GLUCOPHAGE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GLUCOPHAGE (GLUCOPHAGE).
Metformin primarily decreases hepatic glucose production (gluconeogenesis) and increases peripheral insulin sensitivity, reducing glucose absorption from the gastrointestinal tract. It activates AMP-activated protein kinase (AMPK), leading to inhibition of gluconeogenic enzymes.
| Metabolism | Not metabolized by the liver; no cytochrome P450 involvement; excreted unchanged in urine via tubular secretion. |
| Excretion | Renal elimination of unchanged drug: 90%; fecal: 10% (biliary negligible). |
| Half-life | Terminal elimination half-life: 6.2 hours (range 4.0-8.7 h); prolonged in renal impairment (up to 17.6 h at CrCl <60 mL/min). |
| Protein binding | Negligible (<5% bound to plasma proteins; primarily albumin). |
| Volume of Distribution | Vd: 654 L (9.3 L/kg for a 70 kg adult); indicates extensive tissue distribution (not highly protein-bound). |
| Bioavailability | Oral immediate-release: 50-60% (fed state slightly reduces absorption); extended-release: approximately 50% (under fed conditions). |
| Onset of Action | Oral immediate-release: 2-3 hours for reduction in plasma glucose; extended-release: 4-8 hours. |
| Duration of Action | Immediate-release: 8-12 hours (requires multiple daily dosing); extended-release: 24 hours (once-daily dosing). |
500 mg orally once daily, titrate by 500 mg weekly; max 2000 mg/day divided twice daily; extended-release: 500 mg orally once daily, titrate by 500 mg weekly; max 2000 mg/day once daily.
| Dosage form | TABLET |
| Renal impairment | GFR >= 60: no adjustment; GFR 45-59: reduce dose to 500 mg twice daily; GFR 30-44: reduce dose to 250 mg twice daily or 500 mg once daily; GFR < 30: contraindicated. |
| Liver impairment | Avoid use in severe hepatic impairment (Child-Pugh C); use with caution in Child-Pugh B; no data for mild impairment. |
| Pediatric use | Age 10-16 years: start 500 mg once daily, titrate weekly; max 2000 mg/day divided twice daily; extended-release not recommended in pediatric. |
| Geriatric use | Start at 250 mg once daily; do not titrate to maximum dose; monitor renal function frequently; avoid if GFR < 45. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GLUCOPHAGE (GLUCOPHAGE).
| Breastfeeding | Metformin is excreted into human milk in low amounts. M/P ratio approximately 0.35. Limited data suggest no adverse effects in breastfed infants. Consider monitoring infant for hypoglycemia, especially if mother requires high doses. |
| Teratogenic Risk | First trimester: Limited human data show no increased risk of major malformations. Animal studies at high doses showed no teratogenicity. Second trimester: No specific fetal risks reported. Third trimester: May increase risk of neonatal hypoglycemia if used near term due to placental transfer and potential fetal hyperinsulinism. |
■ FDA Black Box Warning
Lactic acidosis: Rare but serious; risk increases with renal impairment, acute or unstable heart failure, hypoxic states, excessive alcohol intake, use of iodinated contrast agents, advanced age, hepatic impairment, dehydration, surgery, and concurrent use of drugs that impair renal function.
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²); acute or chronic metabolic acidosis, including diabetic ketoacidosis; history of lactic acidosis; hypersensitivity to metformin; severe hepatic dysfunction; acute or unstable heart failure; recent myocardial infarction; sepsis; dehydration; excessive alcohol intake; use of iodinated contrast agents (temporary discontinuation).
| Precautions | Lactic acidosis risk; monitoring of renal function before and during therapy (contraindicated if eGFR <30 mL/min/1.73 m²); temporarily discontinue for iodinated contrast procedures, surgery, or acute illness; avoid in patients with acute or chronic metabolic acidosis; monitor for vitamin B12 deficiency; caution in elderly or those with impaired renal function. |
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| Fetal Monitoring | Monitor maternal renal function, serum glucose, and hemoglobin A1c. Assess for lactic acidosis symptoms. Fetal monitoring: standard prenatal care including ultrasound for growth and anatomy; consider fetal echocardiography if on high doses. |
| Fertility Effects | In women with PCOS, metformin may improve ovulation and fertility. No known adverse effects on male or female fertility beyond those related to underlying condition. |