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Rosiglitazone and Metformin

Pronunciation

(roh si GLI ta zone & met FOR min)

Index Terms

  • Metformin and Rosiglitazone
  • Metformin Hydrochloride and Rosiglitazone Maleate
  • Rosiglitazone Maleate and Metformin Hydrochloride
  • Rosiglitazone/Metformin HCl

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Avandamet: 2/500: Rosiglitazone 2 mg and metformin hydrochloride 500 mg [DSC]

Avandamet: 4/500: Rosiglitazone 4 mg and metformin hydrochloride 500 mg [DSC]

Avandamet: 2/1000: Rosiglitazone 2 mg and metformin hydrochloride 1000 mg [DSC]

Avandamet: 4/1000: Rosiglitazone 4 mg and metformin hydrochloride 1000 mg [DSC]

Brand Names: U.S.

  • Avandamet [DSC]

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Thiazolidinedione

Pharmacology

Rosiglitazone 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, decreases intestinal absorption of glucose, and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

Special Populations: Renal Function Impairment

Plasma and blood half-life of metformin is prolonged and the renal Cl is decreased in proportion to the decrease in CrCl.

Special Populations: Hepatic Function Impairment

Clearance of rosiglitazone was significantly lower in patients with moderate to severe liver disease and Cmax and AUC0-∞ were increased 2- and 3-fold, respectively.

Use: Labeled Indications

Diabetes mellitus, type 2: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (noninsulin dependent, NIDDM).

Contraindications

Hypersensitivity to rosiglitazone or any component of the formulation; initiation in patients with established NYHA class III or IV heart failure; severe renal impairment (eGFR below 30 mL/minute/1.73 m2); acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to rosiglitazone, metformin, or any component of the formulation; any stage of heart failure (eg, NYHA class I, II, III, or IV); history of lactic acidosis, regardless of precipitating factors; history of ketoacidosis with or without coma; serious hepatic impairment; type I diabetes; cardiovascular collapse and disease states associated with hypoxemia (eg, cardiorespiratory insufficiency) which are often associated with hyperlactacidemia; unknown renal function; serum creatinine levels above the upper limit of normal range; pregnancy; breast-feeding; use during stress conditions (eg, severe infection, trauma, surgery) and the recovery phase thereafter; excessive alcohol intake (acute or chronic); severe dehydration

Dosing: Adult

Diabetes mellitus, type 2: Oral:

Initial:

Patients inadequately controlled on diet and exercise alone: Rosiglitazone 2 mg/metformin 500 mg once or twice daily (consider twice daily administration if HbA1c >11% or fasting plasma glucose (FPG) >270 mg/dL.

Patients inadequately controlled on metformin alone: Rosiglitazone 4 mg/day plus current daily dose of metformin administered in 2 divided doses.

Patients inadequately controlled on rosiglitazone alone: Metformin 1,000 mg/day plus current daily dose of rosiglitazone administered in 2 divided doses.

Patients switching from combination therapy of rosiglitazone and metformin as separate tablets: Use current dose.

Titration:

Patients inadequately controlled on diet and exercise alone: If not adequately controlled after 4 weeks, the dose may be increased in increments of rosiglitazone 2 mg/metformin 500 mg per day.

Patients switching from rosiglitazone or metformin alone or combination therapy: May titrate in increments of rosiglitazone 4 mg and/or metformin 500 mg per day; allow adequate time to assess therapeutic response prior to each titration (as separate agents, rosiglitazone and metformin are titrated at intervals of 8 to 12 weeks and 1 to 2 weeks respectively).

Maximum dose: Rosiglitazone 8 mg/metformin 2,000 mg per day in 2 divided doses.

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Dosing: Renal Impairment

eGFR >45mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30 to 45 mL/minute/1.73 m2: Use is not recommended for initiation of therapy; if eGFR falls to <45 mL/minute/1.73 m2 during therapy, consider benefits/risks of continuing therapy.

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

Dosing: Hepatic Impairment

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). Do not initiate rosiglitazone therapy with active liver disease or ALT >2.5 times the upper limit of normal.

Administration

Oral: Administer with meals, generally in divided doses.

Dietary Considerations

Should be taken 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 light.

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

Atazanavir: May increase the serum concentration of Rosiglitazone. 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

Cholestyramine Resin: May decrease the serum concentration of Rosiglitazone. Management: Administer rosiglitazone at least 2 hours prior to cholestyramine in order to minimize the likelihood of an interaction, and monitor patients closely for evidence of reduced rosiglitazone effectiveness. Consider therapy modification

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

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 decrease the metabolism of CYP2C8 Substrates. 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: May enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

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

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification

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

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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

Vasodilators (Organic Nitrates): May enhance the adverse/toxic effect of Rosiglitazone. Specifically, a greater risk of ischemia and other adverse effects has been associated with this combination in some pooled analyses. Monitor therapy

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

Adverse Reactions

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

>10%:

Central nervous system: Headache (7% to 11%)

Endocrine & metabolic: Hypoglycemia (3% to 12%)

Gastrointestinal: Nausea and vomiting (16%), diarrhea (13% to 14%)

Respiratory: Upper respiratory tract infection (9% to 16%)

1% to 10%:

Cardiovascular: Edema (4% to 6%), cardiac failure (≤3%), myocardial infarction (≤3%), cerebrovascular accident (≤2%)

