This appendix explains both the original and updated US Food and Drug Administration's safety warnings in relation to the use of metformin.
Original ALERT: U.S. Boxed Warning for Lactic Acidosis
Lactic acidosis is a rare but serious metabolic complication that can occur because of metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (5 mmol/L or more), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of 5 mcg/mL or more are generally found.
The reported incidence of lactic acidosis in patients receiving metformin is very low (approximately 0.03 cases per 1,000 patient-years, with approximately 0.015 fatal cases per 1,000 patient-years). In more than 20,000 patient-years' exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal function impairment, including intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure (CHF) requiring pharmacologic management, in particular those with unstable or acute CHF who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. Therefore, the risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin and by use of the minimum effective dose of metformin. In particular, accompany treatment of elderly patients with careful monitoring of renal function. Do not initiate metformin treatment in patients 80 years of age and older unless measurement of creatinine clearance (CrCl) demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis. In addition, promptly withhold metformin in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because hepatic function impairment may significantly limit the ability to clear lactate, generally avoid using metformin in patients with clinical or laboratory evidence of hepatic disease. Caution patients against excessive alcohol intake, either acute or chronic, when taking metformin because alcohol potentiates the effects of metformin on lactate metabolism. In addition, temporarily discontinue metformin prior to any intravascular radiocontrast study and for any surgical procedure.
The onset of lactic acidosis is often subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient's health care provider must be aware of the possible importance of such symptoms. Instruct patients to notify their health care provider immediately if these symptoms occur. Withdraw metformin until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of metformin, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of GI symptoms could be caused by lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal (ULN) but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be explained by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
Suspect lactic acidosis in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, immediately discontinue the drug and promptly institute general supportive measures. Because metformin is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery.
Updated Safety Announcement, April 8, 2016
FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function
The U.S. Food and Drug Administration (FDA) is requiring labeling changes regarding the recommendations for metformin-containing medicines for diabetes to expand metformin's use in certain patients with reduced kidney function. The current labeling strongly recommends against use of metformin in some patients whose kidneys do not work normally. We were asked to review numerous medical studies regarding the safety of metformin use in patients with mild to moderate impairment in kidney function, and to change the measure of kidney function in the metformin drug labeling that is used to determine whether a patient can receive metformin. We have concluded our review, and are requiring changes to the labeling of all metformin-containing medicines to reflect this new information.
Health care professionals should follow the latest recommendations when prescribing metformin-containing medicines to patients with impaired kidney function. Patients should talk to their health care professionals if they have any questions or concerns about taking metformin.
Metformin-containing medicines are available by prescription only and are used along with diet and exercise to lower blood sugar levels in patients with type 2 diabetes (T2D). When untreated, T2D can lead to serious problems, including blindness, nerve and kidney damage, and heart disease. Metformin-containing medicines are available as single-ingredient products and also in combination with other drugs used to treat diabetes (see FDA Approved metformin-containing Medicines). The current drug labeling strongly recommends against metformin use in some patients whose kidneys do not work normally because use of metformin in these patients can increase the risk of developing a serious and potentially deadly condition called lactic acidosis, in which too much lactic acid builds up in the blood.
Table
FDA-approved metformin-containing medicines.
We have concluded from the review of studies published in the medical literature that metformin can be used safely in patients with mild impairment in kidney function and in some patients with moderate impairment in kidney function. We are requiring changes to the metformin labeling to reflect this new information and provide specific recommendations on the drug's use in patients with mild to moderate kidney impairment.
We are also recommending that the measure of kidney function used to determine whether a patient can receive metformin be changed from one based on a single laboratory parameter (blood creatinine concentration) to one that provides a better estimate of kidney function in patients with kidney disease (i.e., glomerular filtration rate estimating equation [eGFR]).
Health care professionals and patients should report side effects involving metformin or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of this page.
Facts about metformin
Metformin-containing medicines are available by prescription only and are used along with diet and exercise to treat type 2 diabetes.
Metformin helps control blood sugar in a number of ways. These include helping the body respond better to the insulin it makes naturally, decreasing the amount of sugar the liver makes, and decreasing the amount of sugar the intestines absorb from food.
Metformin is available as a single-ingredient product and also in combination with other medicines used to treat diabetes. See FDA Approved metformin- containing Medicines.
Common side effects of metformin include diarrhea, nausea, and upset stomach.
Additional information is available at:http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm(Accessed July 1, 2016)
