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.

INVOKAMET XR (NDA-205879)

(CANAGLIFLOZIN; METFORMIN HYDROCHLORIDE)

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

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01/19/2024 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

(Additions and/or revisions underlined)

In patients with type 1 diabetes mellitus, INVOKAMET or INVOKAMET XR 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 INVOKAMET or INVOKAMET XR. INVOKAMET or INVOKAMET XR 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 INVOKAMET or INVOKAMET XR.

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…

6 Adverse Reactions

6.1 Clinical Studies Experience

…

Metformin HCl

(Additions and/or revisions underlined)

The most common adverse reactions (5% or greater incidence) due to initiation of metformin HCl are diarrhea, nausea, vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.

In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients…

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Additional adverse reactions have been identified during post-approval use of canagliflozin and/or metformin. 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.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-Approved Patient Labeling (Medication Guide).

…

Vitamin B12 Deficiency

Inform patients about importance of regular hematological parameters while receiving INVOKAMET or INVOKAMET XR [see Warnings and Precautions (5.11)].

Medication Guide INVOKAMET (in vok’ a met) (canagliflozin and metformin hydrochloride (HCl)) tablets, for oral use and

INVOKAMET (in vok’ a met) XR (canagliflozin and metformin HCl) extended-release tablets, for oral use

(Additions and/or revisions underlined)

Diabetic ketoacidosis (increased ketones in your blood or urine) in people with type 1 and other ketoacidosis. INVOKAMET and INVOKAMET XR can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis. Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery. 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.

10/13/2022 (SUPPL-18)

Approved Drug Label (PDF)

7 Drug Interactions

Addition of Table 7: Clinically Significant Drug Interactions with INVOKAMET/INVOKAMET XR

Additions and revisions underlined:

UGT Enzyme Inducers

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

effectiveness of INVOKAMET/INVOKAMET XR.

Insulin or Insulin Secretagogues

Clinical Impact: The risk of hypoglycemia is increased when INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR initiation and

dosage changes.

08/18/2020 (SUPPL-17)

Approved Drug Label (PDF)

Boxed Warning

Lower Limb Amputation has been removed from the Box Warning

5 Warnings and Precautions

Additions and/or revisions underlined:

5.3 Volume Depletion (formerly Hypotension)

Canagliflozin 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 canagliflozin. 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 INVOKAMET/INVOKAMET XR 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 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 canagliflozin. 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 canagliflozin. INVOKAMET/INVOKAMET XR is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].

6 Adverse Reactions

Addition of ‘Volume Depletion’ to bulleted line listing.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is INVOKAMET or INVOKAMET XR?

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

PATIENT COUNSELING INFORMATION

‘Volume Depletion’ replaces ‘Hypotension’

01/27/2020 (SUPPL-11)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

INVOKAMET/INVOKAMET XR is contraindicated in patients:

With severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or on dialysis [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

5 Warnings and Precautions

Acute Kidney Injury

(Additions and/or revisions underlined)

There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving SGLT2 inhibitors, including canagliflozin.

Increases in serum creatinine and decreases in estimated GFR may also be observed with initiation of INVOKAMET/INVOKAMET XR [see Adverse Reactions (6.1) and Clinical Pharmacology (12.1)].

Lactic Acidosis

(Additions and/or revisions underlined)

INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2 [see Contraindications (4)].

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.

Lower Limb Amputation

(Additions and/or revisions underlined)

An increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET/INVOKAMET XR, 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.

6 Adverse Reactions

Clinical Studies Experience

(Extensive changes; please refer to label)

7 Drug Interactions

(Addition of new tables; please refer to label)

8 Use in Specific Populations

Renal Impairment

Canagliflozin

(Additions and/or revisions underlined)

The efficacy and safety of canagliflozin 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 canagliflozin 300 mg per day had increases in serum potassium, which were transient and similar by the end of study. Patients with renal impairment using canagliflozin 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 (5.5)].

Efficacy and safety studies with canagliflozin did not enroll patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2. Canagliflozin is contraindicated in patients with ESKD on dialysis and in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) who are being treated for glycemic control [see Contraindications (4) and Clinical Pharmacology (12.1)].