Central nervous system: Dizziness (8%), fatigue (6%)

Gastrointestinal: Dyspepsia (10%), abdominal pain (5%), constipation (5%), loose stools (5%)

Hematologic & oncologic: Anemia (4% to 7%)

Infection: Viral infection (5%)

Neuromuscular & skeletal: Bone fracture (≤ 8%; incidence greater in females; usually upper limbs or distal lower limbs), arthralgia (5%), back pain (5%)

Respiratory: Nasopharyngitis (6%), sinusitis (6%), flu-like symptoms (1%)

Miscellaneous: Trauma (8%)

<1% (Limited to important or life-threatening): Increased serum ALT

ALERT: U.S. Boxed Warning

Congestive heart failure:

Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of rosiglitazone/metformin, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, it is important to consider discontinuation or dose reduction of rosiglitazone/metformin.

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

Lactic acidosis:

Postmarketing 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 (more than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and 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, carbonic anhydrase inhibitors such as topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive 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 rosiglitazone/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Edema: Dose-related edema may occur. Use with caution in patients with edema; may increase plasma volume and/or cause fluid retention. Monitor for signs/symptoms of heart failure.

• Fractures: Increased incidence of bone fractures in females treated with rosiglitazone was observed during analysis of long-term trial; majority of fractures occurred in the upper arm, hand and foot (differing from the hip or spine fractures usually associated with postmenopausal osteoporosis). 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 rosiglitazone, may cause or exacerbate congestive heart failure; closely monitor for signs and symptoms of congestive 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. Rosiglitazone may be associated with an increased risk of angina and MI and a higher frequency of cardiovascular events has also been noted in patients with NYHA class I or II heart failure treated with rosiglitazone. Metformin should be used with caution in patients with heart failure requiring pharmacologic management, particularly in unstable or acute heart failure due to risk of lactic acidosis secondary to hypoperfusion. In a scientific statement from the American Heart Association, metformin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]). Use with caution in patients at risk for cardiovascular events and monitor closely. Discontinue if any deterioration in cardiac status occurs.

• Hematologic effects: Rosiglitazone may decrease hemoglobin, hematocrit, and/or WBC count (slight); effects may be related to increased plasma volume and/or dose-related. Changes in hemoglobin and hematocrit generally occurred during the first 3 months after initiation of rosiglitazone therapy and after dose increases. Use rosiglitazone with caution in patients with anemia or depressed leukocyte counts (may reduce hemoglobin, hematocrit, and/or WBC). 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.

• 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, 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, carbonic anhydrase inhibitors 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.Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, 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 rosiglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. In addition to regular ophthalmic exams, diabetic patients with visual symptoms should receive prompt ophthalmic evaluation. Improvement in macular edema may occur with discontinuation of rosiglitazone therapy.

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

Disease-related concerns:

• Hepatic impairment: Use metformin with caution in patients with hepatic impairment due to potential for lactic acidosis. Use rosiglitazone with caution in patients with elevated transaminases (AST or ALT); do not initiate in patients with active liver disease of ALT >2.5 times the upper limit of normal (ULN) at baseline; evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation. During therapy, if ALT >3 times ULN, reevaluate levels promptly and discontinue rosiglitazone if elevation persists or if jaundice occurs at any time during use. Idiosyncratic hepatotoxicity has been reported with another thiazolidinedione agent (troglitazone); avoid use in patients who previously experienced jaundice during troglitazone therapy.

• Ischemic heart disease: Do not initiate rosiglitazone in patients with stable ischemic heart disease due to an increased risk of cardiovascular complications (Fihn 2012).

• Renal impairment: Metformin is substantially excreted by the kidney; assess renal function prior to initiation of therapy using estimated glomerular filtration rate (eGFR). Initiation of therapy is not recommended if eGFR is between 30 to 45 mL/minute/1.73 m2 and is contraindicated if eGFR <30 mL/minute/1.73 m2. Assess benefits/risks of continuing therapy in patients whose eGFR falls below 45 mL/minute/1.73 m2 during therapy. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld 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: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus (insulin-dependent, IDDM).

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

• Iodinated contrast: Temporarily discontinue 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 suspended for any surgical procedures (except minor procedures not associated with restricted intake of food and fluids). Restart only after normal oral intake resumed and normal renal function is verified.

Monitoring Parameters

HbA1c (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 2016a]); serum glucose; signs and symptoms of fluid retention or heart failure; weight; renal function (eGFR) should be performed prior to initiation of therapy and at least annually (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]); blood pressure; liver enzymes (prior to initiation of therapy, then periodically thereafter). Evaluate patients with ALT ≤2.5 times ULN at baseline or during therapy for cause of enzyme elevation. Patients with an elevation in ALT >3 times ULN should be rechecked as soon as possible. If the ALT levels remain >3 times ULN, therapy with rosiglitazone should be discontinued. CBC; vitamin B12 serum concentrations periodically with long-term therapy; folate (if megaloblastic anemia is suspected). Regular ophthalmic examinations.

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, headache, rhinitis, pharyngitis, or joint pain. 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, vision changes, loss of strength and energy, dysphagia, tachycardia, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), or signs of a heart attack (angina; pain in arms, back, neck, jaw, or stomach; shortness of breath; cold sweats; severe dizziness; passing out; severe nausea or vomiting) (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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