This information is not for clinical use. These highlights do not include all the information needed to use Invokana safely and effectively. Before taking Invokana please consult with your doctor. See full prescribing information for Invokana.

Warning

WARNING: 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 large, randomized, placebo-controlled trials in patients with type 2 diabetes who had established cardiovascular disease (CVD) or were at risk for CVD [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.1)]. Monitor patients receiving INVOKANA for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur [see Warnings and Precautions (5.1)]. WARNING: LOWER LIMB AMPUTATION See full prescribing information for complete boxed warning. In patients with type 2 diabetes who have established cardiovascular disease (CVD) or at risk for CVD, INVOKANA has been associated with lower limb amputations, most frequently of the toe and midfoot; some also involved the leg. (5.1) Before initiating, consider factors that may increase the risk of amputation. Monitor patients receiving INVOKANA for infections or ulcers of the lower limbs, and discontinue if these occur. (5.1)

Recent Changes

Boxed Warning 09/2019
Indications and Usage (1) 09/2019
Dosage and Administration (2.2, 2.3) 09/2019
Contraindications (4) 09/2019
Warnings and Precautions (5.1, 5.4) 09/2019
Warnings and Precautions (5.3) 01/2020
Warnings and Precautions (5.11) Removal 09/2019

Indications And Usage

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 a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1) to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease (1) to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria (1). Limitations of Use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1) Limitations of Use INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

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Dosage And Administration

Table 1: Recommended Dosage
estimated glomerular filtration rate eGFR (mL/min/1.73 m2) Recommended Dosage
eGFR ≥ 60 100 mg orally once daily, taken before the first meal of the day. Dose can be increased to 300 mg once daily for additional glycemic control.
eGFR 45 to < 60 100 mg once daily.
eGFR 30 to < 45with albuminuria >300 mg/day.
On dialysis Contraindicated [see Contraindications].

Dosage Forms And Strengths

INVOKANA 100 mg tablets are yellow, capsule-shaped, tablets with "CFZ" on one side and "100" on the other side. INVOKANA 300 mg tablets are white, capsule-shaped, tablets with "CFZ" on one side and "300" on the other side. Tablets: 100 mg, 300 mg (3)

Contraindications

Serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6.1, 6.2)]. Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) who are being treated for glycemic control [see Use in Specific Populations (8.6)]. Patients on dialysis [see Use in Specific Populations (8.6)]. Serious hypersensitivity reaction to INVOKANA (4, 5.9) Severe renal impairment (eGFR < 30 mL/min/1.73 m2) in patients who are being treated for glycemic control (4) On dialysis (4)

Warning and Cautions

Hypotension: Before initiating INVOKANA, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.2) Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue INVOKANA, evaluate and treat promptly. Before initiating INVOKANA, consider risk factors for ketoacidosis. Patients on INVOKANA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis (5.3) Acute kidney injury: Consider temporarily discontinuing in settings of reduced oral intake or fluid losses. If acute kidney injury occurs, discontinue and promptly treat. Monitor renal function during therapy (5.4) Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.5) Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA (5.6) Necrotizing fasciitis of the perineum (Fournier's gangrene): Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment (5.7) Genital mycotic infections: Monitor and treat if indicated (5.8) Hypersensitivity reactions: Discontinue INVOKANA and monitor until signs and symptoms resolve (5.9) Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKANA (5.10) 5.1 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. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6.1)]. 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 INVOKANA, 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 receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur. 5.2 Hypotension INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. 5.3 Ketoacidosis Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including INVOKANA. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA. INVOKANA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)]. Patients treated with INVOKANA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKANA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKANA should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement. In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake, surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified. Before initiating INVOKANA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKANA for at least 3 days prior to surgery [see Clinical Pharmacology (12.2, 12.3)]. Consider monitoring for ketoacidosis and temporarily discontinuing INVOKANA in other clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or post-surgery). Ensure risk factors for ketoacidosis are resolved prior to restarting INVOKANA. Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur. 5.4 Acute Kidney Injury INVOKANA causes intravascular volume contraction [see Warnings and Precautions (5.2)] and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including INVOKANA. Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of INVOKANA [see Adverse Reactions (6.1) and Clinical Pharmacology (12.1)]. Before initiating INVOKANA, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing INVOKANA in the setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue INVOKANA promptly and institute treatment. Renal function should be evaluated prior to initiation of INVOKANA and monitored periodically thereafter. 5.5 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)]. 5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. 5.7 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 5.8 Genital Mycotic Infections INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately. 5.9 Hypersensitivity Reactions Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA. These reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1, 6.2)]. 5.10 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA in the CANVAS trial [see Clinical Studies (14.2)]. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6.1)].