Metformin HCl

(Newly added subsection)

Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. INVOKAMET/INVOKAMET XR is contraindicated in severe renal impairment (eGFR less than 30 mL/min/1.73 m2) or in patients on dialysis [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

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

(Additions and/or revisions underlined)

Stop taking INVOKAMET or INVOKAMET XR and call your doctor right away if you have any of the following symptoms of lactic acidosis. . .

Most people who have had lactic acidosis had other conditions that, in combination with metformin use, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with INVOKAMET or INVOKAMET XR if you:

o are 65 years of age or older.

INVOKAMET XR contains 2 prescription medicines called canagliflozin (INVOKANA) and metformin hydrochloride extended-release (GLUMETZA). INVOKAMET or INVOKAMET XR can be used:

in adults with type 2 diabetes and diabetic kidney disease (nephropathy) with a certain amount of protein in the urine, and canagliflozin is needed to reduce the risk of end stage kidney disease (ESKD), worsening of kidney function, cardiovascular death, and hospitalization for heart failure.

Before taking INVOKAMET or INVOKAMET XR, tell your doctor about all of your medical conditions, including if you:

• have low levels of vitamin B12 or calcium in your blood.

Ketoacidosis is a serious condition, which needs to be treated in a hospital.

For more information about INVOKAMET or INVOKAMET XR, call 1-800-526-7736 or visit our websites at www.invokamet.com or www.invokametxr.com.

01/24/2020 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Ketoacidosis

(Additions and/or revisions underlined)

For patients who undergo scheduled surgery, consider temporarily discontinuing INVOKAMET/INVOKAMET XR for at least 3 days prior to surgery.

Consider monitoring for ketoacidosis and temporarily discontinuing INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR.

Educate patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKAMET/INVOKAMET XR 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 canagliflozin, 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 INVOKAMET/INVOKAMET XR and seek medical attention immediately.

Medication Guide

(Additions and/or revisions underlined)

What are the possible side effects of INVOKAMET or NVOKAMET XR? INVOKAMET or INVOKAMET XR may cause serious side effects including:

See "What is the most important information I should know about INVOKAMET or INVOKAMET XR?”
dehydration. INVOKAMET or INVOKAMET XR can cause some people to become dehydrated (the loss of too much body water). Dehydration may cause you to feel dizzy, faint, lightheaded, or weak, especially when you stand up (orthostatic hypotension).

You may be at higher risk of dehydration if you:

have low blood pressure
take medicines to lower your blood pressure, including diuretics (water pill)
are on a low sodium (salt) diet
have kidney problems
are 65 years of age or older

Talk to your doctor about what you can do to prevent dehydration including how much fluid you should drink on a daily basis.

ketoacidosis (increased ketones in your blood or urine). Ketoacidosis has happened in people who have type 1 diabetes or type 2 diabetes, during treatment with canagliflozin, one of the medicines in INVOKAMET and INVOKAMET XR. Ketoacidosis has also happened in people with diabetes who were sick or who had surgery during treatment with INVOKAMET or INVOKAMET XR. Ketoacidosis is a serious condition, which may need to be treated in a hospital. Ketoacidosis may lead to death. Ketoacidosis can happen with INVOKAMET or INVOKAMET XR, even if your blood sugar is less than 250 mg/dL.

10/29/2018 (SUPPL-7)

Approved Drug Label (PDF)

4 Contraindications

4 CONTRAINDICATIONS

(Additions and/or revisions are underlined)

INVOKAMET/INVOKAMET XR is contraindicated in patients with:

Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2), end stage renal disease (ESRD) or patients on dialysis .

Acute or chronic metabolic acidosis, including diabetic.
Serious hypersensitivity reaction to canagliflozin or metformin, such as anaphylaxis or angioedema

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions are underlined)

…

If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET/INVOKAMET XR. In INVOKAMET/INVOKAMET XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.

Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue INVOKAMET/INVOKAMET XR and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include.

Before initiating INVOKAMET/INVOKAMET XR, obtain an estimated glomerular filtration rate (eGFR).
INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR less than 45 mL/minute/1.73 m2 .
Obtain an eGFR at least annually in all patients taking INVOKAMET/INVOKAMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions: The concomitant use of INVOKAMET/INVOKAMET XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation (e.g. cationic drugs). Therefore, consider more frequent monitoring of patients.

Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.

Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop INVOKAMET/INVOKAMET XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 45 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart INVOKAMET/INVOKAMET XR if renal function is stable.

Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.

INVOKAMET/INVOKAMET XR should be temporarily discontinued while patients have restricted food and fluid intake.

Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal azotemia. When such events occur, discontinue INVOKAMET/INVOKAMET XR.

Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.

Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of INVOKAMET/INVOKAMET XR in patients with clinical or laboratory evidence of hepatic disease.

5.10 Hypersensitivity Reactions

(Additions and/or revisions are underlined)

Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with canagliflozin. These reactions generally occurred within hours to days after initiating canagliflozin. If hypersensitivity reactions occur, discontinue use of INVOKAMET/INVOKAMET XR; treat and monitor until signs and symptoms resolve.

(Additions and/or revisions are underlined)

5.11 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 canagliflozin in the CANVAS trial. Consider factors that contribute to fracture risk prior to initiating INVOKAMET/INVOKAMET XR.

5.11 Bone Fracture

(Additions and/or revisions are underlined)

5.12 Vitamin B12 Levels

(Additions and/or revisions are underlined)

In metformin HCl clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. Measure hematologic parameters on an annual basis and vitamin B12 at 2- to 3-year intervals in patients on INVOKAMET/INVOKAMET XR and manage any abnormalities.

5.13 Increases in Low-Density Lipoprotein (LDL-C)

(Additions and/or revisions are underlined)

Dose-related increases in LDL-C occur with canagliflozin . Monitor LDL-C and treat if appropriate after initiating INVOKAMET/INVOKAMET XR.

5.2 Lower Limb Amputation

(Additions and/or revisions are underlined)

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET/INVOKAMET XR, was observed in CANVAS and CANVAS- R, 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 2 and 3, respectively .

Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving canagliflozin 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 canagliflozin 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 INVOKAMET/INVOKAMET XR, 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 INVOKAMET/INVOKAMET XR for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET/INVOKAMET XR if these complications occur.

5.3 Hypotension

(Additions and/or revisions are underlined)

Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR in patients with one or more of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

5.4 Ketoacidosis

(Additions and/or revisions are underlined)

Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including canagliflozin. Fatal cases of ketoacidosis have been reported in patients taking canagliflozin. INVOKAMET/INVOKAMET XR is not indicated for the treatment of patients with type 1 diabetes mellitus.

Patients treated with INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKAMET/INVOKAMET XR 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 due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.

Before initiating INVOKAMET/INVOKAMET XR consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with INVOKAMET/INVOKAMET XR consider monitoring for ketoacidosis and temporarily discontinuing INVOKAMET/INVOKAMET XR in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).

5.5 Acute Kidney Injury

(Additions and/or revisions are underlined)

Canagliflozin 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 canagliflozin; some reports involved patients younger than 65 years of age.

Before initiating INVOKAMET/INVOKAMET XR, 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 INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR promptly and institute treatment.

Initiation of canagliflozin 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 INVOKAMET/INVOKAMET XR 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. INVOKAMET/INVOKAMET XR is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2.

5.7 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin

(Additions and/or revisions are underlined)

Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKAMET/INVOKAMET XR may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET/INVOKAMET XR.

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

(Additions and/or revisions are underlined)

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 canagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with INVOKAMET/INVOKAMET XR 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 INVOKAMET/INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions are underlined)

…

Pool of Placebo- and Active-Controlled Trials - Canagliflozin

The occurrence of adverse reactions for canagliflozin 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 canagliflozin) 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, canagliflozin was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, canagliflozin 100 mg, and canagliflozin 300 mg, respectively).

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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 canagliflozin, 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 canagliflozin could not be established due to the limited number of cases.

Volume Depletion-Related Adverse Reactions

Canagliflozin results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials, treatment with canagliflozin 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 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 4).

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Impairment in Renal Function

CanagliflozinInitiation of canagliflozin 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 canagliflozin.

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, canagliflozin 100 mg, canagliflozin 300 mg, respectively. At the end of treatment, 4.6%, 3.4%, and 2.2% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively, had a significant renal function decline.

Bone Fracture

TheIn 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, canagliflozin 100 mg, and canagliflozin 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.

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7 Drug Interactions

7.1 Drug Interactions with Metformin

(Additions and/or revisions are underlined)

Carbonic Anhydrase Inhibitors

Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with INVOKAMET/INVOKAMET XR may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.

