HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`INVOKAMET or INVOKAMET XR safely and effectively. See full
`prescribing information for INVOKAMET or INVOKAMET XR.
`
`INVOKAMET® (canagliflozin and metformin hydrochloride (HCl)
`tablets), for oral use
`INVOKAMET® XR (canagliflozin and metformin HCl extended-release
`tablets), for oral use
`Initial U.S. Approval: 2014
`WARNING: LACTIC ACIDOSIS
`See full prescribing information for complete boxed warning.
` Postmarketing cases of metformin-associated lactic acidosis have
`resulted in death, hypothermia, hypotension, and resistant
`bradyarrhythmias. Symptoms included malaise, myalgias, respiratory
`distress, somnolence, and abdominal pain. Laboratory abnormalities
`included elevated blood lactate levels, anion gap acidosis, increased
`lactate/pyruvate ratio; and metformin plasma levels generally
`>5 mcg/mL. (5.1)
` Risk factors include renal impairment, concomitant use of certain
`drugs, age >65 years old, radiological studies with contrast, surgery
`and other procedures, hypoxic states, 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. (5.1)
` If lactic acidosis is suspected, discontinue INVOKAMET or
`INVOKAMET XR and institute general supportive measures in a
`hospital setting. Prompt hemodialysis is recommended. (5.1)
`-------------------------RECENT MAJOR CHANGES-----------------------------
`Indications and Usage (1)
`07/2023
`Dosage and Administration (2.2, 2.3, 2.4, 2.5, 2.7)
`07/2023
`Contraindications (4)
`07/2023
`Warnings and Precautions (5.2)
`07/2023
`----------------------------INDICATIONS AND USAGE---------------------------
`INVOKAMET and INVOKAMET XR are a combination of canagliflozin, a
`sodium-glucose co-transporter 2 (SGLT2) inhibitor, and metformin HCl, a
`biguanide, indicated:
` As an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus (1)
` Canagliflozin is indicated to reduce the risk of major adverse
`cardiovascular events in adults with type 2 diabetes mellitus and
`established cardiovascular disease (1)
` Canagliflozin is indicated to reduce the risk of end-stage kidney disease,
`doubling of serum creatinine, cardiovascular death, and hospitalization for
`heart failure in adults with type 2 diabetes mellitus and diabetic
`nephropathy with albuminuria (1).
`Limitations of Use:
`Not recommended for use to improve glycemic control in patients with type 1
`diabetes mellitus (1)
`-----------------------DOSAGE AND ADMINISTRATION-----------------------
` Individualize starting dose based on the patient’s current regimen and renal
`function (2.2, 2.3, 2.4)
` Initiation of INVOKAMET or INVOKAMET XR is not recommended in
`patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin
`component (2.4)
` INVOKAMET: one tablet, twice daily with meals, recommended starting
`dose of canagliflozin is 50 mg twice daily and metformin HCl 500 mg
`twice daily (2.2)
` INVOKAMET XR: two tablets, once daily with the morning meal.
`Swallow whole. Never crush, cut, or chew (2.2)
` Canagliflozin dose can be increased to a total daily dose of 300 mg in
`patients tolerating 100 mg who have an eGFR of 60 mL/min/1.73 m2 or
`greater and require additional glycemic control. Do not exceed a total daily
`canagliflozin dose of 300 mg (2.2)
`
` Gradually escalate metformin HCl dose to reduce the gastrointestinal side
`effects while not exceeding a total daily dose of 2,000 mg (2.3)
` Assess renal function before initiating and as clinically indicated (2.1, 2.3)
` Dose adjustment for patients with renal impairment may be required (2.4)
` See full prescribing information for INVOKAMET and INVOKAMET XR
`dosage modifications due to drug interactions. (2.5)
` May need to be discontinued at time of, or prior to, iodinated contrast
`imaging procedures (2.6)
` Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible,
`prior to major surgery or procedures associated with prolonged
`fasting (2.7).
