Repaglinide

BRAND NAMES

Prandin: The brand name for repaglinide in the United States.

Novonorm: Used in many other parts of the world, including Europe and Asia.

Gluconorm: The brand name for repaglinide in Canada.

Other brand names: Other brand names include Repaglinide Teva, EUREPA 2 MG TAB, and Repaglide.

Fixed-dose combinations: Repaglinide can also be found in combination with other drugs under names like PrandiMet. 

MECHANISM OF ACTION

Repaglinide reduces blood glucose levels by promoting insulin release from the pancreas. It binds to and closes ATP-sensitive potassium channels in pancreatic β-cells, leading to membrane depolarization. This depolarization opens calcium channels, allowing calcium to enter the cells and trigger insulin secretion. Through this mechanism, repaglinide effectively controls post-meal blood sugar spikes.

PHARMACOKINETICS

Absorption

Repaglinide is quickly and efficiently absorbed following oral administration, enabling a rapid onset of action. This fast absorption makes it effective as a meal-time insulin secretagogue, helping to control postprandial (after-meal) increases in blood glucose levels.

Distribution

The steady-state volume of distribution of repaglinide is 31 L following intravenous administration in healthy volunteers. The drug exhibits extensive plasma protein binding, with more than 98% bound to human serum albumin.

Metabolism

Repaglinide undergoes extensive hepatic metabolism, primarily mediated by the cytochrome P450 enzymes CYP2C8 and CYP3A4, through oxidative and dealkylation pathways. This metabolism produces several metabolites, the major one being a dicarboxylic acid derivative, which lacks significant activity on glucose regulation. A minor metabolic route involves direct glucuronidation. The drug is predominantly excreted via the feces, with only a small fraction eliminated in the urine.

Excretion

Repaglinide is mainly eliminated through the biliary route into the feces (approximately 90%) following extensive hepatic metabolism. A smaller proportion, about 8%, is excreted in the urine.

PHARMACODYNAMICS

Repaglinide is a short-acting insulin secretagogue that lowers blood glucose by stimulating insulin release from pancreatic β-cells. It binds to specific sites on the ATP-sensitive potassium (K⁺_ATP) channels of these cells, leading to membrane depolarization, calcium influx, and subsequent insulin secretion. Its rapid onset and short duration of action make it particularly effective for controlling postprandial (after-meal) blood glucose levels.

ADMINISTRATION

Repaglinide should be taken orally shortly before each main meal, typically within 15 to 30 minutes prior to eating. The dosage is adjusted according to the patient’s meal schedule if a meal is missed, the associated dose of repaglinide should also be omitted.

DOSAGE AND STRENGTH

Repaglinide is available in oral tablet form in strengths of 0.5 mg, 1 mg, and 2 mg. The usual starting dose is 0.5 mg before each main meal, taken within 15–30 minutes prior to eating. The dose may be gradually adjusted based on the patient’s blood glucose response, up to a maximum total daily dose of 16 mg. For patients previously treated with other hypoglycemic agents, the initial dose and titration should be individualized according to their glycemic control and tolerance.

DRUG INTERACTIONS

Repaglinide is subject to several clinically significant drug interactions. It is metabolized mainly by CYP2C8 and CYP3A4 enzymes; therefore, inhibitors of these enzymes such as gemfibrozil, clarithromycin, itraconazole, and ketoconazole can markedly increase repaglinide plasma concentrations and raise the risk of hypoglycemia. Conversely, enzyme inducers like rifampicin, carbamazepine, and phenytoin may lower its plasma levels, reducing its glucose-lowering efficacy. The combination of repaglinide with gemfibrozil is contraindicated due to a substantial increase in drug exposure. Concurrent use with other antidiabetic agents, such as insulin or sulfonylureas, can potentiate hypoglycemic effects. Additionally, beta-blockers, alcohol, and MAO inhibitors may mask or enhance hypoglycemia symptoms, while corticosteroids, diuretics, thyroid hormones, and sympathomimetic agents can diminish repaglinide’s effectiveness.

FOOD INTERACTIONS

Food has a significant impact on the absorption and action of repaglinide. The drug should be taken shortly before meals, as food stimulates insulin secretion and enhances its glucose-lowering effect. Taking repaglinide without eating can lead to hypoglycemia, while skipping a meal should prompt omission of the corresponding dose. High-fat meals may slightly delay the absorption of repaglinide but do not significantly affect its overall effectiveness. Therefore, consistent meal timing and coordination of dosing with food intake are important to maintain optimal blood glucose control and minimize the risk of hypoglycemia.

CONTRAINDICATIONS

Repaglinide is contraindicated in patients with type 1 diabetes mellitus, as it requires functional pancreatic β-cells to be effective, and in those with diabetic ketoacidosis, where insulin therapy is required. It should not be used in individuals with severe liver impairment due to the risk of accumulation and hypoglycemia. The drug is also contraindicated in patients with known hypersensitivity to repaglinide or any of its components. Additionally, concurrent use with gemfibrozil is contraindicated because it can cause dangerously elevated repaglinide levels and severe hypoglycemia.

SIDE EFFECTS

• Hypoglycemia symptoms.

• Upper respiratory tract infection symptoms (stuffy or runny nose, sneezing, sore throat, cough).

• Headache.

• Nausea and diarrhea.

• Back pain and joint pain. 

• Signs of a severe allergic reaction.

• Liver problems.

• Bloody or cloudy urine, or painful urination (potential bladder/kidney issues).

• Fever or a general ill feeling. 

OVERDOSE

• Cold sweats and cool pale skin.

• Headache.

• Rapid heartbeat (tachycardia).

• Feeling sick (nausea) or very hungry.

• Dizziness, drowsiness, unusual tiredness, and weakness.

• Nervousness, anxiety, or tremor (shaking).

• Temporary changes in vision.

• Tingling of the tongue and lips. 

• Confusion or agitation.

• Slurred speech.

• Loss of consciousness or stupor.

• Seizures or convulsions.

TOXICITY

The primary manifestation of repaglinide toxicity is hypoglycemia, which can range from mild symptoms such as sweating, tremors, hunger, and dizziness—to severe outcomes, including confusion, seizures, loss of consciousness, or even coma. Other reported adverse effects at toxic doses may include headache, nausea, and gastrointestinal discomfort. Overdose management focuses on prompt administration of oral glucose for mild cases or intravenous dextrose in severe cases, along with close monitoring of blood glucose levels. Supportive care and symptomatic treatment are essential, and repeated small doses of glucose may be needed due to the prolonged hypoglycemic effect.