Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

INVOKANA (NDA-204042)

(CANAGLIFLOZIN)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/05/2023 (SUPPL-40)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

Newly added subsection:

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 acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (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 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

INVOKANA can cause serious side effects, including:

Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 and other ketoacidosis. INVOKANA can cause ketoacidosis that can be life-threatening and may lead to death. People with type 1 diabetes, type 2 diabetes, or pancreas problems have a high risk of getting ketoacidosis. Ketoacidosis can happen even if your blood sugar is less than 250 mg/dL. Your healthcare provider may ask you to periodically check ketones in your urine or blood. Ketoacidosis can also happen in people who are sick or who have surgery during treatment with INVOKANA. Ketoacidosis is a serious condition which needs to be treated in a hospital. Ketoacidosis may lead to death.
Stop taking INVOKANA and call your healthcare provider or get medical help right away if you get any of the following. If possible, check for ketones in your urine or blood, even if your blood sugar is less than
250 mg/dL:
- nausea o tiredness
- vomiting o trouble breathing
- stomach-area (abdominal) pain o ketones in your urine or blood
  
  . . .
  
  Before taking INVOKANA, tell your doctor about all of your medical conditions, including if you:

have type 1 diabetes or have had diabetic ketoacidosis
have a serious infection.
have a history of infection of the vagina or penis.

. . .

are dehydrated.
have a decrease in your insulin dose.

10/13/2022 (SUPPL-39)

Approved Drug Label (PDF)

7 Drug Interactions

Addition of Table 7: Clinically Significant Drug Interactions with INVOKANA

Additions and revisions underlined:

UGT Enzyme Inducers

Clinical Impact: UGT enzyme inducers decrease canagliflozin exposure which may reduce the

effectiveness of INVOKANA.

Insulin or Insulin Secretagogues

Clinical Impact: The risk of hypoglycemia is increased when INVOKANA is used concomitantly with

insulin secretagogues (e.g., sulfonylurea) or insulin.

Intervention: Concomitant use may require a lower dosage of the insulin secretagogue or insulin to

reduce the risk of hypoglycemia.

Lithium

Clinical Impact: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium

concentrations.

Intervention: Monitor serum lithium concentration more frequently during INVOKANA initiation and

dosage changes.

08/18/2020 (SUPPL-34)

Approved Drug Label (PDF)

Boxed Warning

Box Warning for Lower Limb Amputation has been removed from the label.

4 Contraindications

Removal of bullet regarding patients with severe renal impairment (eGFR < 30ml/min/1.73 m2 who are being treated for glycemic control.

5 Warnings and Precautions

5.2 Volume Depletion (replaces Hypotension)

Additions and/or revisions underlined:

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 m2), 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.

5.3 Ketoacidosis

Additions and/or revisions underlined:

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including INVOKANA. In placebo-controlled trials of patients with type 1 diabetes, the risk of ketoacidosis was increased in patients who received SGLT2 inhibitors compared to patients who received placebo. The risk of ketoacidosis may be greater with higher doses. 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)] …

6 Adverse Reactions

In the bulleted line listing, ‘Volume Depletion’ replaces ‘Hypotension’

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is INVOKANA?

INVOKANA is not for people with type 1 diabetes. It may increase their risk of diabetic ketoacidosis (increased ketones in blood or urine).

INVOKANA is not used to lower blood sugar (glucose) in adults with type 2 diabetes with severe kidney problems.

PATIENT COUNSELING INFORMATION

Volume Depletion’ replaces ‘Hypotension’

01/24/2020 (SUPPL-36)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Ketoacidosis

(Additions and/or revisions underlined)

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.

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 Patient Counseling Information

(Additions and/or revisions underlined)

Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition and that cases of ketoacidosis have been reported during use of INVOKANA, sometimes associated with illness or surgery among other risk factors. Instruct patients to check ketones (when possible) if symptoms consistent with ketoacidosis occur even if blood glucose is not elevated. If symptoms of ketoacidosis (including nausea, vomiting, abdominal pain, tiredness, and labored breathing) occur, instruct patients to discontinue INVOKANA and seek medical attention immediately.

Medication Guide

(Extensive changes; please refer to label)

09/27/2019 (SUPPL-32)

Approved Drug Label (PDF)

Boxed Warning

(additions and/or revisions are underlined)

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.
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.