Adverse Reactions

The following important adverse reactions are described below and elsewhere in the labeling: Lower Limb Amputation [see Boxed Warning and Warnings and Precautions (5.1)] Hypotension [see Warnings and Precautions (5.2)] Ketoacidosis [see Warnings and Precautions (5.3)] Acute Kidney Injury [see Warnings and Precautions (5.4)] Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)] Necrotizing Fasciitis of the Perineum (Fournier's gangrene) [see Warnings and Precautions (5.7)] Genital Mycotic Infections [see Warnings and Precautions (5.8)] Hypersensitivity Reactions [see Warnings and Precautions (5.9)] Bone Fracture [see Warnings and Precautions (5.10)] Most common adverse reactions associated with INVOKANA (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials for Glycemic Control The data in Table 2 is derived from four 26-week placebo-controlled trials where INVOKANA was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 2 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. Table 2: Adverse Reactions from Pool of Four 26–Week Placebo-Controlled Studies Reported in ≥ 2% of INVOKANA-Treated PatientsThe four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. Adverse Reaction Placebo N=646 INVOKANA 100 mg N=833 INVOKANA 300 mg N=834 Urinary tract infectionsUrinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. 3.8% 5.9% 4.4% Increased urinationIncreased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. 0.7% 5.1% 4.6% ThirstThirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infectionsFemale genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infectionsMale genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. 0.7% 4.2% 3.8% Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in CREDENCE, a study in patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/day [see Clinical Studies (14.3)]. These data reflect exposure of 2,201 patients to INVOKANA and a mean duration of exposure to INVOKANA of 137 weeks. The rate of lower limb amputations associated with the use of INVOKANA 100 mg relative to placebo was 12.3 vs 11.2 events per 1000 patient-years, respectively, in CREDENCE, an outcomes study of patients with type 2 diabetes and diabetic nephropathy, with 2.6 years mean duration of follow-up [see Clinical Studies (14.3)]. In CREDENCE, incidence rates of adjudicated events of diabetic ketoacidosis (DKA) were 0.21 (0.5%, 12/2,200) and 0.03 (0.1%, 2/2,197) per 100 patient-years of follow-up with INVOKANA 100 mg and placebo, respectively [see Warnings and Precautions (5.3)]. The incidence of acute kidney injury was similar between INVOKANA 100 mg and placebo in CREDENCE [see Warnings and Precautions (5.4)]. In CREDENCE, the incidence of hypotension was 2.8% and 1.5% on INVOKANA 100 mg and placebo, respectively [see Warnings and Precautions (5.2)]. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 patients to INVOKANA) were consistent with those listed in Table 2. Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: 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. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.2)]. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Warnings and Precautions (5.1)]. Table 3: CANVAS Amputations Placebo N=1441 INVOKANA 100 mg N=1445 INVOKANA 300 mg N=1441 INVOKANA (Pooled) N=2886 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -- 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) Table 4: CANVAS-R Amputations Placebo N=2903 INVOKANA 100 mg (with up-titration to 300 mg) N=2904 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Patients with an amputation, n (%) 25 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -- 1.80 (1.10, 2.93) Renal Cell Carcinoma In the CANVAS trial (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.2)], the incidence of renal cell carcinoma was 0.15% (2/1331) and 0.29% (8/2716) for placebo and INVOKANA, respectively, excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to INVOKANA could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 5) [see Dosage and Administration (2.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.5 and 8.6)]. Table 5: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator GroupIncludes placebo and active-comparator groups % INVOKANA 100 mg % INVOKANA 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and olderPatients could have more than 1 of the listed risk factors 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m2 2.5% 4.7% 8.1% Use of loop diuretic 4.7% 3.2% 8.8% Falls In a pool of nine clinical trials with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment. Genital Mycotic Infections In the pool of four placebo-controlled clinical trials for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively [see Warnings and Precautions (5.8)]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively. In the pooled analysis of 8 randomized trials evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions (5.8)]. Hypoglycemia In all glycemic control trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials of glycemic control [see Clinical Studies (14.1)], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 6) [see Warnings and Precautions (5.6)]. Table 6: Incidence of HypoglycemiaNumber of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population in Randomized Clinical Studies of Glycemic Control Monotherapy (26 weeks) Placebo (N=192) INVOKANA 100 mg (N=195) INVOKANA 300 mg (N=197) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Combination with Metformin (26 weeks) Placebo + Metformin (N=183) INVOKANA 100 mg + Metformin (N=368) INVOKANA 300 mg + Metformin (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)]Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) 0 (0) 1 (0.3) 1 (0.3) In Combination with Metformin (52 weeks) Glimepiride + Metformin (N=482) INVOKANA 100 mg + Metformin (N=483) INVOKANA 300 mg + Metformin (N=485) Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) Severe [N (%)] 15 (3.1) 2 (0.4) 3 (0.6) In Combination with Sulfonylurea (18 weeks) Placebo + Sulfonylurea (N=69) INVOKANA 100 mg + Sulfonylurea (N=74) INVOKANA 300 mg + Sulfonylurea (N=72) Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5) In Combination with Metformin + Sulfonylurea (26 weeks) Placebo + Metformin + Sulfonylurea (N=156) INVOKANA 100 mg + Metformin + Sulfonylurea (N=157) INVOKANA 300 mg + Metformin + Sulfonylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)] 1 (0.6) 1 (0.6) 0 In Combination with Metformin + Sulfonylurea (52 weeks) Sitagliptin + Metformin + Sulfonylurea (N=378) INVOKANA 300 mg + Metformin + Sulfonylurea (N=377) Overall [N (%)] 154 (40.7) 163 (43.2) Severe [N (%)] 13 (3.4) 15 (4.0) In Combination with Metformin + Pioglitazone (26 weeks) Placebo + Metformin + Pioglitazone (N=115) INVOKANA 100 mg + Metformin + Pioglitazone (N=113) INVOKANA 300 mg + Metformin + Pioglitazone (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin (18 weeks) Placebo (N=565) INVOKANA 100 mg (N=566) INVOKANA 300 mg (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) Bone Fracture In the CANVAS trial [see Clinical Studies (14.2)], the incidence rates of all adjudicated bone fracture were 1.09, 1.59, and 1.79 events per 100 patient-years of follow-up to placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The fracture imbalance was observed within the first 26 weeks of therapy and remained through the end of the trial. Fractures were more likely to be low trauma (e.g., fall from no more than standing height), and affect the distal portion of upper and lower extremities [see Warnings and Precautions (5.10)]. Laboratory and Imaging Tests Increases in Serum Creatinine and Decreases in eGFR Initiation of INVOKANA causes an increase in serum creatinine and decrease in estimated GFR. In patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury [see Warnings and Precautions (5.4) and Mechanism of Action (12.1)]. The acute effect on eGFR reverses after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with INVOKANA. Increases in Serum Potassium In a pooled population of patients (N=723) in glycemic control trials with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg. In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)]. In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed with INVOKANA 100 mg relative to placebo. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C) In the pool of four glycemic control placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups. Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups. Increases in Hemoglobin In the pool of four placebo-controlled trials of glycemic control, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. Decreases in Bone Mineral Density Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.1)]. At 2 years, patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%. 6.2 Postmarketing Experience Additional adverse reactions have been identified during post-approval use of INVOKANA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Ketoacidosis Acute Kidney Injury Anaphylaxis, Angioedema Urosepsis and Pyelonephritis Necrotizing Fasciitis of the Perineum (Fournier's gangrene)

