INVOKAMET

Clinical safety rating: caution

Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).

How it works

INVOKAMET is a combination of canagliflozin, an SGLT2 inhibitor, and metformin, a biguanide. Canagliflozin inhibits sodium-glucose cotransporter 2 in the renal proximal tubules, reducing glucose reabsorption and increasing urinary glucose excretion. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity.

What the body does with it

Metabolism	Canagliflozin: UGT1A9 and UGT2B4 glucuronidation (major), CYP3A4 (minor). Metformin: not metabolized; excreted unchanged in urine.
Excretion	Canagliflozin (SGLT2 inhibitor): ~33% renal (1% unchanged, ~33% as glucuronide metabolites), ~52% fecal. Metformin (biguanide): 90% renal unchanged via tubular secretion.
Half-life	Canagliflozin: 10–13 hours (multiple dosing); Metformin: 6.2 hours (plasma). Accumulation occurs in renal impairment.
Protein binding	Canagliflozin: 99% bound (primarily albumin). Metformin: negligible (<5% bound to plasma proteins).
Volume of Distribution	Canagliflozin: Vd/F 88 L (not weight-normalized; extensive tissue distribution). Metformin: 1–3 L/kg (high tissue uptake, mainly in erythrocytes and GI tract).
Bioavailability	Canagliflozin: ~65% oral (high-fat meal reduces absorption by ~40% but clinically insignificant). Metformin: 50–60% oral (under fasting; reduced by food).
Onset of Action	Glycemic effects begin within 1–2 hours (both components); peak glucose lowering at 4–6 hours.
Duration of Action	Duration of glucose lowering approximately 24 hours (canagliflozin). Metformin duration ~16–20 hours (immediate-release). Sustained with regular dosing.

Classification & Brands

Dosing & administration

Oral: Starting dose: 5 mg canagliflozin/500 mg metformin hydrochloride extended-release twice daily; titrate based on efficacy and tolerability, maximum 150 mg/1000 mg twice daily.

Dosage form	TABLET
Renal impairment	eGFR ≥60 mL/min/1.73 m²: No dose adjustment. eGFR 45-59: Maximum 50 mg/500 mg twice daily. eGFR <45: Contraindicated.
Liver impairment	Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Use not recommended. Child-Pugh Class C: Contraindicated.
Pediatric use	Safety and efficacy not established in pediatric patients.
Geriatric use	Use caution in patients aged ≥75 years due to increased risk of volume depletion and renal impairment. Consider lower starting doses and monitor renal function. Avoid initiation if eGFR <60 mL/min/1.73 m².

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).

Breastfeeding	No human data on canagliflozin/metformin in breast milk. Canagliflozin is excreted in rat milk; metformin is excreted in human milk in low amounts (M/P ratio ~0.35). Due to potential for neonatal adverse effects (hypoglycemia, renal effects), breastfeeding is not recommended during therapy.
Teratogenic Risk	INVOKAMET (canagliflozin/metformin) carries a risk of fetal harm. First trimester: limited human data, but animal studies suggest potential for renal malformations; risk cannot be excluded. Second/third trimester: exposure associated with increased fetal/neonatal adverse outcomes including hypoglycemia, hypocalcemia, and metabolic acidosis; avoid use.

Warnings & precautions

■ FDA Black Box Warning

Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication; acute renal failure and other risk factors increase the risk. Discontinue if suspected.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Severe renal impairment (eGFR <30 mL/min/1.73 m²)","End-stage renal disease or dialysis","Acute or chronic metabolic acidosis (including diabetic ketoacidosis)","History of serious hypersensitivity reaction to canagliflozin or metformin","Concomitant use of alcohol-containing products (for metformin component)"]

Clinical Precautions

Precautions

["Lactic acidosis","Hypotension","Ketoacidosis","Acute kidney injury","Urosepsis and pyelonephritis","Hypoglycemia with concomitant use of insulin or sulfonylureas","Necrotizing fasciitis of the perineum (Fournier gangrene)","Genital mycotic infections","Volume depletion","Increased LDL-C"]

Clinical Tips & Counseling

Drug interactions

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INVOKAMET

Clinical safety rating: caution

Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).

How it works

What the body does with it

Metabolism	Canagliflozin: UGT1A9 and UGT2B4 glucuronidation (major), CYP3A4 (minor). Metformin: not metabolized; excreted unchanged in urine.
Excretion	Canagliflozin (SGLT2 inhibitor): ~33% renal (1% unchanged, ~33% as glucuronide metabolites), ~52% fecal. Metformin (biguanide): 90% renal unchanged via tubular secretion.
Half-life	Canagliflozin: 10–13 hours (multiple dosing); Metformin: 6.2 hours (plasma). Accumulation occurs in renal impairment.
Protein binding	Canagliflozin: 99% bound (primarily albumin). Metformin: negligible (<5% bound to plasma proteins).
Volume of Distribution	Canagliflozin: Vd/F 88 L (not weight-normalized; extensive tissue distribution). Metformin: 1–3 L/kg (high tissue uptake, mainly in erythrocytes and GI tract).
Bioavailability	Canagliflozin: ~65% oral (high-fat meal reduces absorption by ~40% but clinically insignificant). Metformin: 50–60% oral (under fasting; reduced by food).
Onset of Action	Glycemic effects begin within 1–2 hours (both components); peak glucose lowering at 4–6 hours.
Duration of Action	Duration of glucose lowering approximately 24 hours (canagliflozin). Metformin duration ~16–20 hours (immediate-release). Sustained with regular dosing.

Classification & Brands

Dosing & administration

Oral: Starting dose: 5 mg canagliflozin/500 mg metformin hydrochloride extended-release twice daily; titrate based on efficacy and tolerability, maximum 150 mg/1000 mg twice daily.

Dosage form	TABLET
Renal impairment	eGFR ≥60 mL/min/1.73 m²: No dose adjustment. eGFR 45-59: Maximum 50 mg/500 mg twice daily. eGFR <45: Contraindicated.
Liver impairment	Child-Pugh Class A: No dose adjustment. Child-Pugh Class B: Use not recommended. Child-Pugh Class C: Contraindicated.
Pediatric use	Safety and efficacy not established in pediatric patients.
Geriatric use	Use caution in patients aged ≥75 years due to increased risk of volume depletion and renal impairment. Consider lower starting doses and monitor renal function. Avoid initiation if eGFR <60 mL/min/1.73 m².

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).

Breastfeeding	No human data on canagliflozin/metformin in breast milk. Canagliflozin is excreted in rat milk; metformin is excreted in human milk in low amounts (M/P ratio ~0.35). Due to potential for neonatal adverse effects (hypoglycemia, renal effects), breastfeeding is not recommended during therapy.
Teratogenic Risk	INVOKAMET (canagliflozin/metformin) carries a risk of fetal harm. First trimester: limited human data, but animal studies suggest potential for renal malformations; risk cannot be excluded. Second/third trimester: exposure associated with increased fetal/neonatal adverse outcomes including hypoglycemia, hypocalcemia, and metabolic acidosis; avoid use.

Warnings & precautions

■ FDA Black Box Warning

Lactic acidosis: Metformin-associated lactic acidosis is a rare but serious complication; acute renal failure and other risk factors increase the risk. Discontinue if suspected.