metformin/pioglitazone (Rx)

Brand and Other Names:ACTOplus Met, ACTOplus Met XR
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

metformin/pioglitazone

tablet

  • 500mg/15mg
  • 850mg/15mg

tablet, extended-release

  • 1,000mg/15mg
  • 1,000mg/30mg

Type 2 Diabetes Mellitus

Patients on metformin monotherapy: 15-30 mg/day pioglitazone plus dose of metformin at time of initiating therapy

Patients on pioglitazone monotherapy: 1000-1700 mg metformin/day plus dose of pioglitazone at time of initiating therapy

Not to exceed 45 mg pioglitazone/2550 mg metformin/day

Dosage Modifications

Renal impairment: Do not use

Hepatic impairment

  • Baseline ALT <2.5 xULN: Use caution
  • Baseline ALT ≥2.5 xULN: Do not administer
  • ALT >3 xULN or jaundice after initiating therapy: Discontinue

Renal impairment

  • Obtain eGFR before starting metformin
  • eGFR <30 mL/min/1.73 m²: Contraindicated
  • eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
  • Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
  • If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
  • If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug

Safety and efficacy not established

Type 2 Diabetes Mellitus

Same as adult dosing

Do not administer to patients >80 years before assessing renal function and determined to be normal

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Interactions

Interaction Checker

and metformin/pioglitazone

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              Serious - Use Alternative (16)

              • baricitinib

                pioglitazone will increase the level or effect of baricitinib by decreasing elimination. Avoid or Use Alternate Drug. Coadministration of baricitinib with strong organic anion transporter 3 (OAT3) inhibitors is not recommended.

              • 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.

              • eluxadoline

                pioglitazone increases levels of eluxadoline by decreasing metabolism. Avoid or Use Alternate Drug. Decrease eluxadoline dose to 75 mg PO BID if coadministered with OATP1B1 inhibitors. .

              • ethanol

                ethanol, pioglitazone. Other (see comment). Contraindicated. Comment: Excessive EtOH consumption may alter glycemic control. Some sulfonylureas may produce a disulfiram like rxn.

                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.

              • gemfibrozil

                gemfibrozil will increase the level or effect of pioglitazone by decreasing metabolism. Avoid or Use Alternate Drug.

              • ioversol

                ioversol increases levels of metformin by decreasing renal clearance. Contraindicated. Acute renal failure or lactic acidosis may result. D/c metformin 48 hr before and after imaging study.

              • methylene blue

                methylene blue will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.

              • ranolazine

                ranolazine will increase the level or effect of metformin by decreasing elimination. Avoid or Use Alternate Drug. Limit metformin dose to 1700 mg/day when used together with ranolazine 1000 mg twice daily; monitor closelly for signs or symptoms of metformin toxicity

              • risdiplam

                risdiplam will increase the level or effect of metformin by decreasing elimination. Avoid or Use Alternate Drug. Risdiplam inhibits MATE1 and MATE2-K. If unable to avoid coadministration with MATE substrates, consider dosage reduction of MATE substrate.

              • selegiline

                selegiline will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.

              • selegiline transdermal

                selegiline transdermal will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.

              • tafenoquine

                tafenoquine will increase the level or effect of metformin by Other (see comment). Avoid or Use Alternate Drug. Tafenoquine inhibits organic cation transporter-2 (OCT2) and multidrug and toxin extrusion (MATE) transporters in vitro. Avoid coadministration with OCT2 or MATE substrates. If coadministration cannot be avoided, monitor for substrate-related toxicities and consider dosage reduction if needed based on product labeling of the coadministered drug.

              • tedizolid

                tedizolid will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.

              • tranylcypromine

                tranylcypromine will increase the level or effect of metformin by unspecified interaction mechanism. Avoid or Use Alternate Drug.

              • trilaciclib

                trilaciclib will decrease the level or effect of metformin by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of trilaciclib (OCT2, MATE1, and MATE-2K inhibitor) with substrates where minimal increased concentration in kidney or blood may lead to serious or life-threatening toxicities.

              • tucatinib

                pioglitazone will increase the level or effect of tucatinib by Other (see comment). Avoid or Use Alternate Drug. Coadministration of tucatinib (a CYP2C8 substrate) with a strong or moderate CYP2C8 inhibitors increases tucatinib plasma concentrations and risk of toxicities.

              Monitor Closely (242)

              • 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.

                albiglutide, pioglitazone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.

              • amiodarone

                amiodarone will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

              • aripiprazole

                aripiprazole, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • amlodipine

                amlodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • aripiprazole

                aripiprazole, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • asenapine

                asenapine, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

                asenapine, 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. .

              • atogepant

                pioglitazone will decrease the level or effect of atogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • atorvastatin

                pioglitazone increases toxicity of atorvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • axitinib

                pioglitazone decreases levels of axitinib 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.

