Dosing & Uses
Dosage Forms & Strengths
empagliflozin/metformin
tablet, immediate-release
- 5mg/500mg
- 5mg/1000mg
- 12.5mg/500mg
- 12.5mg/1000mg
tablet, extended-release
- 5mg/1000mg
- 10mg/1000mg
- 12.5mg/1000mg
- 25mg/1000mg
Type 2 Diabetes Mellitus
Indicated as adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) when treatment with both empagliflozin and metformin is appropriate
Individualize starting dose based on the patient’s current drug regimen
Empagliflozin, when used in combination with metformin, is also indicated in T2DM to reduce risk of
- Cardiovascular death in adults with established cardiovascular disease
- Cardiovascular death and hospitalization for heart failure in adults with heart failure
Immediate-release tablet
- Take twice daily with meals (ie, divide total daily dose into 2 doses/day)
- Empagliflozin total daily dose: 10 mg
- For additional glycemic control, empagliflozin may be increased to maximum total daily dose of 25 mg in patients tolerating 10 mg/day and metformin may be increased to maximum total daily dose of 2,000 mg/day, with gradual escalation to reduce gastrointestinal adverse reactions with metformin
-
Switching to Synjardy
- Patients on metformin: Switch to tablet containing empagliflozin 5 mg with a similar total daily dose (TDD) of metformin
- Patients on empagliflozin: Switch to tablet containing metformin 500 mg with a similar TDD of empagliflozin
- Patients already treated with empagliflozin and metformin: Switch to tablet containing the same total daily doses of each component
Extended-release tablet
- Recommended empagliflozin dose: 10 mg PO qDay
- For additional glycemic control, empagliflozin may be increased to maximum of 25 mg qDay in patients tolerating 10 mg once daily
- Metformin may be increased to maximum once 2,000 mg qDay, with gradual escalation to reduce gastrointestinal adverse reactions
-
Switching to Synjardy XR
- Patients on metformin: Switch to XR tablet containing a similar TDD of metformin and a total daily dose of empagliflozin 10 mg
- Patients on empagliflozin: Switch to XR tablet containing the same TDD of empagliflozin and a TDD of metformin extended-release 1000 mg
- Patients already treated with empagliflozin and metformin: Switch to XR tablet containing the same TDD of empagliflozin and a similar TDD of metformin
Dosage Modifications
Renal impairment
- eGFR <45 mL/min/1.73 m2: Contraindicated
Iodinated contrast imaging procedures
-
Discontinue empagliflozin/metformin before or at the time of an iodinated contrast imaging procedure in the following:
- Patients with an eGFR 45 to <60 mL/min/1.73 m2
- Patients with a history of liver disease, alcoholism or heart failure
- Patients who will be administered intra-arterial iodinated contrast
- Re-evaluate eGFR 48 hr after the imaging procedure; restart dose if renal function is stable
Hepatic impairment
- Avoid use in patients with clinical or laboratory evidence of hepatic disease
- Use of metformin in patients with hepatic impairment has been associated with lactic acidosis
Dosing Considerations
Before initiation
- Assess renal function and periodically, thereafter
- Correct volume depletion before initiating if not previously treated with empagliflozin
Limitations of use
- Not for patients with type 1 diabetes; it may increase risk of diabetic ketoacidosis in these patients
Dosage Forms & Strengths
empagliflozin/metformin
tablet, immediate-release
- 5mg/500mg
- 5mg/1000mg
- 12.5mg/500mg
- 12.5mg/1000mg
Type 2 Diabetes Mellitus
Indicated as adjunct to diet and exercise to improve glycemic control in patients aged ≥10 years with type 2 diabetes mellitus (T2DM) when treatment with both empagliflozin and metformin is appropriate
<10 years: Safety and efficacy not established
≥10 years - immediate-release tablet
- Individualize starting dose based on the patient’s current drug regimen
- Take orally twice daily with meals (ie, divide total daily dose into 2 doses/day); gradually escalate dose to reduce gastrointestinal adverse effects associated with metformin
- Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total daily dosage of empagliflozin 25 mg and metformin 2,000 mg
Dosage Modifications
Renal impairment
- eGFR <45 mL/min/1.73 m2: Contraindicated
Hepatic impairment
- Avoid use in patients with clinical or laboratory evidence of hepatic disease
- Use of metformin in patients with hepatic impairment has been associated with lactic acidosis
Dosing Considerations
Before initiation
- Assess renal function and periodically, thereafter
- Correct volume depletion before initiating if not previously treated with empagliflozin
Limitations of use
- Not for patients with type 1 diabetes mellitus; it may increase risk of diabetic ketoacidosis in these patients
Monitor renal function more frequently after initiating drug in elderly patients, and then adjust dose based on renal function
Renal function abnormalities can occur after initiating empagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function
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 (204)
- 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.
