Dosing & Uses
Dosage Forms & Strengths
metformin/rosiglitazone
tablet
- 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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Edema (6% to 25% )
Upper respiratory infections (16-20%)
Diarrhea (12.7% to 14%)
Hypoglycemia (12% )
1-10%
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
Metformin
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
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 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
Contraindications
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
Cautions
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.
Pharmacology
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
Pharmacokinetics
Half-Life
- Rosiglitazone: Approximately 4 hr
- Metformin: Approximately 6 hr
Bioavailability
- Rosiglitazone: 99%
- Metformin: 50-60%
Peak Plasma
- Rosiglitazone
- - Time: 0.95 hr
- - Concentration: 242 ng/mL
- - AUC: 1442 ng.hr/mL
- Metformin
- - Time: 2.97 hr
- - Concentration: 1106 ng/mL
- - AUC: 7116 ng/mL
Vd
- Rosiglitazone: 17.6 L
- Metformin: 650 L
Metabolism
- Rosiglitazone: Extensively, in liver by CYP2C8
- Metformin: Not metabolized
Excretion
- Rosiglitazone: Urine 64%, bile 23%
- Metformin: Urine 90%
Dialyzable
- Rosiglitazone: No data
- Metformin: HD: yes
Images
Patient Handout
Formulary
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