REPAGLINIDE AND METFORMIN HYDROCHLORIDE
Clinical safety rating: safe
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
Repaglinide stimulates insulin secretion from pancreatic beta cells by closing ATP-sensitive potassium channels, leading to membrane depolarization and calcium influx. Metformin decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Repaglinide: Primarily metabolized by CYP2C8 and CYP3A4. Metformin: Not metabolized; excreted unchanged in urine. |
| Excretion | Repaglinide: 90% biliary (feces), 8% renal; Metformin: 90% renal (unchanged), 10% fecal. |
| Half-life | Repaglinide: 1 hour (terminal); Metformin: 6.2 hours (terminal, range 4-9 hours). |
| Protein binding | Repaglinide: >98% bound primarily to albumin; Metformin: negligible (<5%) bound to plasma proteins. |
| Volume of Distribution | Repaglinide: 31 L (approx 0.44 L/kg); Metformin: 654 ± 358 L (approx 9.3 L/kg). |
| Bioavailability | Repaglinide: 63% (oral); Metformin: 50-60% (oral). |
| Onset of Action | Oral: 15-30 minutes for both components. |
| Duration of Action | Repaglinide: 4-6 hours (prandial glucose regulator); Metformin: 12-24 hours (therapeutic effect). |
Oral: 1 mg repaglinide/500 mg metformin twice daily, taken within 30 minutes of meals; titrate gradually up to a maximum of 4 mg repaglinide/2000 mg metformin per day in divided doses.
| Dosage form | TABLET |
| Renal impairment | Contraindicated if eGFR <30 mL/min/1.73 m². For eGFR 30-45 mL/min/1.73 m², maximum metformin dose is 1000 mg/day; use lower repaglinide doses with caution. Initiation not recommended if eGFR <45 mL/min/1.73 m². |
| Liver impairment | Contraindicated in Child-Pugh Class B or C hepatic impairment. Use with caution in mild impairment (Child-Pugh A) with reduced doses of both components. |
| Pediatric use | Not established for use in pediatric patients under 18 years of age. |
| Geriatric use | Start at lowest dose (e.g., 0.5 mg repaglinide/250 mg metformin) due to increased risk of hypoglycemia and renal impairment; titrate slowly and monitor renal function regularly. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Alcohol and contrast dye can increase risk of lactic acidosis Can cause lactic acidosis a rare but serious metabolic complication.
| FDA category | Human |
| Breastfeeding | Repaglinide: excreted in rat milk, unknown in humans; avoid breastfeeding. Metformin: excreted in human milk; M/P ratio ~0.35; infant plasma levels <0.5% maternal weight-adjusted dose; considered compatible by most authorities. Use with caution, monitor infant for hypoglycemia. |
| Teratogenic Risk |
■ FDA Black Box Warning
Metformin: Lactic acidosis risk, particularly in patients with renal impairment, hypoxia, sepsis, or hepatic impairment. Repaglinide: No black box warning.
| Common Effects | Diarrhea |
| Serious Effects |
["Renal disease or renal dysfunction (e.g., serum creatinine ≥1.5 mg/dL in males, ≥1.4 mg/dL in females, or abnormal creatinine clearance)","Acute or chronic metabolic acidosis, including diabetic ketoacidosis","Hypersensitivity to repaglinide, metformin, or any component","Type 1 diabetes mellitus","Concomitant use with gemfibrozil"]
| Precautions | ["Lactic acidosis","Hypoglycemia","Cardiovascular mortality (controversial with sulfonylureas)","Hepatic impairment","Renal impairment","Vitamin B12 deficiency","Acute alcohol intoxication","Surgery or radiologic studies with iodinated contrast"] |
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| Pregnancy Category C. Repaglinide: limited human data; animal studies show no teratogenicity but fetal toxicity at high doses. Metformin: crosses placenta; some studies suggest increased risk of preeclampsia and perinatal mortality, but no major malformations; risk of neonatal hypoglycemia. First trimester: unknown risk; second/third trimester: possible fetal growth restriction, macrosomia from maternal diabetes; avoid unless benefit outweighs risk. |
| Fetal Monitoring | Maternal: blood glucose, HbA1c, renal function, hepatic function. Fetal: ultrasound for growth and anatomy, fetal echocardiography, nonstress test and biophysical profile in third trimester. Neonatal: monitor for hypoglycemia and hyperbilirubinemia. |
| Fertility Effects | Repaglinide: no known direct effect. Metformin: may improve ovulation in polycystic ovary syndrome; no adverse effects on spermatogenesis. Overall, no known negative impact on fertility. |