Dosing & Uses
Dosage Forms & Strengths
empagliflozin/linagliptin/metformin
tablet
- 5mg/2.5mg/1000mg
- 12.5mg/2.5mg/1000mg
- 10mg/5mg/1000mg
- 25mg/5mg/1000mg
Type 2 Diabetes Mellitus
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM)
Empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with T2DM and established cardiovascular disease
Individualize starting dose based on the patient’s current regimen
Monitor effectiveness and tolerability, and adjust dosing as appropriate
Maximum recommended daily dose of empagliflozin 25 mg/linagliptin 5 mg/metformin 2000 mg
Patients on metformin with or without linagliptin
- Switch to Trijardy XR containing a similar total daily dose (TDD) of metformin, a TDD of empagliflozin 10 mg, and linagliptin 5 mg
- Patients on metformin and any regimen containing empagliflozin, with or without linagliptin H4
- Switch to Trijardy XR containing a similar TDD of metformin, the same TDD of empagliflozin, and linagliptin 5 mg
Dosage regimen with morning meal
- For metformin TDD 1000 mg: Take Trijardy XR 10 mg/5 mg/1000 mg OR 25 mg/5 mg/1000 mg PO as a single tablet once daily
- For metformin TDD 2000 mg: Take Trijardy XR 5 mg/2.5 mg/1000 mg OR 12.5 mg/2.5 mg/1000 mg PO as 2 tablets together once daily
Dosage Modifications
Renal impairment
- Mild (eGFR ≥45 mL/min/1.73 m2): No dosage adjustment necessary
- Moderate-to-severe (eGFR <45 mL/min/1.73 m2): Should not be initiated or continued
- Severe renal impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease (ESRD), or patients on dialysis: Contraindicated
Hepatic impairment
- Not recommended; use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis
Discontinuation for iodinated contrast imaging procedures
- Discontinue treatment at the time of, or before, an iodinated contrast imaging procedure in patients with an eGFR <60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast
- Reevaluate eGFR 48 hr after the imaging procedure; restart Trijardy XR if renal function is stable
Dosing Considerations
Prior to initiating treatment
- Assess renal function and periodically thereafter
- In patients with volume depletion, correct this condition
Limitations of use
- Not recommended for patients with type 1 diabetes or for treatment of diabetic ketoacidosis
- Not studied in patients with a history of pancreatitis; it is unknown whether patients with a history of pancreatitis are at an increased risk for developing pancreatitis while using Trijardy XR
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results

Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor

Contraindicated (0)
Serious - Use Alternative (27)
- amobarbital
amobarbital will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- apalutamide
apalutamide will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
- benazepril
linagliptin increases toxicity of benazepril by Mechanism: unspecified interaction mechanism. Avoid or Use Alternate Drug. Increased risk for adverse/toxic effects, specifically, increased risk of angioedema.
- 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.
- dabrafenib
dabrafenib will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- 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.
- fexinidazole
fexinidazole will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.
- idelalisib
idelalisib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates
- 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.
- ivosidenib
ivosidenib will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
- lasmiditan
lasmiditan increases levels of linagliptin by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- lorlatinib
lorlatinib will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- 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.
- secobarbital
secobarbital will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- 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.
- sotorasib
sotorasib will decrease the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.
- 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.
- tepotinib
tepotinib will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.
- tipranavir
tipranavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.
- tucatinib
tucatinib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.
Monitor Closely (259)
- 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.
- aprepitant
aprepitant will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- armodafinil
armodafinil will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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. .
atazanavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
atazanavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - 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.
- berotralstat
berotralstat will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.
- 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.
- bexarotene
bexarotene will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- bosentan
bosentan will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- 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.
- calcitriol
calcitriol will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- captopril
captopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
linagliptin increases toxicity of captopril by Mechanism: unspecified interaction mechanism. Use Caution/Monitor. Increased adverse/toxic effects, specifically, increased risk of angioedema. - carbamazepine
carbamazepine will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
carbamazepine will decrease the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp inducer. - cariprazine
cariprazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- cenobamate
cenobamate will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
- 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.
ceritinib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - chlorpromazine
chlorpromazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.
