Limitations of Use

INVOKANA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1)] .

INVOKANA is not recommended for use to improve glycemic control in adults with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2. INVOKANA is likely to be ineffective in this setting based upon its mechanism of action.

2.1 Prior to Initiation of INVOKANA

Assess renal function before initiating INVOKANA and as clinically indicated [see Dosage and Administration (2.3)and Warnings and Precautions (5.3)] .

In patients with volume depletion, correct this condition before initiating INVOKANA [see Warnings and Precautions (5.3)and Use in Specific Populations (8.5, 8.6)] .

2.2 Recommended Dosage and Administration

•

The recommended dosage of INVOKANA is 100 mg orally once daily, taken before the first meal of the day.

•

For additional glycemic control, the dosage of INVOKANA may be increased to the maximum recommended dosage of 300 mg once daily.

2.3 Recommended Dosage in Patients with Renal Impairment

Table 1 provides dosage recommendations for patients with renal impairment, based on estimated glomerular filtration rate (eGFR).

2.4 Concomitant Use with UDP-Glucuronosyl transferase (UGT) Enzyme Inducers

When co-administering INVOKANA with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the dosage of INVOKANA based on renal function [see Drug Interactions (7)]:

•

In patients with eGFR 60 mL/min/1.73 m 2or greater, increase the dosage to 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily. The maximum recommended dosage of INVOKANA is 300 mg once daily.

•

In patients with eGFR less than 60 mL/min/1.73 m 2, increase to a maximum recommended dosage of 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily.

2.5 Temporary Interruption for Surgery

Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)].

5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, INVOKANA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INVOKANA. INVOKANA is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA.

Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, 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 (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKANA [see Clinical Pharmacology (12.2)]; however, there have been postmarketing reports of ketoacidosis and/or 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 INVOKANA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA.

Withhold INVOKANA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5)] .

Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur.

5.2 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 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating patients with type 2 diabetes mellitus 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.

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.

5.3 Volume Depletion

INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)] . There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.

5.4 Urosepsis and Pyelonephritis

There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA. Treatment with INVOKANA 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)] .

5.5 Hypoglycemia with Concomitant Use with Insulin or 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)] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.6 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.

5.7 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.

5.8 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)] .

5.9 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)] .

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.

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)

8.1 Pregnancy

8.2 Lactation

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 HbA 1Cwith 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 m 2) [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 (5.3)] .

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 m 2[see Clinical Pharmacology (12.3)] .

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)] .

12.1 Mechanism of Action

SGLT2, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RT G), and thereby increases urinary glucose excretion (UGE).

Canagliflozin increases the delivery of sodium to the distal tubule by blocking SGLT2-dependent glucose and sodium reabsorption. This is believed to increase tubuloglomerular feedback and reduce intraglomerular pressure.

12.2 Pharmacodynamics

Following single and multiple oral doses of canagliflozin in patients with type 2 diabetes, dose-dependent decreases in RT Gand increases in urinary glucose excretion were observed. From a starting RT Gvalue of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RT Gthroughout the 24-hour period. Data from single oral doses of canagliflozin in healthy volunteers indicate that, on average, the elevation in urinary glucose excretion approaches baseline by about 3 days for doses up to 300 mg once daily. Maximal suppression of mean RT Gover the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 trials. The reductions in RT Gled to increases in mean UGE of approximately 100 g/day in patients with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. In patients with type 2 diabetes given 100 to 300 mg once daily over a 16-day dosing period, reductions in RT Gand increases in urinary glucose excretion were observed over the dosing period. In this trial, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose trials in healthy and type 2 diabetic patients, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose.

12.3 Pharmacokinetics

The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median T max) of canagliflozin occurs within 1 to 2 hours post-dose. Plasma C maxand AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t 1/2) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin HCl, sulfonylurea, metformin HCl and sulfonylurea, metformin HCl and sitagliptin, metformin HCl and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other anti-hyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin HCl and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin HCl. INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.

INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin HCl Extended-Release

A total of 1,450 patients with type 2 diabetes inadequately controlled on metformin HCl monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin HCl.

The mean age was 56 years, 52% of patients were male, and the mean baseline eGFR was 90 mL/min/1.73 m 2. Patients tolerating maximally required metformin HCl dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin HCl monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin HCl.

As shown in Table 13 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA 1Cfrom baseline compared to glimepiride when added to metformin HCl therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA 1Ccompared to glimepiride, and the relative treatment difference was -0.12% (95% CI: –0.22; –0.02). As shown in Table 13, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Table 13: Results from 52–Week Clinical Study Comparing INVOKANA to Glimepiride in Combination with Metformin HCl *

Efficacy Parameter	INVOKANA 100 mg + Metformin HCl (N=483)	INVOKANA 300 mg + Metformin HCl (N=485)	Glimepiride (titrated) + Metformin HCl (N=482)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl is considered non-inferior to glimepiride + metformin HCl because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001
HbA 1C(%)
Baseline (mean)	7.78	7.79	7.83
Change from baseline (adjusted mean)	-0.82	-0.93	-0.81
Difference from glimepiride (adjusted mean) (95% CI) †	-0.01 ‡ (-0.11; 0.09)	-0.12 ‡ (-0.22; -0.02)
Percent of patients achieving HbA 1C< 7%	54	60	56
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	165	164	166
Change from baseline (adjusted mean)	-24	-28	-18
Difference from glimepiride (adjusted mean) (95% CI) †	-6 (-10; -2)	-9 (-13; -5)
Body Weight
Baseline (mean) in kg	86.8	86.6	86.6
% change from baseline (adjusted mean)	-4.2	-4.7	1.0
Difference from glimepiride (adjusted mean) (95% CI) †	-5.2 § (-5.7; -4.7)	-5.7 § (-6.2; -5.1)

Figure 1: Mean HbA 1CChange at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin HCl and Sulfonylurea

A total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin HCl (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled trial to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin HCl and sulfonylurea. The mean age was 57 years, 56% of patients were male, and the mean baseline eGFR was 88 mL/min/1.73 m 2. Patients already on protocol-specified doses of metformin HCl and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin HCl and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin HCl and sulfonylurea.

As shown in Table 17 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA 1Creduction compared to sitagliptin 100 mg when added to metformin HCl and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

Table 17: Results from 52-Week Clinical Study Comparing INVOKANA to Sitagliptin in Combination with Metformin HCl and Sulfonylurea *

Efficacy Parameter	INVOKANA 300 mg + Metformin HCl and Sulfonylurea (N=377)	Sitagliptin 100 mg + Metformin HCl and Sulfonylurea (N=378)
* Intent-to-treat population using last observation in study prior to glycemic rescue therapy † Least squares mean adjusted for baseline value and stratification factors ‡ INVOKANA + metformin HCl+ sulfonylurea is considered non-inferior to sitagliptin + metformin HCl + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%. § p<0.001
HbA 1C(%)
Baseline (mean)	8.12	8.13
Change from baseline (adjusted mean)	-1.03	-0.66
Difference from sitagliptin (adjusted mean) (95% CI) †	-0.37 ‡ (-0.50; -0.25)
Percent of patients achieving HbA 1C< 7%	48	35
Fasting Plasma Glucose (mg/dL)
Baseline (mean)	170	164
Change from baseline (adjusted mean)	-30	-6
Difference from sitagliptin (adjusted mean) (95% CI) †	-24 (-30; -18)
Body Weight
Baseline (mean) in kg	87.6	89.6
% change from baseline (adjusted mean)	-2.5	0.3
Difference from sitagliptin (adjusted mean) (95% CI) †	-2.8 § (-3.3; -2.2)

Figure 2: Mean HbA 1CChange at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease

The CANVAS and CANVAS-R trials were multicenter, multi-national, randomized, double-blind parallel group, with similar inclusion and exclusion criteria. Patients eligible for enrollment in both CANVAS and CANVAS-R trials were: 30 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease (66% of the enrolled population) or were 50 years of age or older and had two or more other specified risk factors for cardiovascular disease (34% of the enrolled population).

