HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`
`
`INVOKANA® safely and effectively. See full prescribing information for
`
`
`
`INVOKANA.
`
`
`INVOKANA (canagliflozin) tablets, for oral use
`
`Initial U.S. Approval: 2013
`
`
`
`WARNING: LOWER LIMB AMPUTATION
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`• In patients with type 2 diabetes who have established cardiovascular
`
`
`
`
`
`disease (CVD) or at risk for CVD, INVOKANA has been associated
`
`
`
`
`with lower limb amputations, most frequently of the toe and midfoot;
`
`
`some also involved the leg (5.1)
`
`
`
`• Before initiating, consider factors that may increase the risk of
`
`
`amputation. Monitor patients receiving INVOKANA for infections or
`
`
`
`ulcers of the lower limbs, and discontinue if these occur. (5.1)
`
`
`
`
`
`-------------------------RECENT MAJOR CHANGES----------------------------­
`Boxed Warning
`07/2017
`
`
`Warnings and Precautions (5.1)
`07/2017
`
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------­
`
`INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor
`
`
`indicated as an adjunct to diet and exercise to improve glycemic control in
`
`
`
`
`adults with type 2 diabetes mellitus (1)
`
`
`
`
`Limitation of Use:
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)
`
`
`
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`• The recommended starting dose is 100 mg once daily, taken before the first
`
`
`
`
`meal of the day (2.1)
`
`
`
`• Dose can be increased to 300 mg once daily in patients tolerating
`
`
`
`
`
`
`
`INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2
`
`
`
`
`
`
`
`
`
`or greater and require additional glycemic control (2.1)
`
`
`
`
`
`• Assess renal function before initiating and periodically thereafter. (2.2)
`
`
`
`
`
`
`
`
`• Limit the dose of INVOKANA to 100 mg once daily in patients who have
`
`an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.2)
`
`
`
`
`
`
`
`
`
`• Initiation or use of INVOKANA is not recommended if eGFR is below
`45 mL/min/1.73 m2 (2.2)
`
`
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`
`Tablets: 100 mg, 300 mg (3)
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`• History of serious hypersensitivity reaction to INVOKANA (4)
`
`
`
`
`
`• Severe renal impairment, ESRD, or on dialysis (4)
`
`
`
`---------------------------WARNINGS AND PRECAUTIONS-------------------­
`
`
`
`
`• Lower Limb Amputation: See boxed warning (5.1)
`• Hypotension: Before initiating INVOKANA, assess volume status and
`
`
`
`
`correct hypovolemia in patients with renal impairment, the elderly, in
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: LOWER LIMB AMPUTATION
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage
`
`
`2.2 Patients with Renal Impairment
`
`
`2.3 Concomitant Use with UDP-Glucuronosyl
`
`
`Transferase (UGT) Enzyme Inducers
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB.
`
`
`Monitor for signs and symptoms during therapy (5.2)
`
`
`
`• Ketoacidosis: Assess patients who present with signs and symptoms of
`
`
`metabolic acidosis for ketoacidosis, regardless of blood glucose level. If
`
`
`
`suspected, discontinue INVOKANA, evaluate and treat promptly. Before
`
`
`initiating INVOKANA, consider risk factors for ketoacidosis. Patients on
`
`
`
`INVOKANA may require monitoring and temporary discontinuation of
`
`
`therapy in clinical situations known to predispose to ketoacidosis (5.3)
`
`
`
`• 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 (5.4)
`
`
`• Hyperkalemia: Monitor potassium levels in patients with impaired renal
`
`
`
`function and in patients predisposed to hyperkalemia (2.2, 5.5, 6.1, 8.6)
`
`
`
`
`
`• Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of
`
`
`urinary tract infections and treat promptly, if indicated (5.6)
`
`
`
`
`
`• Hypoglycemia: Consider a lower dose of insulin or the insulin
`
`
`secretagogue to reduce the risk of hypoglycemia when used in combination
`
`
`with INVOKANA (5.7)
`
`
`• Genital mycotic infections: Monitor and treat if indicated (5.8)
`
`
`
`