`--------------------DOSAGE FORMS AND STRENGTHS----------------------
`INVOKAMET tablets:
` Canagliflozin 50 mg and metformin HCl 500 mg (3)
` Canagliflozin 50 mg and metformin HCl 1,000 mg (3)
` Canagliflozin 150 mg and metformin HCl 500 mg (3)
` Canagliflozin 150 mg and metformin HCl 1,000 mg (3)
`INVOKAMET XR extended-release tablets:
` Canagliflozin 50 mg and metformin HCl 500 mg (3)
` Canagliflozin 50 mg and metformin HCl 1,000 mg (3)
` Canagliflozin 150 mg and metformin HCl 500 mg (3)
` Canagliflozin 150 mg and metformin HCl 1,000 mg (3)
`-------------------------------CONTRAINDICATIONS------------------------------
` Severe renal impairment (eGFR less than 30 mL/min/1.73 m2) (4)
` Metabolic acidosis, including diabetic ketoacidosis (4, 5.1)
` Serious hypersensitivity reaction to canagliflozin or metformin HCl (4, 5.9)
`---------------------------WARNINGS AND PRECAUTIONS--------------------
` Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other
`Ketoacidosis: Consider ketone monitoring in patients at risk for
`ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting
`blood glucose levels and discontinue INVOKAMET or INVOKAMET XR
`if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis
`before restarting (5.2)
` Lower Limb Amputation: Consider factors that may increase the risk of
`amputation before initiating INVOKAMET or INVOKAMET XR. Monitor
`patients for infection or ulcers of lower limb and discontinue if these
`occur (5.3)
` Volume Depletion: May result in acute kidney injury. Before initiating,
`assess and correct volume status in patients with renal impairment, elderly
`patients, or patients on loop diuretics. Monitor for signs and symptoms
`during therapy (5.4)
` Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of
`urinary tract infections and treat promptly, if indicated (5.5)
` Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to
`reduce the risk of hypoglycemia when used in combination (5.6)
` Necrotizing fasciitis of the perineum (Fournier’s gangrene): Serious,
`life-threatening cases have occurred in both females and males. Assess
`patients presenting with pain or tenderness, erythema, or swelling in the
`genital or perineal area, along with fever or malaise. If suspected, institute
`prompt treatment (5.7)
` Genital mycotic infections: Monitor and treat if indicated (5.8)
` Hypersensitivity reactions: Discontinue and monitor until signs and
`symptoms resolve (5.9)
` Bone fracture: Consider factors that contribute to fracture risk before
`initiating INVOKAMET or INVOKAMET XR (5.10)
` Vitamin B12
`levels.
`deficiency: Metformin HCl may lower vitamin B12
`Measure hematological parameters annually and vitamin B12
`at 2- to 3-year
`intervals and manage any abnormalities (5.11)
`------------------------------ADVERSE REACTIONS----------------------------
` Most common adverse reactions associated with canagliflozin (5% or
`greater incidence): female genital mycotic infections, urinary tract
`infection, and increased urination (6.1)
` Most common adverse reactions associated with metformin HCl (5% or
`greater incidence) are diarrhea, nausea, vomiting, flatulence, asthenia,
`indigestion, abdominal discomfort, and headache (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Janssen
`Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`1
`
`Reference ID: 5202255
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`------------------------------DRUG INTERACTIONS------------------------------
` Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis.
`Consider more frequent monitoring (7)
` Drugs that Reduce Metformin Clearance: May increase risk of lactic
`acidosis. Consider benefits and risks of concomitant use (7)
` See full prescribing information for additional drug interactions and
`information on interference of INVOKAMET and INVOKAMET XR with
`laboratory tests. (7)
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------
` Pregnancy: Advise females of the potential risk to a fetus especially during
`the second and third trimesters (8.1)
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1 Prior to Initiation of INVOKAMET or
`INVOKAMET XR
`2.2 Dosage Overview
`2.3 Recommended Dosage and Administration
`2.4 Recommended Dosage for Patients with Renal
`Impairment
`2.5 Concomitant Use with UDP-
`Glucuronosyltransferase (UGT) Enzyme Inducers
`2.6 Discontinuation for Iodinated Contrast Imaging
`Procedures
`2.7
`Temporary Interruption for Surgery
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Lactic Acidosis
`5.2 Diabetic Ketoacidosis in Patients with Type 1
`Diabetes Mellitus and Other Ketoacidosis
`5.3
`Lower Limb Amputation
`5.4 Volume Depletion
`5.5 Urosepsis and Pyelonephritis
`5.6 Hypoglycemia with Concomitant Use of
`Sulfonylurea or Insulin
`5.7 Necrotizing Fasciitis of the Perineum (Fournier’s
`Gangrene)
`5.8 Genital Mycotic Infections
`5.9 Hypersensitivity Reactions
`5.10 Bone Fracture
`5.11 Vitamin B12
`Levels
`6 ADVERSE REACTIONS
`6.1 Clinical Studies Experience
`
` Lactation: Not recommended when breastfeeding (8.2)
` Females and Males of Reproductive Potential: Advise premenopausal
`females of the potential for an unintended pregnancy (8.3)
` Geriatrics: Higher incidence of adverse reactions related to reduced
`intravascular volume. Assess renal function more frequently (6.1, 8.5)
` Renal impairment: Higher incidence of adverse reactions related to
`hypotension and renal function (8.6)
` Hepatic impairment: Avoid use in patients with hepatic impairment (8.7)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`Revised: 07/2023
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6
`Renal Impairment
`8.7
`Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`14 CLINICAL STUDIES
`14.1 Glycemic Control Trials in Adults with Type 2
`Diabetes Mellitus
`14.2 Canagliflozin Cardiovascular Outcomes in
`Patients with Type 2 Diabetes Mellitus and
`Atherosclerotic Cardiovascular Disease
`14.3 Canagliflozin Renal and Cardiovascular
`Outcomes in Patients with Diabetic Nephropathy
`and Albuminuria
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`Reference ID: 5202255
`
`2
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`FULL PRESCRIBING INFORMATION
`WARNING: 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
`[see Warnings and Precautions (5.1)].
