Lactic Acidosis: Postmarketing cases of metformin-associated lactic acidosis, including fatal cases, were reported. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant bradyarrhythmias have occurred with severe acidosis. Additional findings included elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate:pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET®/INVOKAMET® XR. Prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin.
Educate patients and their families about the symptoms of lactic acidosis and if symptoms occur instruct them to discontinue INVOKAMET®/INVOKAMET® XR and report these symptoms to their healthcare provider.
Recommendations to reduce the risk include:
Renal Impairment: Obtain an eGFR before initiation and at least annually thereafter, and more frequently in patients at increased risk of renal impairment.
Drug Interactions: More frequent monitoring is recommended when administered with drugs that impair renal function, result in hemodynamic change, interfere with acid-base balance, or increase metformin accumulation (eg, cationic drugs).
Age 65 or Greater: Assess renal function more frequently in elderly patients.
Radiological Studies with Contrast: Stop INVOKAMET®/INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR of 45 to 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET®/INVOKAMET® XR if renal function is stable.
Surgery and Other Procedures: Discontinue INVOKAMET®/INVOKAMET® XR while patients have restricted food and fluid intake.
Hypoxic States: Discontinue INVOKAMET®/INVOKAMET® XR in conditions associated with hypoxemia.
Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET®/INVOKAMET® XR.
Hepatic Impairment: Avoid use of INVOKAMET®/INVOKAMET® XR in patients with evidence of hepatic disease.
Lower-Limb Amputation: 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, randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower-limb amputations was observed at both the 100-mg and 300-mg once-daily dosage regimens.
Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving canagliflozin in the two trials). Some patients had multiple amputations, some involving both lower limbs.
Lower-limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.
Before initiating, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur.
Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET®/INVOKAMET® XR, particularly in the elderly, and in patients with impaired renal function, low systolic blood pressure, or on diuretics or medications that interfere with the renin-angiotensin-aldosterone system. Before initiating INVOKAMET®/INVOKAMET® XR, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
Ketoacidosis: Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been identified in patients with type 1 and 2 diabetes mellitus receiving SGLT2 inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. Before initiating INVOKAMET®/INVOKAMET® XR, consider factors in patient history that may predispose to ketoacidosis. Monitor for ketoacidosis and temporarily discontinue in clinical situations known to predispose to ketoacidosis.
Acute Kidney Injury: Canagliflozin causes intravascular volume contraction and can cause acute kidney injury. Acute kidney injury, requiring hospitalization and dialysis, has been reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney injury. Consider temporarily discontinuing INVOKAMET®/INVOKAMET® XR in any setting of reduced oral intake or fluid losses; monitor patients for signs and symptoms of acute kidney injury. If it occurs, promptly discontinue and treat.
Initiation of canagliflozin may increase serum creatinine and decrease eGFR. Evaluate renal function prior to initiation and periodically thereafter. Dose adjustment and more frequent renal function monitoring are recommended in patients with an eGFR <60 mL/min/1.73 m2.
Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including canagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate for signs and symptoms and treat promptly.
Use With Medications Known to Cause Hypoglycemia
Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required.
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Monitor for a need to lower the dose of INVOKAMET®/INVOKAMET® XR.
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Necrotizing fasciitis of the perineum, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, has been identified in postmarketing surveillance in female and male patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKAMET®/INVOKAMET® XR. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKAMET®/INVOKAMET® XR.
Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections, especially in uncircumcised males or patients with prior infections. Monitor and treat appropriately.
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET®/INVOKAMET® XR; treat and monitor until signs and symptoms resolve.
Bone Fracture: Increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using canagliflozin. Prior to initiation, consider factors that contribute to fracture risk.
Vitamin B12 Levels: Metformin may lower vitamin B12 levels. Measure hematological parameters annually and vitamin B12 at 2- to 3-year intervals and manage any abnormalities.
Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. After initiation, monitor LDL-C and treat if appropriate.