Update on Metformin (Glucophage®) Therapy and the Risk of Lactic Acidosis: Change in FDA-Approved Package Insert

by William H. Bush, Jr, MD, and Michael A. Bettmann, MD, ACR Committee on Drugs and Contrast Media

Reprinted with permission of the American College of Radiology

In the February 1997 issue of the ACR Bulletin, the ACR Committee on Drugs and Contrast Media (chairman, Bernard F. King, Jr., MD) issued an opinion and recommendations for the use of intravascular contrast material in patients receiving metformin therapy (Glucophage®) for control of their diabetes. Subsequently, Bristol-Myers Squibb, working in consultation with the ACR Committee on Drugs and Contrast Media, petitioned the Food and Drug Administration (FDA) to change some of the wording and recommendations in the package information that accompanies Glucophage® to more accurately reflect the true risk involved with intravascular contrast media. Two basic changes have been made in the FDA-approved package information:

• "Contraindications" now will refer specifically to temporarily discontinuing metformin (Glucophage®) when patients are undergoing radiological studies involving intravascular administration of iodinated contrast material.
  
  
• "Precautions" concerning radiological studies that use intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiogram, angiography, and computed tomography scans with contrast material) will now read:

Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving Glucophage® (see Contraindications). Therefore, in patients in whom any such study is planned, Glucophage® should be discontinued at the time of or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

(Note the requirement to stop metformin 48 hours before the contrast study has been eliminated).

Because metformin (Glucophage®) is eliminated by the kidney through filtration and tubular secretion, impairment of renal function can lead to persistence of metformin and development of lactic acidosis. Approximately 90 percent of the absorbed drug is eliminated by the renal route within the first 24 hours. Withholding the drug for 48 hours after administration of intravascular iodinated contrast material allows metformin to clear and provides an opportunity to assess any alteration in renal function caused by the administered intravascular contrast.

Renal function measurements may not show elevated serum creatinine despite a decrease in glomerular filtration rate (GFR) or creatinine clearance until the GFR has dropped substantially. This is particularly important to remember when evaluating older patients, patients with diminished muscle mass, or patients whose kidneys are affected by other processes (e.g., drugs or hypoperfusion). If an intravascular contrast medium is administered, these patient factors related to renal function should be kept in mind when measuring serum creatinine before restarting metformin (Glucophage®) therapy. If the serum creatinine level is abnormal, the need for and use of an intravascular contrast medium should be evaluated carefully.

Communication between the radiologist, the patient's clinician, and the patient will be necessary to establish the procedure for reassessing renal function and restarting metformin after the contrast study. The exact procedure will likely vary depending on the practice setting.

In summary, these are the changes in the FDA-approved package insert:

• Metformin should be withheld before intravascular administration of contrast but not necessarily before other contrast uses (e.g., oral, intrathecal or intraarticular).
  
  
• Metformin should be stopped at or before the administration of intravascular contrast. It is not necessary to stop metformin 48 hours before the exam.

Bristol-Myers Squibb and the FDA should be commended for their interest and willingness to expedite the package insert changes, thereby facilitating patient care and the safe performance of contrast-enhanced intravascular studies in patients taking metformin.

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