GLUCOPHAGE XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GLUCOPHAGE XR (GLUCOPHAGE XR).
Biguanide; decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Not metabolized by the liver; excreted unchanged in urine via tubular secretion. |
| Excretion | Renal: 90% unchanged; fecal: minimal (<5%) |
| Half-life | Terminal elimination half-life: 17.6 hours (range 9.1–40.6 hours); clinical context: reflects slow absorption from extended-release matrix; accumulation occurs with renal impairment |
| Protein binding | Negligible (<5%); does not bind significantly to plasma proteins |
| Volume of Distribution | 654 L (absolute), 5.7 L/kg (based on 70 kg); clinical meaning: extensive tissue distribution, primarily sequestered in erythrocytes and GI tract |
| Bioavailability | Oral extended-release: approximately 55% (fasted), increased to ~70% with food; absolute bioavailability of immediate-release is 50–60% |
| Onset of Action | Oral extended-release: reduction in fasting plasma glucose within 1–3 days; maximal effect by 2–4 weeks |
| Duration of Action | Approximately 24 hours with once-daily dosing; clinical note: trough concentrations maintain glucose-lowering effect over dosing interval |
Metformin XR: initial 500 mg orally once daily with evening meal, increase by 500 mg weekly; max 2000 mg per day (as XR, given once or divided twice daily).
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR 30-45 mL/min: do not initiate; if already on, reduce to 500 mg XR once daily and monitor renal function. eGFR <30 mL/min: contraindicated. |
| Liver impairment | Contraindicated in patients with hepatic impairment, including those with Child-Pugh class B or C cirrhosis. |
| Pediatric use | Not approved for use in pediatric patients <18 years for XR formulation; immediate-release metformin is approved for type 2 diabetes in children ≥10 years. |
| Geriatric use | Start at low dose (500 mg XR once daily); avoid max doses; monitor renal function closely; not recommended if eGFR <45 mL/min. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GLUCOPHAGE XR (GLUCOPHAGE XR).
| Breastfeeding | Metformin is excreted into breast milk in low amounts. M/P ratio is approximately 0.35-0.4. Relative infant dose is <1% of maternal weight-adjusted dose, considered safe. Monitor infant for signs of hypoglycemia or gastrointestinal effects, though risk is low. |
| Teratogenic Risk | Metformin (GLUCOPHAGE XR) is FDA Pregnancy Category B. First trimester: No increased risk of major malformations reported in human studies, but data are limited. Second/third trimester: No evidence of fetal toxicity; however, placental transfer occurs. Theoretical risk of fetal acidosis or hypoglycemia, but not confirmed. Some studies suggest potential reduction in gestational diabetes complications. |
■ FDA Black Box Warning
Lactic acidosis: rare but serious metabolic complication; risk increases with conditions such as renal impairment, sepsis, dehydration, and acute heart failure.
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73 m^2)","Acute or chronic metabolic acidosis","History of lactic acidosis","Hypersensitivity to metformin"]
| Precautions | ["Lactic acidosis risk","Renal impairment (eGFR <30 mL/min/1.73 m^2 contraindicated)","Acute kidney injury","Sepsis","Dehydration","Hepatic impairment","Acute alcohol intoxication","Concomitant use of iodinated contrast media (temporary discontinuation)","Vitamin B12 deficiency"] |
| Food/Dietary | Take with food to minimize gastrointestinal adverse effects; avoid excessive alcohol intake (may increase risk of lactic acidosis). No specific food restrictions, but consistent carbohydrate intake is advised for glycemic control. |
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| Fetal Monitoring | Monitor maternal blood glucose, renal function (serum creatinine, eGFR), and lactic acidosis symptoms. In pregnancy, monitor fetal growth and well-being via ultrasound, and if used for gestational diabetes, perform glucose tolerance testing postpartum. |
| Fertility Effects | Metformin may improve ovulation and fertility in women with polycystic ovary syndrome (PCOS) by reducing insulin resistance and hyperandrogenism. No adverse effects on male fertility reported; limited data. |
| Clinical Pearls | XR formulation reduces GI side effects; titrate slowly from 500 mg daily with evening meal. Assess renal function before starting and annually; contraindicated if eGFR <30. Hold for iodinated contrast studies and resume after 48 hours if renal function stable. Not associated with hypoglycemia unless combined with insulin or sulfonylureas. Monitor for lactic acidosis if patient develops hypoxic conditions. |
| Patient Advice | Take once daily with the evening meal to reduce stomach upset. · Swallow tablets whole; do not crush, chew, or cut. · Do not use if you have severe kidney disease or are going to receive contrast dye. · Report symptoms of lactic acidosis: unusual tiredness, muscle pain, stomach discomfort, trouble breathing, slow or irregular heartbeat. · Avoid heavy alcohol consumption while on this medication. |