              • 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 increases effects of pioglitazone by pharmacodynamic synergism. Use Caution/Monitor. Based on the mechanism of action, bexarotene capsules may increase the action of insulin enhancing agents, resulting in hypoglycemia. Hypoglycemia has not been associated with bexarotene monotherapy.

              • 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 pioglitazone by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypoglycemia.

                bitter melon increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Risk of hypoglycemia.

              • brexpiprazole

                brexpiprazole decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • cannabidiol

                cannabidiol will increase the level or effect of pioglitazone by decreasing metabolism. Modify Therapy/Monitor Closely. Cannabidiol may potentially inhibit CYP2C8 activity. Consider reducing the dose when concomitantly using CYP2C8 substrates.

              • bumetanide

                bumetanide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • bupropion

                bupropion increases levels of metformin by Other (see comment). Use Caution/Monitor. Comment: Bupropion may inhibit OCT2 mediated renal excretion of metformin.

              • captopril

                captopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.

              • carbamazepine

                carbamazepine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • cariprazine

                cariprazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • cephalexin

                cephalexin increases toxicity of metformin by decreasing renal clearance. Use Caution/Monitor. particularly in patients who may have other risk factors for metformin toxicity. .

              • ceritinib

                ceritinib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • chlorpromazine

                chlorpromazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • cholic acid

                pioglitazone increases toxicity of cholic acid by decreasing elimination. Modify Therapy/Monitor Closely. Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP). May exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is necessary, monitor serum transaminases and bilirubin.

              • cimetidine

                cimetidine will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

                cimetidine will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • cinnamon

                cinnamon increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Potential for hypoglycemia.

                cinnamon increases effects of pioglitazone 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.

                ciprofloxacin increases effects of pioglitazone 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.

              • clarithromycin

                clarithromycin will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • clevidipine

                clevidipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • clozapine

                clozapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

                clozapine, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • colesevelam

                colesevelam increases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • dienogest/estradiol valerate

                pioglitazone will decrease the level or effect of dienogest/estradiol valerate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Advise women to use alternative method of contraception or back-up method when moderate or weak enzyme inducer is used with combination contraceptives. Back-up contraception should be continued for 28 days after discontinuing medication to ensure contraceptive reliability.

              • conjugated estrogens

                conjugated estrogens decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • corticotropin

                corticotropin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • dabrafenib

                dabrafenib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • dalfampridine

                metformin, dalfampridine. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Metformin and dalfampridine are organic cation transporter 2 (OCT2) substrates; both drugs may compete for renal tubular uptake and could potentially increase systemic exposure of either drug when administered concomitantly.

              • darunavir

                darunavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • desogestrel

                desogestrel decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • diatrizoate

                diatrizoate increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • diatrizoate meglumine/diatrizoate sodium

                diatrizoate meglumine/diatrizoate sodium increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • diazoxide

                diazoxide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • dichlorphenamide

                dichlorphenamide, metformin. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis.

              • dienogest/estradiol valerate

                dienogest/estradiol valerate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • diethylpropion

                diethylpropion decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • digoxin

                digoxin, metformin. Either increases levels of the other by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor. Measure serum digoxin concentrations before initiating metformin. Monitor patients who take both metformin and digoxin for possible digoxin toxicity and lactic acidosis. Reduce the digoxin and/or metformin dose as necessary.

              • diltiazem

                diltiazem decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

                diltiazem will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • dofetilide

                dofetilide will increase the level or effect of metformin by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

              • dulaglutide

                dulaglutide, pioglitazone. 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.

              • dolutegravir

                dolutegravir will increase the level or effect of metformin by decreasing renal clearance. Modify Therapy/Monitor Closely. Dolutegravir inhibits the renal organic cation transporter, OCT2; when used with metformin, limit total daily dose of metformin to 1,000 mg either when starting metformin or dolutegravir; when stopping dolutegravir, adjustment of metformin dose may be necessary; monitor blood glucose when initiating concomitant use and after withdrawal of dolutegravir

              • drospirenone

                drospirenone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • dulaglutide

                dulaglutide, metformin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • enalapril

                enalapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.

              • entecavir

                entecavir, metformin. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Coadministration of entecavir with metformin may increase the risk of lactic acidosis.

              • 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.

              • erythromycin base

                erythromycin base will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • erythromycin lactobionate

                erythromycin lactobionate will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • erythromycin stearate

                erythromycin stearate will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • escitalopram

                escitalopram increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.

              • estradiol

                estradiol decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • estrogens conjugated synthetic

                estrogens conjugated synthetic decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • estropipate

                estropipate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • ethacrynic acid

                ethacrynic acid decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • ethinylestradiol

                pioglitazone decreases levels of ethinylestradiol by unknown mechanism. Use Caution/Monitor.

                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. .

              • exenatide injectable solution

                exenatide injectable solution, pioglitazone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.

