INVOKAMET XR
Clinical safety rating: caution
Comprehensive clinical and safety monograph for INVOKAMET XR (INVOKAMET XR).
Combination of canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, which reduces renal glucose reabsorption and lowers blood glucose, and metformin, an activator of AMP-activated protein kinase (AMPK) that decreases hepatic glucose production and improves insulin sensitivity.
| Metabolism | Canagliflozin: Primarily via O-glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites; minimal CYP450 involvement. Metformin: Not metabolized; excreted unchanged in urine. |
| Excretion | Canagliflozin is primarily excreted as unchanged drug in urine (approximately 33%) and feces (approximately 41%), with about 7% as metabolites in urine and 34% as metabolites in feces. Metformin is excreted unchanged in urine (90-100% of absorbed dose) via tubular secretion and glomerular filtration. |
| Half-life | Canagliflozin: mean terminal elimination half-life is 13.1 hours (range 11-16 hours) for the 300 mg dose, consistent with once-daily dosing. Metformin: terminal elimination half-life is approximately 6.2 hours (range 4-9 hours) in patients with normal renal function; prolonged in renal impairment. |
| Protein binding | Canagliflozin: 99% bound to plasma proteins, primarily albumin. Metformin: negligible protein binding (<5% bound) and distributes into erythrocytes. |
| Volume of Distribution | Canagliflozin: mean Vd/F is approximately 119 L after single dose (1.7 L/kg for 70 kg patient), indicating extensive tissue distribution. Metformin: apparent Vd is 654 L (9.3 L/kg), suggesting extensive distribution to tissues. |
| Bioavailability | Canagliflozin: absolute bioavailability is approximately 65% (dose-independent), with food reducing peak concentration but not extent of absorption. Metformin extended-release: bioavailability is 55-70% (less than immediate-release), with food increasing extent of absorption (high-fat meal increases Cmax by 36% and AUC by 56%). |
| Onset of Action | Canagliflozin: peak plasma concentration achieved in 1-2 hours; clinical effect on urinary glucose excretion begins within 3 hours. Metformin: peak plasma concentration in 2-4 hours; reduction in fasting plasma glucose occurs within a few days. |
| Duration of Action | Canagliflozin: once-daily dosing maintains SGLT2 inhibition over 24 hours, with glucose-lowering effect sustained. Metformin: duration of action is 12-24 hours, with extended-release formulation providing gradual decline in glucose levels. |
| Molecular Weight | 444.52 |
Maximum daily dose: canagliflozin 300 mg/metformin ER 2000 mg orally once daily with the morning meal. Initial dose: canagliflozin 50 mg/metformin ER 500 mg orally twice daily or canagliflozin 150 mg/metformin ER 1000 mg orally once daily; for patients not currently on metformin, start with canagliflozin 50 mg/metformin ER 500 mg orally twice daily; for patients on metformin, switch to INVOKAMET XR based on current metformin dose.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | eGFR 45-59 mL/min/1.73 m2: limit to canagliflozin 100 mg daily; eGFR 30-44 mL/min/1.73 m2: contraindicated; eGFR <30 mL/min/1.73 m2: contraindicated. |
| Liver impairment | No specific dose adjustment guidelines; avoid in patients with severe hepatic impairment (Child-Pugh class C) due to metformin component. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no weight-based guidelines available. |
| Geriatric use | Start with the lowest dose due to increased risk of renal impairment, volume depletion, and hypotension; monitor renal function especially in patients aged ≥75 years. |
| 1st trimester | Avoid; associated with increased risk of hypoglycemia and not recommended due to lack of safety data; animal studies show fetal harm. |
| 2nd trimester | Avoid; may cause fetal harm; alternative treatments preferred. |
| 3rd trimester | Avoid; may cause fetal harm; not recommended during pregnancy. |
Clinical note
Comprehensive clinical and safety monograph for INVOKAMET XR (INVOKAMET XR).
| Placental transfer | Canagliflozin crosses the placenta; human data limited but animal studies show transfer and fetal effects. |
| Breastfeeding | Not recommended during breastfeeding due to potential for hypoglycemia in the infant and lack of human data; consider alternative treatments. |
| Lactation Rating |
■ FDA Black Box Warning
Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication. Risk factors include renal impairment, age ≥65 years, radiological studies with contrast, surgery, hypoxic states, excessive alcohol intake, hepatic impairment, and acute decompensated heart failure. Discontinue if lactic acidosis is suspected.
