REPAGLINIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for REPAGLINIDE (REPAGLINIDE).

How it works

Repaglinide is a meglitinide analog that lowers blood glucose by stimulating insulin secretion from pancreatic beta cells. It binds to the sulfonylurea receptor (SUR) on the ATP-sensitive potassium channel (K-ATP channel), closing the channel and causing membrane depolarization, leading to calcium influx and exocytosis of insulin-containing granules.

What the body does with it

Metabolism	Extensively metabolized by the liver via CYP2C8 and CYP3A4 isoenzymes. Metabolites are inactive and undergo biliary excretion. Approximately 90% of the dose is excreted in feces, with less than 8% in urine.
Excretion	Approximately 90% of the absorbed dose is excreted in the feces via bile (as metabolites and unchanged drug), and about 8% is excreted in the urine. Renal elimination of unchanged drug is negligible (<0.1%).
Half-life	Terminal elimination half-life is approximately 1 hour (range 0.5–1.5 hours). This short half-life supports its use for prandial glucose control, with minimal risk of prolonged hypoglycemia.
Protein binding	>98% bound primarily to albumin, with minor binding to α1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 0.15 L/kg, suggesting limited extravascular distribution (mainly confined to extracellular fluid).
Bioavailability	Oral bioavailability is about 63% (range 56–70%) due to first-pass hepatic metabolism. Absorption is rapid and complete.
Onset of Action	Oral: Onset occurs within 15–30 minutes after administration, corresponding to peak plasma concentrations at ~1 hour.
Duration of Action	Duration of action is about 4–6 hours when taken before meals, aligning with postprandial glucose excursions. Longer duration may occur with higher doses or in hepatic impairment.

Classification & Brands

Dosing & administration

0.5-4 mg orally within 30 minutes before each meal (2-4 times daily). Maximum single dose: 4 mg; maximum total daily dose: 16 mg.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥40 mL/min. For GFR 30-39 mL/min: initiate with 0.5 mg before meals and titrate cautiously. For GFR <30 mL/min: not recommended.
Liver impairment	Child-Pugh Class A: initiate with 0.5 mg before meals and titrate cautiously. Child-Pugh Class B: no data; use with caution. Child-Pugh Class C: contraindicated.
Pediatric use	Not approved for use in pediatric patients. Safety and efficacy not established.
Geriatric use	Initiate at 0.5 mg before meals due to increased risk of hypoglycemia. Titrate slowly based on glycemic response.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for REPAGLINIDE (REPAGLINIDE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Caution advised; consider benefit vs risk. Monitor infant for hypoglycemia.
Teratogenic Risk	FDA Pregnancy Category C. No adequate studies in pregnant women. Animal studies show fetal toxicity at high doses. Risk cannot be ruled out; use only if benefit outweighs risk. First trimester: potential for teratogenicity based on animal data. Second and third trimesters: may cause neonatal hypoglycemia if used near term.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Type 1 diabetes mellitus or diabetic ketoacidosis","Severe hepatic impairment","Concomitant use of gemfibrozil","Hypersensitivity to repaglinide or any component of the formulation"]

Clinical Precautions

Precautions

["Hypoglycemia: More frequent in elderly, debilitated, or malnourished patients, those with renal or hepatic impairment, or with erratic food intake.","Cardiovascular risk: May be associated with increased risk of myocardial ischemia; caution in patients with ischemic heart disease.","Hepatic impairment: Use with caution; dose adjustment may be necessary.","Drug interactions: Coadministration with gemfibrozil is contraindicated due to increased hypoglycemia risk; caution with other CYP2C8 and CYP3A4 inhibitors/inducers."]

Clinical Tips & Counseling

Drug interactions

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REPAGLINIDE

Clinical safety rating: caution

Comprehensive clinical and safety monograph for REPAGLINIDE (REPAGLINIDE).

How it works

What the body does with it

Metabolism	Extensively metabolized by the liver via CYP2C8 and CYP3A4 isoenzymes. Metabolites are inactive and undergo biliary excretion. Approximately 90% of the dose is excreted in feces, with less than 8% in urine.
Excretion	Approximately 90% of the absorbed dose is excreted in the feces via bile (as metabolites and unchanged drug), and about 8% is excreted in the urine. Renal elimination of unchanged drug is negligible (<0.1%).
Half-life	Terminal elimination half-life is approximately 1 hour (range 0.5–1.5 hours). This short half-life supports its use for prandial glucose control, with minimal risk of prolonged hypoglycemia.
Protein binding	>98% bound primarily to albumin, with minor binding to α1-acid glycoprotein.
Volume of Distribution	Volume of distribution is approximately 0.15 L/kg, suggesting limited extravascular distribution (mainly confined to extracellular fluid).
Bioavailability	Oral bioavailability is about 63% (range 56–70%) due to first-pass hepatic metabolism. Absorption is rapid and complete.
Onset of Action	Oral: Onset occurs within 15–30 minutes after administration, corresponding to peak plasma concentrations at ~1 hour.
Duration of Action	Duration of action is about 4–6 hours when taken before meals, aligning with postprandial glucose excursions. Longer duration may occur with higher doses or in hepatic impairment.

Classification & Brands

Dosing & administration

0.5-4 mg orally within 30 minutes before each meal (2-4 times daily). Maximum single dose: 4 mg; maximum total daily dose: 16 mg.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥40 mL/min. For GFR 30-39 mL/min: initiate with 0.5 mg before meals and titrate cautiously. For GFR <30 mL/min: not recommended.
Liver impairment	Child-Pugh Class A: initiate with 0.5 mg before meals and titrate cautiously. Child-Pugh Class B: no data; use with caution. Child-Pugh Class C: contraindicated.
Pediatric use	Not approved for use in pediatric patients. Safety and efficacy not established.
Geriatric use	Initiate at 0.5 mg before meals due to increased risk of hypoglycemia. Titrate slowly based on glycemic response.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for REPAGLINIDE (REPAGLINIDE).

Breastfeeding	Unknown if excreted in human milk. M/P ratio not established. Caution advised; consider benefit vs risk. Monitor infant for hypoglycemia.
Teratogenic Risk	FDA Pregnancy Category C. No adequate studies in pregnant women. Animal studies show fetal toxicity at high doses. Risk cannot be ruled out; use only if benefit outweighs risk. First trimester: potential for teratogenicity based on animal data. Second and third trimesters: may cause neonatal hypoglycemia if used near term.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

None

Side Effect Profile

Serious Effects

Absolute Contraindications

["Type 1 diabetes mellitus or diabetic ketoacidosis","Severe hepatic impairment","Concomitant use of gemfibrozil","Hypersensitivity to repaglinide or any component of the formulation"]