              • 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.

                exenatide injectable suspension, pioglitazone. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Concurrent use may increase risk of hypoglycemia; monitor glucose levels.

              • felodipine

                felodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • fleroxacin

                fleroxacin increases effects of pioglitazone 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.

              • 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.

              • fluvastatin

                pioglitazone increases toxicity of fluvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • fluvoxamine

                fluvoxamine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.

              • fosamprenavir

                fosamprenavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • fosinopril

                fosinopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.

              • fosphenytoin

                fosphenytoin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • 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.

                gemifloxacin increases effects of pioglitazone 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

                pioglitazone will increase the level or effect of glecaprevir/pibrentasvir by decreasing metabolism. Use Caution/Monitor. Caution when coadministering glecaprevir/pibrentasvir with OATP1B1/OATP1B3 inhibitors

              • glucagon intranasal

                glucagon intranasal decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • glycopyrrolate

                glycopyrrolate increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. May require a dose reduction.

              • goserelin

                goserelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • histrelin

                histrelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • hydroxyprogesterone caproate

                hydroxyprogesterone caproate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • ifosfamide

                pioglitazone increases toxicity of ifosfamide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inducers may increase the metabolism of ifosfamide to its active alkylating metabolites. CYP3A4 inducers may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde. Closely monitor patients taking ifosfamide with CYP3A4 inducers for toxicities and consider dose adjustment.

              • 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.

                iloperidone, pioglitazone. 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.

              • insulin aspart

                insulin aspart increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

                pioglitazone, 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.

              • indinavir

                indinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • insulin aspart

                metformin, insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • insulin aspart protamine/insulin aspart

                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.

                pioglitazone, 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

                pioglitazone, 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.

                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.

              • insulin degludec/insulin aspart

                pioglitazone, insulin degludec/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                metformin, insulin degludec/insulin aspart. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • insulin detemir

                pioglitazone, 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.

                metformin, insulin detemir. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                insulin detemir increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

              • 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.

                pioglitazone, insulin glargine. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                insulin glargine increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

              • insulin glulisine

                pioglitazone, 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.

                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.

                insulin glulisine increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

              • insulin inhaled

                pioglitazone, insulin inhaled. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                metformin, insulin inhaled. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • insulin isophane human/insulin regular human

                pioglitazone, insulin isophane human/insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                metformin, insulin isophane human/insulin regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • insulin lispro

                insulin lispro increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

                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.

                pioglitazone, 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

                pioglitazone, insulin lispro protamine/insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                metformin, insulin lispro protamine/insulin lispro. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

              • insulin NPH

                insulin NPH increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

                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.

                pioglitazone, 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

                pioglitazone, 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 regular human. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Antidiabetic agents are often used in combination; dosage adjustments may be required when initiating or discontinuing antidiabetic agents.

                insulin regular human increases toxicity of pioglitazone by unknown mechanism. Use Caution/Monitor. Insulin may increase the fluid retention associated with thiazolidinediones (peroxisome proliferator-activated receptor [PPAR]-gamma agonists).

              • 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. .

              • isavuconazonium sulfate

                pioglitazone will decrease the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • ioflupane I 123

                ioflupane I 123 increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • iohexol

                iohexol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • iopamidol

                iopamidol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • iopromide

                iopromide increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • ioversol

                ioversol increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • ioxilan

                ioxilan increases toxicity of metformin by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Administration of intravascular iodinated contrast agents in metformin-treated patients has led to rare cases of acute decrease in renal function and the occurrence of lactic acidosis. The American College of Radiology Guidelines (2018) recommend temporarily stopping metformin in patients with eGFR is <30 mL/min/1.73 m2 or who are undergoing arterial catheter studies that might result in emboli to the renal arteries. Continue to withhold metformin for 48 hr subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal. .

              • isocarboxazid

                isocarboxazid will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.

              • isoniazid

                isoniazid decreases effects of metformin by unspecified interaction mechanism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • isradipine

                isradipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • ketoconazole

                ketoconazole will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • ketotifen, ophthalmic

                ketotifen, ophthalmic, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Combination may result in thrombocytopenia (rare). Monitor CBC.

                ketotifen, ophthalmic, metformin. Other (see comment). Use Caution/Monitor. Comment: Combination may result in thrombocytopenia (rare). Monitor CBC.

              • lanreotide

                lanreotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • letermovir

                letermovir, pioglitazone. Either increases levels of the other by Other (see comment). Use Caution/Monitor. Comment: Coadminstration of letermovir, an OATP1B1/3 substrate, with OATP1B1/3 inhibitors may increase letermovir plasma concentrations. Monitor glucose levels.

              • 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.

                levofloxacin increases effects of pioglitazone by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.

              • levonorgestrel intrauterine

                levonorgestrel intrauterine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • linagliptin

                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

              • 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.

                liraglutide, pioglitazone. 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.