- amiloride
empagliflozin, amiloride. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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. .
- benazepril
benazepril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- bendroflumethiazide
empagliflozin, bendroflumethiazide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- 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
empagliflozin, bumetanide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
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.
- chlorothiazide
empagliflozin, chlorothiazide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- captopril
captopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- 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
empagliflozin, chlorpropamide. 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 SGLT2 inhibitors.
- chlorthalidone
empagliflozin, chlorthalidone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- 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.
- 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.
- 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, 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.
dulaglutide, empagliflozin. 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 increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- ethacrynic acid
empagliflozin, ethacrynic acid. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- 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.
- 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 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.
- furosemide
empagliflozin, furosemide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- glimepiride
empagliflozin, glimepiride. 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 SGLT2 inhibitors.
- glipizide
empagliflozin, glipizide. 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 SGLT2 inhibitors.
- glucagon intranasal
glucagon intranasal decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- glyburide
empagliflozin, glyburide. 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 SGLT2 inhibitors.
- 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.
- histrelin
histrelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- hydrochlorothiazide
empagliflozin, hydrochlorothiazide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- indapamide
empagliflozin, indapamide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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
empagliflozin, insulin aspart. 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 SGLT2 inhibitors.
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. - insulin aspart protamine/insulin aspart
empagliflozin, 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.
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. - 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.
empagliflozin, insulin degludec. 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 SGLT2 inhibitors. - insulin degludec/insulin aspart
empagliflozin, insulin degludec/insulin aspart. 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 SGLT2 inhibitors.
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
empagliflozin, insulin detemir. 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 SGLT2 inhibitors.
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 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.
empagliflozin, insulin glargine. 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 SGLT2 inhibitors. - 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.
empagliflozin, insulin glulisine. 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 SGLT2 inhibitors. - insulin inhaled
empagliflozin, insulin inhaled. 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 SGLT2 inhibitors.
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
empagliflozin, 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
empagliflozin, insulin lispro. 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 SGLT2 inhibitors.
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
empagliflozin, 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
empagliflozin, insulin NPH. 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 SGLT2 inhibitors.
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. - insulin regular human
empagliflozin, insulin regular human. 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 SGLT2 inhibitors.
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. - 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. .
- letermovir
letermovir will increase the level or effect of empagliflozin by unspecified interaction mechanism. Use Caution/Monitor. Monitor glucose concentrations.
- 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.
- 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.
- lithium
empagliflozin decreases levels of lithium by Other (see comment). Use Caution/Monitor. Comment: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations; monitor serum lithium concentration more frequently during therapy initiation and dosage changes.
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. - 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 empagliflozin 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 metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
lonapegsomatropin decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - lopinavir
lopinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
- methyclothiazide
empagliflozin, methyclothiazide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- metolazone
empagliflozin, metolazone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- moexipril
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
empagliflozin, nateglinide. 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 SGLT2 inhibitors.
- 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.
- 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 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.
- 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.
- 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.
- procainamide
metformin will increase the level or effect of procainamide by basic (cationic) drug competition for renal tubular clearance. 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 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 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
empagliflozin, repaglinide. 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 SGLT2 inhibitors.
- 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. .
- 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 empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somapacitan decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - somatrogon
somatrogon decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatrogon decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - somatropin
somatropin decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatropin decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - spironolactone
empagliflozin, spironolactone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- 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.
- 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
empagliflozin, tolazamide. 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 SGLT2 inhibitors.
- tolbutamide
empagliflozin, tolbutamide. 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 SGLT2 inhibitors.
- 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.
