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Pioglitazone and Metformin

Pronunciation

(pye oh GLI ta zone & met FOR min)

Index Terms

  • Metformin Hydrochloride and Pioglitazone Hydrochloride
  • Pioglitazone HCl/Metformin HCl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral: 15/500: Pioglitazone 15 mg and metformin hydrochloride 500 mg; 15/850: Pioglitazone 15 mg and metformin hydrochloride 850 mg

Actoplus Met:

15/500: Pioglitazone 15 mg and metformin hydrochloride 500 mg

15/850: Pioglitazone 15 mg and metformin hydrochloride 850 mg

Tablet, variable release, oral:

Actoplus Met XR:

15/1000: Pioglitazone 15 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

30/1000: Pioglitazone 30 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

Brand Names: U.S.

  • Actoplus Met
  • Actoplus Met XR

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Thiazolidinedione

Pharmacology

Pioglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity.

Metformin decreases hepatic glucose production, decreasing intestinal absorption of glucose, and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Use: Labeled Indications

Type 2 diabetes mellitus: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and metformin is appropriate.

Contraindications

Hypersensitivity to pioglitazone, metformin, or any component of the formulation; established NYHA class III or IV heart failure, severe renal impairment (eg, eGFR <30 mL/minute/1.73 m2); metabolic acidosis, including diabetic ketoacidosis.

Note: The manufacturer recommends to temporarily discontinue pioglitazone/metformin or pioglitazone/metformin ER in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials; may result in acute alteration of renal function.

Dosing: Adult

Diabetes mellitus, type 2: Oral:

Immediate release tablet:

Initial: Pioglitazone 15 mg/metformin 500 mg twice daily or pioglitazone 15 mg/metformin 850 mg tablets once daily

Patients with heart failure (NYHA Class I or II): Initial: Pioglitazone 15 mg/metformin 500 mg once daily or pioglitazone 15 mg/metformin 850 mg once daily. Note: Not recommended in patients with symptomatic heart failure.

Inadequately controlled on metformin monotherapy: Pioglitazone 15 mg/metformin 500 mg twice daily or pioglitazone 15 mg/metformin 850 mg once or twice daily (depending on the dose of metformin already being taken).

Inadequately controlled on pioglitazone monotherapy: Pioglitazone 15 mg/metformin 500 twice daily or pioglitazone 15 mg/metformin 850 mg once daily.

Dose titration: If necessary, may titrate gradually with careful monitoring of adverse effects (eg, weight gain, edema, signs/symptoms of heart failure). Maximum daily dose: Pioglitazone 45 mg/metformin 2,550 mg. Note: Metformin daily doses >2,000 mg may be better tolerated if given 3 times daily.

Extended-release tablet: Initial (includes patients with NYHA Class I or II heart failure): Pioglitazone 15 to 30 mg/metformin 1,000 mg once daily. If necessary, titrate gradually with careful monitoring of adverse effects (eg, weight gain, edema, signs/symptoms of heart failure). Maximum daily dose: Pioglitazone 45 mg/metformin 2,000 mg.

Inadequately controlled on metformin or pioglitazone monotherapy: Pioglitazone 15 mg/metformin 1,000 mg twice daily or pioglitazone 30 mg/metformin 1,000 mg once daily.

Dosage adjustment for hypoglycemia with combination therapy:

With an insulin secretagogue (eg, sulfonylurea): Decrease the insulin secretagogue dose.

With insulin: Decrease insulin dose by 10% to 25%.

Dosage adjustment with strong CYP2C8 inhibitors (eg, gemfibrozil): Maximum recommended dose: Pioglitazone 15 mg and metformin 850 mg daily (immediate release) or pioglitazone 15 mg/metformin 1,000 mg daily (extended release).

Dosing: Geriatric

Immediate-release or extended-release tablet: Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor). Generally, elderly patients should not be titrated to the maximum; do not use in patients ≥80 years of age unless normal renal function has been established.

Dosing: Renal Impairment

Immediate-release or variable-release tablet:

Manufacturer's labeling: Note: Assess renal function prior to initiation of therapy and periodically thereafter.

