Dosing and uses of Avandamet (metformin-rosiglitazone)
Adult dosage forms and 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
Pediatric dosage forms and strengths
Safety and efficacy not established
Avandamet (metformin-rosiglitazone) adverse (side) 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
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
Contraindications
Hypersensitivity to rosiglitazone or metformin
Heart failure NYHA Class III-IV
Metabolic acidosis, including diabetic ketoacidosis
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
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
Therapy with thiazolidinediones may result in ovulation in premenopausal anovulatory women
Rosiglitazone: Associated with rare cases of new onset or worsening of macular edema
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 and 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 of Avandamet (metformin-rosiglitazone)
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
