Dosing & Uses
Dosage Forms & Strengths
canagliflozin/metformin
tablet
- 50mg/500mg
- 50mg/1000mg
- 150mg/500mg
- 150mg/1000mg
tablet, extended-release
- 50mg/500mg
- 50mg/1000mg
- 150mg/500mg
- 150mg/1000mg
Type 2 Diabetes Mellitus
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with canagliflozin and metformin appropriate
Additionally, canagliflozin is indicated to reduce the risk of end-stage renal disease (ESRD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with T2DM and diabetic nephropathy with albuminuria ˃300 mg/day
Dosage overview
- Gradually escalate metformin dose to reduce gastrointestinal side effects while not exceeding a metformin total daily dose (TDD) of 2000 mg
- Adjust dose based on effectiveness and tolerability; not to exceed TDD of 300 mg/2000 mg
Starting dose based on current patient regimen
-
Not treated with either canagliflozin or metformin
- Invokamet: 50mg/500mg PO BID
- Invokamet XR: 2 tablets (50mg/500mg) PO qDay
-
Patients on metformin
- Invokamet: 1 tablet PO BID where the TDD contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin
- Invokamet XR: 2 tablets PO qDay where the TDD contains canagliflozin 100 mg and the same, or nearest appropriate, daily dose of metformin
-
Patients on canagliflozin
- Invokamet: 1 tablet PO BID where the TDD contains the same daily dose of canagliflozin and metformin 1000 mg
- Invokamet XR: 2 tablets PO qDay where the TDD contains the same daily dose of canagliflozin and metformin 1000 mg
-
Patients on canagliflozin and metformin
- Invokamet: 1 tablet PO BID where the TDD contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin
- Invokamet XR: 2 tablets PO qDay where the TDD contains the same daily dose of canagliflozin and the same, or nearest appropriate, daily dose of metformin
-
Patients requiring additional glycemic control
- For patients with eGFR ≥60 mL/min/1.73 m2
- Invokamet: For patients tolerating canagliflozin 50 mg BID, increase canagliflozin dose to 150 mg BID, with gradual metformin dose escalation based on tolerability
- Invokamet XR: For patients tolerating canagliflozin 100 mg qDay, increase canagliflozin dose to 300 mg qDay, with gradual metformin dose escalation based on tolerability
-
Patients on evening dose of metformin extended-release
- Skip last evening dose before starting canagliflozin/metformin (regular or XR) the following morning
Dosage Modifications
UDP-glucuronosyl transferase (UGT) enzyme inducers
-
GFR ≥60 mL/min/1.73 m2
- May increase canagliflozin dose to 200 mg qDay if currently tolerating 100 mg/day
- May increase canagliflozin dose to 300 mg qDay if currently tolerating 200 mg/day
-
eGFR <60 mL/min/1.73 m2
- May increase canagliflozin dose to 200 mg qDay if currently tolerating 100 mg/day
- Consider adding another antihyperglycemic agent in patients who require additional glycemic control
Renal impairment
- Obtain eGFR before starting metformin and periodically thereafter
- eGFR ≥60 mL/min/1.73 m2: No dosage adjustment required
- eGFR 45 to <60 mL/min/1.73 m2: Limit canagliflozin TDD to 100 mg
- eGFR 30 to <45 mL/min/1.73 m2: Limit canagliflozin TDD to 100 mg; assess benefit/risk of continuing drug
- eGFR <45 mL/min/1.73 m2 or on dialysis: Contraindicated
Dosing Considerations
Assess renal function before initiating and periodically thereafter
Correct volume depletion before initiating in patients not previously treated with canagliflozin
Not for treatment of type 1 diabetes or diabetic ketoacidosis
Therapy may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (13)
- contrast media (iodinated)
contrast media (iodinated) increases levels of metformin by decreasing renal clearance. Contraindicated. Acute renal failure or lactic acidosis may result. D/c metformin 48 hr before and after imaging study.
- ethanol
ethanol increases toxicity of metformin by Other (see comment). Contraindicated. Comment: Excessive EtOH consumption may alter glycemic control. Some sulfonylureas may produce a disulfiram like rxn; alcohol may potentiate the risk of lactic acidosis.
- ioversol
ioversol increases levels of metformin by decreasing renal clearance. Contraindicated. Acute renal failure or lactic acidosis may result. D/c metformin 48 hr before and after imaging study.
- methylene blue
methylene blue will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.
- pacritinib
pacritinib will increase the level or effect of metformin by Other (see comment). Avoid or Use Alternate Drug. Concomitant administration of pacritinib (OCT1 inhibitor) with OCT1 substrates may increase the plasma concentrations of these substrates.