empagliflozin, torsemide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion. - trandolapril
trandolapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- triamterene
empagliflozin, triamterene. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
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, empagliflozin. 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
1-10%
Urinary tract infection (7.6-9.3%)
Decreased vitamin B12 levels (7%)
Increased LDL-C (4.6-6.5%)
Female genital mycotic infections (5.4-6.4%)
Dyslipidemia (2.9-3.9%)
Increased urination (3.2-3.4%)
Male genital mycotic infections (1.6-3.1%)
Nausea (1.1-2.3%)
Hypoglycemia, with monotherapy (1.4-1.8%)
<1%
Volume depletion
Impaired renal function
Postmarketing Reports
Ketoacidosis
Urosepsis and pyelonephritis
Angioedema
Skin reactions (e.g., rash, urticaria)
Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Acute kidney injury
Constipation
Necrotizing fasciitis of the perineum (Fournier’s gangrene)
Warnings
Black Box Warnings
Lactic acidosis
- Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation
- Risk increases with renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure
- Onset is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress)
- Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate
- If acidosis is suspected, discontinue drug and hospitalize the patient immediately
- Obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for development of renal impairment (e.g., the elderly), monitor renal function more frequently
- Risk of metformin-associated lactic acidosis increases with age; elderly patients (>65 years) have greater likelihood of having hepatic, renal, or cardiac impairment than younger patients; assess renal function more frequently in elderly patients
Contraindications
Moderate-to-severe renal disease (eGFR <45 mL/min/1.73 m2), end-stage renal disease, or dialysis
Acute or chronic metabolic acidosis, including diabetic ketoacidosis (treat ketoacidosis with insulin)
History of serious hypersensitivity reaction to empagliflozin or metformin
Cautions
Lactic acidosis is a metabolic complication that can occur due to metformin accumulation during treatment and is fatal in ~50% of cases (see Black Box Warnings)
Serious hypersensitivity reactions, (eg, angioedema) in patients receiving treatment reported postmarketing; discontinue therapy and treat promptly if it occurs per standard of care
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 100.4ºF 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
Empagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after initiating, particularly in patients with renal impairment, elderly patients, patients with low systolic blood pressure, or patients taking diuretics; before initiating therapy, assess for volume contraction and correct volume status if indicated; monitor for signs and symptoms of hypotension after initiating therapy and increase monitoring in clinical situations where volume contraction is expected
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
Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia; when such events occur, discontinue therapy
Administration of intravascular iodinated contrast agents in metformintreated patients has led to an acute decrease in renal function and occurrence of lactic acidosis; stop treatment at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between <60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast; re-evaluate eGFR 48 hours after imaging procedure, and restart therapy if renal function is stable
There have been postmarketing reports of serious hypersensitivity reactions, (eg, angioedema) in patients treated with empagliflozin; if a hypersensitivity reaction occurs, discontinue therapy permanently; treat promptly per standard of care, and monitor until signs and symptoms resolve
Metformin associated with decreased vitamin B12 levels without clinical manifestations; the decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation; measurement of hematologic parameters on an annual basis is advised in patients receiving therapy and any apparent abnormalities should be appropriately investigated and managed; certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful
Genital mycotic infections may occur with empagliflozin; patients with history of genital mycotic infections and uncircumcised males are more susceptible; monitor and treat as appropriate
Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving empagliflozin reported; treatment increases risk for urinary tract infections; evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated
Empagliflozin may increase LDL-C
No clinical studies were established for conclusive evidence of macrovascular risk reduction with empagliflozin/metformin
Volume depletion
- Therapy can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine; acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors reported postmarketing
- Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension
- Before initiating therapy in patients with one or more of these characteristics, assess volume status and renal function; in patients with volume depletion, correct this condition before initiating treatment; monitor for signs and symptoms of volume depletion, and renal function after initiating therapy
Renal impairment
- Empagliflozin causes intravascular volume contraction and can cause renal impairment; there have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors; some reports involved patients younger than 65 years of age
- 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); monitor patients for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
- Empagliflozin increases serum creatinine and decreases eGFR; patients with hypovolemia may be more susceptible to these changes; renal function abnormalities can occur after initiating therapy; renal function should be evaluated prior to initiation of treatment and monitored periodically thereafter; more frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2
Lactic acidosis
- Metformin-associated lactic acidosis has been characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL; metformin decreases liver uptake of lactate increasing lactate blood levels which may increase risk of lactic acidosis, especially in patients at risk