`• Hypersensitivity reactions: Discontinue INVOKANA and monitor until
`
`
`
`signs and symptoms resolve (5.9)
`
`
`
`• Bone fracture: Consider factors that contribute to fracture risk before
`
`
`
`initiating INVOKANA (5.10)
`
`
`• Increased LDL-C: Monitor LDL-C and treat if appropriate (5.11)
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`• Most common adverse reactions associated with INVOKANA (5% or
`
`
`
`greater incidence): female genital mycotic infections, urinary tract
`
`infection, and increased urination (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------------------------------­
`
`• UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider
`
`
`
`
`increasing dose from 100 mg to 300 mg (2.3, 7.1)
`
`
`
`
`
`• 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: INVOKANA is not recommended when breastfeeding (8.2)
`
`
`
`
`
`• Geriatrics: Higher incidence of adverse reactions related to reduced
`
`
`
`
`intravascular volume (5.2, 8.5)
`
`
`• Renal impairment: Higher incidence of adverse reactions related to reduced
`
`
`
`intravascular volume and renal function (2.2, 5.4, 8.6)
`
`
`• Hepatic impairment: Not recommended with severe hepatic
`
`
`impairment (8.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`Guide.
`
`
`Revised: 07/2017
`
`
`
`
`
`Lower Limb Amputation
`5.1
`
`
`5.2 Hypotension
`
`
`5.3 Ketoacidosis
`
`5.4 Acute Kidney Injury and Impairment in Renal
`
`
`
`
`
`Function
`
`
`5.5 Hyperkalemia
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`5.7 Hypoglycemia with Concomitant Use with Insulin
`
`
`and Insulin Secretagogues
`
`
`
`5.8 Genital Mycotic Infections
`
`
`5.9 Hypersensitivity Reactions
`
`
`5.10 Bone Fracture
`
`
`
` 1
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`
`
`
`Increases in Low-Density Lipoprotein (LDL-C)
`
`5.11
`
`
`5.12 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`
`6.1 Clinical Studies Experience
`
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 UGT Enzyme Inducers
`
`
`
`
`7.2 Digoxin
`
`
`
`7.3 Positive Urine Glucose Test
`
`
`7.4
`Interference with 1,5-anhydroglucitol (1,5-AG)
`
`
`Assay
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`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 Monotherapy
`
`
`
`14.2 Combination Therapy
`
`
`
`14.3 Studies in Special Populations
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`Reference ID: 4129174
`
`
`
` 2
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` WARNING: LOWER LIMB AMPUTATION
` • An approximately 2-fold increased risk of lower limb amputations associated with
`
`
`INVOKANA use was observed in CANVAS and CANVAS-R, two large,
`
` randomized, placebo-controlled trials in patients with type 2 diabetes who had
`
`
`
` established cardiovascular disease (CVD) or were at risk for CVD.
`
`• Amputations of the toe and midfoot were most frequent; however, amputations
`
`
`
`involving the leg were also observed. Some patients had multiple amputations,
`
`
` some involving both limbs.
`
`
` • Before initiating, consider factors that may increase the risk of amputation, such as
`
`
`a history of prior amputation, peripheral vascular disease, neuropathy, and
`
`
` diabetic foot ulcers.
`
`
`
`
` • Monitor patients receiving INVOKANA for infection, new pain or tenderness,
`
`sores or ulcers involving the lower limbs, and discontinue if these complications
`
`occur [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic
`
`
`control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].
`
`
`
`
`
`Limitation of Use
`
`
`
`
`INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of
`
`diabetic ketoacidosis.
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`The recommended starting dose of INVOKANA (canagliflozin) is 100 mg once daily, taken
`
`
`
`
`before the first meal of the day. In patients tolerating INVOKANA 100 mg once daily who have
`an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can
`
`
`
`
`to 300 mg once daily [see Warnings and Precautions (5.4), Clinical
`
`
`be
`increased
`
`
`
`
`Pharmacology (12.2), and Patient Counseling Information (17)].