              • lurasidone

                lurasidone, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • lopinavir

                lopinavir decreases effects of metformin 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.

              • marijuana

                marijuana decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

                marijuana decreases effects of pioglitazone by pharmacodynamic antagonism. Use Caution/Monitor.

              • mecasermin

                mecasermin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Additive hypoglycemic effects.

                mecasermin increases effects of pioglitazone by pharmacodynamic synergism. Use Caution/Monitor. Additive hypoglycemic effects.

              • medroxyprogesterone

                medroxyprogesterone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • mifepristone

                mifepristone will increase the level or effect of pioglitazone by Other (see comment). Use Caution/Monitor. Inhibits CYP2C8/2C9; use smallest recommended doses for substrates and 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.

              • mipomersen

                mipomersen, pioglitazone. Either increases toxicity of the other by Other (see comment). Use Caution/Monitor. Comment: Both drugs have potential to increase hepatic enzymes; monitor LFTs.

              • 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.

                moxifloxacin increases effects of pioglitazone 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.

              • nefazodone

                nefazodone will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • nelfinavir

                nelfinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • niacin

                niacin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • nicardipine

                nicardipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • nifedipine

                nifedipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • nilotinib

                nilotinib decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • nimodipine

                nimodipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • nisoldipine

                nisoldipine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • nizatidine

                nizatidine will increase the level or effect of metformin by decreasing renal clearance. Modify Therapy/Monitor Closely.

              • norelgestromin

                norelgestromin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • norethindrone

                norethindrone decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • norgestimate

                norgestimate decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • octreotide

                octreotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • ofloxacin

                ofloxacin increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Quinolone antibiotic administration may result in hyper- or hypoglycemia. Gatifloxacin is most likely to produce dysglycemia; moxifloxacin is least likely.

                ofloxacin increases effects of pioglitazone 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.

                olanzapine, pioglitazone. 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.

              • opuntia ficus indica

                opuntia ficus indica increases effects of pioglitazone by pharmacodynamic synergism. Use Caution/Monitor.

              • ombitasvir/paritaprevir/ritonavir & dasabuvir

                ombitasvir/paritaprevir/ritonavir & dasabuvir 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.

              • paclitaxel

                pioglitazone will increase the level or effect of paclitaxel by Other (see comment). Use Caution/Monitor. Paclitaxel levels/toxicity may increase when coadministered with CYP2C8 inhibitors

              • paclitaxel protein bound

                pioglitazone will increase the level or effect of paclitaxel protein bound by Other (see comment). Use Caution/Monitor. Paclitaxel levels/toxicity may increase when coadministered with CYP2C8 inhibitors

              • paliperidone

                paliperidone, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

                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.

              • pitavastatin

                pioglitazone increases toxicity of pitavastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • pasireotide

                pasireotide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • patiromer

                patiromer will decrease the level or effect of metformin by drug binding in GI tract. Use Caution/Monitor. May administer 3 hours apart

              • pentamidine

                pentamidine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • perindopril

                perindopril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.

              • perphenazine

                perphenazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • phendimetrazine

                phendimetrazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • phenelzine

                phenelzine will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.

              • phentermine

                phentermine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • phenytoin

                phenytoin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • ponatinib

                pioglitazone increases toxicity of ponatinib by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • pravastatin

                pioglitazone increases toxicity of pravastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • procainamide

                metformin will increase the level or effect of procainamide by basic (cationic) drug competition for renal tubular clearance. Use Caution/Monitor.

              • procarbazine

                procarbazine will increase the level or effect of metformin by unspecified interaction mechanism. Use Caution/Monitor.

              • prochlorperazine

                prochlorperazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • progesterone intravaginal gel

                progesterone intravaginal gel decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • progesterone micronized

                progesterone micronized decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • progesterone, natural

                progesterone, natural decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • promethazine

                promethazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • quetiapine

                quetiapine, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

                quetiapine, pioglitazone. 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.

              • rifabutin

                rifabutin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • 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.

              • rifampin

                rifampin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • risperidone

                risperidone, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

                risperidone, metformin. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • ritonavir

                ritonavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • rosuvastatin

                pioglitazone increases toxicity of rosuvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • sacubitril/valsartan

                pioglitazone will increase the level or effect of sacubitril/valsartan by Other (see comment). Use Caution/Monitor. The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1; coadministration with OATP1B1 inhibitors may increase valsartan systemic exposure

              • saquinavir

                saquinavir decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Reports of hyperglycemia due to insulin resistance with protease inhibitors. .

              • selexipag

                pioglitazone will increase the level or effect of selexipag by decreasing metabolism. Modify Therapy/Monitor Closely. Reduce selexipag dose to once daily if coadministered with moderate CYP2C8 inhibitors.

              • sertraline

                sertraline increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.