` Risk factors for metformin-associated lactic acidosis include renal impairment,
`concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors 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 [see Warnings and Precautions (5.1)].
` Steps to reduce the risk of and manage metformin-associated lactic acidosis in these
`high risk groups are provided in the full prescribing information [see Dosage and
`Administration (2.2, 2.3), Contraindications (4), Warnings and Precautions (5.1), Drug
`Interactions (7), and Use in Specific Populations (8.6, 8.7)].
`immediately discontinue
`If metformin-associated
`lactic acidosis
`is suspected,
`INVOKAMET or INVOKAMET XR and institute general supportive measures in a
`hospital setting. Prompt hemodialysis
`is recommended
`[see Warnings and
`Precautions (5.1)].
`
`
`
`INDICATIONS AND USAGE
`1
`INVOKAMET and INVOKAMET XR are a combination of canagliflozin and metformin HCl
`indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus.
`Canagliflozin is indicated to reduce the risk of major adverse cardiovascular events
`(cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with
`type 2 diabetes mellitus and established cardiovascular disease (CVD).
`Canagliflozin is indicated to reduce the risk of end-stage kidney disease (ESKD), doubling of
`serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with
`type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day.
`
`Reference ID: 5202255
`
`3
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`Limitations of Use
`INVOKAMET or INVOKAMET XR is not recommended for use to improve glycemic control
`in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.2)].
`2 DOSAGE AND ADMINISTRATION
`2.1 Prior to Initiation of INVOKAMET or INVOKAMET XR
`Assess renal function before initiating INVOKAMET or INVOKAMET XR and as clinically
`indicated [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.4),
`Contraindications (4)].
`In patients with volume depletion, correct this condition before initiating INVOKAMET or
`INVOKAMET XR [see Warnings and Precautions (5.4) and Use in Specific Populations (8.5,
`8.6)].
`2.2 Dosage Overview
`INVOKAMET
`Take one tablet of INVOKAMET orally twice daily with meals [see Dosage and
`Administration (2.3)].
`INVOKAMET XR
`Take two tablets of INVOKAMET XR orally once daily with the morning meal [see Dosage and
`Administration (2.3)]. Swallow each tablet whole and never crush, cut, or chew.
`2.3 Recommended Dosage and Administration
`Individualize the starting dose of INVOKAMET or INVOKAMET XR based on the patient’s
`current regimen and renal function [see Dosage and Administration (2.4)]. Table 1 presents the
`recommended starting dosage of INVOKAMET and INVOKAMET XR based on the patient’s
`current regimen. For the available strengths of the canagliflozin and metformin components in
`INVOKAMET and INVOKAMET XR, see Dosage Forms and Strengths (3).
`Table 1.
`Recommended Starting Dosage Based on the Patient’s Current Regimen
`Current Regimen
`INVOKAMET
`INVOKAMET XR
`Recommended Dosage
`Recommended Dosage
`Administered as one tablet, orally,
`Administered as two tablets, orally, once
`twice daily with meals
`daily with the morning meal
`Total daily dosage is canagliflozin 100 mg and metformin HCl 1,000 mg
`Total daily dosage is canagliflozin 100 mg and the nearest appropriate total daily
`dosage of metformin HCl
`The same total daily dosage of canagliflozin and a total daily dosage of
`metformin HCl 1,000 mg
`
`Not treated with either
`canagliflozin or metformin HCl
`Metformin HCl*
`
`Canagliflozin
`
`Reference ID: 5202255
`
`4
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`The same total daily dosage of canagliflozin and the nearest appropriate total daily
`Canagliflozin and
`dosage of metformin HCl
`metformin HCl*
`For patients taking an evening dosage of metformin HCl extended-release tablets, skip the last dose before
`*
`starting INVOKAMET or INVOKAMET XR the following morning.