- chlorpropamide
chlorpropamide, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia.
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.
- clobazam
clobazam will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- colchicine
colchicine will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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 will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
darunavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
darunavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. . - deferasirox
deferasirox will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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, linagliptin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
dulaglutide, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.
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. - efavirenz
efavirenz will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
efavirenz will decrease the level or effect of linagliptin by Other (see comment). Use Caution/Monitor. Reports of hyperglycemia due to insulin resistance with protease inhibitors. - 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.
- enalapril
enalapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- elagolix
elagolix will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
elagolix decreases levels of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. - eliglustat
eliglustat increases levels of linagliptin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.
- encorafenib
encorafenib, linagliptin. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
- 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.
- enzalutamide
enzalutamide will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- estradiol
estradiol decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- estrogens conjugated synthetic
estrogens conjugated synthetic will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
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.
- etravirine
etravirine will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.
- fedratinib
fedratinib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
- felbamate
felbamate will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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 linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
fosamprenavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. . - fosaprepitant
fosaprepitant will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- fosinopril
fosinopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- fosphenytoin
fosphenytoin will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
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.
- glecaprevir/pibrentasvir
glecaprevir/pibrentasvir will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- 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.
glimepiride, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia. - 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.
glipizide, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia. - 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.
- glyburide
glyburide, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia.
- 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.
- griseofulvin
griseofulvin will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- hydrocortisone
hydrocortisone will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- hydroxyprogesterone caproate (DSC)
hydroxyprogesterone caproate (DSC) decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- iloperidone
iloperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- imidapril
imidapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.
- indapamide
empagliflozin, indapamide. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration of empagliflozin with diuretics results in increased urine volume and frequency of voids, which might enhance the potential for volume depletion.
- indinavir
indinavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
indinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
indinavir decreases effects of linagliptin 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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
linagliptin, 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.
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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
linagliptin, 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.
- istradefylline
istradefylline will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.
istradefylline will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates. - 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.
- itraconazole
itraconazole will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- ketoconazole
ketoconazole will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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.
- lenacapavir
lenacapavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.
- 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.
- levoketoconazole
levoketoconazole will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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. - lonafarnib
lonafarnib will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Lonafarnib is a weak P-gp inhibitor. Monitor for adverse reactions if coadministered with P-gp substrates where minimal concentration changes may lead to serious or life-threatening toxicities. Reduce P-gp substrate dose if needed.
- lonapegsomatropin
lonapegsomatropin decreases effects of empagliflozin by Other (see comment). Use Caution/Monitor. Comment: Closely monitor blood glucose when treated with antidiabetic agents. Lonapegsomatropin may decrease insulin sensitivity, particularly at higher doses. Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents.
lonapegsomatropin decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - lonapegsomatropin
lonapegsomatropin decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Closely monitor blood glucose when treated with antidiabetic agents. Lonapegsomatropin may decrease insulin sensitivity, particularly at higher doses. Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents.
lonapegsomatropin decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Closely monitor blood glucose when treated with antidiabetic agents. Lonapegsomatropin may decrease insulin sensitivity, particularly at higher doses. Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other antihyperglycemic agents.
lonapegsomatropin decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
lonapegsomatropin decreases effects of linagliptin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - lopinavir
lopinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
lopinavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
lopinavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. . - 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.
- 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.
- 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.
- mifepristone
mifepristone will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- 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.
- mitotane
mitotane decreases levels of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.
- 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.
- nafcillin
nafcillin will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- 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.
- nefazodone
nefazodone will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- nelfinavir
nelfinavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
nelfinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
nelfinavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. . - nevirapine
nevirapine will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
nevirapine will decrease the level or effect of linagliptin by Other (see comment). Use Caution/Monitor. 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.
- oxcarbazepine
oxcarbazepine decreases levels of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- paclitaxel protein bound
paclitaxel protein bound will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- paliperidone
paliperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.