              • shark cartilage

                shark cartilage increases effects of pioglitazone by pharmacodynamic synergism. Use Caution/Monitor. Theoretical interaction.

                shark cartilage increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor. Theoretical interaction.

              • simvastatin

                pioglitazone increases toxicity of simvastatin by Other (see comment). Use Caution/Monitor. Comment: OATP1B1 inhibitors may increase risk of myopathy.

              • sirolimus

                sirolimus decreases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • somapacitan

                somapacitan decreases effects of pioglitazone by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone products may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating somapacitan. .

                somapacitan decreases effects of metformin by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Growth hormone products may decrease insulin sensitivity, particularly at higher doses. Antidiabetic agents may require dose adjustment after initiating somapacitan. .

              • St John's Wort

                St John's Wort will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • somatropin

                somatropin decreases levels of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • stiripentol

                stiripentol will increase the level or effect of pioglitazone by Other (see comment). Modify Therapy/Monitor Closely. Stiripentol is a CYP2C8 inhibitor. Consider dosage reduction for CYP2C8 substrates if adverse effects are experienced when coadministered.

              • sulfamethoxypyridazine

                sulfamethoxypyridazine increases effects of metformin by unspecified interaction mechanism. Use Caution/Monitor. Risk of hypoglycemia.

                sulfamethoxypyridazine increases effects of pioglitazone by unspecified interaction mechanism. Use Caution/Monitor. Risk of hypoglycemia.

              • tacrolimus

                tacrolimus decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • tazemetostat

                pioglitazone will decrease the level or effect of tazemetostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tecovirimat

                tecovirimat will increase the level or effect of pioglitazone by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor. Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19. Monitor for adverse effects if coadministered with substrates of these enzymes. Monitor blood glucose and monitor for hypoglycemic symptoms.

              • 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.

              • teriflunomide

                teriflunomide increases levels of pioglitazone by Other (see comment). Use Caution/Monitor. Comment: Teriflunomide inhibits CYP2C8; caution when coadministered with CYP2C8 substrates.

              • 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, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Tipranavir's effect on oral hypoglycemics via hepatic CYP2C9 unknown; carefully monitor blood glucose.

              • 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.

              • triamcinolone acetonide injectable suspension

                triamcinolone acetonide injectable suspension decreases effects of pioglitazone by pharmacodynamic antagonism. Use Caution/Monitor. Corticosteroids may diminish hypoglycemic effect of antidiabetic agents. Monitor blood glucose levels carefully.

              • torsemide

                torsemide decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • trandolapril

                trandolapril increases toxicity of metformin by unspecified interaction mechanism. Use Caution/Monitor. Increases risk for hypoglycemia and lactic acidosis.

              • triamcinolone acetonide injectable suspension

                triamcinolone acetonide injectable suspension decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Corticosteroids may diminish hypoglycemic effect of antidiabetic agents. Monitor blood glucose levels carefully.

              • trifluoperazine

                trifluoperazine decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor. Patient should be closely observed for loss of blood glucose control; when drugs are withdrawn from a patient receiving metformin, patient should be observed closely for hypoglycemia.

              • trimethoprim

                trimethoprim increases levels of metformin by Other (see comment). Use Caution/Monitor. Comment: Trimethoprim may inhibit active renal tubular secretion of metformin (eg, via OCT2, MATE1); dose adjustments may be necessary.

              • triptorelin

                triptorelin decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • trospium chloride

                metformin will decrease the level or effect of trospium chloride by increasing renal clearance. Use Caution/Monitor. Coadministration reduced steady state trospium systemic exposure (decreased AUC and Cmax) by competing for renal tubular secretion

              • ubrogepant

                pioglitazone will decrease the level or effect of ubrogepant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Dose adjustment is recommended with concomitant use of ubrogepant and moderate and weak CYP3A4 inducers. (see Dosage Modifications)

              • valsartan

                pioglitazone will increase the level or effect of valsartan by Other (see comment). Use Caution/Monitor. The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1; coadministration with OATP1B1 inhibitors may increase valsartan systemic exposure

              • vandetanib

                vandetanib increases levels of metformin by Other (see comment). Modify Therapy/Monitor Closely. Comment: Vandetanib inhibits the uptake of substrates of organic cation transporter type 2 (OCT2).

              • verapamil

                verapamil decreases effects of metformin by Other (see comment). Use Caution/Monitor. Comment: Verapamil may inhibit hepatic uptake of metformin by OCT1 and/or other transporters.

              • vilazodone

                vilazodone increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.

              • vorinostat

                vorinostat decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

              • vortioxetine

                vortioxetine increases effects of metformin by pharmacodynamic synergism. Use Caution/Monitor.

              • xipamide

                xipamide decreases levels of pioglitazone by increasing renal clearance. Use Caution/Monitor.

                xipamide decreases levels of metformin by increasing renal clearance. Use Caution/Monitor.