4 Contraindications

(additions and/or revisions are underlined)

Serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or angioedema
Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m^2) who are being treated for glycemic control
Patients on dialysis

5 Warnings and Precautions

5.1 Lower Limb Amputation

(additions and/or revisions are underlined)

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.

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.

5.4 Acute Kidney Injury

(additions and/or revisions are underlined)

INVOKANA causes intravascular volume contraction 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. 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.

6 Adverse Reactions

6.1 Clinical Studies Experience

(extensive revisions; please refer to labeling for complete information)

7 Drug Interactions

7.1 UGT Enzyme Inducers

(additions and/or revisions are underlined)

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 m^2 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 m^2, 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.

8 Use in Specific Populations

8.6 Renal Impairment

(additions and/or revisions are underlined)

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). 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.

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. INVOKANA is contraindicated in patients with ESKD on dialysis.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(additions and/or revisions are underlined)

What is INVOKANA?

INVOKANA is a prescription medicine used:
- along with diet and exercise to lower blood sugar (glucose) in adults with type 2 diabetes.
- to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes who have known cardiovascular disease.
- to reduce the risk of end stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine.
INVOKANA is not for people with type 1 diabetes.
INVOKANA is not for people with diabetic ketoacidosis (increased ketones in blood or urine).

It is not known if INVOKANA is safe and effective in children under 18 years of age.

10/29/2018 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Acute Kidney Injury

(Additions and/or revisions are underlined)

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 any 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.

Initiation of INVOKANA may increase serum creatinine and decrease eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function should be evaluated prior to initiation of INVOKANA and monitored periodically

Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of INVOKANA is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.

5.7 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

(Newly added subsection)

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.

5.10 Bone Fracture

(Additions and/or revisions are underlined)

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. Consider factors that contribute to fracture risk prior to initiating INVOKANA.

6 Adverse Reactions

(Additions and/or revisions are underlined)

…

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

…

6.1 Clinical Studies Experience

Additions and/or revisions are underlined)

…

Pool of Placebo-Controlled Trials

The data in Table 1 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. …

Pool of Placebo- and Active-Controlled Trials

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.

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 1. 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).

….

Renal Cell Carcinoma

In the CANVAS trial (mean duration of follow-up of 5.7 years), 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.

…

Impairment in Renal Function

Initiation of INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 5). The effect on eGFR was observed to reverse after treatment discontinuation suggesting acute hemodynamic changes may play a role in the renal function changes observed with INVOKANA.

In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

Patients with moderate renal impairment at baseline experience larger mean changes in eGFR relative to patients with normal or mildly impaired renal function. In a trial in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2), the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9%, 18%, and 22.5% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. At the end of treatment, 4.6%, 3.4%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had a significant renal function decline.

Genital Mycotic Infections

In the pool of four placebo-controlled clinical trials, 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.

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 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis.

Hypoglycemia

In all clinical 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, episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 6).

Bone Fracture

In the CANVAS trial, 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.

Laboratory and Imaging Tests

Increases in Serum Potassium

In a pooled population of patients (N=723) 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.

…

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

...

In 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

…

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.

…

Laboratory Tests

Inform patients that due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine .

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.

Medication Guide

(Additions and/or revisions are underlined)

…

What is INVOKANA?

INVOKANA is a prescription medicine used:
- along with diet and exercise to lower blood sugar (glucose) in adults with type 2 diabetes.
- to reduce the risk of major cardiovascular events such as heart attack, stroke or death in adults with type 2 diabetes who have known cardiovascular disease.
INVOKANA is not for people with type 1 diabetes.
INVOKANA is not for people with diabetic ketoacidosis (increased ketones in blood or urine).

It is not known if INVOKANA is safe and effective in children under 18 years of age.

…

What are the possible side effects of INVOKANA? INVOKANA may cause serious side effects including:

See “What is the most important information I should know about INVOKANA?”

…

a rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take INVOKANA. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around your anus and genitals:
- pain or tenderness o swelling o redness of the skin (erythema)

…

What are the ingredients of INVOKANA?

Active ingredient: canagliflozin

Inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. In addition, the tablet coating contains iron oxide yellow E172 (100 mg tablet only), macrogol/PEG, polyvinyl alcohol, talc, and titanium dioxide.