- paroxetine
paroxetine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- pasireotide
pasireotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- patiromer
patiromer will decrease the level or effect of metformin by drug binding in GI tract. Modify Therapy/Monitor Closely. Separate administration by at least 3 hr from patiromer
- pentamidine
pentamidine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- pentobarbital
pentobarbital will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- phenobarbital
phenobarbital will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- 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 will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
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. - pioglitazone
pioglitazone will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- procainamide
metformin will increase the level or effect of procainamide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.
- prednisone
prednisone will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- primidone
primidone will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
- 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.
- rifabutin
rifabutin will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- rifampin
rifampin will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
rifampin will decrease the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp inducer. - rifapentine
rifapentine will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer.
- 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 increases levels of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity. .
ritonavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
ritonavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. . - rucaparib
rucaparib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.
- saquinavir
saquinavir 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 linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
saquinavir will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - sarecycline
sarecycline will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.
- sertraline
sertraline increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.
- shark cartilage
shark cartilage increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Theoretical interaction.
- sirolimus
sirolimus decreases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- somapacitan
somapacitan decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somapacitan decreases effects of linagliptin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somapacitan decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - somatrogon
somatrogon decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatrogon decreases effects of linagliptin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatrogon decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - somatropin
somatropin decreases effects of empagliflozin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatropin decreases effects of linagliptin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone.
somatropin decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone (GH) analogs may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating growth hormone. - St John's Wort
St John's Wort will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer
St John's Wort will decrease the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp inducer. - 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.
- stiripentol
stiripentol, linagliptin. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.
stiripentol will increase the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol. - tacrolimus
tacrolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.
- tazemetostat
tazemetostat will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- tecovirimat
tecovirimat will decrease the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.
- 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. .
tipranavir decreases effects of linagliptin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .
tipranavir will decrease the level or effect of linagliptin by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp inducer. - 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.
tolazamide, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia. - 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.
- tolbutamide
tolbutamide, linagliptin. Other (see comment). Use Caution/Monitor. Comment: When linagliptin is used in combination with sulfonylureas, a lower dose of the sulfonylurea may be required to reduce risk of hypoglycemia.
- 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.
topiramate will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Use of alternative treatments is strongly recommended when linagliptin is to be administered with a CYP3A4 inducer - 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 (67)
- acetazolamide
acetazolamide will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- 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.
- anastrozole
anastrozole will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- 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.
- cyclophosphamide
cyclophosphamide will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- 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.
- larotrectinib
larotrectinib will increase the level or effect of linagliptin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- lofepramine
lofepramine increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- lycopus
lycopus increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).
- maitake
maitake increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (animal research).
- maprotiline
maprotiline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- memantine
memantine will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
- mesterolone
mesterolone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- methyclothiazide
methyclothiazide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
methyclothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose. - methylprednisolone
methylprednisolone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown.
- methyltestosterone
methyltestosterone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- metolazone
metolazone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.
- midodrine
metformin will increase the level or effect of midodrine by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
- nettle
nettle increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).
- nifedipine
nifedipine increases levels of metformin by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.
- nortriptyline
nortriptyline increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- ofloxacin
metformin will increase the level or effect of ofloxacin by basic (cationic) drug competition for renal tubular clearance. Minor/Significance Unknown.
ofloxacin, metformin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Potential dysglycemia. - oxandrolone
oxandrolone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- oxymetholone
oxymetholone increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
- patiromer
patiromer, empagliflozin. cation binding in GI tract. Minor/Significance Unknown. No observed clinically important interaction. No separation of dosing required.
- pegvisomant
pegvisomant increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.
