INVOKAMET
Clinical safety rating: caution
Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).
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.
| 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. |
| Molecular Weight | 444.53 |
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. |
| 1st trimester | INVOKAMET (canagliflozin/metformin) is not recommended during the first trimester due to potential risks associated with metformin (limited human data) and canagliflozin (animal studies show renal toxicity). Use only if clearly needed and no safer alternative exists. |
| 2nd trimester | INVOKAMET is not recommended in the second trimester. Canagliflozin may affect fetal renal development. Metformin has been associated with some adverse outcomes in animal studies. Avoid use unless benefits outweigh risks. |
| 3rd trimester | INVOKAMET is contraindicated in the third trimester due to the risk of canagliflozin causing fetal renal abnormalities and metformin potentially causing neonatal hypoglycemia and lactic acidosis. Also, canagliflozin may cause volume depletion in the mother. |
Clinical note
Comprehensive clinical and safety monograph for INVOKAMET (INVOKAMET).
| Placental transfer | Metformin crosses the placenta freely; canagliflozin is expected to cross the placenta based on animal studies. Both drugs have demonstrated fetal exposure in animal models, with canagliflozin showing accumulation in fetal tissues. |
■ 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.
| Serious Effects |
Severe renal impairment (eGFR <30 mL/min/1.73 m²)End-stage renal disease or dialysisAcute or chronic metabolic acidosis, including diabetic ketoacidosisHypersensitivity to canagliflozin, metformin, or any component of the productConcomitant use of carbonic anhydrase inhibitors (e.g., topiramate) due to increased risk of lactic acidosis
| 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 |
| Food/Dietary | Avoid excessive alcohol consumption (increases risk of lactic acidosis). No specific food restrictions besides standard diabetic diet. Take with food to reduce metformin GI side effects. |
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| Breastfeeding | Metformin is excreted into human milk in small amounts, and canagliflozin is excreted in animal milk. The effects on the nursing infant are unknown. Avoid breastfeeding while using INVOKAMET due to the potential for serious adverse reactions in the infant, including hypoglycemia and renal effects. Consider alternative therapies. |
| Lactation Rating | L4 - Hazardous |
| 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. |
| Fetal Monitoring | Monitor maternal renal function (serum creatinine, eGFR), blood glucose, and electrolytes. Fetal monitoring includes serial ultrasound for growth and amniotic fluid volume due to potential for oligohydramnios. Neonatal monitoring for hypoglycemia, hypocalcemia, and metabolic acidosis after delivery. |
| Fertility Effects | Both canagliflozin and metformin may affect fertility. Canagliflozin caused reversible ovarian cyclicity changes in female rats. Metformin may improve ovulation in women with PCOS but has unknown effects on male fertility. Human data are limited; advise caution in patients planning pregnancy. |
| Clinical Pearls | Invokamet (canagliflozin/metformin) combines an SGLT2 inhibitor with metformin. Monitor renal function before initiation and periodically; eF GFR must be ≥30 mL/min/1.73m2 for canagliflozin. Discontinue at eGFR <30. Canagliflozin increases risk of lower limb amputations, especially toes. Assess for volume depletion in patients on diuretics, elderly, or with renal impairment. Hold for 3 days before surgery due to ketoacidosis risk. May cause hyperkalemia in renal impairment or with K+ sparing drugs. |
| Patient Advice | Take with meals to reduce gastrointestinal upset from metformin. · Drink plenty of water to prevent dehydration and urinary tract infections. · Report symptoms of genital yeast infections (itching, discharge) or urinary tract infections (burning, frequency). · Seek immediate medical attention if you experience severe abdominal pain, nausea, vomiting, or fruity-smelling breath (signs of ketoacidosis). · Inform your doctor before any surgery; you may need to stop this medication 3 days prior. · Monitor for signs of lower limb amputation (new pain, tenderness, sores, or infections in legs or feet). · Avoid excessive alcohol intake due to increased risk of lactic acidosis with metformin. |