Version May 2024
Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally >5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years of age, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information. If metformin-associated lactic acidosis is suspected, immediately discontinue canagliflozin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Dosage guidance:
Clinical considerations: Correct volume depletion, if present, prior to initiation. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) to avoid hypoglycemia (AACE/ACE [Garber 2020]).
Diabetes mellitus, type 2, treatment:
Note: Additional therapeutic considerations may apply; refer to individual agents for information.
Individualize dose based on patient's current antidiabetic regimen. May gradually increase dose based on effectiveness and tolerability.
Patients naive to canagliflozin or metformin: Oral: Initial: Canagliflozin 100 mg/metformin 1 g per day in 2 divided doses (immediate release) or once daily (extended release).
Patients on metformin: Oral: Initial: Canagliflozin 100 mg/day plus similar total daily dose of metformin in 2 divided doses (immediate release) or once daily (extended release). Patients taking an evening dose of metformin extended release should skip their last dose before starting canagliflozin/metformin extended release the following morning.
Patients on canagliflozin: Oral: Initial: Metformin 1 g/day plus same total daily dose of canagliflozin in 2 divided doses (immediate release) or once daily (extended release).
Patients switching from combination therapy of canagliflozin and metformin as separate tablets: Oral: Administer same total daily dose of canagliflozin plus similar total daily dose of metformin in 2 divided doses (immediate release) or once daily (extended release).
Patients switching from immediate release to extended release: Oral: Use current total daily dose.
Maximum: Oral: Canagliflozin 300 mg/metformin 2 g per day.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: The glycemic efficacy of canagliflozin decreases as kidney function declines.
eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 45 to <60 mL/minute/1.73 m2: Limit the dose of canagliflozin to 100 mg/day. No dosage adjustment is required for metformin.
eGFR 30 to <45 mL/minute/1.73 m2:
Initiation of therapy: Initiation of therapy with canagliflozin/metformin is not recommended. Refer also to individual agents.
Continuation of existing therapy: If eGFR falls between 30 and <45 mL/minute/1.73 m2 during therapy, consider benefits/risks of continuing therapy. If continued, limit the dose of canagliflozin to 100 mg/day; metformin may be continued at a reduced dose up to a maximum of 500 mg twice daily with close monitoring of kidney function (ADA [Lipska 2011]; Inzucchi 2014).
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
Hemodialysis: Use is contraindicated.
The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in patients with diabetes and chronic liver disease with impaired hepatic function may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett 2010; Crowley 2017; Zhang 2014). For canagliflozin, no dosage adjustment is necessary in patients with mild or moderate hepatic impairment according to the manufacturer's labeling; use of canagliflozin is not recommended in severe hepatic impairment.
Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).
See individual agents.
History of serious hypersensitivity (eg, anaphylaxis, angioedema) to canagliflozin, metformin, or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2) or patients on dialysis; acute or chronic metabolic acidosis (including diabetic ketoacidosis).
Canadian labeling: Additional contraindications (not in US labeling): Renal function unknown or end-stage renal disease; unstable and/or insulin-dependent (type I) diabetes mellitus; acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma, history of ketoacidosis with or without coma; history of lactic acidosis (regardless of precipitating factors); excessive alcohol intake (acute or chronic); severe hepatic dysfunction or clinical or laboratory evidence of hepatic disease; cardiovascular collapse and disease states associated with hypoxemia including cardiorespiratory insufficiency, which are often associated with hyperlactacidemia; stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); severe dehydration or shock; pregnancy; breastfeeding; period of time around administration of iodinated contrast materials.
Concerns related to adverse effects:
• Bone fracture: An increased incidence of bone fracture has been reported in the CANVAS clinical trial program (composed of the CANVAS and CANVAS-R trials); fractures were observed as early as 12 weeks after treatment initiation in the CANVAS trial (Neal 2017; Watts 2016; manufacturer's labeling). The similarly designed CANVAS-R trial (n=5,812) did not show an increased fracture risk when analyzed separately from the CANVAS trial (n=4,330); reasons for this conflicting data within the CANVAS program are not clear (Zhou 2019). Meta-analyses and pooled analyses (excluding CANVAS trial) have not demonstrated a risk of increased fractures (Ruanpeng 2017; Tang 2016; Watts 2016), and fracture risk was not increased in the CREDENCE trial (Perkovic 2019). Consider patient's risk of fracture prior to initiation.
• Genital mycotic infections: Canagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections or uncircumcised males are at greater risk.
• Hyperkalemia: Canagliflozin may cause hyperkalemia. Predisposing factors for hyperkalemia include renal impairment, higher doses (eg, 300 mg daily), and concomitant use of potassium-sparing diuretics, angiotensin-converting-enzyme [ACE] inhibitors, and angiotensin receptor blockers (ARBs) (Weir 2014). In the CREDENCE trial, use of canagliflozin 100 mg daily in patients with a mean eGFR ~56 ± 18 mL/minute/1.73 m2 did not increase the risk of hyperkalemia compared to placebo (Perkovic 2019).
