metformin/rosiglitazone (Discontinued)

>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

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 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

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