The brands listed are trademarks of their respective owners and are not trademarks of Janssen Pharmaceuticals, Inc. Active ingredient made in Belgium. Manufactured for: Janssen Pharmaceuticals, Inc., Titusville, NJ 08560. Manufactured by: Janssen Ortho LLC, Gurabo, PR 00778 or Janssen Cilag SpA, Latina, Italy. Licensed from Mitsubishi Tanabe Pharma Corporation. © 2013 Janssen Pharmaceutical Companies

10/26/2018 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

5.8 Necrotizing Fasciitis of the Perineum (Fornier’s Gangrene)

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

6.2 Postmarketing Experience

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s gangrene)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of INVOKANA? INVOKANA may cause serious side effects, including:

See “What is the most important information I should know about INVOKANA?”

Addition of the following:

A rare but serious bacterial infection that causes damage to the tissue under the skin (necrotizing fasciitis) in the area between and around the anus and genitals (perineum). Necrotizing fasciitis of the perineum has happened in women and men who take INVOKANA. Necrotizing fasciitis of the perineum may lead to hospitalization, may require multiple surgeries, and may lead to death. Seek medical attention immediately if you have fever or you are feeling very weak, tired or uncomfortable (malaise) and you develop any of the following symptoms in the area between and around the anus and genitals:

o pain or tenderness o swelling o redness of skin (erythema)

PATIENT COUNSELING INFORMATION

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

07/25/2017 (SUPPL-26)

Approved Drug Label (PDF)

Boxed Warning

(section added)

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.

5 Warnings and Precautions

5.1 Lower Limb Amputation

(new subsection added)

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. The amputation data for CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively.

6 Adverse Reactions

(addition underlined)

Lower Limb Amputation
Hypotension
Ketoacidosis
Acute Kidney Injury and Impairment in Renal Function
Hyperkalemia [Urosepsis and Pyelonephritis
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Genital Mycotic Infections
Hypersensitivity Reactions
Bone Fracture
Increases in Low-Density Lipoprotein (LDL-C)

6.1 Clinical Studies Experience

(additions underlined)

….

Lower Limb Amputation

(please refer to label to view Table 2 and Table 3)

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MRDICATION GUIDE

(additions underlined)

What is the most important information I should know about INVOKANA?
INVOKANA can cause important side effects, including:

Amputations. INVOKANA may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body.

You may be at a higher risk of lower limb amputation if you:

have a history of amputation
have heart disease or are at risk for heart disease
have had blocked or narrowed blood vessels, usually in your leg
have damage to the nerves (neuropathy) in your leg
have had diabetic foot ulcers or sores

Call your doctor right away if you have new pain or tenderness, any sores, ulcers, or infections in your leg or foot. Your doctor may decide to stop your INVOKANA for a while if you have any of these signs or symptoms.
Talk to your doctor about proper foot care.
…

PATIENT COUNSELING INFORMATION

(additions underlined)

…

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.

…

02/01/2017 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Studies Experience

Pool of Placebo- and Active-Controlled Trials

Addition of % signs:

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.

08/17/2016 (SUPPL-22)

Approved Drug Label (PDF)

5 Warnings and Precautions

Ketoacidosis

Addition of:

Fatal cases of ketoacidosis have been reported in patients taking INVOKANA.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - What are the possible side effects of INVOKANA?

INVOKANA may cause serious side effects including:

See “What is the most important information I should know about INVOKANA?”

ketoacidosis (increased ketones in your blood or urine). … Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death.

PCI - Ketoacidosis

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of INVOKANA. Instruct patients to check ketones …

05/20/2016 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

Acute Kidney Injury and Impairment in Renal Function

INVOKANA causes intravascular volume contraction and can cause renal impairment. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving INVOKANA; some reports involved patients younger than 65 years of age.

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 any 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.

INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may bemore susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA. Renal function should be evaluated prior to initiation of INVOKANA and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m2. Use of INVOKANA is not recommended when eGFR is persistently less than 45 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.

03/28/2016 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

History of a serious hypersensitivity reaction to Invokana, such as anaphylaxis or angioedema.

5 Warnings and Precautions

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.

6 Adverse Reactions

Postmarketing Experience

Anaphylaxis, Angioedema