Metformin

Dolutegravir inhibits OCT2 and potentially MATE1, may increase plasma concentrations of metformin.

Metformin is contraindicated with topiramate due to risk of metabolic acidosis.

Carbonic anhydrase inhibitor that decreases serum bicarbonate and induces metabolic acidosis, increasing risk for lactic acidosis when used with metformin.

Iodixanol may increase risk of metformin-induced lactic acidosis, possibly by worsening renal function. Stop metformin before iodixanol administration in patients with renal impairment, hepatic impairment, alcoholism, or heart failure.

Reduces metformin clearance by inhibiting renal tubular transport, increasing systemic exposure and lactic acidosis risk.

Carbonic anhydrase inhibitor that decreases serum bicarbonate and induces metabolic acidosis, increasing risk for lactic acidosis when used with metformin.

Reduces metformin clearance by inhibiting renal tubular transport, increasing systemic exposure and lactic acidosis risk.

Iodixanol may increase risk of metformin-induced lactic acidosis, possibly by worsening renal function. Stop metformin prior to iodixanol administration in patients with eGFR 30-60 mL/min/1.73 m² or hepatic impairment, alcoholism, or heart failure.

Iodinated contrast agents increase risk of metformin-induced lactic acidosis, possibly by worsening renal function. Stop metformin at or prior to IOHEXOL administration in patients with eGFR 30-60 mL/min/1.73m², hepatic impairment, alcoholism, heart failure, or intra-arterial contrast use.

Stop metformin at or prior to IOMERVU administration in patients with eGFR 30-60 mL/min/1.73m², hepatic impairment, alcoholism, or heart failure. Iodinated contrast agents increase risk of metformin-induced lactic acidosis through worsening renal function.

Iodinated contrast agents increase risk of metformin-induced lactic acidosis, possibly by worsening renal function. Stop metformin at time of or prior to iopamidol injection in patients with eGFR 30-60 mL/min/1.73 m² or history of hepatic impairment, alcoholism, or heart failure.

Iodinated contrast agents increase risk of metformin-induced lactic acidosis, possibly by worsening renal function. Stop metformin at or prior to IOPROMIDE administration in patients with eGFR 30-60 mL/min/1.73 m2, hepatic impairment, alcoholism, heart failure, or intra-arterial contrast use.

Iodinated contrast agents increase risk of metformin-induced lactic acidosis, possibly through worsening renal function. Stop metformin at or prior to IOVERSOL administration in patients with eGFR 30-60 mL/min/1.73 m² or with hepatic impairment, alcoholism, or heart failure.

May increase risk of lactic acidosis with metformin. Consider more frequent monitoring.

Reduces metformin clearance by inhibiting renal tubular transport, increasing systemic exposure and lactic acidosis risk.

Reduces metformin clearance by inhibiting renal tubular transport, increasing systemic exposure and lactic acidosis risk.

Carbonic anhydrase inhibitor that decreases serum bicarbonate and induces metabolic acidosis, increasing risk for lactic acidosis when used with metformin.

Potentiates metformin's effect on lactate metabolism, increasing lactic acidosis risk with excessive intake.

Diuretic that produces hyperglycemia and may lead to loss of glycemic control when used with metformin.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

Cephalexin increases plasma metformin concentrations and decreases renal clearance of metformin. Careful monitoring and dose adjustment of metformin is recommended.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

Increases digoxin concentrations; magnitude unclear. Requires monitoring and dose adjustment.

Dolutegravir may increase plasma concentrations of metformin via OCT2 or MATE1 inhibition; monitor for adverse effects.

Dolutegravir inhibits renal OCT2 and MATE1 transporters, which may increase plasma concentrations of metformin.

Dolutegravir inhibits OCT2 and MATE1, potentially increasing metformin plasma concentrations. Monitor renal function and metformin levels.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

INREBIC may decrease renal clearance of metformin via OCT2 and MATE1/2-K inhibition. Monitor for adverse reactions and consider dose modifications.

Single-dose study showed variable decreases in glyburide AUC and Cmax; clinical significance uncertain. Steady-state coadministration showed no pharmacokinetic/pharmacodynamic changes.

Metformin plasma levels may be elevated with glycopyrrolate, increasing pharmacologic and toxic effects. Monitor response and consider dose reduction.