The integrated analysis of the CANVAS and CANVAS-R trials compared the risk of Major Adverse Cardiovascular Event (MACE) between canagliflozin and placebo when these were added to and used concomitantly with standard of care treatments for diabetes and atherosclerotic cardiovascular disease. The primary endpoint, MACE, was the time to first occurrence of a three-part composite outcome which included cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.

In CANVAS, patients were randomly assigned 1:1:1 to canagliflozin 100 mg, canagliflozin 300 mg, or matching placebo. In CANVAS-R, patients were randomly assigned 1:1 to canagliflozin 100 mg or matching placebo, and titration to 300 mg was permitted at the investigator's discretion (based on tolerability and glycemic needs) after Week 13. Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases.

A total of 10,134 patients were treated (4,327 in CANVAS and 5,807 in CANVAS-R; total of 4,344 randomly assigned to placebo and 5,790 to canagliflozin) for a mean exposure duration of 149 weeks (223 weeks [4.3 years] in CANVAS and 94 weeks [1.8 years] in CANVAS-R) .Approximately 78% of the trial population was White, 13% was Asian, and 3% was Black or African American. The mean age was 63 years and approximately 64% were male.

The mean HbA 1Cat baseline was 8.2% and mean duration of diabetes was 13.5 years with 70% of patients having had diabetes for 10 years or more. Approximately 31%, 21% and 17% reported a past history of neuropathy, retinopathy and nephropathy, respectively, and the mean eGFR 76 mL/min/1.73 m 2. At baseline, patients were treated with one (19%) or more (80%) antidiabetic medications including metformin HCl (77%), insulin (50%), and sulfonylurea (43%).

At baseline, the mean systolic blood pressure was 137 mmHg, the mean diastolic blood pressure was 78 mmHg, the mean LDL was 89 mg/dL, the mean HDL was 46 mg/dL, and the mean urinary albumin to creatinine ratio (UACR) was 115 mg/g. At baseline, approximately 80% of patients were treated with renin angiotensin system inhibitors, 53% with beta-blockers, 13% with loop diuretics, 36% with non-loop diuretics, 75% with statins, and 74% with antiplatelet agents (mostly aspirin). During the trial, investigators could modify anti-diabetic and cardiovascular therapies to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure. More patients receiving canagliflozin compared to placebo initiated anti-thrombotics (5.2% vs 4.2%) and statins (5.8% vs 4.8%) during the trial.

For the primary analysis, a stratified Cox proportional hazards model was used to test for non-inferiority against a pre-specified risk margin of 1.3 for the hazard ratio of MACE.

In the integrated analysis of CANVAS and CANVAS-R trials, canagliflozin reduced the risk of first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.86 (0.75, 0.97). Refer to Table 20. Vital status was obtained for 99.6% of patients across the trials. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 3.

Figure 3: Time to First Occurrence of MACE

14.3 Renal and Cardiovascular Outcomes in Patients with Diabetic Nephropathy and Albuminuria

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation Trial (CREDENCE) was a multinational, randomized, double-blind, placebo-controlled trial comparing canagliflozin with placebo in patients with type 2 diabetes mellitus, an eGFR ≥ 30 to < 90 mL/min/1.73 m 2and albuminuria (urine albumin/creatinine > 300 to ≤ 5,000 mg/g) who were receiving standard of care including a maximum-tolerated, labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

The primary objective of CREDENCE was to assess the efficacy of canagliflozin relative to placebo in reducing the composite endpoint of end stage kidney disease (ESKD), doubling of serum creatinine, and renal or CV death.

Patients were randomized to receive canagliflozin 100 mg (N=2,202) or placebo (N=2,199) and treatment was continued until the initiation of dialysis or renal transplantation.

The median follow-up duration for the 4,401 randomized subjects was 137 weeks. Vital status was obtained for 99.9% of subjects.

