empagliflozin/metformin (Rx)

Brand and Other Names:Synjardy, Synjardy XR
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Dosing & Uses

AdultPediatricGeriatric

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 adults when treatment with both empagliflozin and metformin is appropriate

Individualize starting dose based on the patient’s current drug regimen

Not to exceed 25 mg/2000 mg per day

Immediate-release tablet

  • Take twice daily with meals, with gradual dose escalation to reduce the GI adverse effects due to 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

  • Take once daily with a meal in the morning, with gradual dose escalation to reduce the GI adverse effects due to metformin
  • 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
  • Not for treatment of diabetic ketoacidosis

<18 years: Safety and efficacy not established

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

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Interactions

Interaction Checker

and empagliflozin/metformin

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              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 (203)

              • 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

                hydroxyprogesterone caproate 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.

              • 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. Use Caution/Monitor. May administer 3 hours apart

              • 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 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

                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 (82)

              • 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.

              • pegvisomant

                pegvisomant increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • potassium acid phosphate

                potassium acid phosphate increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Interaction especially seen in the treatment of hypokalemia.

              • potassium chloride

                potassium chloride increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Interaction especially seen in the treatment of hypokalemia.

              • potassium citrate

                potassium citrate increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Interaction especially seen in the treatment of hypokalemia.

              • prednisolone

                prednisolone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.

              • prednisone

                prednisone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.

              • protriptyline

                protriptyline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • quinine

                metformin will increase the level or effect of quinine by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • sage

                sage increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • stevia

                stevia increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • sulfamethoxazole

                sulfamethoxazole will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • testosterone

                testosterone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • testosterone buccal system

                testosterone buccal system increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • testosterone topical

                testosterone topical increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • tongkat ali

                tongkat ali increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Risk of hypoglycemia.

              • trazodone

                trazodone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • triamterene

                metformin will increase the level or effect of triamterene by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • trimethoprim

                metformin will increase the level or effect of trimethoprim by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.

              • trimipramine

                trimipramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • vanadium

                vanadium increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

              • verapamil

                metformin will increase the level or effect of verapamil by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.

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              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)

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              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

              Empagliflozin increases the risk for urinary tract infections (eg, urosepsis, pyelonephritis)

              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
                • Hypoglycemia risk increased with insulin and insulin secretagogues (eg, sulfonylureas); a lower dose of insulin or the insulin secretagogue may be required
                • 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
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              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.

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              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
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              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

              Storage

              Controlled room temperature (25°C [77°F]); excursions permitted to 15-30°C (59-86°F)

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              Images

              No images available for this drug.
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              Patient Handout

              A Patient Handout is not currently available for this monograph.
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              Formulary

              FormularyPatient Discounts

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              The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.