Usual Adult Dose for Diabetes Type 2

Individualize dose based on safety, efficacy, and prior therapy; asses the risk versus benefit of initiating with combination therapy versus monotherapy

• Initial dose: rosiglitazone 2 mg/metformin 500 mg orally once or twice a day
• If glycosylated hemoglobin (HbA1c) is greater than 11% or fasting plasma glucose (FPG) is greater than 270 mg/dL: consider a starting dose of rosiglitazone 2 mg/metformin 500 mg orally twice a day

Titration: Increase in increments of rosiglitazone 2 mg/metformin 500 mg per day in divided doses if not adequately controlled after 4 weeks

Patients Inadequately Controlled on Rosiglitazone Monotherapy:

• Initial dose: Current rosiglitazone dose plus metformin 1000 mg per day orally in 2 divided doses

Patients Inadequately Controlled on Metformin Monotherapy:

• Initial dose: Current metformin dose plus rosiglitazone 4 mg per day orally in 2 divided doses

Patients currently receiving rosiglitazone and metformin as individual components:

• Switch to combination product containing the same dose of each component

• Titration: Allow sufficient time to assess adequacy of response; increase in increments of rosiglitazone 4 mg/metformin 500 mg per day in divided doses; allow 1 to 2 weeks to assess metformin dose increase; allow 8 to 12 weeks to assess rosiglitazone dose increase
• Maximum dose: rosiglitazone 8 mg/metformin 2000 mg per day

Comments:

• This drug should be given in divided doses with meals.
• Gradual dose escalation is recommended in order to reduce the gastrointestinal side effects of metformin and allow for determination of the minimum effective dose.
• Coadministration with insulin is not recommended.

Use: To improve glycemic control in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise.

Renal Dose Adjustments

Obtain eGFR prior to initiating therapy:

• eGFR less than 30 mL/min/1.73 m2: Use is contraindicated
• eGFR 30 to 45 mL/min/1.73 m2: Initiating therapy is not recommended
• eGFR that falls below 30 mL/min/1.73 m2 during therapy: Discontinue therapy
• eGFR that falls below 45 mL/min/1.73 m2 during therapy: Assess risks versus benefit of continued therapy
• eGFR greater than 45 mL/min/1.73 m2: No dose adjustments recommended

IODINATED CONTRAST PROCEDURE:

• For patients with eGFR between 30 and 60 mL/min/1.73 m2: Stop this drug at the time of, or before imaging procedure; re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.

Liver Dose Adjustments

Not recommended in patients with active liver disease or in patients with ALT elevations 2.5 times the upper limit of normal (2.5 x ULN).

• If ALT elevations greater than 3 x ULN develop during therapy, recheck liver enzymes as soon as possible; if ALT remains greater than 3 x ULN, treatment should be discontinued.
• If symptoms suggestive of liver dysfunction develop, liver enzymes should be checked; if jaundice develops, treatment should be discontinued
• In the presence of hepatic disease or hepatic dysfunction of sufficient magnitude to predispose patient to lactic acidosis, treatment should be discontinued.

Dose Adjustments

Elderly: Initial and maintenance dose should be conservative due to the potential for decreased renal function; dose adjustments should be based on renal function which should be routinely monitored.

If signs or symptoms of heart failure develop, dose reduction or drug discontinuation should be considered.

Precautions

US BOXED WARNINGS:
Congestive Heart Failure:

• Thiazolidinediones, including rosiglitazone, may cause or exacerbate congestive heart failure.
• After initiation of therapy and with any dosage increase, observe patients carefully for signs and symptoms of heart failure including excessive, rapid weight gain, dyspnea, and/or edema; if signs and symptoms of heart failure develop, manage in accordance to current standards of care.
• Drug discontinuation or dosage reduction should be considered in patients showing signs and symptoms of heart failure; this drug is not recommended in patients with symptomatic heart failure.
• Initiation in patients with established NYHA Class III or IV heart failure is contraindicated.

Lactic Acidosis:

• Lactic acidosis is a rare, but serious complication that may occur due to metformin accumulation.
• Increased risk is associated with renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.
• Onset is often subtle, accompanied by nonspecific symptoms such as malaise, myalgia, respiratory distress, increasing somnolence, and nonspecific gastrointestinal distress.
• Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
• If acidosis is suspected, immediately discontinue drug and hospitalize patient.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis: Data not available
Peritoneal dialysis: Data not available

Other Comments

Administration advice:

• Take twice a day with food

General:

• Temporarily stop treatment prior to radiologic studies utilizing iodinated contrast materials and for surgical procedures when restricted food or fluid intake is expected; may resume once adequate renal function is confirmed.
• Coadministration with insulin is not recommended.
• This drug should not be used in patients with symptomatic heart failure.
• For rosiglitazone, reductions in fasting blood glucose may be seen after 1 week, however, it may take 6 to 8 weeks for full therapeutic effect to be realized.
• Hypoglycemia may occur if used in combination with other hypoglycemic agents; dose reduction of concomitant drug may be necessary.
• This drug should not be used in patients with type 1 diabetes or diabetic ketoacidosis.

Monitoring:

• Observe closely for signs and symptoms of heart failure
• Hepatic: Monitor liver enzymes baseline and periodically
• Renal: Assess renal function baseline, repeat at least annually and more often as clinically indicated.
• Hematologic: Measure hematologic parameters at baseline, and annually
• Monitor glycemic control

Patient advice:

• This drug may cause edema; patients experiencing rapid weight gain, shortness of breath or other symptoms of heart failure should notify their health care professional promptly.
• Premenopausal anovulatory women may be at risk for pregnancy while on this drug; pregnancy risk should be discussed with patient and adequate contraception offered.
• Patients with unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine should be advised to report these symptoms to their health care professional.
• Inform patients about the risk of lactic acidosis, conditions that might predispose them to its occurrence, and symptoms to watch for and report.
• Advise patient that this drug will need to be temporarily stopped if undergoing radiologic studies with intravascular iodinated contrast materials or surgical procedures that will limit food or fluid intake.
• Advise patients on the risks of excessive alcohol intake.
• Tell patients that while gastrointestinal symptoms might be common when initiating treatment, gastrointestinal problems after initiation should be reported