Prior to initiation:

eGFR ≥30 to 45 mL/minute/1.73 m2: Initiation of therapy is not recommended.

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

During therapy:

eGFR ≥30 to <45 mL/minute/1.73 m2: Assess benefits and risks of continuing treatment.

eGFR <30 mL/minute/1.73 m2: Discontinue treatment.

Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommend prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE, 2008]). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw, 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska, 2011):

eGFR ≥60 mL/minute/1.73 m2: No contraindications, monitor renal function annually

eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months

eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2

eGFR <30 mL/minute/1.73 m2: Discontinue use

Dosing: Hepatic Impairment

Immediate-release or variable-release tablet: The manufacturer recommends to avoid metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett, 2010; Zhang, 2014). Use of pioglitazone should be done with caution or avoided .

Administration

Administer with meals.

Extended release: Tablets should be swallowed whole; do not crush, split, or chew. Inactive tablet ingredients may be eliminated in the feces as a soft mass that resembles the original tablet.

Dietary Considerations

Administer with meals. Avoid ethanol. Dietary modification based on ADA recommendations is a part of therapy. Monitor for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Clopidogrel: May increase the serum concentration of Pioglitazone. Monitor therapy

CYP2C8 Inducers (Strong): May increase the metabolism of CYP2C8 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP2C8 Substrates. Management: Seek alternatives to the CYP2C8 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

Gemfibrozil: May decrease the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Limit pioglitazone maximum adult dose to 15 mg/day, and consider dose reduction of rosiglitazone, when used in combination with gemfibrozil. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: Pioglitazone may enhance the adverse/toxic effect of Insulin. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Lumacaftor: May increase the serum concentration of CYP2C8 Substrates. Lumacaftor may decrease the serum concentration of CYP2C8 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Antidiabetic Agents (Thiazolidinedione). Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

RifAMPin: May increase the metabolism of Antidiabetic Agents (Thiazolidinedione). Management: Consider alternatives to the concomitant use of rifampin with thiazolidinedione antidiabetic agents. Monitor patients receiving these combinations for decreased effects of the thiazolidinedione derivative. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: Antidiabetic Agents (Thiazolidinedione) may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Adverse Reactions

Percentages of adverse effects as reported with the combination product. Also see individual agents.

>10%:

Cardiovascular: Lower extremity edema (3% to 11%)

Respiratory: Upper respiratory tract infection (12% to 16%)

1% to 10%:

Central nervous system: Headache (2% to 6%), dizziness (5%)

Endocrine & metabolic: Weight gain (3% to 7%)

Gastrointestinal: Diarrhea (5% to 6%), nausea (4% to 6%)

Genitourinary: Urinary tract infection (5% to 6%)

Hematologic & oncologic: Anemia (≤2%)

Respiratory: Sinusitis (4% to 5%)

ALERT: U.S. Boxed Warning

Congestive heart failure:

Thiazolidinediones, including pioglitazone, which is a component of pioglitazone/metformin, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of pioglitazone/metformin and after dose increases, monitor patients carefully for signs and symptoms of heart failure (eg, excessive, rapid weight gain, dyspnea, edema). If heart failure develops, manage the heart failure according to the current standards of care. Furthermore, consider discontinuation or dose reduction of pioglitazone/metformin.

Pioglitazone/metformin is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone/metformin in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

Lactic acidosis:

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL. Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information. If metformin-associated lactic acidosis is suspected, immediately discontinue pioglitazone/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Bladder cancer: Clinical trial data suggest an increased risk of bladder cancer in patients exposed to pioglitazone; risk may be increased with duration of use (more than 12 months). Avoid use in patients with active bladder cancer and consider risks vs. benefits prior to initiating therapy in patients with a history of bladder cancer.

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported with pioglitazone; use with caution in patients with edema. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with pioglitazone (most noted after first year of treatment); majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use. According to the American Diabetes Association guidelines, thiazolidinediones should be avoided in patients with fracture risk factors (ADA 2016a).

