaglinide should not exceed 6 mg.

Dosage Forms and Strengths

• 0.5 mg tablets- white, biconvex tablets embossed with the Novo Nordisk bull symbol.

• 1 mg tablets- yellow, biconvex tablets, embossed with the Novo Nordisk bull symbol.

• 2 mg tablets- peach, biconvex tablets, embossed with the Novo Nordisk bull symbol.

Contraindications

Repaglinide is contraindicated in patients with:

• Concomitant use of Gemfibrozil.

• Hypersensitivity to Repaglinide or any inactive ingredients.

Warnings and Precautions

Hypoglycemia:

• Severe hypoglycemia can cause seizures, which may be life-threatening, and lead to death.

• Sometimes hypoglycemia can impair concentration, which places an individual and others at risk in situations like driving and operating machinery.

• Symptomatic awareness of hypoglycemia is less pronounced in patients with longstanding diabetes or diabetic nerve disease, using medications that block the sympathetic nervous system and recurrent hypoglycemia.

• Hypoglycemia can happen suddenly, and symptoms vary for each individual.

• Factors that increase the risk of hypoglycemia include changes in the level of physical activity, changes in meal patterns, concomitant use with other antidiabetic agents, and changes to co-administered medication.

• Renal impairment individuals are at higher risk of hypoglycemia.

• Individuals should administer Repaglinide before meals and be instructed to skip the dose if a meal is skipped.

• The dose of Repaglinide should be reduced in those who experience hypoglycemia.

• Individuals should shelf-monitor their blood glucose levels in order to prevent and manage hypoglycemia.

• Caregivers and patients must be educated to recognize and manage hypoglycemia.

Serious Cardiovascular Adverse Reactions With Concomitant Use With NPH-Insulin:

• It is not advised to use Repaglinide in combination with NPH-insulin.

Macrovascular Outcomes:

• There has been no conclusive evidence of macrovascular risk reduction with Repaglinide.

Side Effects

• Upper respiratory infection.

• Headache.

• Sinusitis.

• Arthralgia.

• Nausea.

• Diarrhea.

• Back pain.

• Rhinitis.

• Constipation.

• Vomiting.

• Paresthesia.

• Chest pain.

• Bronchitis.

• Dyspepsia.

• Urinary tract infection.

• Tooth disorder.

• Allergy.

• Alopecia.

• Hemolytic anemia.

• Pancreatitis.

• Stevens-Johnson syndrome.

• Severe hepatic dysfunction, including jaundice and hepatitis.

Drug Interactions

• Gemfibrozil.

• Clopidogrel.

• Cyclosporine.

• CYP2C8 and CYP3A4 inhibitors- Ketoconazole, Itraconazole, Clarithromycin, Erythromycin, Trimethoprim, Gemfibrozil, Montelukast, Deferasirox, and Clopidogrel.

• CYP2C8 and CYP3A4 inducers- Rifampin, Barbiturates, and Carbamazepine.

• Drugs that may increase the risk of hypoglycemia- Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, Fluoxetine, Disopyramide, Fibrates, Monoamine oxidase inhibitors, Pentoxifylline, Nonsteroidal anti-inflammatory agents (NSAIDs), Pramlintide, Propoxyphene, Salicylates, Somatostatin analogs, and Sulphonamides.

• Drugs that decrease the blood glucose lowering effect of Repaglinide- Olanzapine and Clozapine, Calcium channel antagonists, and Corticosteroids.

Uses in the Special Population Pregnancy:

• Repaglinide comes under pregnancy Category C.

• There were no adequate and well-controlled studies on pregnant women.

• It is unknown whether Repaglinide can cause fetal harm when administered to a pregnant woman.

• Repaglinide should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers:

• It is not known whether Repaglinide is excreted in human milk, but some oral agents are excreted by this route.

• In case of discontinuing Repaglinide, where diet alone is inadequate, insulin therapy should be initiated to maintain blood glucose levels.

Pediatric Use:

• The safety and effectiveness of Repaglinide have not been established in pediatric patients.

Geriatric Use:

• In clinical studies of 24 weeks, 415 patients were over 65 years of age, and none were greater than 75 years of age.

• In one-year, active-controlled trials, no difference was seen in effectiveness and adverse events.

• There was no increase in the frequency and severity of hypoglycemia in older subjects.

Renal Impairment:

• Pharmacokinetic studies of Repaglinide were conducted in individuals with mild to moderate renal impairment (CrCl = 40 to 80 mL/min) and severe renal impairment (CrCl = 20 to 40 mL/min).

• No initial dose adjustment is needed in patients with mild to moderate renal dysfunction.

• However, patients with severe renal impairment should start Repaglinide therapy with a 0.5 mg dose and be carefully monitored.

• There were no studies in patients with creatinine clearances below 20 mL/min or patients requiring hemodialysis.