`Recommended Dosage for Additional Glycemic Control
`INVOKAMET
`Canagliflozin may be increased to the maximum recommended dosage of 150 mg twice daily in
`patients tolerating 50 mg twice daily and metformin may be increased to the maximum
`recommended dosage of 1,000 mg twice daily, with gradual escalation to reduce gastrointestinal
`adverse reactions with metformin [see Adverse Reactions (6.1)].
`INVOKAMET XR
`Canagliflozin may be increased to the maximum recommended dosage of 300 mg once daily in
`patients tolerating 100 mg once daily and metformin may be increased to the maximum
`recommended dosage of 2,000 mg once daily, with gradual escalation to reduce gastrointestinal
`adverse reactions with metformin [see Adverse Reactions (6.1)].
`2.4 Recommended Dosage for Patients with Renal Impairment
`Initiation of INVOKAMET or INVOKAMET XR is not recommended in patients with an eGFR
`
`less than 45 mL/min/1.73 m2, due to the metformin component.
` Table 2 provides dosage recommendations for patients with renal impairment, based on eGFR
`[see Use in Specific Populations (8.6) and Clinical Studies (14.3)].
`Recommended Dosage in Patients with Renal Impairment
`Table 2
`Estimated Glomerular Filtration Rate
`Recommended Dosage
`[eGFR (mL/min/1.73 m2)]
`eGFR 45 to less than 60
`The maximum recommended dosage of canagliflozin is 100 mg daily.
`eGFR 30 to less than 45
`Assess the benefit risk of continuing INVOKAMET or
`INVOKAMET XR. The maximum recommended dosage of
`canagliflozin is 100 mg daily.
`Contraindicated. If eGFR falls below 30 during treatment; discontinue
`INVOKAMET or INVOKAMET XR [see Contraindications (4)].
`2.5 Concomitant Use with UDP-Glucuronosyltransferase (UGT) Enzyme Inducers
`When co-administering INVOKAMET or INVOKAMET XR with an inducer of UGT (e.g.,
`rifampin, phenytoin, phenobarbital, ritonavir), increase the total daily dosage of canagliflozin
`based on renal function [see Drug Interactions (7)]:
` In patients with eGFR 60 mL/min/1.73 m2 or greater, increase the total daily dosage of
`
`
`canagliflozin to 200 mg in patients currently tolerating a total daily dosage of canagliflozin
`100 mg. The maximum recommended dosage of canagliflozin is 300 mg daily.
`
`eGFR less than 30
`
`Reference ID: 5202255
`
`5
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`Tablet
`Identifiers*
`CM 155
`CM 551
`CM 215
`CM 611
`
` In patients with eGFR less than 60 mL/min/1.73 m2, increase the total daily dosage of
`
`canagliflozin to a maximum of 200 mg in patients currently tolerating a total daily dosage of
`canagliflozin 100 mg.
`2.6 Discontinuation for Iodinated Contrast Imaging Procedures
`Discontinue INVOKAMET or INVOKAMET XR at the time of, or prior to, an iodinated
`contrast imaging procedure in patients with an eGFR of less than 60 mL/min/1.73 m2; in patients
`with a history of liver disease, alcoholism or heart failure; or in patients who will be
`administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging
`procedure; restart INVOKAMET or INVOKAMET XR if renal function is stable [see Warnings
`and Precautions (5.1)].
`2.7 Temporary Interruption for Surgery
`Withhold INVOKAMET or INVOKAMET XR at least 3 days, if possible, prior to major surgery
`or procedures associated with prolonged fasting. Resume INVOKAMET or INVOKAMET XR
`when the patient is clinically stable and has resumed oral intake [see Warnings and
`Precautions (5.2) and Clinical Pharmacology (12.2)].
