HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`INVOKAMET® safely and effectively. See full prescribing information
`
`
`
`
`
`
`for INVOKAMET.
`
`INVOKAMET (canagliflozin and metformin hydrochloride) tablets, for
`
`
`
`
`
`oral use
`
`Initial U.S. Approval – 2014
`
`
`
`
`
`
` WARNING: LACTIC ACIDOSIS and LOWER LIMB AMPUTATION
`
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`Lactic Acidosis
`
`
`
`
`• 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 and institute
`
`
`
`
`
`general supportive measures in a hospital setting. Prompt hemodialysis
`
`
`is recommended. (5.1)
`
`
`Risk of Lower Limb Amputation
`
`
`
`
` • In patients with type 2 diabetes who have established cardiovascular
`
`
`disease (CVD) or at risk for CVD, canagliflozin, a component of
`
`
`
`
`
`INVOKAMET, has been associated with lower limb amputations, most
`
`
`frequently of the toe and midfoot; some also involved the leg. (5.2)
`
`
`
`
`• Before initiating, consider factors that may increase the risk of
`
`
`amputation. Monitor patients receiving INVOKAMET for infections
`
`
`or ulcers of the lower limbs, and discontinue if these occur. (5.2)
`
`
`-------------------------RECENT MAJOR CHANGES----------------------------­
`Boxed Warning
`07/2017
`
`
`Boxed Warning
`08/2017
`
`
`Warnings and Precautions (5.1)
`08/2017
`
`
`
`Warnings and Precautions (5.2)
`07/2017
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`INVOKAMET is a sodium-glucose co-transporter 2 (SGLT2) inhibitor and
`
`
`
`
`biguanide combination product indicated as an adjunct to diet and exercise to
`
`
`
`
`
`improve glycemic control in adults with type 2 diabetes mellitus when
`
`
`
`
`
`treatment with both canagliflozin and metformin is appropriate (1)
`
`
`
`
`
`
`Limitation of use:
`
`
`Not for treatment of type 1 diabetes or diabetic ketoacidosis (1)
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`• Individualize based on the patient’s current regimen (2)
`
`
`
`
`• Take one INVOKAMET tablet twice daily with meals, recommended
`
`
`
`
`starting dose of canagliflozin is 50 mg twice daily and metformin 500 mg
`
`
`
`
`
`
`twice daily (2.1)
`
`
`• Canagliflozin dose can be increased to 150 mg twice daily in patients
`
`
`
`
`
`
`
`tolerating canagliflozin 50 mg twice daily who have 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 (2.1)
`
`
`• Gradually escalate metformin dose to reduce the gastrointestinal side
`
`
`
`
`
`
`effects while not exceeding total daily dose of 2000 mg (2.1)
`
`
`
`
`• Assess renal function before initiating and periodically thereafter (2.2)
`
`
`
`
`
`
`• INVOKAMET is contraindicated in patients with an estimated glomerular
`
`filtration rate (eGFR) below 45 mL/min/1.73 m2 (2.2)
`
`
`
`
`• Limit the dose of canagliflozin component to 50 mg twice daily in patients
`
`
`
`
`
`
`with an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.2)
`
`
`
`
`
`
`• INVOKAMET may need to be discontinued at time of, or prior to,
`
`
`
`
`iodinated contrast imaging procedures (2.4)
`
`
`
`--------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`Film-coated tablets:
`
`
`
`
`
`
`
`• Canagliflozin 50 mg and metformin hydrochloride 500 mg
`
`
`
`
`
`
`
`
`• Canagliflozin 50 mg and metformin hydrochloride 1,000 mg
`
`
`
`
`
`
`
`
`Reference ID: 4138265
`
`
`
`
`
`• Canagliflozin 150 mg and metformin hydrochloride 500 mg
`
`
`
`
`
`
`
`
`• Canagliflozin 150 mg and metformin hydrochloride 1,000 mg (3)
`
`
`
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`• Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2),
`
`
`
`
`
`
`
`
`
`
`end stage renal disease or dialysis (4, 5.1, 5.5)
`
`
`
`• Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1)
`
`
`
`
`
`• History of serious hypersensitivity reaction to canagliflozin or
`
`
`
`metformin (4, 5.10)
`
`---------------------------WARNINGS AND PRECAUTIONS-------------------­
`
`• Lactic acidosis: See boxed warning (5.1)
`
`
`
`
`
`• Lower limb amputation: See boxed warning (5.2)
`
`
`
`• Hypotension: Before initiating INVOKAMET, assess volume status and
`
`
`
`correct hypovolemia in patients with renal impairment, the elderly, in
`
`
`
`patients with low systolic blood pressure, or on diuretics, ACEi, or ARB.
