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.
Metformin primarily decreases hepatic glucose production by inhibiting mitochondrial complex I, reducing gluconeogenesis. It also improves insulin sensitivity, increases peripheral glucose uptake, and delays intestinal glucose absorption.
| Metabolism | Metformin is excreted unchanged in urine; minimal hepatic metabolism. Substrate of OCT2 and MATE transporters for renal excretion. |
| Excretion | Renal excretion of unchanged drug accounts for approximately 90% of elimination; fecal excretion accounts for the remainder (<10%). No biliary excretion. |
| Half-life | Terminal elimination half-life is approximately 6.2 hours (range 4-8.7 hours) in patients with normal renal function. Prolonged in renal impairment, up to 17.6 hours when GFR <60 mL/min. |
| Protein binding | Negligible (<5% bound to plasma proteins). |
| Volume of Distribution | Vd 654 ± 358 L (approximately 9.3 L/kg in adults), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability: 50-60% (immediate-release); extended-release: 50-60% with food slightly increasing absorption. Absolute bioavailability: 55%. |
| Onset of Action | Oral immediate-release: 2-3 hours for reduction in blood glucose; extended-release: 4-7 hours. |
| Duration of Action | Oral: 12-24 hours (immediate-release: 12-20 hours; extended-release: up to 24 hours). Duration is dose-dependent and influenced by renal function. |
| Molecular Weight | 165.62 |
Oral, immediate-release: 500 mg twice daily or 850 mg once daily; maximum 2550 mg/day in divided doses. Extended-release: 500-1000 mg once daily; maximum 2000 mg/day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR 30-45: reduce dose by 50%; eGFR <30: contraindicated. Hold if eGFR drops below 30 due to acute kidney injury. Check eGFR before initiation and at least annually. |
| Liver impairment | Avoid use in severe hepatic impairment (Child-Pugh class C). Use with caution in moderate impairment (Child-Pugh class B) due to increased risk of lactic acidosis. |
| Pediatric use | Approved for age ≥10 years. Immediate-release: start 500 mg once daily, increase weekly by 500 mg/day to a max of 2000 mg/day in divided doses. Maximum 2000 mg/day. |
| Geriatric use | Start at lowest dose (500 mg once daily) with gradual titration. Monitor renal function closely; eGFR may decline with age. Do not initiate if eGFR <45. |
| 1st trimester | Metformin crosses the placenta. Studies do not show increased risk of major malformations. Use if clearly needed. |
| 2nd trimester | Metformin is not associated with fetal toxicity. Use if benefits outweigh risks for conditions like GDM or PCOS. |
| 3rd trimester | Metformin may be continued if clinically indicated. No increased risk of neonatal hypoglycemia or adverse outcomes. |
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 |
| Placental transfer | Metformin crosses the placenta. Umbilical cord plasma concentrations are approximately 50-100% of maternal concentrations. |
| Breastfeeding |
■ FDA Black Box Warning
Lactic acidosis: Metformin can cause rare but serious lactic acidosis, especially in patients with renal impairment, acute heart failure, sepsis, or liver disease. Discontinue metformin in patients with conditions associated with hypoxemia or severe dehydration.
| Common Effects | Diarrhea |
| Serious Effects |
Hypersensitivity to metformin or any componentAcute or chronic metabolic acidosis (including diabetic ketoacidosis)Severe renal impairment (eGFR <30 mL/min/1.73 m²)Acute conditions that may alter renal function (e.g., dehydration, severe infection, shock)Radiologic contrast use (temporarily discontinue)
| Precautions | Lactic acidosis risk: avoid in renal impairment (eGFR <30 mL/min/1.73 m²), acute conditions altering renal function, or hypoxia., Vitamin B12 deficiency: long-term use may decrease absorption; monitor annually., Iodinated contrast: temporarily discontinue before procedures with intravascular contrast., Surgery: withhold for 48 hours post-surgery until renal function stable., Increased risk in elderly, debilitated, or those with hepatic impairment. |
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| Metformin is excreted into breast milk in small amounts. Infant exposure is estimated to be <1% of maternal weight-adjusted dose. No adverse effects reported. Compatible with breastfeeding. |
| Lactation Rating | L2 (Safer) |
| Teratogenic Risk | First trimester: Large studies (e.g., the Metformin in Gestational Diabetes trial) have not shown an increased risk of major congenital anomalies. Second and third trimesters: Metformin is commonly used for gestational diabetes and type 2 diabetes; fetal exposure during this period is not associated with increased malformation risk. However, long-term effects (e.g., metabolic) are not fully excluded. |
| Fetal Monitoring | Maternal: Blood glucose levels, HbA1c, renal function, liver function, vitamin B12 levels (long-term). Fetal: Fetal growth ultrasonography (due to risk of macrosomia if glycemic control inadequate). In pregnancy, monitor for hypoglycemia. |
| Fertility Effects | In women with polycystic ovary syndrome (PCOS), metformin can restore ovulation and improve fertility by reducing insulin resistance and hyperinsulinemia. No adverse effects on male fertility; may improve semen quality in men with insulin resistance. |
| Food/Dietary | Avoid excessive alcohol intake (≥3 drinks/day) due to increased risk of lactic acidosis. No specific food restrictions; take with food to reduce gastrointestinal side effects. |
| Clinical Pearls | Monitor renal function before initiation and annually; contraindicated if eGFR <30 mL/min/1.73 m². Hold for 48 hours after contrast dye or before surgery. Avoid in patients with hepatic impairment or alcohol abuse due to lactic acidosis risk. Titrate dose slowly to minimize GI side effects; consider extended-release if intolerant. Check vitamin B12 levels annually, especially with long-term use. |
| Patient Advice | Take with meals to reduce stomach upset. · Do not drink excessive alcohol while taking this medication. · Report any symptoms of lactic acidosis: unusual muscle pain, trouble breathing, severe drowsiness, or slow/irregular heartbeat. · If you miss a dose, skip it and take the next dose at the usual time; do not double dose. · Monitor your blood sugar regularly as directed. |