September 11, 1996

Dear Colleague:

In the first full year following its introduction, Glucophage (metformin hydrochloride tablets) has been very well received by U.S. physicians as an adjunct to diet for the treatment of non-insulin dependent diabetes mellitus (NIDDM). In fact, over 1 million patients have been prescribed Glucophage,1 because Glucophage is as efficacious as sulfonylureas but does not produce hypoglycemia, it stabilizes or decreases body weight and insulin levels and has a modest favorable effect on lipids. With this widespread use, Bristol-Myers Squibb would like to reinforce the importance of appropriate patient selection in order to minimize the risk of lactic acidosis and maintain the safety record that Glucophage has demonstrated in many years of clinical use outside of the U.S. The attached review article by Drs. Bailey and Turner, recently published in the New England Journal of Medicine*, provides an excellent overview of the worldwide clinical experience with Glucophage, including guidelines on appropriate patient selection. The purpose of this letter is to highlight the key considerations in selecting appropriate patients for Glucophage therapy.

Lactic acidosis is a potentially life-threatening condition that has been associated with Glucophage therapy in rare cases. The reported worldwide incidence of Glucophage-associated lactic acidosis is approximately 3 cases per 100,000 patient-years exposure.2 A review of international experience has shown that in nearly all of these cases, Glucophage was prescribed to patients having contraindications to therapy, most of which involved renal compromise.

The risk of lactic acidosis with Glucophage therapy can be minimized by avoiding its use in patients at risk for significant drug accumulation (e.g. renal impairment) or in patients at an increased risk for developing lactic acidosis independent of therapy because of impaired ability to clear lactate (e.g. conditions associated with tissue hypoperfusion or hypoxic states, or substantial liver impairment). In Canada, for example, a surveillance program and follow-up over ten years involving 56,000 patient-years experience with Glucophage resulted in no reported cases of lactic acidosis. This success was attributed to strict adherence to prescribing guidelines.3

Accordingly, while most patients with NIDDM can be safely treated with Glucophage, there are certain patients who should not be placed on this medication. There are also clinical circumstances under which Glucophage therapy should be withheld or discontinued. Specific guidelines in the package insert include the following:

* Glucophage is contraindicated in, and therefore should not be prescribed to, patients with evidence of renal disease or dysfunction (e.g., as suggested by serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females or abnormal creatinine clearance) due to the potential for drug accumulation and development of lactic acidosis.

* Because intravenous iodinated contrast media can cause an acute decline in renal function, patients on Glucophage should have therapy withdrawn prior to the procedure and reinstated only when renal function is known to be normal. This will avoid drug accumulation in those cases where kidney function is adversely affected by the contrast media.

* Therapy should not be initiated or should be withheld in acutely ill patients and/or those who are hemodynamically unstable, such as those presenting with cardiovascular shock, septicemia or acute myocardial infarction. These patients are at risk of developing tissue hypoperfusion (which can lead to lactic acidosis) and renal insufficiency (which can cause drug accumulation.)

* Glucophage should be avoided in patients with impaired hepatic function or excessive alcohol intake, because their ability to clear lactate is impaired.1

Finally, it is generally accepted medical practice to manage acutely ill diabetic patients with insulin therapy instead of oral agents, which are usually inadequate to control hyperglycemia in these situations. Pregnant diabetic patients should also be managed with insulin.

I hope you find this information helpful in guiding your selection of patients for Glucophage therapy. Glucophage can play an important role in the treatment of NIDDM when used in the appropriate patients. Many years of international experience suggest that an emphasis on appropriate patient selection will continue to build a positive record for Glucophage in the U.S. as well.

Sincerely,

Dennis R. Cryer, M.D.
Vice President Medical
Cardiovascular/Metabolic/Women's Health Care Products

Please see accompanying full prescribing information for Glucophage (metformin hydrochloride tablets) 500 mg, including the boxed WARNING regarding Lactic Acidosis, and the Patient Package insert.

References
1. Based on the Walsh America/PMSI Oral Antidiabetic Patient's Tracking Analysis, February, 1996.
2. Glucophage Package Insert.
3. Lucis, OJ, The status of metformin in Canada, Can Med Assoc J. 1983; 128:24-26.

* NEJM (February 29, 1996; 334(9):574-579)

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