              • ziprasidone

                ziprasidone, 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.

                ziprasidone, pioglitazone. Other (see comment). Use Caution/Monitor. Comment: Atypical antipsychotics have been associated with hyperglycemia that may alter blood glucose control; monitor glucose levels closely.

              • zonisamide

                zonisamide increases toxicity of metformin by Other (see comment). Use Caution/Monitor. Comment: Decreases serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis.

              Minor (149)

              • agrimony

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

                agrimony increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • American ginseng

                American ginseng increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • amitriptyline

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

                amitriptyline increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • amobarbital

                amobarbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • amoxapine

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

              • amoxapine

                amoxapine increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • anamu

                anamu increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Theoretical interaction.

                anamu increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Theoretical interaction.

              • aprepitant

                aprepitant will increase the level or effect of pioglitazone 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.

              • armodafinil

                armodafinil will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • artemether/lumefantrine

                artemether/lumefantrine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • atazanavir

                atazanavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • bendroflumethiazide

                bendroflumethiazide decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • bosentan

                bosentan will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • budesonide

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

                budesonide will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

                budesonide decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

              • butabarbital

                butabarbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • chlorothiazide

                chlorothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • butalbital

                butalbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • chlorothiazide

                chlorothiazide decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • chlorthalidone

                chlorthalidone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

                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 pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • clomipramine

                clomipramine increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • clonidine

                clonidine, pioglitazone. Other (see comment). Minor/Significance Unknown. Comment: Decreased symptoms of hypoglycemia. Mechanism: decreased hypoglycemia induced catecholamine production.

                clonidine decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Diminished symptoms of hypoglycemia.

                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.

              • conivaptan

                conivaptan will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • cornsilk

                cornsilk increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • cornsilk

                cornsilk increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • cortisone

                cortisone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

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

                cortisone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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 pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • cyclopenthiazide

                cyclopenthiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • damiana

                damiana decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Theoretical interaction.

                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.

                danazol increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • darifenacin

                darifenacin will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • deflazacort

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

              • darunavir

                darunavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • dasatinib

                dasatinib will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • deferasirox

                deferasirox will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • deflazacort

                deflazacort decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

              • desipramine

                desipramine increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

                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.

                devil's claw increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • dexamethasone

                dexamethasone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

                dexamethasone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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

              • DHEA, herbal

                DHEA, herbal will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.

                doxepin increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • dronedarone

                dronedarone will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • elderberry

                elderberry increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (in vitro research).

              • efavirenz

                efavirenz will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • elderberry

                elderberry increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (in vitro research).

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • etravirine

                etravirine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • eucalyptus

                eucalyptus increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Theoretical interaction.

                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.

              • fluconazole

                fluconazole will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • fludrocortisone

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

                fludrocortisone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

                fludrocortisone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

              • fluoxymesterone

                fluoxymesterone increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • fo-ti

                fo-ti increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

                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 pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Colenol, a compound found in Coleus root, may stimulate insulin release.

              • forskolin

                forskolin increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Colenol, a compound found in Coleus root, may stimulate insulin release.

              • fosamprenavir

                fosamprenavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • 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 pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).

                gotu kola increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).

              • grapefruit

                grapefruit will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • 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.

              • griseofulvin

                griseofulvin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • guanfacine

                guanfacine decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Diminished symptoms of hypoglycemia.

                guanfacine, pioglitazone. 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.

                gymnema increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • horse chestnut seed

                horse chestnut seed increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown.

                horse chestnut seed increases effects of pioglitazone 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 pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

                hydrochlorothiazide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • hydrocortisone

                hydrocortisone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

                hydrocortisone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

                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 pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • imipramine

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

              • indapamide

                indapamide decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

                indapamide decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • indinavir

                indinavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • L-methylfolate

                metformin decreases levels of L-methylfolate by unspecified interaction mechanism. Minor/Significance Unknown.

              • juniper

                juniper increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • isoniazid

                isoniazid will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

                isoniazid decreases effects of pioglitazone by unspecified interaction mechanism. Minor/Significance Unknown.

              • juniper

                juniper increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • lofepramine

                lofepramine increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • lumefantrine

                lumefantrine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • lycopus

                lycopus increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • lycopus

                lycopus increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (theoretical interaction).

              • maitake

                maitake increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. Increased risk of hypoglycemia (animal research).

                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.

                maprotiline increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • marijuana

                marijuana will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. 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.

                mesterolone increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • mestranol

                pioglitazone decreases levels of mestranol by unknown mechanism. 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.

              • methyclothiazide

                methyclothiazide decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • methylprednisolone

                methylprednisolone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown.

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

                methylprednisolone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • methyltestosterone

                methyltestosterone increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

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

              • metolazone

                metolazone decreases effects of pioglitazone by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

                metolazone decreases effects of metformin by pharmacodynamic antagonism. Minor/Significance Unknown. Thiazide dosage >50 mg/day may increase blood glucose.