- ranolazine
ranolazine will increase the level or effect of metformin by decreasing elimination. Avoid or Use Alternate Drug. Limit metformin dose to 1700 mg/day when used together with ranolazine 1000 mg twice daily; monitor closelly for signs or symptoms of metformin toxicity
- risdiplam
risdiplam will increase the level or effect of metformin by decreasing elimination. Avoid or Use Alternate Drug. Risdiplam inhibits MATE1 and MATE2-K. If unable to avoid coadministration with MATE substrates, consider dosage reduction of MATE substrate.
- selegiline
selegiline will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.
- selegiline transdermal
selegiline transdermal will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.
- tafenoquine
tafenoquine will increase the level or effect of metformin by Other (see comment). Avoid or Use Alternate Drug. Tafenoquine inhibits organic cation transporter-2 (OCT2) and multidrug and toxin extrusion (MATE) transporters in vitro. Avoid coadministration with OCT2 or MATE substrates. If coadministration cannot be avoided, monitor for substrate-related toxicities and consider dosage reduction if needed based on product labeling of the coadministered drug.
- tedizolid
tedizolid will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.
- tranylcypromine
tranylcypromine will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.
- trilaciclib
trilaciclib will decrease the level or effect of metformin by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of trilaciclib (OCT2, MATE1, and MATE-2K inhibitor) with substrates where minimal increased concentration in kidney or blood may lead to serious or life-threatening toxicities.
Monitor Closely (230)
- acetazolamide
acetazolamide increases toxicity of metformin by Other (see comment). Use Caution/Monitor. Comment: Decreases serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
- albiglutide
albiglutide, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.
- aliskiren
aliskiren and canagliflozin both increase serum potassium. Use Caution/Monitor.
- amiloride
amiloride and canagliflozin both increase serum potassium. Use Caution/Monitor.
- amiodarone
amiodarone will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- amlodipine
amlodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- aripiprazole
aripiprazole, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- asenapine
asenapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- atazanavir
atazanavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- azilsartan
azilsartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- benazepril
benazepril and canagliflozin both increase serum potassium. Use Caution/Monitor.
benazepril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - benzphetamine
benzphetamine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- betrixaban
canagliflozin increases levels of betrixaban by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Decrease betrixaban dose to 80 mg PO once, then 40 mg PO qDay if coadministered with a P-gp inhibitor.
- betamethasone
betamethasone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- bictegravir
bictegravir will increase the level or effect of metformin by decreasing renal clearance. Modify Therapy/Monitor Closely. Bictegravir inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE1) in vitro. Coadministration with OCT2 and MATE1 substrates may increase their plasma concentrations. Metformin dose reduction may be required.
- bitter melon
bitter melon increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypoglycemia.
- brexpiprazole
brexpiprazole decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- bumetanide
bumetanide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- bupropion
bupropion increases levels of metformin by Other (see comment). Use Caution/Monitor. Comment: Bupropion may inhibit OCT2 mediated renal excretion of metformin.
- candesartan
candesartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- captopril
captopril and canagliflozin both increase serum potassium. Use Caution/Monitor. Monitor potassium
captopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - carbamazepine
carbamazepine decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent.
- cariprazine
cariprazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- cephalexin
cephalexin increases toxicity of metformin by decreasing renal clearance. Use Caution/Monitor. particularly in patients who may have other risk factors for metformin toxicity. .
- ceritinib
ceritinib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- chlorpromazine
chlorpromazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- chlorpropamide
chlorpropamide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- cimetidine
cimetidine will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- cinnamon
cinnamon increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Potential for hypoglycemia.
- ciprofloxacin
ciprofloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Hyper and hypoglycemia have been reported in patients treated concomitantly with quinolones and antidiabetic agents. Careful monitoring of blood glucose is recommended.
- citalopram
citalopram increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- clevidipine
clevidipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- clozapine
clozapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- colesevelam
colesevelam increases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- conjugated estrogens
conjugated estrogens decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- corticotropin
corticotropin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- cyclosporine
cyclosporine and canagliflozin both increase serum potassium. Use Caution/Monitor.
- dabrafenib
dabrafenib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- dalfampridine
metformin, dalfampridine. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Metformin and dalfampridine are organic cation transporter 2 (OCT2) substrates; both drugs may compete for renal tubular uptake and could potentially increase systemic exposure of either drug when administered concomitantly.