Adverse Effects
>10%
Upper respiratory tract infection (8-10.3%)
Urinary tract infection (9.6-10.2%)
Metformin
- Hypoglycemia (13.7%)
- Diarrhea (12.5%)
1-10%
Nasopharyngitis (5.8-8.1%)
Diarrhea (2.2-6.6%)
Constipation (5.1-5.8%)
Gastroenteritis (2.9-5.8%)
Headache (5.1%)
Empagliflozin
- Urinary tract infection (7.6-9.3%)
- Increased LDL cholesterol (4.6-6.5%)
- Female genital mycotic infections (5.4-6.4%)
- Dyslipidemia (2.9-3.9%)
- Male genital mycotic infections (1.6-3.1%)
- Increased hematocrit (2.8%)
- Arthralgia (2.3-2.4%)
- Nausea (1.1-2.3%)
- Thirst (1.5-1.7%)
Linagliptin
- Nasopharyngitis (6.1-7%)
- Diarrhea (3-3.3%)
- Increased uric acid (2.7%)
- Cough (1.4-2.1%)
Metformin
- Decreased vitamin B-12 (~7%)
- Nausea (6.7%)
- Diarrhea (>5%)
- Nausea/vomiting (>5%)
- Flatulence (>5%)
- Abdominal discomfort (>5%)
- Indigestion (>5%)
- Asthenia (>5%)
- Headache (>5%)
<1%
Hypoglycemia (0.7%)
Postmarketing Reports
Acute pancreatitis, including fatal pancreatitis
Ketoacidosis
Urosepsis and pyelonephritis
Necrotizing fasciitis of the perineum (Fournier gangrene)
Hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions)
Severe and disabling arthralgia
Bullous pemphigoid
Skin reactions (eg, rash, urticaria)
Mouth ulceration, stomatitis
Warnings
Black Box Warnings
Lactic Acidosis
- Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias
- Onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain)
- Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL
- Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment
- Steps to reduce the risk of and to manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information
- If lactic acidosis is suspected, discontinue treatment and institute general supportive measures in a hospital setting
- Prompt hemodialysis is recommended
Contraindications
Severe renal impairment (eGFR <30 mL/min/1.73 m2), ESRD, or dialysis
Metabolic acidosis, including diabetic ketoacidosis
Hypersensitivity to empagliflozin, linagliptin, metformin, or any of the excipients in the product
Cautions
Drug combination not indicated for treatment of type 1 diabetes mellitus
Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported (see Black Box Warnings)
Postmarketing cases of serious urinary tract infections, including urosepsis, were reported; evaluate for signs and symptoms and treat appropriately
Serious hypersensitivity reactions, (eg, angioedema) in patients treated with empagliflozin reported postmarketing; discontinue therapy and treat promptly if it occurs per standard of care
There have been reports of acute pancreatitis, including fatal pancreatitis; if pancreatitis suspected, promptly discontinue
Heart failure observed with 2 other DPP-4 inhibitors; consider risks and benefits in patients with known risk factors for heart failure; monitor for signs and symptoms
Empagliflozin causes intravascular volume contraction; symptomatic hypotension may occur after starting therapy; postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis; assess volume status and correct
Necrotizing fasciitis of the perineum (Fournier gangrene) reported in postmarketing surveillance with SGLT2 inhibitors; it is a rare life-threatening necrotizing infection requiring urgent surgical intervention
Hypersensitivity reactions reported with linagliptin; onset of reactions occurred within the first 3 months after initiating linagliptin; exercise caution with history of angioedema to another DPP-4 inhibitor
In controlled clinical trials of metformin, a decrease to subnormal levels of serum vitamin B-12 levels, without clinical manifestations, was observed
Empagliflozin increases the risks of genital mycotic infections; patients with a history of genital mycotic infections were more likely to develop genital mycotic infections; monitor and treat appropriately
Increased LDL cholesterol may occur with empagliflozin; monitor LDL cholesterol and treat per standard of care
Severe and disabling arthralgia in patients taking DPP-4 inhibitors has been reported; consider discontinuing drug if DPP-4 inhibitor is a cause for severe joint pain
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use
Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level; if suspected, discontinue Trijardy XR, evaluate, and treat promptly; before initiating treatment, consider risk factors for ketoacidosis; may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis
Consider temporarily discontinuing therapy in any setting of reduced oral intake (eg, acute illness, fasting) or fluid losses (eg, gastrointestinal illness or excessive heat exposure); monitor for signs and symptoms of acute kidney injury; if acute kidney injury occurs, discontinue therapy promptly and institute treatment
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
Drug interaction overview