Metformin plasma levels may be elevated with glycopyrrolate coadministration, increasing pharmacologic and toxic effects. Monitor response and consider dose reduction.

Coadministration with metformin may increase the risk of hypoglycemia.

Produces hyperglycemia and may lead to loss of glycemic control when used with metformin.

Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed.

Produces hyperglycemia and may lead to loss of glycemic control when used with metformin.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

Patiromer binds metformin, potentially reducing systemic exposure and clinical efficacy. Separate dosing by at least 3 hours.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

Produces hyperglycemia and may lead to loss of glycemic control when used with metformin.

Metformin treatment in patients with type 2 diabetes decreases serum folate and may decrease vitamin B12 absorption.

EVRYSDI may increase plasma concentrations of metformin, a MATE1/MATE2-K substrate. Avoid coadministration; if unavoidable, monitor for toxicities and consider dosage reduction.

Cases of interactions reported with metformin, an OCT2 substrate. Trimethoprim inhibits OCT2 transporter.

Insulin secretagogue that increases hypoglycemia risk when coadministered with metformin.

Tafenoquine may increase metformin concentrations through OCT2/MATE transporter inhibition, potentially increasing toxicity risk. Monitor for toxicity and consider dosage reduction.

Tafenoquine may increase metformin concentrations via OCT2/MATE transporter inhibition, raising toxicity risk. Monitor for toxicities and consider dosage reduction.

Produce hyperglycemia and may lead to loss of glycemic control when used with metformin.

Co-administration reduced steady-state systemic exposure of trospium by approximately 29% for AUC and 34% for Cmax; effect on trospium efficacy unknown.

Miglitol reduced mean AUC and Cmax values for metformin by 12-13%, but this difference was not statistically significant.

Warn patients against excessive alcohol intake ( 7 ) Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC inf C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [ See Warnings and Precautions (5.1) and Drug Interactions (7) .] Topiramate 5 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 5 mg metformin 1.25 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC AUC = AUC inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 Ratio of arithmetic means, p-value of difference < 0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 AUC 0-24hr reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01

Potential for drug-drug interaction due to possible competition for active tubular secretion via base-secreting system.

Warn patients against excessive alcohol intake ( 7 ) Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC inf C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [ See Warnings and Precautions (5.1) and Drug Interactions (7) .] Topiramate 5 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 5 mg metformin 1.25 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC AUC = AUC inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 Ratio of arithmetic means, p-value of difference < 0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 AUC 0-24hr reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01

Warn patients against excessive alcohol intake ( 7 ) Drug Interactions In Vivo Assessment of Drug Interactions Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 AUC AUC = AUC inf C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg metformin 0.91 Ratio of arithmetic means 0.93 Furosemide 40 mg 850 mg metformin 1.09 1.22 Nifedipine 10 mg 850 mg metformin 1.16 1.21 Propranolol 40 mg 850 mg metformin 0.90 0.94 Ibuprofen 400 mg 850 mg metformin 1.05 1.07 Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [ See Warnings and Precautions (5.1) and Drug Interactions (7) . ] Cimetidine 400 mg 850 mg metformin 1.40 1.61 Carbonic anhydrase inhibitors may cause metabolic acidosis [ See Warnings and Precautions (5.1) and Drug Interactions (7) .] Topiramate 5 mg At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC 0-12h 5 mg metformin 1.25 1.17 Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure Coadministered Drug Dose of Coadministered Drug All metformin hydrochloride and coadministered drugs were given as single doses Dose of Metformin Hydrochloride Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 AUC AUC = AUC inf unless otherwise noted C max No dosing adjustments required for the following: Glyburide 5 mg 850 mg glyburide 0.78 Ratio of arithmetic means, p-value of difference < 0.05 0.63 Furosemide 40 mg 850 mg furosemide 0.87 0.69 Nifedipine 10 mg 850 mg nifedipine 1.10 AUC 0-24hr reported 1.08 Propranolol 40 mg 850 mg propranolol 1.01 1.02 Ibuprofen 400 mg 850 mg ibuprofen 0.97 Ratio of arithmetic means 1.01 Cimetidine 400 mg 850 mg cimetidine 0.95 1.01