`
`
`
`Monitor for signs and symptoms during therapy (5.3)
`
`
`• Ketoacidosis: Assess patients who present with signs and symptoms of
`
`metabolic acidosis for ketoacidosis, regardless of blood glucose level. If
`
`
`
`suspected, discontinue INVOKAMET, evaluate and treat promptly. Before
`
`initiating INVOKAMET, consider risk factors for ketoacidosis. Patients on
`
`
`INVOKAMET may require monitoring and temporary discontinuation of
`
`
`
`therapy in clinical situations known to predispose to ketoacidosis (5.4)
`
`
`
`• Acute kidney injury and impairment in renal function: Consider
`
`
`
`
`
`temporarily discontinuing in settings of reduced oral intake or fluid losses.
`
`
`
`If acute kidney injury occurs, discontinue and promptly treat. Monitor renal
`
`
`
`
`function during therapy (5.5)
`
`
`• Hyperkalemia: Monitor potassium levels in patients with impaired renal
`
`
`
`function and in patients predisposed to hyperkalemia (2.2, 5.6, 6.1, 8.6)
`
`
`
`
`• Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of
`
`
`
`urinary tract infections and treat promptly, if indicated (5.7)
`
`
`
`
`• Hypoglycemia: Consider a lower dose of insulin or the insulin
`
`
`secretagogue to reduce the risk of hypoglycemia when used in combination
`
`
`with INVOKAMET (5.8)
`
`
`
`• Genital mycotic infections: Monitor and treat if indicated (5.9)
`
`
`
`
`• Hypersensitivity reactions: Discontinue INVOKAMET and monitor until
`
`
`
`
`signs and symptoms resolve (5.10)
`
`
`• Bone fracture: Consider factors that contribute to fracture risk before
`
`
`
`initiating INVOKAMET (5.11)
`
`
`• Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor
`
`
`
`
`hematologic parameters annually (5.12)
`
`
`
`• Increased LDL-C: Monitor LDL-C and treat if appropriate (5.13)
`
`
`
`------------------------------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 (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.
`
`------------------------------DRUG INTERACTIONS-----------------------------­
`
`• Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`
`
`
`
`Consider more frequent monitoring (7.1)
`
`• Drugs that reduce metformin clearance (such as ranolazine, vandetanib,
`
`
`
`dolutegravir, and cimetidine) may increase the accumulation of metformin.
