We highly recommend enabling Javascript while using the BlackBoxRX site.


Lactic Acidosis

  • Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.
  • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
  • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.
  • If metformin-associated lactic acidosis is suspected, immediately discontinue medication and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended


  • Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and general supportive care measures promptly instituted. Metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions). Prompt hemodialysis is recommended to correct the acidosis and tremove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery (See Labeling for Contraindications and Precautions)

Vitamin B12 Deficiency

  • Certain individuals ( those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3 year intervals in patients on metformin and manage any abnormalities.

Concomitant Use with Insulin and Insulin Secretagogues

  • Insulin and insulin secretagogues are known to cause hypoglycemia. Metformin may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin.

Risk of Lower Limb Amputation - Canagliflozin/Metformin

  • An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET/INVOKAMET XR, was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD.
  • Amputations of the toe and midfoot were most frequent; however, amputations involving the leg were also observed. Some patients had multiple amputations, some involving both limbs.
  • Before initiating, consider factors that may increase the risk of amputation, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers.
  • Monitor patients receiving INVOKAMET/INVOKAMET XR for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

FDA and Industry Communications

Index to FDA Drug Safety Information

Medication Guides

Patient Medication Guide

Package Inserts


Additional Information

Updated February 2020