- If metformin-associated lactic acidosis suspected, institute general supportive measures promptly in a hospital setting, along with immediate discontinuation of therapy; in treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions); hemodialysis has often resulted in reversal of symptoms and recovery
- Educate patients and their families about symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue therapy and report symptoms to their healthcare provider
Ketoacidosis
- Drug not indicated for treatment of type 1 diabetes mellitus
- Assess patients who present with signs and symptoms consistent with severe metabolic acidosis for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with therapy may be present even if blood glucose levels are <250 mg/dl; if ketoacidosis is suspected, drug should be discontinued, patient should be evaluated, and prompt treatment should be instituted; treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement
- Before initiating therapy, consider factors in patient history that may predispose to ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse
- Consider temporarily discontinuing therapy for at least 3 days for patients who undergo scheduled surgery
- Monitor for ketoacidosis and temporarily discontinuing therapy in other clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or post-surgery)
- Restart once the patient’s oral intake is back to baseline and any other risk factors for ketoacidosis (blood acid buildup) are resolved
Drug interaction overview
-
Empagliflozin
- Serious life-threatening condition requiring urgent hospitalization identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors
- In adult patients, the risk of hypoglycemia may be increased when the drug is used in combination with insulin secretagogues (eg, sulfonylurea) or insulin; in pediatric patients aged >10 years, the risk of hypoglycemia was higher with empagliflozin regardless of insulin use
- Risk of hypoglycemia may be lowered by reduction in dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin
- Inform patients using these concomitant medications and pediatric patients of risk of hypoglycemia and educate them on signs and symptoms of hypoglycemia
- Urine glucose tests is not recommended in patients taking SGLT2 inhibitors, as SGLT2 inhibitors, increase urinary glucose excretion and lead to positive urine glucose tests; use alternative methods to monitor glycemic control
- 1,5-AG assay is not recommended, as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors; use alternative methods to monitor glycemic control
-
Metformin
- Alcohol is known to potentiate metformin’s effect on lactate metabolism; warn patients against excessive alcohol intake while in therapy
- Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
- Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis; coadministration with carbonic anhydrase inhibitors may increase the risk of lactic acidosis
- Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control; these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid
Pregnancy
Pregnancy
Not recommended during second and third trimester of pregnancy based on animal data
Limited available data with use in pregnant women is not sufficient to determine a drug-associated risk for major birth defects and miscarriages
Metformin may result in ovulation in some anovulatory women; discuss the potential for unintended pregnancy with premenopausal women
Animal data
- In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during period of renal development corresponding to the late second and third trimesters of human pregnancy
- Doses ~13-times the maximum clinical dose caused renal pelvic and tubule dilatations were reversible
- Not teratogenic in rats and rabbits up to 300 mg/kg/day, which approximates 48-times and 128-times, respectively, the maximum clinical dose of 25 mg when administered during organogenesis
Clinical considerations
- Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity
Lactation
There is no information regarding presence in human milk, the effects on breastfed infant or on milk production
Empagliflozin is present in the milk of lactating rats
Since human kidney maturation occurs in utero and during first 2 years of life when lactational exposure may occur, there may be risk to developing human kidney
Because of potential for serious adverse reactions in a breastfed infant, including potential for empagliflozin to affect postnatal renal development, advise patients that use of drug combination is not recommended while breastfeeding
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
Empagliflozin: 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: Decreases hepatic glucose production; decreases GI glucose absorption; increases target cell insulin sensitivity
Absorption
Empagliflozin
- Peak plasma concentration: 259 nmol/L (10-mg dose); 687 nmol/hr (25-mg dose)
- AUC: 1870 nmol⋅hr/L (10-mg dose); 4740 nmol⋅hr/L (25-mg dose)
Metformin
- Absolute bioavailability: ~50-60% (fasting)
Distribution
Empagliflozin
- Vd (steady-state): 73.8 L
- Protein bound: 86.2%
Metformin
- Protein bound: >90%
Metabolism
Empagliflozin
- No major metabolites were detected in human plasma and the most abundant metabolites were 3 glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide)
Metformin
- Does not undergo hepatic metabolism nor biliary excretion
Elimination
Empagliflozin
- Half-life: 12.4 hr
- Oral clearance: 10.6 L/hr
- Excretion: 41.2% (feces); 54.4% (urine)
Metformin
- Following oral administration, ~90% of the absorbed drug is eliminated via the renal route within the first 24 hr, with a plasma elimination half-life of ~6.2 hr
- Half-life:~ 17.6 hr
Administration
Oral Administration
When initiating, gradually increase dose to avoid GI adverse effects from metformin
Take with meal(s)
Extended-release
- Swallow extended-release tablets whole; do not split, crush, dissolve, or chew before swallowing
- There have been reports of incompletely dissolved tablets being eliminated in the feces for other tablets containing metformin extended-release; if a patient reports seeing tablets in feces, the healthcare provider should assess adequacy of glycemic control
- 10 mg/1000 mg XR and 25 mg/1000 mg XR tablets should be taken as a single tablet once daily
- 5 mg/1000 mg XR and 12.5 mg/1000 mg XR tablets should be taken as 2 tablets together once daily
Missed dose
- Take missed dose as soon as possible
- Do not double next dose
Storage
Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)
Images
Formulary
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