- darunavir
darunavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- desogestrel
desogestrel decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- diatrizoate
diatrizoate increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- diatrizoate meglumine/diatrizoate sodium
diatrizoate meglumine/diatrizoate sodium increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- diazoxide
diazoxide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- dichlorphenamide
dichlorphenamide, metformin. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis.
- dienogest/estradiol valerate
dienogest/estradiol valerate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- diethylpropion
diethylpropion decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- digoxin
digoxin, metformin. Either increases levels of the other by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor. Measure serum digoxin concentrations before initiating metformin. Monitor patients who take both metformin and digoxin for possible digoxin toxicity and lactic acidosis. Reduce the digoxin and/or metformin dose as necessary.
canagliflozin increases levels of digoxin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Digoxin AUC and peak serum concentration increased when coadministered with canagliflozin. - diltiazem
diltiazem decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- drospirenone
drospirenone and canagliflozin both increase serum potassium. Use Caution/Monitor.
- dofetilide
dofetilide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- dolutegravir
dolutegravir will increase the level or effect of metformin by decreasing renal clearance. Modify Therapy/Monitor Closely. Dolutegravir inhibits the renal organic cation transporter, OCT2; when used with metformin, limit total daily dose of metformin to 1,000 mg either when starting metformin or dolutegravir; when stopping dolutegravir, adjustment of metformin dose may be necessary; monitor blood glucose when initiating concomitant use and after withdrawal of dolutegravir
- drospirenone
drospirenone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- dulaglutide
dulaglutide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
dulaglutide, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - enalapril
enalapril and canagliflozin both increase serum potassium. Use Caution/Monitor.
enalapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - entecavir
entecavir, metformin. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration of entecavir with metformin may increase the risk of lactic acidosis.
- eplerenone
eplerenone and canagliflozin both increase serum potassium. Use Caution/Monitor.
- eprosartan
eprosartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- erdafitinib
metformin increases levels of erdafitinib by decreasing renal clearance. Modify Therapy/Monitor Closely. Consider alternatives that are not OCT2 substrates or consider reducing the dose of OCT2 substrates based on tolerability.
- escitalopram
escitalopram increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- estradiol
estradiol decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- estrogens conjugated synthetic
estrogens conjugated synthetic decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- estropipate
estropipate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- ethacrynic acid
ethacrynic acid decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- ethinylestradiol
ethinylestradiol decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- ethiodized oil
ethiodized oil increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- etonogestrel
etonogestrel decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- everolimus
everolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- exenatide injectable solution
exenatide injectable solution, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.
- exenatide injectable suspension
exenatide injectable suspension, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.
- felodipine
felodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- finerenone
canagliflozin and finerenone both increase serum potassium. Modify Therapy/Monitor Closely. Finerenone dose adjustment based on current serum potassium concentration. Monitor serum potassium and adjust finerenone dose as described in the prescribing information as necessary.
- fleroxacin
fleroxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.
- fluoxetine
fluoxetine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- fluphenazine
fluphenazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- fluvoxamine
fluvoxamine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- fosamprenavir
fosamprenavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- fosinopril
fosinopril and canagliflozin both increase serum potassium. Use Caution/Monitor.
fosinopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - fosphenytoin
fosphenytoin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- glimepiride
glimepiride, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- gemifloxacin
gemifloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.
- glipizide
glipizide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- glucagon intranasal
glucagon intranasal decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- glyburide
glyburide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- glycopyrrolate
glycopyrrolate increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. May require a dose reduction.
- goserelin
goserelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- heparin
heparin and canagliflozin both increase serum potassium. Use Caution/Monitor.
- histrelin
histrelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- hydroxyprogesterone caproate (DSC)
hydroxyprogesterone caproate (DSC) decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- iloperidone
iloperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- imidapril
imidapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- indinavir
indinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- insulin aspart
insulin aspart, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
metformin, insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
canagliflozin, insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin aspart protamine/insulin aspart
metformin, insulin aspart protamine/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
canagliflozin, insulin aspart protamine/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin degludec
metformin, insulin degludec. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
canagliflozin, insulin degludec. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin degludec/insulin aspart
canagliflozin, insulin degludec/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
metformin, insulin degludec/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin detemir
metformin, insulin detemir. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin detemir, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
canagliflozin, insulin detemir. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin glargine
metformin, insulin glargine. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin glargine, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
canagliflozin, insulin glargine. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin glulisine
metformin, insulin glulisine. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
canagliflozin, insulin glulisine. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin glulisine, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin. - insulin inhaled
canagliflozin, insulin inhaled. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
metformin, insulin inhaled. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin isophane human/insulin regular human
canagliflozin, insulin isophane human/insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
metformin, insulin isophane human/insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin lispro
canagliflozin, insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin lispro, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
metformin, insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin lispro protamine/insulin lispro
canagliflozin, insulin lispro protamine/insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
metformin, insulin lispro protamine/insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - insulin NPH
metformin, insulin NPH. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
canagliflozin, insulin NPH. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin NPH, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin. - insulin regular human
metformin, insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
insulin regular human, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
canagliflozin, insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents. - iodixanol
iodixanol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- irbesartan
irbesartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- ioflupane I 123
ioflupane I 123 increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- iohexol
iohexol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- iopamidol
iopamidol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- iopromide
iopromide increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- ioversol
ioversol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- ioxilan
ioxilan increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .
- isocarboxazid
isocarboxazid will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.
- isoniazid
isoniazid decreases effects of metformin by unspecified interaction mechanism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- isradipine
isradipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- ketotifen, ophthalmic
ketotifen, ophthalmic, metformin. Other (see comment). Use Caution/Monitor. Comment: Combination may result in thrombocytopenia (rare). Monitor CBC.
- lanreotide
lanreotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- letermovir
letermovir will increase the level or effect of canagliflozin by unspecified interaction mechanism. Use Caution/Monitor. Monitor glucose concentrations.
- leuprolide
leuprolide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- levofloxacin
levofloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.
- levonorgestrel intrauterine
levonorgestrel intrauterine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- levonorgestrel oral
levonorgestrel oral decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- levothyroxine
levothyroxine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- linezolid
linezolid will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.
- liothyronine
liothyronine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- liotrix
liotrix decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- liraglutide
liraglutide, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.
- lisinopril
lisinopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
lisinopril and canagliflozin both increase serum potassium. Use Caution/Monitor. - lithium
metformin decreases levels of lithium by Other (see comment). Use Caution/Monitor. Comment: SGLT2 inhibitors with lithium may decrease serum lithium concentrations; monitor serum lithium concentration more frequently during therapy initiation and dosage changes.
canagliflozin decreases levels of lithium by Other (see comment). Use Caution/Monitor. Comment: SGLT2 inhibitors with lithium may decrease serum lithium concentrations; monitor serum lithium concentration more frequently during therapy initiation and dosage changes. - lonapegsomatropin
lonapegsomatropin decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Closely monitor blood glucose when treated with antidiabetic agents. Lonapegsomatropin may decrease insulin sensitivity, particularly at higher doses. Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents.
lonapegsomatropin decreases effects of canagliflozin by Other (see comment). Use Caution/Monitor. Comment: Closely monitor blood glucose when treated with antidiabetic agents. Lonapegsomatropin may decrease insulin sensitivity, particularly at higher doses. Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents. - lopinavir
lopinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- losartan
losartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- lurasidone
lurasidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- marijuana
marijuana decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- mecasermin
mecasermin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Additive hypoglycemic effects.
- medroxyprogesterone
medroxyprogesterone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- methamphetamine
methamphetamine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- methazolamide
methazolamide increases toxicity of metformin by Other (see comment). Use Caution/Monitor. Comment: Decreases serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
- moexipril
moexipril and canagliflozin both increase serum potassium. Use Caution/Monitor.
moexipril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - moxifloxacin
moxifloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.
- nateglinide
nateglinide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- nelfinavir
nelfinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- niacin
niacin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- nicardipine
nicardipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- nifedipine
nifedipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- nilotinib
nilotinib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- nimodipine
nimodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- nisoldipine
nisoldipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- nizatidine
nizatidine will increase the level or effect of metformin by decreasing renal clearance. Modify Therapy/Monitor Closely.
- norelgestromin
norelgestromin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- norethindrone
norethindrone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- norgestimate
norgestimate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- octreotide
octreotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- ofloxacin
ofloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.
- olanzapine
olanzapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- olmesartan
olmesartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- omacetaxine
omacetaxine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)
ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC) increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function; concomitant metformin use in patients with renal insufficiency or hepatic impairment not recommended.
- ondansetron
ondansetron increases levels of metformin by Other (see comment). Use Caution/Monitor. Comment: Ondansetron inhibition of transporters (MATE or OCTs), which are responsible for active renal secretion of metformin may play a role.