`Consider the benefits and risks of concomitant use (7.1)
`
`
`
`
`• Alcohol can potentiate the effect of metformin on lactate metabolism. Warn
`
`
`
`
`
`
`patients against excessive alcohol intake (7.1)
`
`
`• UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider
`
`
`
`
`
`
`increasing canagliflozin dose from 50 mg to 150 mg twice daily (2.3, 7.2)
`
`
`
`
`
`
`
`• Digoxin: Monitor digoxin levels (7.2)
`
`
`
`
`
`-----------------------USE IN SPECIFIC POPULATIONS----------------------­
`
`• Pregnancy: Advise females of the potential risk to a fetus especially during
`
`
`
`
`
`the second and third trimesters (8.1)
`
`
`
`• Lactation: INVOKAMET is 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 (5.3, 6.1, 8.5)
`
`
`• Renal impairment: Higher incidence of adverse reactions related to reduced
`
`
`
`intravascular volume and renal function (2.2, 5.5, 8.6)
`
`
`
`
` 1
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
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`• Hepatic Impairment: Avoid use in patients with hepatic impairment (8.7)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: LACTIC ACIDOSIS AND LOWER LIMB
`
`
`AMPUTATION
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage
`
`2.2 Recommended Dosage for Patients with Renal
`
`
`
`Impairment
`
`2.3 Concomitant Use with UDP-Glucuronosyl
`
`
`Transferase (UGT) Enzyme Inducers
`
`2.4 Discontinuation for Iodinated Contrast Imaging
`
`
`
`Procedures
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`Lactic Acidosis
`5.1
`
`
`5.2
`Lower Limb Amputation
`
`
`5.3 Hypotension
`
`
`5.4 Ketoacidosis
`
`5.5 Acute Kidney Injury and Impairment in Renal
`
`
`
`
`
`Function
`
`
`5.6 Hyperkalemia
`
`
`5.7 Urosepsis and Pyelonephritis
`
`
`5.8 Hypoglycemia with Concomitant Use of
`
`
`Sulfonylurea or Insulin
`
`
`5.9 Genital Mycotic Infections
`
`
`5.10 Hypersensitivity Reactions
`
`
`5.11 Bone Fracture
`
`
` 5.12 Vitamin B12 Levels
`
`
`
`5.13
`Increases in Low-Density Lipoprotein (LDL-C)
`
`
`5.14 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Drug Interactions with Metformin
`
`
`7.2 Drug Interactions with Canagliflozin
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`
`
`
`Revised: 08/2017
`
`
`
`
`
`Lactation
`8.2
`
`
`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 Canagliflozin as Initial Combination Therapy with
`
`Metformin
`
`14.2 Canagliflozin as Add-on Combination Therapy
`
`
`with Metformin
`
`14.3 Canagliflozin Compared to Glimepiride, Both as
`
`
`Add-on Combination Therapy with Metformin
`
`14.4 Canagliflozin as Add-on Combination Therapy
`
`
`with Metformin and Sitagliptin
`
`14.5 Canagliflozin as Add-on Combination Therapy
`
`
`with Metformin and Sulfonylurea
`
`14.6 Canagliflozin Compared to Sitagliptin, Both as
`
`
`Add-on Combination Therapy with Metformin and
`
`Sulfonylurea
`
`
`14.7 Canagliflozin as Add-on Combination Therapy
`
`with Metformin and Pioglitazone
`
`
`14.8 Canagliflozin as Add-on Combination Therapy
`
`
`
`
`with Insulin (With or Without Other
`
`
`Anti-Hyperglycemic Agents, Including Metformin)
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are
`
`
`
`not listed.
`
`
`
`Reference ID: 4138265
`
`
`
` 2
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`

`

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`
`
`
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`
`
` FULL PRESCRIBING INFORMATION
`
`
` 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
`
`is often subtle, accompanied only by
`metformin-associated
`lactic acidosis
`
`
`
` 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.
`
`
` • 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), Contraindications (4), Warnings and Precautions (5.1),
`
`
` Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
`
`
`
`•
`
` If metformin-associated lactic acidosis is suspected, immediately discontinue
`
`
`
` INVOKAMET and institute general supportive measures in a hospital setting.
`
`
` Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`
`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,
`
`
`
`
`
`Reference ID: 4138265
`
`
`
` 3
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
`
`
`
` sores or ulcers involving the lower limbs, and discontinue if these complications
`
` occur [see Warnings and Precautions (5.2)].
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`INVOKAMET (canagliflozin and metformin hydrochloride) is indicated as an adjunct to diet and
`
`
`exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with
`
`both canagliflozin and metformin is appropriate.