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²)End-stage renal disease or dialysisHistory of serious hypersensitivity reaction to canagliflozinDiabetic ketoacidosisType 1 diabetes mellitus
| Precautions | Lactic acidosis risk (see black box warning), Hypotension and volume depletion, Ketoacidosis (including atypical cases with normal blood glucose), Acute kidney injury and renal impairment, Urosepsis and pyelonephritis, Hypoglycemia when used with insulin or sulfonylureas, Necrotizing fasciitis of the perineum (Fournier gangrene), Lower limb amputation risk (associated with canagliflozin), Vitamin B12 deficiency (chronic metformin use) |
| Food/Dietary | Avoid excessive alcohol consumption due to increased risk of lactic acidosis. Take with food to reduce gastrointestinal intolerance but avoid high-fat meals as they may delay absorption. No specific food interactions beyond standard metformin and canagliflozin precautions. |
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| L5 |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: limited human data; animal studies show renal pelvis dilation and delayed ossification at exposures 5-20 times human exposure. Second and third trimesters: increased risk of acute kidney injury and hypoglycemia in neonates; avoid use particularly in second and third trimesters. |
| Fetal Monitoring | Monitor renal function (serum creatinine, eGFR) prior to and during therapy; assess for volume depletion and hypotension; monitor blood glucose and ketones; fetal ultrasound if used inadvertently during second/third trimester due to risk of renal anomalies. |
| Fertility Effects | No significant effects on fertility observed in animal studies at exposures up to 100 times human exposure. In male rats, decreased epididymal sperm count at high doses; clinical significance unknown. |
| Clinical Pearls | INVOKAMET XR is a fixed-dose combination of canagliflozin (SGLT2 inhibitor) and metformin extended-release. Use caution in renal impairment: contraindicated if eGFR <30 mL/min/1.73m²; do not initiate if eGFR <45. Monitor for lactic acidosis, especially with metformin component. Assess volume status before starting; risk of hypotension in elderly or on diuretics. Canagliflozin increases risk of lower-limb amputations, especially in patients with prior amputation, peripheral vascular disease, or neuropathy. Monitor for Fournier gangrene (necrotizing fasciitis of perineum); advise immediate medical attention for genital pain/tenderness. May cause hyperkalemia; monitor potassium in patients with renal impairment or on medications affecting potassium. Avoid in severe hepatic impairment. |
| Patient Advice | Take once daily with the largest meal to reduce gastrointestinal side effects; swallow tablets whole, do not crush or chew. · Stay well-hydrated to prevent dehydration; drink plenty of fluids during illness, hot weather, or exercise. · Report symptoms of lactic acidosis (unusual tiredness, muscle pain, stomach discomfort, trouble breathing, slow heartbeat) or ketoacidosis (nausea, vomiting, abdominal pain, tiredness, trouble breathing) immediately. · Seek medical attention for any signs of genital infection (redness, swelling, itching, discharge, fever) or pain/tenderness in the groin or perineum, especially if accompanied by fever or malaise. · Monitor blood glucose regularly. Avoid alcohol excessively as it may increase risk of lactic acidosis. · If you have a history of amputation, peripheral vascular disease, or neuropathy, discuss risks of lower-limb amputation with your doctor. · Do not use if you have severe kidney disease, are on dialysis, or have metabolic acidosis. · If you are undergoing surgery or prolonged fasting, your doctor may temporarily stop this medication. |