              • metronidazole

                metronidazole will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • midodrine

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

              • miconazole vaginal

                miconazole vaginal will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • modafinil

                modafinil will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • nelfinavir

                nelfinavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • nettle

                nettle increases effects of metformin by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).

                nettle increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown. (Theoretical interaction).

              • nevirapine

                nevirapine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • nifedipine

                nifedipine increases levels of metformin by enhancing GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

              • nifedipine

                nifedipine will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • nilotinib

                nilotinib will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • nortriptyline

                nortriptyline increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

                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.

                ofloxacin, pioglitazone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Potential dysglycemia.

              • oxandrolone

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

                oxandrolone increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • oxcarbazepine

                oxcarbazepine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • oxymetholone

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

              • oxymetholone

                oxymetholone increases effects of pioglitazone by pharmacodynamic synergism. Minor/Significance Unknown.

              • pegvisomant

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

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

              • pentobarbital

                pentobarbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • potassium acid phosphate

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

              • phenobarbital

                phenobarbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • phenytoin

                phenytoin will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • posaconazole

                posaconazole will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • potassium acid phosphate

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

              • potassium chloride

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

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

              • potassium citrate

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

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

              • prednisolone

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

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

              • prednisone

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

                prednisone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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

              • primidone

                primidone will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • protriptyline

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

              • protriptyline

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

              • quinine

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

              • quinupristin/dalfopristin

                quinupristin/dalfopristin will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • rifapentine

                rifapentine will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • ritonavir

                ritonavir will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • rufinamide

                rufinamide will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • sage

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

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

              • secobarbital

                secobarbital will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • stevia

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

              • stevia

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

              • sulfamethoxazole

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

              • testosterone

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

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

              • testosterone buccal system

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

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

              • testosterone topical

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

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

              • tongkat ali

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

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

              • topiramate

                topiramate will decrease the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • trazodone

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

              • trazodone

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

              • triamterene

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

              • trimethoprim

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

              • trimipramine

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

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

              • vanadium

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

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

              • verapamil

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

                verapamil will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • voriconazole

                voriconazole will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

              • zafirlukast

                zafirlukast will increase the level or effect of pioglitazone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

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              Adverse Effects

              >10%

              Lower limb edema (2.9-11.3%)

              Upper respiratory infection (12-16)

              1-10%

              Weight gain (2.9-6.7%)

              Diarrhea (4.8-5.8%)

              Nausea (3.6-5.8%)

              Urinary tract infection (5.3-5.8%)

              Dizziness (4.8-5.4%)

              Headache (4.6-5.3%)

              Sinusitis (4.4-5%)

              Edema (3%)

              Postmarketing Reports

              Hepatitis and hepatic enzyme elevations to >3 XUL, including very rare incidences of hepatic failure with and without fatal outcome

              Cholestatic, hepatocellular, and mixed hepatocellular liver injury

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              Warnings

              Black Box Warnings

              Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast

              Congestive heart failure

              • Thiazolidinediones, including pioglitazone and rosiglitazone, cause or exacerbate congestive heart failure in some patients
              • Monitor carefully after initiation or dose increases for signs and symptoms of heart failure (including excessive, rapid weight gain; dyspnea; and/or edema); if these signs or symptoms develop, manage heart failure according current standards of care; consider discontinuing or reducing dose
              • Not recommended in patients with symptomatic heart failure; initiation of these drugs in patients with established NYHA class III or IV heart failure is contraindicated

              Lactic acidosis

              • Characterized by elevated blood lactate levels (>5 mmol/L)
              • Rare but serious complication that can occur because of metformin accumulation; increased risk with sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure
              • Subtle onset with nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, nonspecific abdominal distress)
              • Monitor lab for decreased serum pH, increased anion gap, and elevated blood lactate If suspected, discontinue drug and hospitalize patient immediately
              • Metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions); prompt hemodialysis is recommended to correct the acidosis and to remove accumulated metformin

              Contraindications

              Hypersensitivity

              Severe renal disease: eGFR <30 ml/min/1.73 m²

              Acute or chronic metabolic acidosis, including DKA with or without coma

              NYHA Class III or IV heart failure

              Cautions

              Temporarily discontinue in patients undergoing radiologic exams using iodinated contrast agents

              Do not initiate in patients aged ≥80 years CrCl demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis

              Withhold metformin in presence of any condition associated with hypoxemia, dehydration, or sepsis

              Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia); lactic acidosis is a medical emergency that must be treated in a hospital setting

              Pioglitazone may cause fluid retention and cause or exacerbate existing heart failure

              Edema; thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin

              Pioglitazone exerts its antihyperglycemic effect only in presence of insulin; therefore, do not use in type 1 diabetes mellitus or for treatment of diabetic ketoacidosis