• Hypersensitivity reactions: Hypersensitivity reactions (eg, angioedema, anaphylaxis), some serious, generally occurs within hours to days after therapy initiation.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose cotransporter-2 (SGLT2) inhibitors, including canagliflozin; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Risk may be increased with higher doses. Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy at least 3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis.
• Lactic acidosis: Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue use in patients with conditions associated with dehydration, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
• Lower limb amputation: An increased risk of lower limb amputations associated with canagliflozin use was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two large, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Amputations involved the toe, midfoot, or less frequently the leg (above or below the knee). Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating factors. Prior to initiation consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care.
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving canagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis.
• Renal effects: Acute kidney injury has been reported with canagliflozin. Prior to initiation, consider risk factors for acute kidney injury (eg, hypovolemia, chronic renal insufficiency, heart failure, use of concomitant medications [eg, diuretics, ACE inhibitors, angiotensin receptor blockers, or nonsteroidal anti-inflammatory drugs). Temporarily discontinue use with reduced oral intake or fluid losses; discontinue use if acute kidney injury occurs. Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the CREDENCE trial, patients with type 2 diabetes and chronic kidney disease (ie, eGFR 30 to 90 mL/minute/1.73 m2) and receiving canagliflozin had a greater decline in eGFR at 3 weeks compared to placebo; however, further decline in eGFR tended to be slower with canagliflozin over a median follow-up of 2.6 years (Perkovic 2019).
• Urinary tract infection: Serious urinary infections including urosepsis and pyelonephritis requiring hospitalization have been reported with canagliflozin; treatment increases the risk for urinary tract infections.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency.
• Volume depletion: Intravascular volume depletion manifesting as acute transient changes in creatinine or symptomatic hypotension may occur; risk may be increased in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), elderly patients, or patients on loop diuretics. Acute kidney injury requiring dialysis and hospitalization has also been reported. Assess volume status prior to initiation in patients at risk of hypotension and correct if depleted.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Use IR tablets after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery. ER tablets may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2020; Melissas 2013). After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC0-∞ increased by 21%) and bioavailability (increased by 50%) (Padwal 2011). Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved (Deden 2018).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
• Heart failure: Metformin may be used in patients with stable heart failure (HF); use cautiously or avoid in hypoperfusion (ADA 2023). Risk of lactic acidosis may be increased secondary to hypoperfusion. In a scientific statement from the AHA, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use of metformin in patients with HF may be associated with reduced mortality and reduction in hospital readmission for HF (Crowley 2017; Eurich 2013).
• Hepatic impairment: Use metformin cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Glycemic efficacy of canagliflozin may be decreased in patients with renal impairment. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.
Special populations:
• Older adult: Use with caution; risk of metformin associated lactic acidosis increases with age. Patients ≥65 years of age may have an increased risk of symptoms related to intravascular volume depletion (eg, hypotension, orthostatic hypotension, postural dizziness, syncope, and dehydration) during canagliflozin therapy.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or for glycemic control in patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Hospitalized patients: Use of SGLT2 inhibitors (eg, canagliflozin) is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
• Iodinated contrast: Administration of iodinated contrast agents has been associated with post-contrast acute kidney injury; in patients taking metformin, acute decreases in renal function have been associated with an increased risk of lactic acidosis due to reduced metformin excretion (ACR 2021; manufacturer’s labeling). Refer to metformin monograph for additional information.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).
• Surgical procedures: Consider temporary discontinuation of canagliflozin-containing products 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Invokamet: Canagliflozin 50 mg and metformin hydrochloride 500 mg, Canagliflozin 150 mg and metformin hydrochloride 500 mg, Canagliflozin 50 mg and metformin hydrochloride 1000 mg, Canagliflozin 150 mg and metformin hydrochloride 1000 mg
Tablet Extended Release 24 Hour, Oral:
Invokamet XR: Canagliflozin 50 mg and metformin hydrochloride 500 mg, Canagliflozin 150 mg and metformin hydrochloride 500 mg, Canagliflozin 50 mg and metformin hydrochloride 1000 mg, Canagliflozin 150 mg and metformin hydrochloride 1000 mg
No
Tablet, 24-hour (Invokamet XR Oral)
50-500 mg (per each): $11.97
50-1000 mg (per each): $11.97
150-500 mg (per each): $11.97
150-1000 mg (per each): $11.97
Tablets (Invokamet Oral)
50-500 mg (per each): $11.97
50-1000 mg (per each): $11.97
150-500 mg (per each): $11.97
150-1000 mg (per each): $11.97
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Invokamet: Canagliflozin 50 mg and metformin hydrochloride 500 mg, Canagliflozin 50 mg and metformin hydrochloride 850 mg [DSC], Canagliflozin 150 mg and metformin hydrochloride 500 mg, Canagliflozin 150 mg and metformin hydrochloride 850 mg [DSC], Canagliflozin 50 mg and metformin hydrochloride 1000 mg, Canagliflozin 150 mg and metformin hydrochloride 1000 mg
Oral:
Immediate release: Administer twice daily with meals.