- opuntia ficus indica
opuntia ficus indica increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- paliperidone
paliperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- paroxetine
paroxetine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- pasireotide
pasireotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- patiromer
patiromer will decrease the level or effect of metformin by drug binding in GI tract. Modify Therapy/Monitor Closely. Separate administration by at least 3 hr from patiromer
- pentamidine
pentamidine and canagliflozin both increase serum potassium. Use Caution/Monitor.
pentamidine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. - perindopril
perindopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
perindopril and canagliflozin both increase serum potassium. Use Caution/Monitor. - perphenazine
perphenazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- phenobarbital
phenobarbital decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent.
- phendimetrazine
phendimetrazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- phenelzine
phenelzine will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.
- phentermine
phentermine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- phenytoin
phenytoin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
phenytoin decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent. - potassium acid phosphate
potassium acid phosphate and canagliflozin both increase serum potassium. Modify Therapy/Monitor Closely.
- procainamide
metformin will increase the level or effect of procainamide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- potassium chloride
potassium chloride and canagliflozin both increase serum potassium. Use Caution/Monitor.
- potassium citrate
potassium citrate and canagliflozin both increase serum potassium. Use Caution/Monitor.
- potassium citrate/citric acid
canagliflozin and potassium citrate/citric acid both increase serum potassium. Use Caution/Monitor.
- potassium phosphates, IV
potassium phosphates, IV and canagliflozin both increase serum potassium. Use Caution/Monitor.
- procarbazine
procarbazine will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.
- prochlorperazine
prochlorperazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- progesterone intravaginal gel
progesterone intravaginal gel decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- progesterone micronized
progesterone micronized decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- progesterone, natural
progesterone, natural decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- promethazine
promethazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- quetiapine
quetiapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- quinapril
quinapril and canagliflozin both increase serum potassium. Use Caution/Monitor.
quinapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis. - quinidine
quinidine will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- ramipril
ramipril and canagliflozin both increase serum potassium. Use Caution/Monitor.
- ramipril
ramipril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- rasagiline
rasagiline will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.
- repaglinide
repaglinide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- rifampin
rifampin decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent.
- risperidone
risperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- ritonavir
ritonavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
ritonavir decreases levels of canagliflozin by increasing metabolism. Use Caution/Monitor. Coadministration with potent UGT enzyme inducers: Consider increasing dose to 300 mg qDay if 100 mg/day tolerate and additional glycemic control required (eGFR must be >60 mL/min/1.73 m2 to increase dose); if eGFR <60 mL/min/1.73 m2, consider using a different antihyperglycemic agent. - sacubitril/valsartan
sacubitril/valsartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- saquinavir
saquinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- sertraline
sertraline increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- shark cartilage
shark cartilage increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Theoretical interaction.
- sirolimus
sirolimus decreases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- somapacitan
somapacitan decreases effects of canagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone products may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating somapacitan. .
somapacitan decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone products may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating somapacitan. . - somatropin
somatropin decreases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- spironolactone
spironolactone and canagliflozin both increase serum potassium. Use Caution/Monitor.
- succinylcholine
succinylcholine and canagliflozin both increase serum potassium. Use Caution/Monitor.
- sulfamethoxypyridazine
sulfamethoxypyridazine increases effects of metformin by unspecified interaction mechanism. Use Caution/Monitor. Risk of hypoglycemia.
- tacrolimus
tacrolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
tacrolimus and canagliflozin both increase serum potassium. Use Caution/Monitor. - telmisartan
telmisartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- temsirolimus
temsirolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- tenofovir DF
tenofovir DF increases levels of metformin by decreasing renal clearance. Use Caution/Monitor. Increased risk of lactic acidosis.
- thioridazine
thioridazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- thyroid desiccated
thyroid desiccated decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- tibolone
tibolone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- tipranavir
tipranavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- tolazamide
tolazamide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- tolbutamide
tolbutamide, canagliflozin. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Consider a lower dose of insulin or insulin secretagogue to avoid hypoglycemia when coadministered with canagliflozin.
- topiramate
topiramate increases toxicity of metformin by Other (see comment). Use Caution/Monitor. Comment: Decreases serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.
- torsemide
torsemide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- trandolapril
trandolapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
trandolapril and canagliflozin both increase serum potassium. Use Caution/Monitor. - triamcinolone acetonide injectable suspension
triamcinolone acetonide injectable suspension decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Corticosteroids may diminish hypoglycemic effect of antidiabetic agents. Monitor blood glucose levels carefully.
- triamterene
triamterene and canagliflozin both increase serum potassium. Use Caution/Monitor.