Drug Interactions

UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Adjust canagliflozin dose (2.3, 7.1) Digoxin: Monitor digoxin levels (7.2) 7.1 UGT Enzyme Inducers Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. For patients with eGFR 60 mL/min/1.73 m2 or greater, if an inducer of UGTs (e.g., 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 less than 60 mL/min/1.73 m2, if an inducer of UGTs (e.g., 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. Consider adding another antihyperglycemic agent in patients who require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 7.2 Digoxin There was an increase in the AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3)]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. 7.3 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 tests. Use alternative methods to monitor glycemic control. 7.4 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: Advise females of the potential risk to a fetus especially during the second and third trimesters. (8.1) Lactation: Not recommended when breastfeeding (8.2) Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume (5.2, 8.5) Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function (2.3, 5.4, 8.6) Hepatic impairment: Not recommended with severe hepatic impairment (8.7) 8.1 Pregnancy Risk Summary 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 the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC. The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA1C >7 and has been reported to be as high as 20–25% in women with a HbA1C >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Animal Data Canagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC. 8.2 Lactation Risk Summary There is no information regarding the presence of INVOKANA in human milk, the effects on the breastfed infant, or the effects on milk production. Canagliflozin is present in the milk of lactating rats [see Data]. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA is not recommended while breastfeeding. Data Animal Data Radiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. 8.4 Pediatric Use Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use In 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA [see Clinical Studies (14.1)]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). 8.6 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 less than 50 mL/min/1.73 m2) [see Clinical Studies (14.1)]. 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 study. Patients with renal impairment using INVOKANA for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury [see Warnings and Precautions (5.4)]. 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. INVOKANA is contraindicated in patients with ESKD on dialysis [see Contraindications (4) and Clinical Pharmacology (12.1)]. 8.7 Hepatic Impairment No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3)].