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate heart failure; closely monitor for signs and symptoms of heart failure (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if heart failure develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic heart failure; initiation of therapy is contraindicated in patients with NYHA class III or IV heart failure. If used in patients with NYHA class I or II (systolic) heart failure, initiate at lowest dosage and monitor closely. In addition, metformin should be discontinued in patients who develop hypoxic states (eg, cardiovascular collapse [shock], acute heart failure, acute myocardial infarction, other conditions with hypoxemia) due to risk of lactic acidosis.

• Hematologic effects: Pioglitazone may decrease hemoglobin/hematocrit; effects may be related to increased plasma volume. Changes in hemoglobin and hematocrit generally occurred during the first 4 to 12 weeks of therapy. Use with caution in patients with anemia.

• Hepatic effects: Hepatic failure, including fatalities, has been reported with pioglitazone. Monitor for signs/symptoms of liver injury closely during therapy; discontinuation of therapy may be necessary.

• Hypoglycemia: Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, debilitated or malnourished patients, and in patients with adrenal or pituitary insufficiency.

• Lactic acidosis: [US Boxed Warning]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if lactic acidosis is suspected; prompt hemodialysis is recommended. Discontinue metformin in patients with conditions associated with dehydration, sepsis, hypoperfusion, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams. Improvement in macular edema may occur with discontinuation of pioglitazone therapy.

• Weight gain: Dose-related weight gain observed with pioglitazone use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Diabetes, type 1: Mechanism of pioglitazone requires the presence of endogenous insulin; therefore, use in type 1 diabetes (insulin dependent, IDDM) or diabetic ketoacidosis is not recommended.

• Hepatic impairment: Avoid use of metformin in patients with hepatic impairment or with clinical or laboratory evidence of hepatic disease due to potential for lactic acidosis. Evaluate hepatic function prior to initiating therapy; initiate with caution in patients with mildly abnormal hepatic tests. Promptly evaluate hepatic function if signs/symptoms of hepatic injury (eg, dark urine, fatigue, anorexia, jaundice, right upper abdominal discomfort). Depending on the results of hepatic testing and whether an alternative etiology is identified, discontinuation of therapy may be recommended. Do not reinitiate therapy if serum ALT >3 x ULN and total bilirubin >2 x ULN and no alternative etiology is identified. Use with caution for lesser elevations of ALT or bilirubin and with alternative probable cause identified. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.

• Renal impairment: Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment (use is contraindicated in severe renal impairment [eGFR <30 mL/minute/1.73 m2]). Monitor renal function prior to initiation; obtain an eGFR at least annually in all patients and may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin associated lactic acidosis occurred more in patients with significant renal impairment; withhold metformin in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed. Risk of lactic acidosis increases with age.

• Premenopausal/anovulatory females: Use pioglitazone with caution in premenopausal, anovulatory women; may result in a resumption of ovulation, increasing the risk of pregnancy. Use of adequate contraception in premenopausal women is recommended.

Dosage form specific issues:

• Extended release tablet: Insoluble tablet shell may remain intact and be visible in the stool.

Other warnings/precautions:

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism and increase risk of lactic acidosis.

• Iodinated contrast: The manufacturer recommends temporary discontinuation of metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015).

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Metformin therapy should be temporarily suspended for any surgical procedures requiring restricted intake of food and fluids due to increased risk for volume depletion, hypotension, and renal impairment.

• Vitamin B12 concentrations: Metformin may impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12 serum concentrations periodically with long-term therapy.

Monitoring Parameters

Hemoglobin A1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016b]), serum glucose; signs and symptoms of edema or heart failure; liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation in all patients and during treatment if signs/symptoms of liver dysfunction arise. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices); monitor renal function prior to initiation of therapy and at least annually. Check vitamin B12 and folate if anemia is present. Routine ophthalmic exams recommended; patients reporting visual deterioration should have a prompt referral to an ophthalmologist and consideration should be given to discontinuing pioglitazone. Signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency).

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies were not conducted with this combination. Refer to individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, diarrhea, flatulence, or headache. Have patient report immediately to prescriber signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, or muscle pain or cramps), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), bone pain, loss of strength and energy, vision changes, pain with urination, blood in urine, polyuria, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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