Drugs That Reduce Metformin Clearance

Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use.

Alcohol

Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.

Drugs Affecting Glycemic Control

Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET/INVOKAMET XR, monitor for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET/INVOKAMET XR, monitor for hypoglycemia.

7.2 Drug Interactions with Canagliflozin

(Additions and/or revisions are underlined)

UGT Enzyme Inducers

Rifampin: Rifampin lowered canagliflozin exposure which may reduce the efficacy of INVOKAMET/INVOKAMET XR. If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKAMET/INVOKAMET XR, consider increasing the total daily dose of canagliflozin to 300 mg if patients are currently tolerating INVOKAMET/INVOKAMET XR with a total daily dose of canagliflozin 100 mg, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control.

Digoxin

Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET/INVOKAMET XR with concomitant digoxin for a need to adjust dose of either drug.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Based on animal data showing adverse renal effects, INVOKAMET/INVOKAMET XR is not recommended during the second and third trimesters of pregnancy.

Limited data with INVOKAMET, INVOKAMET XR or canagliflozin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

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8.2 Lactation

(Additions and/or revisions are underlined)

Risk Summary

There is no information regarding the presence of INVOKAMET, INVOKAMET XR or canagliflozin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin 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 INVOKAMET/INVOKAMET XR is not recommended while breastfeeding.

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8.4 Pediatric Use

(Additions and/or revisions are underlined)

Safety and effectiveness of INVOKAMET/INVOKAMET XR in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

INVOKAMET and INVOKAMET XR

Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, monitor renal function more frequently after initiating INVOKAMET/INVOKAMET XR in the elderly and then adjust dose based on renal function.

Canagliflozin

In 13 clinical trials of canagliflozin, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to canagliflozin. Of these patients, 1,534 patients 65 years and older and 196 patients 75 years and older were exposed to the combination of canagliflozin and metformin.

8.7 Hepatic Impairment

(Additions and/or revisions are underlined)

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. INVOKAMET/INVOKAMET XR is not recommended in patients with hepatic impairment.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in Warnings and Precautions (5.1). Advise patients to discontinue INVOKAMET/INVOKAMET XR immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Once a patient is stabilized on INVOKAMET/INVOKAMET XR, gastrointestinal symptoms, which are common during initiation of metformin, are unlikely to recur. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.

Counsel patients against excessive alcohol intake while receiving INVOKAMET/INVOKAMET XR.

Inform patients about importance of regular testing of renal function and hematological parameters while receiving INVOKAMET/INVOKAMET XR.

Instruct patients to inform their doctor that they are taking INVOKAMET/INVOKAMET XR prior to any surgical or radiological procedure, as temporary discontinuation of INVOKAMET/INVOKAMET XR may be required until renal function has been confirmed to be normal.

Lower Limb Amputation:

Inform patients that INVOKAMET/INVOKAMET XR 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.

Hypotension:

Inform patients that symptomatic hypotension may occur with INVOKAMET/INVOKAMET XR 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.

Ketoacidosis:

Inform patients that ketoacidosis is a serious life-threatening condition. Cases of ketoacidosis have been reported during use of canagliflozin. 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 INVOKAMET/INVOKAMET XR and seek medical advice immediately.

Acute Kidney Injury:

Inform patients that acute kidney injury has been reported during use of canagliflozin. Advise patients to seek medical advice immediately if they have reduced oral intake (such as due to acute illness or fasting), or increased fluid losses (such as due to vomiting, diarrhea, or excessive heat exposure), as it may be appropriate to temporarily discontinue INVOKAMET/INVOKAMET XR use in those settings.

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.

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

Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKAMET/INVOKAMET XR. 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.

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

Inform female patients that vaginal yeast infection (e.g., vulvovaginitis) may occur and provide them with information on the signs and symptoms of a vaginal yeast infection. Advise them of treatment options and when to seek medical advice.

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.

Hypersensitivity Reactions:

Inform patients that serious hypersensitivity reactions, such as urticaria, rash, anaphylaxis, and angioedema, have been reported with canagliflozin. Advise patients to report immediately any signs or symptoms suggesting allergic reaction and to discontinue drug until they have consulted prescribing physicians.