The population was 67% White, 20% Asian, and 5% Black or African American; 32% were of Hispanic or Latino ethnicity. The mean age was 63 years and 66% were male.

At randomization, the mean HbA 1cwas 8.3%, the median urine albumin/creatinine was 927 mg/g, the mean eGFR was 56.2 mL/min/1.73 m 2, 50% had prior CV disease, and 15% reported a history of heart failure. The most frequent antihyperglycemic agents (AHA) medications used at baseline were insulin (66%), biguanides (58%), and sulfonylureas (29%). Nearly all subjects (99.9%) were on ACEi or ARB at randomization, approximately 60% were taking an anti-thrombotic agent (including aspirin), and 69% were on a statin.

The primary composite endpoint in the CREDENCE study was the time to first occurrence of ESKD (defined as an eGFR < 15 mL/min/1.73 m 2, initiation of chronic dialysis or renal transplant), doubling of serum creatinine, and renal or CV death. Canagliflozin 100 mg significantly reduced the risk of the primary composite endpoint based on a time-to-event analysis [HR: 0.70; 95% CI: 0.59, 0.82; p<0.0001] (see Figure 4). The treatment effect reflected a reduction in progression to ESKD, doubling of serum creatinine and cardiovascular death as shown in Table 21 and Figure 4. There were few renal deaths during the trial. Canagliflozin 100 mg also significantly reduced the risk of hospitalization for heart failure [HR: 0.61; 95% CI: 0.47 to 0.80; p<0.001].

The Kaplan-Meier curve (Figure 4) shows time to first occurrence of the primary composite endpoint of ESKD, doubling of serum creatinine, renal death, or CV death. The curves begin to separate by Week 52 and continue to diverge thereafter.

Figure 4: CREDENCE: Time to First Occurrence of the Primary Composite Endpoint

Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

Inform patients that INVOKANA can cause potentially fatal ketoacidosis and that type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are risk factors.

Educate all patients on precipitating factors (such as insulin dose reduction or missed doses, infection, reduced caloric intake, ketogenic diet, surgery, dehydration, and alcohol abuse) and symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing). Inform patients that blood glucose may be normal even in the presence of ketoacidosis.

Advise patients that they may be asked to monitor ketones. If symptoms of ketoacidosis occur, instruct patients to discontinue INVOKANA and seek medical attention immediately [see Warnings and Precautions (5.1)].

Lower Limb Amputation

Inform patients that INVOKANA is associated with an increased risk of amputations. Counsel patients about the importance of routine preventative foot care. Instruct patients to monitor for new pain or tenderness, sores or ulcers, or infections involving the leg or foot and to seek medical advice immediately if such signs or symptoms develop [see Warnings and Precautions (5.2)] .

Volume Depletion

Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions (5.3)] . Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.

Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues

Inform patients that hypoglycemia has been reported when INVOKANA is used with insulin or insulin secretagogues. Educate patients or caregivers on the signs and symptoms of hypoglycemia [see Warnings and Precautions (5.5)].

Serious Urinary Tract Infections

Inform patients of the potential for urinary tract infections, which may be serious. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur [see Warnings and Precautions (5.4)] .

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier's gangrene) have occurred with INVOKANA. Counsel patients to promptly seek medical attention if they develop pain or tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, along with a fever above 100.4°F or malaise [see Warnings and Precautions (5.6)] .

Genital Mycotic Infections in Females (e.g., Vulvovaginitis)

Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)] .

Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis)

Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions (5.7)] .

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.8)] .

Bone Fracture

Inform patients that bone fractures have been reported in patients taking INVOKANA. Provide them with information on factors that may contribute to fracture risk [see Warnings and Precautions (5.9)] .

Pregnancy

Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKANA [see Use in Specific Populations (8.1)] . Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Lactation

Advise women that breastfeeding is not recommended during treatment with INVOKANA [see Use in Specific Populations (8.2)].

Laboratory Tests

Inform patients that due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine [see Drug Interactions (7)] .

Missed Dose

If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.