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). |
| Molecular Weight | 129.16 |
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 | Metformin is generally avoided during the first trimester due to potential risks of malformations; however, studies show no significant increase in major birth defects. Use only if clearly needed for glycemic control. |
| 2nd trimester | Considered relatively safe; may be used for gestational diabetes or pre-existing diabetes. Assess benefit-risk. |
| 3rd trimester | Considered relatively safe; may be used for gestational diabetes or pre-existing diabetes. Monitor for neonatal hypoglycemia. |
Clinical note
Comprehensive clinical and safety monograph for GLUCOPHAGE (GLUCOPHAGE).
| Placental transfer | Metformin crosses the placenta readily, achieving fetal concentrations similar to maternal levels. |
| Breastfeeding | Metformin transfers into breast milk in low amounts. No adverse effects have been reported in breastfed infants. Usually considered compatible with breastfeeding, but monitor infant for gastrointestinal effects. |
■ 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/1.73m²)Acute or chronic metabolic acidosis (including diabetic ketoacidosis)Hypersensitivity to metformin or any component
| 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. |
| Food/Dietary | Excessive alcohol intake may increase risk of lactic acidosis. Avoid high-fat meals as they can delay absorption; take with food to minimize gastrointestinal upset. |
Loading safety data…
| Lactation Rating | L2 (Safer) |
| 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. |
| 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. |
| Clinical Pearls | Assess renal function before initiation and annually; hold for iodinated contrast studies to prevent lactic acidosis; monitor vitamin B12 levels with long-term use; use with caution in patients with CHF (avoid in NYHA Class III/IV). |
| Patient Advice | Take with meals to reduce GI side effects. · Report symptoms of lactic acidosis: unexplained muscle pain, weakness, trouble breathing, unusual drowsiness, slow/irregular heartbeat. · Do not drink excessive alcohol while taking metformin. · Monitor blood glucose as directed and keep all follow-up appointments. |