- trifluoperazine
trifluoperazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- trimethoprim
trimethoprim increases levels of metformin by Other (see comment). Use Caution/Monitor. Comment: Trimethoprim may inhibit active renal tubular secretion of metformin (eg, via OCT2, MATE1); dose adjustments may be necessary.
trimethoprim and canagliflozin both increase serum potassium. Use Caution/Monitor. - triptorelin
triptorelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- valsartan
valsartan and canagliflozin both increase serum potassium. Use Caution/Monitor.
- trospium chloride
metformin will decrease the level or effect of trospium chloride by increasing renal clearance. Use Caution/Monitor. Coadministration reduced steady state trospium systemic exposure (decreased AUC and Cmax) by competing for renal tubular secretion
- vandetanib
vandetanib increases levels of metformin by Other (see comment). Modify Therapy/Monitor Closely. Comment: Vandetanib inhibits the uptake of substrates of organic cation transporter type 2 (OCT2).
- verapamil
verapamil decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Verapamil may inhibit hepatic uptake of metformin by OCT1 and/or other transporters.
- vilazodone
vilazodone increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- voclosporin
voclosporin and canagliflozin both increase serum potassium. Use Caution/Monitor.
- vorinostat
vorinostat decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
Minor (63)
- agrimony
agrimony increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- American ginseng
American ginseng increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- amitriptyline
amitriptyline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- amoxapine
amoxapine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- anamu
anamu increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Theoretical interaction.
- bendroflumethiazide
bendroflumethiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- budesonide
budesonide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- chlorothiazide
chlorothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- chlorthalidone
chlorthalidone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- chromium
chromium increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- clomipramine
clomipramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- clonidine
clonidine decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Diminished symptoms of hypoglycemia.
clonidine, metformin. Other (see comment). Minor/Significance Unknown. Comment: Decreased symptoms of hypoglycemia. Mechanism: decreased hypoglycemia induced catecholamine production. - cornsilk
cornsilk increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).
- cortisone
cortisone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- cyanocobalamin
metformin decreases levels of cyanocobalamin by unspecified interaction mechanism. Minor/Significance Unknown. It may take several years of metformin therapy to develop vitamin B12 deficiency.
- cyclopenthiazide
cyclopenthiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- damiana
damiana decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Theoretical interaction.
- danazol
danazol increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- deflazacort
deflazacort decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- desipramine
desipramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- devil's claw
devil's claw increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- dexamethasone
dexamethasone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- diltiazem
diltiazem will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
- doxepin
doxepin increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- elderberry
elderberry increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (in vitro research).
- eucalyptus
eucalyptus increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Theoretical interaction.
- famotidine
famotidine increases levels of metformin by decreasing renal clearance. Minor/Significance Unknown.
- fludrocortisone
fludrocortisone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- fluoxymesterone
fluoxymesterone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- fo-ti
fo-ti increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- folic acid
metformin decreases levels of folic acid by unspecified interaction mechanism. Minor/Significance Unknown.
- forskolin
forskolin increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Colenol, a compound found in Coleus root, may stimulate insulin release.
- furosemide
metformin decreases levels of furosemide by unspecified interaction mechanism. Minor/Significance Unknown.
furosemide increases levels of metformin by unspecified interaction mechanism. Minor/Significance Unknown. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia. - gotu kola
gotu kola increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).
- guanfacine
guanfacine decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Diminished symptoms of hypoglycemia.
guanfacine, metformin. Other (see comment). Minor/Significance Unknown. Comment: Decreased symptoms of hypoglycemia. Mechanism: decreased hypoglycemia induced catecholamine production. - gymnema
gymnema increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- horse chestnut seed
horse chestnut seed increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- hydrochlorothiazide
hydrochlorothiazide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
hydrochlorothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose. - hydrocortisone
hydrocortisone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- ibuprofen/famotidine
ibuprofen/famotidine increases levels of metformin by decreasing renal clearance. Minor/Significance Unknown.
- imipramine
imipramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- indapamide
indapamide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- juniper
juniper increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).
- L-methylfolate
metformin decreases levels of L-methylfolate by unspecified interaction mechanism. Minor/Significance Unknown.
- lofepramine
lofepramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- lycopus
lycopus increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).
- maitake
maitake increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (animal research).
- maprotiline
maprotiline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- memantine
memantine will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
- mesterolone
mesterolone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- methyclothiazide
methyclothiazide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
methyclothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose. - methylprednisolone
methylprednisolone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- methyltestosterone
methyltestosterone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- metolazone
metolazone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- midodrine
metformin will increase the level or effect of midodrine by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
- nettle
nettle increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).
