CANAGLIFLOZIN
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Sodium-glucose cotransporter 2 (SGLT2) inhibitor; reduces renal glucose reabsorption, increasing urinary glucose excretion.
| Metabolism | Primarily via O-glucuronidation by UGT1A9 and UGT2B4; minimal CYP450 involvement. |
| Excretion | Renal: 33% (primarily tubular secretion, ~1% unchanged in urine; remainder as glucuronide metabolites); Fecal: 52% (as parent drug and metabolites); Biliary: minor (enterohepatic circulation suspected but not quantified). |
| Half-life | Terminal elimination half-life: 10.6–13.1 hours (single dose); steady-state: ~12.9 hours. Clinically, supports once-daily dosing with sustained SGLT2 inhibition over 24 hours. |
| Protein binding | ~99% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution (Vd/F): 83.5 L (approximately 1.19 L/kg for a 70 kg individual). High Vd indicates extensive extravascular distribution. |
| Bioavailability | Oral bioavailability: ~65% (absolute bioavailability not determined but estimated from mass balance studies; high-fat meals reduce absorption but no dose adjustment needed). |
| Onset of Action | Oral: Urinary glucose excretion increases within 3 hours; maximal effect on glycemic control observed after 2–4 weeks of therapy. |
| Duration of Action | The pharmacodynamic effect (urinary glucose excretion) persists for ≥24 hours, allowing once-daily dosing. Steady-state achieved in 4–5 days. |
100 mg orally once daily; may increase to 300 mg once daily for additional glycemic control.
| Dosage form | TABLET |
| Renal impairment | eGFR >=45 mL/min/1.73 m2: no adjustment. eGFR 30-44: not recommended for glycemic control; limited data. eGFR <30: contraindicated. |
| Liver impairment | No adjustment required for mild to moderate hepatic impairment (Child-Pugh A or B). Not studied in severe (Child-Pugh C); use not recommended. |
| Pediatric use | Not approved for pediatric patients; safety and efficacy not established. |
| Geriatric use | No dose adjustment based on age alone. Monitor renal function (eGFR) more frequently; higher risk of volume depletion and hypotension in elderly patients. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Rifampin decreases canagliflozin levels May increase risk of hypotension with diuretics Can cause genital mycotic infections and volume depletion.
| Breastfeeding | Excreted into rat milk; unknown in humans. M/P ratio not established. Use during breastfeeding is not recommended due to potential risk of neonatal hypoglycemia and renal effects. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show renal toxicity and delayed ossification at exposures ≥4 times human dose. Second/Third trimester: Avoid due to risk of fetal renal tubular maturation interference and potential neonatal hyperbilirubinemia. |
■ FDA Black Box Warning
None.
| Common Effects | Genital mycotic infections |
| Serious Effects |
["History of serious hypersensitivity reaction to canagliflozin or any excipient","Severe renal impairment (eGFR <30 mL/min/1.73 m²) or dialysis","End-stage renal disease"]
| Precautions | ["Hypotension","Ketoacidosis (including euglycemic ketoacidosis)","Acute kidney injury and impairment in renal function","Urosepsis and pyelonephritis","Hypoglycemia with concomitant insulin or sulfonylurea use","Necrotizing fasciitis of the perineum (Fournier gangrene)","Genital mycotic infections","Increased LDL-C","Volume depletion"] |
| Food/Dietary | No specific food interactions. However, taking with food reduces nausea and improves tolerability. Avoid excessive alcohol intake as it may increase risk of ketoacidosis. No grapefruit interaction reported. |
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| Fetal Monitoring |
| Monitor maternal renal function (serum creatinine, eGFR), blood glucose, urine ketones, and blood pressure. Fetal ultrasound for renal development anomalies in second trimester. Neonatal monitoring for hypoglycemia and renal function. |
| Fertility Effects | No direct human fertility data; animal studies show no impairment of fertility (rats). Theoretical risk from metabolic changes and renal effects. |
| Clinical Pearls | Canagliflozin is a SGLT2 inhibitor used for type 2 diabetes, heart failure with reduced ejection fraction, and diabetic nephropathy. Monitor for euglycemic diabetic ketoacidosis (euDKA) even if blood glucose is normal. Assess volume status; risk of intravascular volume depletion, especially in elderly and those on diuretics or RAS inhibitors. Increase in LDL-C is modest; monitor lipids. Check renal function before initiation and periodically; avoid if eGFR < 30 mL/min/1.73 m². Cases of Fournier gangrene reported; counsel patients on genital hygiene and symptoms of perineal infection. |
| Patient Advice | Take once daily with the first meal of the day to reduce gastrointestinal side effects. · Drink plenty of fluids to prevent dehydration and urinary tract infections. · Report any signs of genital itching, redness, or discharge, or pain in the perineum. · Seek immediate medical attention for symptoms of ketoacidosis: nausea, vomiting, abdominal pain, tiredness, trouble breathing. · Do not use if you have type 1 diabetes or history of diabetic ketoacidosis. · Monitor blood sugar regularly; can cause hypoglycemia when combined with insulin or sulfonylureas. · Inform your doctor if you are pregnant, breastfeeding, or planning surgery. |