Hepatic Impairment:

• A study was conducted on 12 patients with chronic liver disease.

• Individuals with moderate to severe liver impairment had higher and more prolonged serum concentrations, and hence, Repaglinide should be used with caution.

• Longer intervals between dose adjustments may be required to allow full assessment of response.

Overdose:

• On overdosage, it leads to severe hypoglycemic reactions with coma, seizure, and other neurological impairments, which may require immediate hospitalization.

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

• Close monitoring is required until the physician is assured that the person is out of danger.

• The individual should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur.

Description:

• Repaglinide is an oral blood-glucose-lowering drug of the glinide class.

Clinical Pharmacology:

Mechanism of Action:

• Repaglinide lowers blood glucose levels by inducing the release of insulin by the beta cells of the pancreas. Insulin release is glucose-dependent, which diminishes at low glucose concentrations.

• Repaglinide closes ATP-dependent potassium channels in the beta cell membrane by binding at recognizable sites. This leads to an opening of calcium channels and thus results in increased calcium influx, which induces insulin secretion.

Pharmacokinetics

Absorption:

• Repaglinide is rapidly absorbed within 60 minutes.

Distribution:

• Repaglinide binds to 98 percent of albumin and is associated with a reduction in glycated albumin than sulfonylureas.

Metabolism and Excretion:

• Repaglinide is metabolized completely by oxidative biotransformation and direct conjugation with glucuronic acid after either an intravenous or oral dose. The major metabolites are aromatic amine (M1), oxidized dicarboxylic acid (M2), and acyl glucuronide (M7).

• Metabolites usually do not contribute to the glucose-lowering effect of Repaglinide.

• Within 96 hours after dosing, 90 percent was recovered in the feces and approximately eight percent in the urine.

• Repaglinide acts as a substrate for active hepatic uptake transporter.

• Repaglinide is inactivated and eliminated mainly through the liver.

Clinical Inferences

Repaglinide in Combination With Metformin:

• Repaglinide and Metformin combination was studied in 83 patients who were not satisfactorily controlled on exercise and diet but under Metformin therapy.

• Repaglinide dosage was analyzed for four to eight weeks, followed by a three-month maintenance period.

• Metformin and Repaglinide combination therapy resulted in a significant improvement in HbA1c and fasting plasma glucose (FPG) compared to monotherapy.

• In this study, the combination therapy of Repaglinide and Metformin showed dose-sparing effects with respect to Repaglinide, where Metformin dosage was kept constant.

• The improvement in HbA1c and fasting plasma glucose (FPG) was achieved at a lower daily Repaglinide with combination dosage than in the monotherapy.

Repaglinide in Combination With Pioglitazone:

• A combination therapy regimen of Pioglitazone and Repaglinide was compared to Repaglinide and Pioglitazone monotherapy in a 24-week trial that enrolled 246 patients who were treated with Metformin monotherapy.

• Repaglinide dosage was analyzed during the first 12 weeks, followed by a maintenance period. Combination therapy resulted in significant improvement in HbA1c and fasting plasma glucose (FPG) compared to monotherapy.

• The changes from baseline for completers in fasting plasma glucose and HbA1c include -39.8 mg/dL and -0.1 % for Repaglinide, -35.3 mg/dL, and for Pioglitazone, it was -0.1 % and -92.4 mg/dL and -1.9 % for the combination.

• The combination therapy group showed dose-sparing effects to Repaglinide, where the Pioglitazone dose was kept constant.

• The improvement in HbA1c and fasting plasma glucose of the combination group was achieved at a lower daily dose of Repaglinide than monotherapy.

Repaglinide in Combination With Rosiglitazone:

• A combination therapy regimen of Rosiglitazone and Repaglinide was compared to monotherapy in a 24-week trial that contained 252 patients previously treated with Metformin.

• Combination therapy resulted in significant improvement in HbA1c and fasting plasma glucose compared to monotherapy.

• In the combination therapy, the glycemic effects were dose-sparing with respect to both Repaglinide and Rosiglitazone dosage.

• The improvement in HbA1c and fasting plasma glucose of the combination therapy group was achieved with a lower daily dose of Repaglinide and Rosiglitazone, as compared to monotherapy.

Available Forms of Repaglinide

• Repaglinide tablets are supplied as biconvex tablets- 0.5 mg (white), 1 mg (yellow), and 2 mg (peach) strengths.

• 0.5 mg tablets bottles contain 100 NDC- (white) bottles of 500 NDC.

• 1 mg tablets bottles of 100 NDC - (yellow) bottles of 500 NDC.

• 2 mg tablets bottles of 100 NDC - (peach) bottles of 500 NDC.

• Store at 20° to 25° C.

• Protect from moisture and keep the bottles tightly closed.

• Dispense in tight containers with safety closures.