- nifedipine
nifedipine increases levels of metformin by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- nortriptyline
nortriptyline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- ofloxacin
metformin will increase the level or effect of ofloxacin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
ofloxacin, metformin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Potential dysglycemia. - oxandrolone
oxandrolone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- oxymetholone
oxymetholone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- patiromer
patiromer, canagliflozin. cation binding in GI tract. Minor/Significance Unknown. No observed clinically important interaction. No separation of dosing required.
- pegvisomant
pegvisomant increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
Adverse Effects
>10%
canagliflozin
- Female genital mycotic infections (10.4-11.4%)
metformin
- Diarrhea (53.2%)
- Nausea/vomiting (25.5%)
- Flatulence (12.1%)
1-10%
canagliflozin
- Increased urination (4.6-5.3%)
- Male genital mycotic infections (3.7-4.2%)
- Vulvovaginal pruritus (1.6-3%)
- Thirst (2.3-2.8%)
- Falls (1.3-2.1%)
- Constipation (1.8-2.3%)
- Bone fractures (1.1-1.5%)
- Nausea (2.2-2.3%)
- Abdominal pain (1.7-1.8%)
volume depletion
- Overall population (2.3-3.4%)
- Age >75 yr (4.9-8.7%)
- eGFR <60/mL/min/1.73 mL² (4.7-8.1%)
- Use of loop diuretic (3.2-8.8%)
metformin
- Asthenia (9.2%)
- Indigestion (7.1%)
- Abdominal discomfort (6.4%)
- Headache (5.7%)
Postmarketing Reports
Angioedema
Acute kidney injury and impairment of renal function
canagliflozin
- Acute kidney injury and impairment in renal function
metformin
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
- Anaphylaxis
- Urosepsis and Pyelonephritis
Warnings
Black Box Warnings
Metformin
- 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/Liter), 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 astopiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment
- Steps to reduce 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 therapy and institute general supportive measures in a hospital setting; prompt hemodialysis recommended
Contraindications
Moderate renal impairment (eGFR <30 mL/min/1.73 m²), which may also result from conditions such as shock, acute MI, and septicemia; ESRD, or patients on dialysis
Acute or chronic metabolic acidosis, including diabetic ketoacidosis (see Black Box Warnings)
History of a serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema
Cautions
Alcohol potentiates effect of metformin on lactate metabolism and this may increase risk of metformin-associated lactic acidosis; warn patients against excessive alcohol intake while receiving therapy
Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension, and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake
Before initiating therapy, obtain an estimated glomerular filtration rate and obtain an eGFR at least annually; assess more frequently in patients at increased risk for development of renal impairment
Consider temporarily discontinuing in settings of reduced oral intake or fluid losses; if acute kidney injury occurs, discontinue and promptly treat; monitor renal function during therapy
Hyperkalemia reported with canagliflozin; monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia
Canagliflozin increases risk for genital mycotic infections; treat if indicated
Increases risk of urinary tract infections (UTIs), including life-threatening urosepsis and pyelonephritis that started as UTIs; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated
Metformin may lower vitamin B12 levels without manifestations; monitor hematologic parameters annually
Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, reported; consider factors that contribute to fracture risk prior to initiating therapy
Hypersensitivity reactions, including angioedema and anaphylaxis reported with canagliflozin; these reactions generally occurred within hours to days after initiating canagliflozin; if hypersensitivity reactions occur, discontinue therapy; treat and monitor until signs and symptoms resolve
Several of the postmarketing cases of metformin-associated lactic acidosis occurred in settings of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia); cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia; when such events occur, discontinue therapy
Lower limb amputation
- Increased risk of lower limb amputations associated with canagliflozin use was observed in 2 large, randomized, placebo-controlled trials (CANVAS AND CANVAS-R) in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD
- Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed; some patients had multiple amputations, some involving both limbs
- Before initiating, consider factors that may increase the risk of amputation (eg, history of prior amputation, peripheral vascular disease, neuropathy, diabetic foot ulcers)
- Monitor for infection, new pain or tenderness, and sores or ulcers involving the lower limbs; discontinue if these complications occur
- Counsel patients about importance of routine preventative foot care
Ketoacidosis
- Risk of ketoacidosis may be greater with higher doses; fatal cases of ketoacidosis have been reported in patients taking canagliflozin; therapy is not indicated for treatment of patients with type 1diabetes mellitus
- Fatal ketoacidosis associated with SGLT2 inhibitors
- Monitor for signs of ketoacidosis and advise patients to seek immediate medical attention for symptoms (eg, difficulty breathing, nausea, vomiting, abdominal pain, confusion, unusual fatigue or sleepiness)
- Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level