`3 DOSAGE FORMS AND STRENGTHS
`INVOKAMET (canagliflozin and metformin HCl) tablets are available as follows:
`Canagliflozin
`Metformin HCl
`Color/Shape
`Strength
`Strength
`50 mg
`500 mg
`white/capsule-shaped
`50 mg
`1,000 mg
`beige/capsule-shaped
`150 mg
`500 mg
`yellow/capsule-shaped
`150 mg
`1,000 mg
`purple/capsule-shaped
`* Embossing appears on both sides of tablet.
`INVOKAMET XR (canagliflozin and metformin HCl) extended-release tablets are available as
`follows:
`Metformin HCl
`Canagliflozin
`Strength
`Strength
`500 mg
`50 mg
`1,000 mg
`50 mg
`500 mg
`150 mg
`1,000 mg
`150 mg
`* Embossing appears on one side only of tablet.
`
`Color/Shape
`
`almost white to light orange/oblong, biconvex
`pink/oblong, biconvex
`orange/oblong, biconvex
`reddish brown/oblong, biconvex
`
`Tablet
`Identifiers*
`CM1
`CM3
`CM2
`CM4
`
`Reference ID: 5202255
`
`6
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`4 CONTRAINDICATIONS
`INVOKAMET or INVOKAMET XR is contraindicated in patients:
` With severe renal impairment (eGFR less than 30 mL/min/1.73 m2) [see Warnings and
`Precautions (5.1) and Use in Specific Populations (8.6)].
` With acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and
`Precautions (5.2)].
` With serious hypersensitivity reaction to canagliflozin or metformin HCl, such as anaphylaxis or
`angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6)].
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`There have been post-marketing cases of metformin-associated lactic acidosis, including fatal
`cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as
`malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however,
`hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
`Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations
`(>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an
`increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin
`decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of
`lactic acidosis, especially in patients at risk.
`If metformin-associated lactic acidosis is suspected, general supportive measures should be
`instituted promptly in a hospital setting, along with immediate discontinuation of INVOKAMET
`or INVOKAMET XR. In INVOKAMET or 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 is dialyzable, with a clearance of up to
`170 mL/min 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 or 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
`
`7
`
`Reference ID: 5202255
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`include [see Dosage and Administration (2.4) and Clinical
`
`patient’s renal function
`Pharmacology (12.3)].
` Before initiating INVOKAMET or INVOKAMET XR, obtain an estimated glomerular
`filtration rate (eGFR).
`INVOKAMET or INVOKAMET XR is contraindicated in patients with an eGFR less
`than 30 mL/min/1.73 m2 [see Contraindications (4)].
`taking INVOKAMET or
`least annually
`in all patients
` Obtain an eGFR at
`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 or 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) [see Drug Interactions (7)]. 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 [see
`Use in Specific Populations (8.5)].
`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 or 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. Re-evaluate eGFR 48 hours after the imaging
`procedure, and restart INVOKAMET or 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 or 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 or
`INVOKAMET XR.
`
`Reference ID: 5202255
`
`8
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`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 or 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 or INVOKAMET XR in patients with clinical or
`laboratory evidence of hepatic disease.
`5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other
`Ketoacidosis
`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 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 INVOKAMET or
`INVOKAMET XR [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 INVOKAMET or INVOKAMET XR, promptly evaluate, and treat
`ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting
`INVOKAMET or INVOKAMET XR.
`
`9
`
`Reference ID: 5202255
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`Withhold INVOKAMET or INVOKAMET XR, if possible, in temporary clinical situations that
`could predispose patients to ketoacidosis. Resume INVOKAMET or INVOKAMET XR when
`the patient is clinically stable and has resumed oral intake [see Dosage and Administration
`(2.7)].
`Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to
`discontinue INVOKAMET or INVOKAMET XR and seek medical attention immediately if
`signs and symptoms occur.
`5.3 Lower Limb Amputation
`An increased risk of lower limb amputations associated with canagliflozin, a component of
`in CANVAS
`INVOKAMET or
`INVOKAMET XR, versus placebo was observed
`per
`per
`(5.9 vs 2.8 events
`1000 patient-years)
`and CANVAS-R
`(7.5 vs 4.2 events
`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 4 and 5, respectively [see Adverse Reactions (6.1)].
`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 or 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 or INVOKAMET XR
`for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or
`ulcers involving the lower limbs, and discontinue INVOKAMET or INVOKAMET XR if these
`complications occur.
`5.4 Volume Depletion
`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
`
`10
`
`Reference ID: 5202255
`
`Novo Nordisk Exhibit 2531
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00010
`
`

`

`(eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at
`increased risk for v