Canagliflozin; metformin hydrochloride (INVOKAMET® and INVOKAMET® XR)
For more on this Drug Safety Labeling Change, click here and here.
For full prescribing information, click here.
Updated Boxed Warning: Canagliflozin; metformin hydrochloride (INVOKAMET®)
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Risk of Lower Limb Amputation
In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, canagliflozin, a component of INVOKAMET, has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg.
Before initiating, consider factors that may increase the risk of amputation. Monitor patients receiving INVOKAMET for infections or ulcers of the lower limbs, and discontinue if these occur.
Updated Boxed Warning: Canagliflozin; metformin hydrochloride (INVOKAMET® XR)
WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
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 (> 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally > 5 µg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, 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 INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended
Risk of Lower Limb Amputation
An approximately twofold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, 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 for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.
Public Information from the FDA and Medscape
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Cite this: Drug Safety Warnings and Updates: July-September 2017 - Medscape - Jan 03, 2018.