- Consider risk factors for ketoacidosis prior to initiating therapy; consider factors in patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse; patients may require temporary discontinuation of therapy in clinical situations that may predispose to ketoacidosis
Necrotizing fascitis
- Necrotizing fasciitis of the perineum (Fournier gangrene) reported with SGLT2 inhibitors
- Signs and symptoms include tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell
- If suspected, discontinue SGLT2 inhibitor and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary
Renal impairment
- Therapy causes intravascular volume contraction and can cause renal impairment; acute kidney injury, some requiring hospitalization and dialysis reported
- Before initiating therapy, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs)
- Consider temporarily discontinuing therapy in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure)
- Canagliflozin increases serum creatinine and decreases eGFR; ensure normal renal function before initiating and at least annually thereafter
Lactic acidosis
- Risk increases with degree of renal dysfunction and age (see Black Box Warnings)
- Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk oflactic acidosis, especially in patients at risk
- Metformin-associated lactic acidosis cases associated primarily with significant renal impairment; risk of metformin accumulation and metformin-associated lactic acidosis increases with severity of renal impairment; metformin substantially excreted by kidney
- Metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
- Onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain
- If suspected, discontinue therapy immediately and institute general supportive measures in hospital setting; prompt hemodialysis recommended
- Metformin use in patients with impaired hepatic function has been associated with cases of lactic acidosis; this may be due to impaired lactate clearance resulting in higher lactate blood levels; avoid use of this drug in patients with clinical or laboratory evidence of hepatic disease
- Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue therapy and report symptoms to healthcare provider
Iodinated contrast imaging procedures
- Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 45-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
Hypoglycemia
- Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue; a lower dose of insulin or insulin secretagogue may be required
- Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (eg, sulfonylureas, insulin) or ethanol
Hypotension
- Canagliflozin causes intravascular volume contraction
- Symptomatic hypotension can occur after initiating, particularly with eGFR <60 mL/min/1.73 m², elderly patients, coadministration with diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, ACE inhibitors, angiotensin receptor blockers), or patients with low systolic blood pressure
- Assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or on diuretics, ACE inhibitors, or ARB; monitor for signs and symptoms during therapy
Pregnancy & Lactation
Pregnancy
Canagliflozin
- Based on animal data showing adverse renal effects, not recommended during the second and third trimesters of pregnancy
- Data are limited in pregnant women and are not sufficient to determine a drug associated risk for major birth defects or miscarriage
Metformin
- Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day; determination of fetal concentrations demonstrated a partial placental barrier to metformin
Clinical considerations
- Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications
- Poorly controlled diabetes increases fetal risk for major birth defects, stillbirth, and macrosomia related morbidity
Lactation
Breastfeeding not recommended
Canagliflozin
- No information regarding distribution in human milk or effects on the breastfed infant or milk production
- Present in milk of lactating rats
- Since human kidney maturation occurs in utero and during the first 2 yr of life when lactational exposure may occur, there may be risk to the developing human kidney
Metformin
- Excreted into milk in rats and reaches levels comparable to those in plasma; breastfeeding not recommended
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Canagliflozin: Selective sodium-glucose transporter-2 (SGLT2) inhibitor; SGLT2 is expressed in the proximal renal tubules and is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen; SGLT2 inhibitors reduce glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion
Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose
Absorption
Bioavailability: 65% (canagliflozin); 50-60% (metformin)
Distribution
Protein bound: 99% (canagliflozin); negligible (metformin)
Vd: 119 L (canagliflozin); 654 L (metformin)
Metabolism
Metformin: Excreted unchanged in the urine and does not undergo hepatic metabolism
Canagliflozin
- O-glucuronidation is the major metabolic elimination pathway, which is mainly glucuronidated by UGT1A9 and UGT2B4 to 2 inactive O-glucuronide metabolites
- CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (~7%) in humans
Elimination
Half-life, metformin: 6.2 hr (plasma); 17.6 hr (blood); depicts erythrocyte compartmentalization
Clearance
- Canagliflozin: 192 mL/min (systemic); 1.3-1.55 mL/min (renal)
- Metformin (renal): 3.5 x CrCl, which indicates that tubular secretion is the major route of elimination
Excretion
- Canagliflozin: 33% urine, mainly as O-glucuronide metabolites
- Metformin: 90% urine
Administration
Oral Administration
Regular tablet: Take BID with morning and evening meals
Extended-release: Take once daily with morning meal
Extended-release: Swallow whole; do not crush, cut, or chew
Images
Formulary
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