IMPORTANT SAFETY INFORMATION

WARNING: LOWER-LIMB AMPUTATION

      • An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA^® use 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 INVOKANA^® for infection, new pain or tenderness, sores, or ulcers involving the lower limbs, and discontinue if these complications occur. 

CONTRAINDICATIONS    
       • History of a serious hypersensitivity reaction to INVOKANA^®, such as anaphylaxis or angioedema       

       • Severe renal impairment (eGFR <30 mL/min/1.73 m² ), end-stage renal disease, or patients on dialysis

 WARNINGS and PRECAUTIONS

       • Lower-Limb Amputation: An approximately 2-fold increased risk of lower-limb amputations associated with INVOKANA^® use was observed in CANVAS and CANVAS-R, two large,

         randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. In

         CANVAS, INVOKANA^®-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, INVOKANA^®-treated patients

         and placebo-treated patients had 7.5 and 4.2 amputations per 1000 patients per year, respectively. 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 patients with impaired renal

          function (eGFR <60 mL/min/1.73 m²), elderly patients, patients on either diuretics or medications that interfere with the renin‐angiotensin‐aldosterone system, or patients with low

          systolic blood pressure. Before initiating in patients with ≥1 of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after

          initiating. 

      •  Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have 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, including pancreatic insulin deficiency, caloric restriction disorders, and alcohol abuse. In patients treated with INVOKANA^®, consider monitoring for ketoacidosis

           and temporarily discontinuing in clinical situations known to predispose to ketoacidosis (eg, prolonged fasting due to acute illness or surgery).

      •  Acute Kidney Injury and Impairment in Renal Function: INVOKANA^® causes intravascular volume contraction and can cause renal impairment. Postmarketing reports of acute kidney injury, some

           requiring hospitalization and dialysis, were reported; some reports involved patients younger than 65 years of age. Before initiation, consider factors that may predispose patients to acute kidney

           injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications. 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 acute kidney injury occurs, discontinue promptly and institute treatment.

           INVOKANA^® increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiation. Renal

           function should be evaluated 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.

      • Hyperkalemia: INVOKANA^® can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion or medications that interfere

          with the renin‐angiotensin‐aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically in patients with impaired renal function and in patients

          predisposed to hyperkalemia due to medications or other medical conditions.

      • Urosepsis and Pyelonephritis: There have been reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors,

          including INVOKANA^®. Treatment with SGLT2 inhibitors increases this risk. Evaluate patients 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 to minimize the risk of hypoglycemia when used in combination with INVOKANA^®.
      • Genital Mycotic Infections: INVOKANA^® increases risk of genital mycotic infections. Patients with history of these infections and uncircumcised males were more likely to develop these 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 per standard of care, 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^®.  Consider factors that contribute to fracture

          risk prior to initiating INVOKANA^®. 

      • Increases in Low‐Density Lipoprotein (LDL‐C): Dose‐related increases in LDL‐C can occur with INVOKANA^®. Monitor LDL-C and treat per standard of care after initiating.

      • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA^®.

 DRUG INTERACTIONS
    • UGT Enzyme Inducers: Rifampin: Co-administration of INVOKANA^® with rifampin decreased INVOKANA^® area under the curve (AUC) by 51% and therefore may decrease efficacy. If an inducer of

        UGT enzymes must be co-administered with INVOKANA^®, consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA^® 100 mg once daily, have an

        eGFR ≥60 mL/min/1.73 m², and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR <60 mL/min/1.73 m²  who require additional glycemic    

        control.

    • Digoxin: There was an increase in the AUC and mean peak drug concentration of digoxin (20% and 36%, respectively) 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 as SGLT2 inhibitors increase urinary glucose excretion and

        will lead to positive urine glucose test results. 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 as measurements of 1,5-AG are unreliable in assessing glycemic control

        in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

 USE IN SPECIFIC POPULATIONS

     • Pregnancy: Based on animal data showing adverse renal effects, INVOKANA^® is not recommended during the second and third trimesters of pregnancy. Limited data with INVOKANA^® in

         pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to mother and fetus associated with poorly controlled diabetes in

         pregnancy.

     • Nursing Mothers: There is no information regarding the presence of INVOKANA^® in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for

         serious adverse reactions in a breastfed infant, advise women that use of INVOKANA^® is not recommended while breastfeeding.

     • Pediatric Use: Safety and effectiveness in patients <18 years of age have not been established.

     • Geriatric Use: 2034 patients ≥65 years and 345 patients ≥75 years were exposed to INVOKANA^® in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to

         reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300‐mg dose, compared to younger patients; 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 (‒0.61% with INVOKANA^® 100 mg

         and ‒0.74% with INVOKANA^® 300 mg) compared to younger patients (‒0.72% with INVOKANA^® 100 mg and ‒0.87% with INVOKANA^® 300 mg).

     • Renal Impairment: Efficacy and safety were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/1.73 m²). These patients had less overall glycemic

         efficacy and a higher occurrence of adverse reactions related to reduced intravascular volume, renal‐related adverse reactions, and decreases in eGFR compared to patients with mild renal

         impairment or normal renal function (eGFR ≥60 mL/min/1.73 m²); patients treated with 300 mg were more likely to experience increases in potassium. INVOKANA^® is not recommended in

         patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), with end‐stage renal disease, or receiving 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, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical

         monitoring, and institute supportive treatment as needed.

 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.

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

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