- Empagliflozin or linagliptin in combination with an insulin secretagogue (eg, sulfonylurea) or insulin was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial; metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue
- Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, dichlorphenamide) frequently decrease serum bicarbonate and induce nonanion gap, hyperchloremic metabolic acidosis
- 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
- Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids, which might enhance the potential for volume depletion
- Alcohol potentiates the effects of metformin on lactate metabolism
- Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer; use of alternatives is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer
- Certain drugs (eg, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, isoniazid) tend to produce hyperglycemia and may lead to loss of glycemic control
- SGLT2 inhibitors increase urinary glucose excretion and lead to positive urine glucose tests
- Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors
Pregnancy & Lactation
Pregnancy
Based on animal data showing adverse renal effects from empagliflozin, use is not recommended during the second and third trimesters of pregnancy
Limited data available with Trijardy XR, linagliptin, or empagliflozin in pregnant women are insufficient to determine a drug-associated risk for major birth defects and miscarriage
Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk
There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
Animal data
- In animal studies, empagliflozin resulted in adverse renal changes in rats when administered during a 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 that were reversible
- No adverse developmental effects were observed when linagliptin or metformin were administered to pregnant rats or rabbits
Clinical considerations
- Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications
- Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity
Females and males of reproductive potential
- Advise the potential for unintended pregnancy with premenopausal women treated with metformin may result in ovulation in some anovulatory women
Lactation
There is limited information regarding the presence of Trijardy XR or its components (empagliflozin, linagliptin, or metformin) in human milk, the effects on the breastfed infant, or the effects on milk production
Limited published studies report that metformin is present in human milk
Empagliflozin and linagliptin are present in rat milk
Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney
Owing to the potential for serious adverse reactions in a breastfed infant, including the potential for empagliflozin to affect postnatal renal development, advise patients that use is not recommended while breastfeeding
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Empagliflozin: 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
Linagliptin: DPP-4 inhibitor; increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzyme; incretins regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and reducing glucagon secretion from pancreatic alpha cells
Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and use; improves glucose tolerance and lowers both basal and postprandial plasma glucose
Absorption
Empagliflozin
- Peak plasma time: 1.5 hr
- Peak plasma concentration (steady-state): 259 nmol/L (10-mg dose); 687 nmol/L (25-mg dose)
- AUC (steady-state): 1870 nmol·hr/L (10-mg dose); 4740 nmol·hr/L (25-mg dose)
Linagliptin
- Absolute bioavailability: ~30%
- May be administered with or without food
Metformin
- Peak plasma time: ~7-8 hr
- Low- and high-fat meals prolonged metformin peak plasma time by ~3 hr, but peak plasma concentration was not affected
Distribution
Empagliflozin
- Vd (steady-state): 73.8 L
- Protein bound: 86.2%
Linagliptin
- Vd: 1110 L (single 5-mg IV dose)
- Protein bound: 70-80%
Metformin
- Vd: 654 L
- Negligibly bound to plasma proteins
Metabolism
Empagliflozin
- Studies suggest that the primary route of metabolism in humans is glucuronidation by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8, and UGT1A9
Elimination
Empagliflozin
- Half-life: 12.4 hr
- Oral clearance: 10.6 L/hr
- Excretion: Feces (41.2%); urine (54.4%)
Linagliptin
- Half-life (steady-state): ~200 hr (terminal): 11 hr (accumulation)
- Renal clearance (steady-state); ~70 mL/min
- Excretion: Enterohepatic system (80%); urine (5%)
Metformin
- Half-life: ~6.2 hr (plasma); 17.6 hr (blood)
Excretion: ~90% (renal)
Administration
Oral Administration
Take qDay with morning meal
Swallow whole; do not split, crush, dissolve, or chew
Storage
Tablet: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Protect from exposure to high humidity
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Formulary
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