`
`
`
`Limitations of Use
`INVOKAMET is not recommended in patients with type 1 diabetes or for the treatment of
`
`
`
`
`
`
`diabetic ketoacidosis.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`INVOKAMET
`Individualize
`the starting dose of
`
`
`
`•
`hydrochloride) based on the patient’s current regimen:
`
`
`
`(canagliflozin and metformin
`
`
`
`−
`
`
`−
`
`
`−
`
`
`−
`
`In patients currently not treated with either canagliflozin or metformin, initiate therapy
`
`
`with INVOKAMET containing canagliflozin 50 mg and metformin 500 mg [see Clinical
`
`
`
`
`Studies (14.1)];
`
`
`In patients on metformin, switch to INVOKAMET containing canagliflozin 50 mg and
`
`
`
`the same, or nearest appropriate, daily dose of metformin;
`
`
`
`In patients on canagliflozin, switch to INVOKAMET containing metformin 500 mg with
`
`
`the same daily dose of canagliflozin;
`
`
`
`
`In patients already treated with canagliflozin and metformin, switch to INVOKAMET
`
`
`
`
`containing the same daily dose of canagliflozin and the same, or nearest appropriate,
`
`daily dose of metformin.
`
`
`• Take one INVOKAMET tablet twice daily with meals; in patients tolerating canagliflozin
`
`
`
`50 mg twice daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional
`
`
`
`
`
`
`
`
`glycemic control, INVOKAMET dose can be increased for the canagliflozin component to
`
`150 mg twice daily, with gradual metformin dose escalation to reduce the gastrointestinal
`
`
`
`
`side effects due to metformin [see Dosage Forms and Strengths (3) and Clinical Studies
`
`
`(14.1)].
`
`
`
`
`In patients with volume depletion not previously treated with canagliflozin, correct this
`
`
`
`condition before initiating INVOKAMET [see Warnings and Precautions (5.3), Use in
`
`
`
`
`
`Specific Populations (8.5, 8.6), and Patient Counseling Information (17)].
`
`
`
`
` 4
`
`
`•
`
`
`
`Reference ID: 4138265
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
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`
`
` • Adjust dosing based on effectiveness and tolerability while not exceeding the maximum
`
`
` recommended daily dose of metformin 2000 mg and canagliflozin 300 mg in patients with an
`
`
`
`
`
`
`
` eGFR of 60 mL/min/1.73 m2 or greater [see Dosage and Administration (2.2)].
`
`
`
`
`
`2.2 Recommended Dosage for Patients with Renal Impairment
`
`
`
`
`• Assess renal function before initiating INVOKAMET and periodically thereafter.
`
`
`
`
`
`•
`
`INVOKAMET is contraindicated in patients with an estimated glomerular filtration rate
`
`(eGFR) below 45 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions
`
`
`
`
`
`(5.1, 5.5)].
`
`
`
`
`
`
`
`
`• Limit the dose of the canagliflozin component to 50 mg twice daily in patients with moderate
`
`renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.
`
`
`
`
`
`
`
`
`2.3 Concomitant Use with UDP-Glucuronosyl Transferase (UGT) Enzyme
`
`Inducers
`
`
`
`
`If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered
`
`
`
`
`
`
`
`
`with INVOKAMET, consider increasing the dose to canagliflozin 150 mg twice daily in patients
`currently tolerating canagliflozin 50 mg twice daily who have an eGFR of 60 mL/min/1.73 m2 or
`
`
`
`
`
`
`
`
`
`
`
`
`greater and require additional glycemic control [see Drug Interactions (7.2)].
`
`
`
`
`
`
`
`
`
`
`Consider another antihyperglycemic agent in patients with an eGFR of 45 to less than
`60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer.