              May cause hypoglycemia; patients receiving therapy in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia; a reduction in dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia; hypoglycemia can also occur when caloric intake is deficient or when strenuous be necessary to reduce the risk of hypoglycemia exercise is not compensated by caloric supplement; hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs

              Rare reports of hepatitis and hepatic enzyme elevations to >3 xULN, including very rare incidences of hepatic failure with and without fatal outcome

              In controlled clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, reported; certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; in these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful

              Metformin is substantially excreted by kidney, and risk of metformin accumulation and lactic acidosis increases with degree of renal impairment

              Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis; therapy is not recommended in patients with hepatic impairment

              Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin/pioglitazone, may result in ovulation in some anovulatory women

              Drug interactions review

              • Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis; concomitant use of these drugs with metformin/pioglitazone combination may increase risk for lactic acidosis; consider more frequent monitoring of these patients
              • Drugs that are eliminated by renal tubular secretion (e.g., cationic drugs such as cimetidine) have potential for interaction with metformin by competing for common renal tubular transport systems, and may increase accumulation of metformin and risk for lactic acidosis; consider more frequent monitoring of these patients
              • Alcohol is known to potentiate the effect of metformin on lactate metabolism; warn patients against excessive alcohol intake while receiving therapy
              • If hypoglycemia occurs in a patient coadministered pioglitazone/metformin and an insulin secretagogue (e.g., sulfonylurea), the dose of insulin secretagogue should be reduced; if hypoglycemia occurs in a patient coadministered and insulin, the dose of insulin should be decreased by 10% to 25%; further adjustments to insulin dose should be individualized based on glycemic response

              Iodinated contrast imaging procedures

              • Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
              • Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable

              Cancer risk

              • Bladder cancer
                • Pioglitazone may be linked to an increased risk of bladder cancer
                • Do not prescribe for patients with active bladder cancer
                • Consider benefit:risk ratio before prescribing in patients with a history of bladder cancer
                • Instruct patients to contact their physician if signs of bladder cancer observed after initiating therapy (eg, blood or red colored urine, new or worsening urinary urgency, pain on urination)
              • Prostate cancer
                • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for prostate cancer (453.3 vs. 449.3 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]
              • Pancreatic cancer
                • 7/22/2015: Compared with nonuse, pioglitazone use was associated with increased risk for pancreatic cancer (81.1 vs. 48.4 per 100,000 person-years) [JAMA 2015 July 21;314(3):265-277]
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              Pregnancy & Lactation

              Pregnancy: Limited data with metformin/pioglitazone or pioglitazone in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage; poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications; poorly controlled diabetes increases fetal risk for major birth defects, still birth, and macrosomia related morbidity

              Lactation: There is no information regarding the presence of metformin/pioglitazone or pioglitazone in human milk; effects on breastfed infant, or effects on milk production; there is insufficient information on effects of metformin on breastfed infant and no available information on effects of metformin on milk production; developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed infant from metformin/pioglitazone or from underlying maternal condition

              Pregnancy Categories

              A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

              B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

              C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

              D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

              X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

              NA: Information not available.

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              Pharmacology

              Mechanism of Action

              Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose

              Pioglitazone: Thiazolidinedione; insulin-sensitizing agent that acts by enhancing peripheral glucose utilization; decreased insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output

              Pharmacokinetics

              Peak plasma time (ACTOplus Met)

              • pioglitazone: 1.7-2 hr
              • metformin: 2.3-2.5 hr

              Peak plasma time (ACTOplus Met XR)

              • pioglitazone: 3-3.5 hr
              • metformin: 6.9-8 hr

              Peak plasma concentration (ACTOplus Met)

              • pioglitazone: 659-608 ng/mL
              • metformin: 1,203-1,827 ng/mL

              Peak plasma concentration (ACTOplus Met XR)

              • pioglitazone: 487-866 ng/mL
              • metformin: 1,322-1,590 ng/mL

              AUC (ACTOplus Met)

              • pioglitazone: 5,671-5,984 ng•hr/mL
              • metformin: 7,599-11,927 ng•hr/mL

              AUC (ACTOplus Met XR)

              • pioglitazone: 5,113-9,177 ng•hr/mL
              • metformin: 12,705-14,787 ng•hr/mL

              Half-Life (ACTOplus Met)

              • pioglitazone: 7.2-8.7 hr
              • metformin: 6.7-17.6 hr

              Half-Life (ACTOplus Met XR)

              • pioglitazone: 5.8-7.6 hr
              • metformin: 11-11.7 hr
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              Images

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              Patient Handout

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

              FormularyPatient Discounts

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

              Tier Description
              1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
              2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
              3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
              4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
              NC NOT COVERED – Drugs that are not covered by the plan.
              Code Definition
              PA Prior Authorization
              Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
              QL Quantity Limits
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              Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.