IMPORTANT SAFETY INFORMATION

Contraindications

• Serious hypersensitivity reaction to INVOKANA^®
• Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) who are being treated for glycemic control
• Patients on dialysis

WARNINGS and PRECAUTIONS

• Lower-Limb Amputation: An increased risk of lower-limb amputations associated with INVOKANA^® use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1000 patient-years), 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 INVOKANA^® 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 INVOKANA^® 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: INVOKANA^® causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA^®, 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 INVOKANA^®, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating.
• 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 INVOKANA^®. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA^®. Before initiating INVOKANA^®, 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: INVOKANA ^® causes intravascular volume contraction and can cause acute kidney injury. Acute kidney injury, requiring hospitalization and dialysis, has been reported. Initiation of INVOKANA^® may increase serum creatinine and decrease eGFR. Before initiation, consider factors that may predispose patients to acute kidney injury. Consider temporarily discontinuing INVOKANA^® 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. Evaluate renal function prior to initiation and monitor periodically thereafter.
• Urosepsis and Pyelonephritis: Serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization have been reported in patients receiving SGLT2 inhibitors, including INVOKANA^®. Treatment with SGLT2 inhibitors increases this risk. Evaluate for signs and symptoms and treat promptly.
• Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: INVOKANA ^® 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.
• 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 INVOKANA^®. Serious outcomes have included hospitalization, multiple surgeries, and death. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA^®.
• Genital Mycotic Infections: INVOKANA ^® 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 INVOKANA^®; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKANA ^®, 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 INVOKANA^®. Prior to initiation, consider factors that contribute to fracture risk.

DRUG INTERACTIONS

• UGT Enzyme Inducers: Co-administration with rifampin lowered INVOKANA^® exposure, which may reduce the efficacy of INVOKANA^®. For patients with eGFR ≥60 mL/min/1.73 m², if an inducer of UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA^®, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA^® 100 mg. The dose may be increased to 300 mg once daily in patients currently tolerating INVOKANA^® 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 INVOKANA^®, increase the dose to 200 mg (taken as two 100 mg tablets) once daily in patients currently tolerating INVOKANA^® 100 mg. Consider adding another antihyperglycemic agent in patients who require additional glycemic control.
• Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin when co-administered with INVOKANA^® 300 mg. Monitor appropriately.
• Positive Urine Glucose Test: 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: 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

• Pregnancy: INVOKANA ^® is not recommended in pregnant women, especially during the second and third trimesters.
• Nursing Mothers: INVOKANA ^® is not recommended while breastfeeding.
• Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.
• Geriatric Use: 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.
• Renal Impairment: The efficacy and safety of INVOKANA^® 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 INVOKANA^® for glycemic control may be more likely to experience hypotension and may be at a higher risk for acute kidney injury. INVOKANA^® is contraindicated in patients with ESKD on dialysis.
• Hepatic Impairment: INVOKANA ^® has not been studied in patients with severe hepatic impairment and is not recommended in this population.

OVERDOSAGE

• In the event of an overdose, contact the Poison Control Center and employ the usual supportive measures.

ADVERSE REACTIONS

• The most common adverse reactions associated with INVOKANA^® (5% or greater incidence) were female genital mycotic infections, urinary tract infections, and increased urination.

INVOKANA^® (canagliflozin) is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• 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)
• to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria >300 mg/day

INVOKANA^® is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Please see full Prescribing Information, including Boxed WARNING, and Medication Guide.

cp-68813v3

Janssen Pharmaceuticals, Inc.

Canagliflozin is licensed from
Mitsubishi Tanabe Pharma Corporation.

---

© Janssen Pharmaceuticals, Inc. 2019
October 2019
cp-104123v1

Janssen Medical Information Center PO Box 200, Titusville, NJ 08560