Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD).
Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular death (CV), and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.
Limitations of Use
INVOKAMET® or INVOKAMET® XR is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.
IMPORTANT SAFETY INFORMATION for INVOKAMET® (canagliflozin/metformin HCl) and INVOKAMET® XR (canagliflozin/metformin HCl extended-release)
WARNING: LACTIC ACIDOSIS
INVOKAMET® or INVOKAMET® XR is contraindicated in patients with:
WARNINGS AND PRECAUTIONS
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET® or 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® or 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® or INVOKAMET® XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR <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® or INVOKAMET® XR if renal function is stable.
Surgery and Other Procedures: Discontinue INVOKAMET® or INVOKAMET® XR while patients have restricted food and fluid intake.
Hypoxic States: Discontinue INVOKAMET® or INVOKAMET® XR in conditions associated with hypoxemia.
Excessive Alcohol Intake: Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.
Hepatic Impairment: Avoid use of INVOKAMET® or INVOKAMET® XR in patients with evidence of hepatic disease.
Type 2 diabetes mellitus and pancreatic disorders are also risk factors for ketoacidosis. INVOKAMET® or INVOKAMET® XR is not indicated for glycemic control in patients with type 1 diabetes mellitus. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKAMET® or INVOKAMET® XR.
Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.
Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (eg, less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKAMET® or INVOKAMET® XR; however, there have been postmarketing reports of ketoacidosis and glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.
Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKAMET® or INVOKAMET® XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKAMET® or INVOKAMET® XR.
Withhold INVOKAMET® or INVOKAMET® XR, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKAMET® or INVOKAMET® XR when the patient is clinically stable and has resumed oral intake.
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.
Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET® or INVOKAMET® XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
Drugs That Reduce Metformin Clearance: Concomitant use of drugs that interfere with common renal tubular transport systems (eg, ranolazine, vandetanib, dolutegravir, and cimetidine) involved in the renal elimination of metformin (eg, organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.
Alcohol: Alcohol is known to potentiate the effect of metformin HCl on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET® or INVOKAMET® XR.
UGT Enzyme Inducers: UGT enzyme inducers decrease canagliflozin exposure which may reduce the effectiveness of INVOKAMET® or INVOKAMET® XR. For patients with eGFR ≥60 mL/min/1.73 m2, if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating INVOKAMET® or INVOKAMET® XR with a total daily dose of canagliflozin 100 mg. The total daily dose of canagliflozin may be increased to 300 mg in patients currently tolerating canagliflozin 200 mg and who require additional glycemic control.
For patients with eGFR <60 mL/min/1.73 m2, if an inducer of UGTs is co-administered with INVOKAMET® or INVOKAMET® XR, increase the total daily dose of canagliflozin to 200 mg in patients currently tolerating canagliflozin 100 mg.
Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when INVOKAMET® or INVOKAMET® XR is used concomitantly with insulin secretagogues (eg, sulfonylurea) or insulin. Concomitant use may require a lower dosage of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET® or INVOKAMET® XR, monitor for hypoglycemia.
Digoxin: Canagliflozin increases digoxin exposure. Monitor patients taking INVOKAMET® or INVOKAMET® XR with concomitant digoxin for a need to adjust dose of digoxin.
Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INVOKAMET® or INVOKAMET® XR initiation and dosage changes.
Drug/Laboratory Test Interference
Positive Urine Glucose Test: SGLT2 inhibitors increase urinary glucose excretion which will lead to positive urine glucose tests. Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
Interference With 1,5-Anhydroglucitol (1,5-AG) Assay: Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Monitoring glycemic control with 1,5-AG assay is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
USE IN SPECIFIC POPULATIONS
Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume, particularly with the 300‐mg dose; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years compared to younger patients.
The initial and maintenance dosing of metformin HCl should be conservative in elderly patients due to potential decreased renal function. Adjust dose based on assessment of renal function.
Renal Impairment: The efficacy and safety of canagliflozin for glycemic control were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m2). These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the study. Patients with renal impairment using canagliflozin for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury.
Efficacy and safety studies with INVOKANA® did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2.
Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.