`
`
`
`
`
`
`
`
`2.4 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`Discontinue INVOKAMET 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 liver
`
`
`
`
`
`
`disease, alcoholism or heart failure; or in patients who will be administered intra-arterial
`
`iodinated contrast. Re-evaluate eGFR 48 hours after
`imaging procedure; restart
`the
`INVOKAMET if renal function is stable [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`INVOKAMET (canagliflozin and metformin hydrochloride) film-coated tablets for oral
`
`administration are available in the following strengths:
`
`
`
`
`
`
`
`
`
`• Canagliflozin 50 mg and metformin hydrochloride 500 mg tablets are immediate-release,
`
`
`
`
`capsule-shaped, white film-coated tablets with “CM” on one side and “155” on the other
`
`side.
`
`
`
`
`
`
`
`
`
`
`• Canagliflozin 50 mg and metformin hydrochloride 1,000 mg tablets are immediate-release,
`
`
`
`
`capsule-shaped, beige, film-coated tablets with “CM” on one side and “551” on the other
`
`side.
`
`
`
`Reference ID: 4138265
`
`
`
` 5
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`
`
`
`
`
`
`
` • Canagliflozin 150 mg and metformin hydrochloride 500 mg tablets are immediate-release,
`
`
` capsule-shaped, yellow, film-coated tablets with “CM” on one side and “215” on the other
`
`
`
`
` side.
`
`
`
`
`
`
`
`
`
` • Canagliflozin 150 mg and metformin hydrochloride 1,000 mg tablets are immediate-release,
`
`
` capsule-shaped, purple, film-coated tablets with “CM” on one side and “611” on the other
`
`
`
` side.
`
` 4 CONTRAINDICATIONS
`
`
`
` INVOKAMET 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 [see Warnings and Precautions (5.1) and Use in
`
`
`
`Specific Populations (8.6)].
`
`
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and
`
`
`
`Precautions (5.4)].
`
`
`
`
`
`
`
`
`
`• History of a serious hypersensitivity reaction to canagliflozin or metformin, such as
`
`
`
`
`
`anaphylaxis or angioedema [see Warnings and Precautions (5.10) and Adverse Reactions
`
`
`(6.1, 6.2)].
`
`
`
`
`
`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.
`
`In INVOKAMET-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.
`
`
`
`Reference ID: 4138265
`
`
`
` 6
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`
`
` Educate patients and their families about the symptoms of lactic acidosis and if these symptoms
`
` occur instruct them to discontinue INVOKAMET 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 [see Dosage and Administration (2.2), Clinical Pharmacology
`
`
`(12.3)].
`
`
`• Before initiating INVOKAMET, obtain an estimated glomerular filtration rate (eGFR).
`
`
`
`
`
`
`•
`
`patients with
`in
`contraindicated
`is
`INVOKAMET
`
` 45 mL/minute/1.73 m2 [see Contraindications (4)].
`
`
`
`
`
`an
`
`eGFR
`
`less
`
`than
`
`
`• Obtain an eGFR at least annually in all patients taking INVOKAMET. 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 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 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 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.
`
`
`
`Reference ID: 4138265
`
`
`
` 7
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`
`
` INVOKAMET 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.
`
` 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.
`
`
`
`
` 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 in patients with clinical or laboratory evidence of
`
`
`
` hepatic disease.
`
` 5.2 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 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)].
`
`
`
`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, 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
`
`
`
`
`
`
`
`
`Reference ID: 4138265
`
`
`
` 8
`
`Novo Nordisk Exhibit 2442
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
`
`
` infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower
`limbs, and discontinue INVOKAMET if these complications occur.
`
`
`
`
`
`5.3 Hypotension
`
`
`Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after
`initiating INVOKAMET [see Adverse Reactions (6.1)] particularly in patients with 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 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
`
`
`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 is not
`indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and
`
`
`
`
`Usage (1)].
`
`
`
`
`Patients treated with INVOKAMET 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 may be present even if blood
`
`
`
`
`glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKAMET 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 consider facto