CANAGLIFLOZIN; 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.
Canagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption, increasing urinary glucose excretion. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
| Metabolism | Canagliflozin is primarily metabolized via O-glucuronidation by UGT1A9 and UGT2B4; minor metabolism via CYP3A4. Metformin is excreted unchanged in urine, not metabolized. |
| Excretion | Canagliflozin: primarily eliminated via hepatic metabolism (glucuronidation), with 33% of dose excreted in feces (as unchanged drug) and <1% in urine unchanged. Metformin: excreted unchanged in urine (90%) via tubular secretion; renal clearance ~510 mL/min. |
| Half-life | Canagliflozin: terminal half-life 10.6 hours (range 9-13 hours) following single dose; steady-state reached by 4-5 days. Metformin: terminal half-life ~6.2 hours (range 4-9 hours); prolonged in renal impairment. |
| Protein binding | Canagliflozin: 99% bound to albumin. Metformin: negligible binding to plasma proteins (<5%). |
| Volume of Distribution | Canagliflozin: apparent Vd 83 L (approximately 1.19 L/kg for 70 kg person), indicating extensive tissue distribution. Metformin: Vd 654 ± 358 L (approximately 9.3 L/kg), consistent with extensive tissue uptake; concentrates in red blood cells and intestine. |
| Bioavailability | Canagliflozin: absolute oral bioavailability 65% (dose-dependent; 65% for 100 mg and 300 mg). Metformin: oral bioavailability 40-60% (decreased by food; immediate release 50-60%, extended release ~40%). |
| Onset of Action | Canagliflozin: onset of urinary glucose excretion within 1-2 hours post-dose; maximal effect on HbA1c seen after 6-8 weeks. Metformin: onset of glycemic effect within 1-3 days; full effect on fasting glucose by 1-2 weeks. |
| Duration of Action | Canagliflozin: duration of SGLT2 inhibition persists for 24 hours, allowing once-daily dosing. Metformin: duration of glucose-lowering effect approximately 24 hours; extended-release formulation provides sustained exposure. |
Initial: canagliflozin 50 mg/metformin hydrochloride 500 mg orally twice daily. Titrate to canagliflozin 150 mg/metformin hydrochloride 1000 mg orally twice daily based on glycemic response and tolerability. Maximum dose: canagliflozin 150 mg twice daily (300 mg/day) and metformin 1000 mg twice daily (2000 mg/day).
| Dosage form | TABLET |
| Renal impairment | eGFR ≥60 mL/min/1.73 m²: no adjustment. eGFR 45–59 mL/min/1.73 m²: limit to canagliflozin 50 mg twice daily (maximum metformin 1000 mg twice daily). eGFR <45 mL/min/1.73 m²: contraindicated. |
| Liver impairment | Child-Pugh class A: use with caution, reduce metformin dose. Child-Pugh class B or C: contraindicated due to metformin component. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | In elderly patients (≥65 years), assess renal function before initiation; eGFR should be ≥45 mL/min/1.73 m². Use lower initial doses and monitor renal function. Caution due to increased risk of volume depletion and renal impairment. |
| 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 | Canagliflozin: M/P ratio not available; present in rat milk, unknown in humans. Metformin: M/P ratio 0.35; excreted into human milk in low amounts. Due to potential for neonatal hypoglycemia and renal effects, breastfeeding not recommended during therapy. |
| Teratogenic Risk | First trimester: Canagliflozin is FDA Pregnancy Category C; metformin is Category B. Canagliflozin associated with increased fetal kidney calcification and possible nephrotoxicity based on animal data; metformin not teratogenic in humans. Second and third trimesters: Canagliflozin may impair fetal renal development; metformin may increase risk of adverse pregnancy outcomes. Avoid in second and third trimesters. |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis (MALA) is a rare but serious adverse effect. Risk factors include renal impairment, hepatic disease, acute congestive heart failure, excessive alcohol intake, and use of iodinated contrast agents.
| Common Effects | Diarrhea |
| Serious Effects |
["Severe renal impairment (eGFR <30 mL/min/1.73 m2)","End-stage renal disease or dialysis","Metabolic acidosis (including diabetic ketoacidosis)","History of lactic acidosis","Acute or chronic metabolic acidosis","Hypersensitivity to canagliflozin or metformin"]
| Precautions | ["Lactic acidosis","Ketoacidosis (including euglycemic ketoacidosis)","Pancreatitis","Hypoglycemia when used with insulin or insulin secretagogues","Renal impairment: assess renal function before initiation and periodically thereafter","Volume depletion, hypotension, and electrolyte imbalances","Urosepsis and pyelonephritis","Lower limb amputations (primarily toe)","Necrotizing fasciitis of the perineum (Fournier gangrene)","Increased LDL-C","Vitamin B12 deficiency with long-term metformin use","Acute kidney injury","Hepatic impairment"] |
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| Fetal Monitoring | Maternal: Renal function (serum creatinine, eGFR) before and during therapy; blood glucose and HbA1c; monitor for hypoglycemia, urinary tract infections, genital mycotic infections, and ketoacidosis. Fetal/neonatal: Consider fetal ultrasound for renal development if exposed in second/third trimester; neonatal monitoring for hypoglycemia if metformin used near term. |
| Fertility Effects | Canagliflozin: No human data on fertility effects; animal studies show no impairment. Metformin: May improve ovulation in women with polycystic ovary syndrome (PCOS); no adverse effect on male or female fertility reported. |
| Food/Dietary | Avoid excessive alcohol intake (≥3 drinks/day) due to increased risk of lactic acidosis. Limit high-fat meals as they may reduce metformin absorption. Canagliflozin effect may be delayed by high-fat food; take with same meal consistently. Grapefruit juice may increase metformin exposure; avoid large quantities. Maintain adequate fluid intake to prevent dehydration. No specific food restrictions for canagliflozin beyond standard diabetes diet. |
| Clinical Pearls | Canagliflozin/metformin combination should be temporarily discontinued prior to surgical procedures requiring restricted oral intake or during acute illness due to risk of ketoacidosis and lactic acidosis, respectively. Monitor renal function before initiation and periodically; eGFR must be >45 mL/min/1.73m² for canagliflozin and >30 mL/min for metformin. Canagliflozin increases risk of lower limb amputations, especially toe and midfoot; educate patients on foot care. Avoid in patients with a history of pancreatitis or severe hepatic impairment. Combination may cause volume depletion; assess volume status in elderly or those on diuretics. Metformin can cause vitamin B12 deficiency; monitor levels annually. Canagliflozin may transiently increase serum creatinine and decrease eGFR; not for use in type 1 diabetes. |
| Patient Advice | Take this medication with meals to reduce stomach upset and improve metformin absorption. · Do not drink alcohol excessively; it increases risk of lactic acidosis. · Report symptoms of ketoacidosis (nausea, vomiting, abdominal pain, tiredness, trouble breathing) even if blood sugar is normal. · Monitor for signs of genital fungal infections (itching, discharge) or urinary tract infections (burning, frequency); seek treatment promptly. · Inspect feet daily for cuts, blisters, or sores; notify healthcare provider of any non-healing wounds. · Avoid skipping meals; maintain adequate hydration to prevent dehydration and kidney problems. · Inform all healthcare providers you are taking this medication before surgery or imaging procedures using contrast dye. · Store at room temperature away from moisture and heat. |