metformin/rosiglitazone (Discontinued)

Brand and Other Names:Avandamet
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Dosing & Uses


Dosage Forms & Strengths



  • 500mg/2mg
  • 500mg/4mg
  • 1000mg/2mg
  • 1000mg/4mg

Type 2 Diabetes

Initial dose

  • 500 mg/2 mg PO qDay or BID
  • HbA1c >11% or fasting plasma glucose (FPG) >270 mg/dL, a starting dose of 500 mg/2 mg PO BID may be considered
  • May titrate by increments of 500 mg/2 mg at 2-week intervals, not to exceed 2000 mg/8 mg per day
  • Monitor for fluid retention or heart failure, renal function, blood pressure, and liver enzymes

Initial dose with prior treatment

  • Metformin 1000 mg/day: 500 mg/2 mg PO q12hr
  • Metformin 2000 mg/day: 1000 mg/2 mg PO q12hr
  • Rosiglitazone 4 mg/day: 500 mg/2 mg PO q12hr
  • Rosiglitazone 8 mg/day: 500 mg/4 mg PO q12hr
  • Combo treatment: dose of rosiglitazone and metformin already being taken
  • May titrate at 2 week intervals; not to exceed 2000 mg/8 mg per day

Dosage Modifications

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



Interaction Checker

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            Adverse Effects


            Edema (6% to 25% )

            Upper respiratory infections (16-20%)

            Diarrhea (12.7% to 14%)

            Hypoglycemia (12% )


            Anemia (4% to 7%)

            Fatigue (6%)

            Headache (6%)

            Sinusitis (6%)

            Arthralgia (5%)

            Back pain (5%)

            Viral infection (5%)

            Frequency Not Defined (serious)

            Angioedema (rare )

            Congestive heart failure

            Death, from cardiovascular causes

            Stevens-Johnson syndrome (rare )

            Lactic acidosis (rare )

            Hepatotoxicity (rare)

            Anaphylaxis (rare )

            Diabetic macular edema

            Pleural effusion

            Pulmonary edema

            Postmarketing Reports


            • Cholestatic, hepatocellular, and mixed hepatocellular liver injury


            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 risk

            • Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients
            • After initiation, 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 current standards of care
            • Furthermore, discontinuation or dose reduction must be considered
            • Not recommended in patients with symptomatic heart failure
            • Initiation with established NYHA Class III or IV heart failure is contraindicated
            • There have been no clinical trials directly comparing cardiovascular risk of rosiglitazone and pioglitazone, another thiazolidinedione

            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
            • 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 old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment; if metformin-associated lactic acidosis is suspected, immediately discontinue


            Hypersensitivity to rosiglitazone or metformin

            Heart failure NYHA Class III-IV

            Metabolic acidosis, including diabetic ketoacidosis with or without coma

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

            Nursing women


            Risk of severe hypoglycemia especially in elderly, debilitated or malnourished, adrenal or pituitary insufficiency, dehydration, heavy alcohol use, hypoxic states, hepatic/renal impairment, stress due to infection, fever, trauma, or surgery

            Rare lactic acidosis may occur due to metformin accumulation; fatal in approx 50% of cases; risk increases with age, degree of renal dysfunction, and with unstable or acute CHF; if metformin-associated lactic acidosis suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of therapy; in patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to170 mL/minute under good hemodynamic conditions); hemodialysis has often resulted in reversal of symptoms and recovery

            Edema; thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin; not recommended for use with insulin

            Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension, and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake

            Several of the postmarketing cases of metformin-associated lactic acidosis occurred in setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia); cardiovascular collapse (shock) acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia; discontinue therapy when such events occur

            Therapy with thiazolidinediones may result in ovulation in premenopausal anovulatory women

            Rosiglitazone: Associated with rare cases of new onset or worsening of macular edema

            Clinical recommendations based upon patient’s renal function

            • Before initiating therapy, obtain an eGFR.
            • Initiation of therapy is not recommended in patients with eGFR between 30 –45 mL/minute/1.73 m²
            • Obtain an eGFR at least annually in all patients receiving therapy
            • In patients at increased risk for development of renal impairment (e.g., the elderly), renal function should be assessed more frequently
            • If eGFR later falls below 45 mL/minute/1.73 m², assess benefit and risk of continuing therapy

            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

            Pregnancy & Lactation

            Pregnancy Category: C

            Lactation: not known if crosses into breast milk, avoid

            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.



            Mechanism of Action

            Rosiglitazone: Lowers glucose by improving target cell response to insulin without increasing pancreatic cell secretion; activates nuclear peroxisome proliferator-activated receptor gamma, which influences the production of gene products involved in glucose and lipid metabolism

            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



            • Rosiglitazone: Approximately 4 hr
            • Metformin: Approximately 6 hr


            • Rosiglitazone: 99%
            • Metformin: 50-60%

            Peak Plasma

            • Rosiglitazone
            • - Time: 0.95 hr
            • - Concentration: 242 ng/mL
            • - AUC: 1442
            • Metformin
            • - Time: 2.97 hr
            • - Concentration: 1106 ng/mL
            • - AUC: 7116 ng/mL


            • Rosiglitazone: 17.6 L
            • Metformin: 650 L


            • Rosiglitazone: Extensively, in liver by CYP2C8
            • Metformin: Not metabolized


            • Rosiglitazone: Urine 64%, bile 23%
            • Metformin: Urine 90%


            • Rosiglitazone: No data
            • Metformin: HD: yes


            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.