Bone Fracture:

Inform patients that bone fractures have been reported in patients taking canagliflozin. Provide them with information on factors that may contribute to fracture risk.

Laboratory Tests:

Inform patients that they will test positive for glucose in their urine while on INVOKAMET/INVOKAMET XR.

Females of Reproductive Age:

Advise pregnant women, and females of reproductive potential of the potential risk to a fetus with treatment with INVOKAMET/INVOKAMET XR. Instruct females of reproductive potential to report pregnancies to their physicians as soon as possible.

Inform females that treatment with INVOKAMET/INVOKAMET XR may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy.

Lactation:

Advise women that breastfeeding is not recommended during treatment with INVOKAMET/INVOKAMET XR.

Administration:

Instruct patients to keep INVOKAMET/INVOKAMET XR in the original bottle to protect from moisture. Advise patients that storage in a pill box or pill organizer is allowed for up to 30 days.

Instruct patients to take INVOKAMET only as prescribed twice daily with food. If a dose is missed, advise patients not to take two doses of INVOKAMET at the same time.

Instruct patients to take INVOKAMET XR only as prescribed once daily with the morning meal. 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 more than two tablets of INVOKAMET XR at the same time.

Instruct patients that INVOKAMET XR must be swallowed whole and never crushed, cut, or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.

Medication Guide

(Extensive changes; please refer to the label)

10/26/2018 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

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

Patients treated with INVOKAMET XR 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 INVOKAMET XR, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

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 under subheading Canagliflozin

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 INVOKAMET XR? INVOKAMET XR may cause serious side effects including:

See "What is the most important information I should know about INVOKAMET XR?”

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 canagliflozin, one of the medicines in INVOKAMET XR. 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 skin (erythema)

PATIENT COUNSELING INFORMATION

Addition of the following:

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)

Inform patients that necrotizing infections of the perineum (Fournier’s gangrene) have occurred with INVOKAMET XR. 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.

08/11/2017 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Lactic Acidosis

(Additions and/or revisions are underlined)

Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include.

...

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Canagliflozin

Ketoacidosis

Acute Kidney Injury and Impairment in Renal Function

Anaphylaxis, Angioedema

Urosepsis and Pyelonephritis

Metformin hydrochloride

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

7 Drug Interactions

7.1 Drug Interactions with Metformin

(Additions and/or revisions are underlined)

Drugs That Reduce Metformin Clearance

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Instruct patients to inform their doctor that they are taking INVOKAMET XR prior to any surgical or radiological procedure, as temporary discontinuation of INVOKAMET XR may be required until renal function has been confirmed to be normal.

07/25/2017 (SUPPL-5)

Approved Drug Label (PDF)

Boxed Warning

(additions underlined)

WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
Lactic Acidosis

Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL .
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.
If metformin-associated lactic acidosis is suspected, immediately discontinue INVOKAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended

Risk of Lower Limb Amputation

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, 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 INVOKAMET for infection, new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue if these complications occur.

5 Warnings and Precautions

5.2 Lower Limb Amputation

(subsection added)

An approximately 2-fold increased risk of lower limb amputations associated with canagliflozin, a component of INVOKAMET, 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, canagliflozin-treated patients and placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In CANVAS-R, canagliflozin-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 [see Adverse Reactions (6.1)].

Before initiating INVOKAMET, 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 INVOKAMET for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKAMET if these complications occur.

6 Adverse Reactions

(addition underlined)

The following adverse reactions are also discussed elsewhere in the labeling:

Lactic Acidosis

Lower Limb Amputation
Hypotension
Ketoacidosis
Acute Kidney Injury and Impairment in Renal Function
Hyperkalemia
Urosepsis and Pyelonephritis
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
Genital Mycotic Infections
Hypersensitivity Reactions
Bone Fracture
Vitamin B12 Deficiency
Increases in Low-Density Lipoprotein (LDL-C)

6.1 Clinical Studies Experience

(additions underlined)

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Lower Limb Amputation

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

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

MEDICATION GUIDE

(additions underlined)

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Amputations. INVOKANA XR 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 INVOKAMET for a while if you have any of these signs or symptoms. Talk to your doctor about proper foot care.

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PATIENT COUNSELING INFORMATION

(additions underlined)

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Lower Limb Amputation: Inform patients that INVOKAMET 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.

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