Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with GLUCOPHAGE or GLUCOPHAGE XR; 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), 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 >5 µg/mL are generally found.
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 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 insufficiency, including both 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 requiring pharmacologic management, in particular those with unstable or acute congestive heart failure 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. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking GLUCOPHAGE or GLUCOPHAGE XR and by use of the minimum effective dose of GLUCOPHAGE or GLUCOPHAGE XR. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. GLUCOPHAGE or GLUCOPHAGE XR treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, GLUCOPHAGE and GLUCOPHAGE XR should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking GLUCOPHAGE or GLUCOPHAGE XR, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, GLUCOPHAGE and GLUCOPHAGE XR should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure (see also PRECAUTIONS).
The onset of lactic acidosis often is 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 physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur (see also PRECAUTIONS). GLUCOPHAGE and GLUCOPHAGE XR should be withdrawn 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 GLUCOPHAGE or GLUCOPHAGE XR, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking GLUCOPHAGE or GLUCOPHAGE XR do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. (See also PRECAUTIONS.)
Lactic acidosis should be suspected 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 GLUCOPHAGE or GLUCOPHAGE XR, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride 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. (See also CONTRAINDICATIONS and PRECAUTIONS.)
Published Studies Related to Glucophage XR (Metformin)
Anagliptin and sitagliptin as add-ons to metformin for patients with type 2
diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled,
phase III clinical trial with a 28-week extension. 
We conducted a 24-week, multicentre, double-blind, randomized study with a
28-week extension to compare the efficacy and safety of anagliptin and
sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients
inadequately controlled on metformin were randomized to either anagliptin (100 mg
twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88)...
Effect of combination therapy with repaglinide and metformin hydrochloride on
glycemic control in Japanese patients with typeĀ 2 diabetes mellitus. 
exercise... CONCLUSIONS: Combination therapy with repaglinide and metformin resulted in an
Lipid profiling reveals different therapeutic effects of metformin and glipizide
in patients with type 2 diabetes and coronary artery disease. 
CONCLUSIONS: Our findings revealed the differential therapeutic effects of
Metformin for non-diabetic patients with coronary heart disease (the CAMERA
study): a randomised controlled trial. 
diabetes... INTERPRETATION: Metformin had no effect on cIMT and little or no effect on
The effect of metformin on apoptosis in a breast cancer presurgical trial. 
presurgical trial... CONCLUSION: Overall, we found no significant modulation of apoptosis by
Clinical Trials Related to Glucophage XR (Metformin)
Evaluate Adherence to Treatment With Glucophage Sachets Versus Tablets in Diabetes Type 2 Patients Previously Treated With Metformin Tablets [Withdrawn]
This is an open-label, multicenter, two-arm, parallel, randomized phase 4 study to compare
the compliance in diabetes type 2 patients treated with Glucophage sachets versus patients
treated with Glucophage tablets.
Bioequivalence Study of 2.5-mg Saxagliptin and 500-mg Glucophage in Tablets and a Fixed-dose Combination Tablet in Healthy Participants [Completed]
Bioequivalence Study of Fixed Dose Combination of 2.5 mg Saxagliptin/850 mg Metformin Tablet Relative to 2.5 mg Onglyza and 850 mg Glucophage Tablets Co-Administered [Completed]
A Study to Evaluate the Effect of Multiple Doses of Isavuconazole on the Pharmacokinetics of Metformin [Completed]
The purpose of this study is to assess the effect of multiple doses of isavuconazole on the
pharmacokinetics of a single dose of metformin. Safety and tolerability of isavuconazole
will be assessed alone and in combination with metformin.
A Study Comparing the Amount of Metformin and After Taking a Combination Tablet vs. Separate Tablets [Completed]
Reports of Suspected Glucophage XR (Metformin) Side Effects
Drug Ineffective (3),
Blood Glucose Increased (3),
Weight Decreased (2),
Wrong Technique in Drug Usage Process (1),
Drug Interaction (1),
Expired Drug Administered (1), more >>