Extended release: Administer once daily with morning meal. Swallow tablets whole; do not crush, cut, or chew.
Bariatric surgery: Tablet: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Consider switching to separate IR components. Antidiabetic medications may be held in the immediate postoperative period due to endocrine and gut hormone shifts induced by surgery, low carbohydrate postoperative diet, and effects of some medications on diuresis (sodium-glucose co-transporter-2 inhibitors).
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Invokamet, Invokamet XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/204353s042,205879s019lbl.pdf#page=56
Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
MetFORMIN may be confused with metroNIDAZOLE
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
Beers Criteria: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to increased risk of urogenital infections, especially in women during the first month of use. In addition, a higher risk of euglycemic diabetic ketoacidosis has been observed in older adults (Beers Criteria [AGS 2023]).
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, excessive alcohol ingestion (acute or chronic) may potentiate the risk of lactic acidosis. Risk X: Avoid combination
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor therapy
Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Risk D: Consider therapy modification
Digoxin: Canagliflozin may increase the serum concentration of Digoxin. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to this combination or use of lower metformin doses. Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining dolutegravir with metformin. Risk D: Consider therapy modification
Erdafitinib: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Consider alternatives to this combination when possible. If combined, monitor for increased effects/toxicities of OCT2 substrates and consider OCT2 substrate dose reductions when appropriate. Risk D: Consider therapy modification
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with MATE1/2-K substrates when possible. If combined, monitor for increased MATE1/2-K substrate toxicities. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with OCT2 substrates when possible. If combined, monitor for increased OCT2 substrate toxicities. Risk D: Consider therapy modification
Fludeoxyglucose F 18: MetFORMIN may diminish the diagnostic effect of Fludeoxyglucose F 18. Management: Consider holding metformin for 48 hours or longer prior to PET scans using fludeoxyglucose F18 (FDG-F18) when imaging of the colon or intestine is required. Consider increased monitoring of blood glucose when metformin is held. Risk D: Consider therapy modification
Foslevodopa: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Fosphenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Gilteritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guar Gum (Partially Hydrolyzed): May decrease the serum concentration of MetFORMIN. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Risk D: Consider therapy modification
LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor therapy
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Canagliflozin may enhance the hypotensive effect of Loop Diuretics. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
MATE1/2-K Inhibitors: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Methylol Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May decrease the serum concentration of Canagliflozin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ondansetron: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Pacritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
PHENobarbital: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Phenytoin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Primidone: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Risk D: Consider therapy modification
RifAMPin: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Risdiplam: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider therapy modification
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Ritonavir: May decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater. Risk D: Consider therapy modification
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Sulfonylureas: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase the serum concentration of Topiramate. Topiramate may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetFORMIN may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of MetFORMIN. Risk C: Monitor therapy
Metformin may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.
Refer to individual monographs for additional information.
Metformin crosses the placenta (ADA 2023).
The manufacturer recommends that alternative therapies be used in pregnant patients during the second and third trimesters.
Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.
Metformin is present in breast milk; excretion of canagliflozin is not known.
Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Refer to individual monographs for additional information.
Individualized medical nutrition therapy based on American Diabetes Association recommendations is an integral part of therapy.
Plasma glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors) (ADA 2023). Monitor renal function (eGFR) prior to therapy initiation and at least annually or at least every 3 to 6 months if eGFR is <60 mL/minute/1.73 m2 (KDIGO 2020). Monitor hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually; folate if megaloblastic anemia is suspected; volume status (eg, BP, hematocrit, electrolytes); serum potassium (periodically after initiation in renal impairment and those predisposed to hyperkalemia); signs/symptoms of genital mycotic infections and urinary tract infection; signs/symptoms of heart failure; lower limb and feet (sores, ulcers, infection). If signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]). Monitor vitamin B12 serum concentrations every 1 to 2 years, particularly in patients who have been treated with metformin for ≥4 years, or in patients with peripheral neuropathy, anemia, or risk factors for vitamin B12 deficiency (eg, malabsorption syndromes, reduced dietary intake) (ADA 2023; KDIGO 2020; manufacturer’s labeling).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2023; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults (AACE [Samson 2023]; ADA 2023):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note : In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2023):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).
Classification of hypoglycemia (ADA 2023):
Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL (SI: <3 mmol/L); threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Canagliflozin: By inhibiting sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, canagliflozin reduces reabsorption of filtered glucose from the tubular lumen and lowers the renal threshold for glucose (RTG). SGLT2 is the main site of filtered glucose reabsorption; reduction of filtered glucose reabsorption and lowering of RTG result in increased urinary excretion of glucose, thereby reducing plasma glucose concentrations.
Metformin: Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization).
Refer to individual agents.
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