`
`
`
`
`In patients with volume depletion, correcting this condition prior to initiation of INVOKANA is
`
`
`
`recommended [see Warnings and Precautions (5.2), Use in Specific Populations (8.5 and 8.6),
`
`
`
`
`and Patient Counseling Information (17)].
`
`
`
`
`
` 3
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`2.2 Patients with Renal Impairment
`
`
`
`Assessment of renal function is recommended prior to initiation of INVOKANA and periodically
`
`
`
`thereafter.
`
`
`The dose of INVOKANA is limited to 100 mg once daily in patients with moderate renal
`
`
`
`impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.
`
`
`
`
`
`Initiation of INVOKANA
`
`45 mL/min/1.73 m2.
`
`
`
`
`is not recommended
`
`in patients with an eGFR less
`
`
`than
`
`
`less
`is persistently
`is not
`recommended when eGFR
`than
`INVOKANA
`Use of
`
`
`
`45 mL/min/1.73 m2 [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`INVOKANA is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see
`
`
`
`Contraindications (4)].
`
`
`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 INVOKANA, consider increasing the dosage to 300 mg once daily in patients currently
`
`
`tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater
`
`
`
`
`
`
` and require additional glycemic control [see Drug Interactions (7.1)].
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`
` INVOKANA 100 mg tablets are yellow, capsule-shaped, film-coated tablets with “CFZ”
`
`•
` on one side and “100” on the other side.
`
`
`
`
`
`
`
`•
`
` INVOKANA 300 mg tablets are white, capsule-shaped, film-coated tablets with “CFZ”
`
`
` on one side and “300” on the other side.
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
` • History of a serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or
`
`
`
`
`
`
`
` angioedema [see Warnings and Precautions (5.9) and Adverse Reactions (6.1, 6.2)].
`
`
`
`
` • Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease
`
`
`
`
`
`
`
` (ESRD), or patients on dialysis [see Warnings and Precautions (5.4) and Use in Specific
`
` Populations (8.6)].
`
`
`
` 4
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`
` 5.1 Lower Limb Amputation
`
`An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA
`
`use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled
`
`
`trials evaluating patients with type 2 diabetes who had either established cardiovascular disease
`
`
`
`or were at risk for cardiovascular disease. In CANVAS, INVOKANA-treated patients and
`
`
`placebo-treated patients had 5.9 and 2.8 amputations per 1000 patients per year, respectively. In
`
`CANVAS-R, INVOKANA-treated patients and placebo-treated patients had 7.5 and 4.2
`
`
`
`amputations per 1000 patients per year, respectively. The risk of lower limb amputations was
`
`
`observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for
`
`CANVAS and CANVAS-R are shown in Tables 2 and 3, respectively [see Adverse Reactions
`
`
`
`(6.1)].
`
`
`
`
`
`Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving
`
`
`
`INVOKANA in the two trials) were the most frequent; however, amputations involving the leg,
`
`
`
`below and above the knee, were also observed (41 out of 140 patients with amputations receiving
`
`INVOKANA in the two trials). Some patients had multiple amputations, some involving both
`
`
`lower limbs.
`
`
`
`Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating
`
`
`
`
`medical events leading to the need for an amputation. The risk of amputation was highest in
`
`
`patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.
`
`
`
`Before initiating INVOKANA, consider factors in the patient history that may predispose to the
`
`
`need for amputations, such as a history of prior amputation, peripheral vascular disease,
`
`
`
`neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine
`
`
`
`preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of
`
`infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower
`
`
`limbs, and discontinue INVOKANA if these complications occur.
`
`
`
`5.2 Hypotension
`
`INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after
`initiating INVOKANA [see Adverse Reactions (6.1)] 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 INVOKANA in patients with one or more of these
`
`
`
`characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms
`
`
`after initiating therapy.
`
`
`
`
` 5
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`5.3 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 INVOKANA. Fatal
`
`
`cases of ketoacidosis have been reported in patients taking INVOKANA. INVOKANA is not
`
`
`indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and
`
`
`
`Usage (1)].
`
`
`
`Patients treated with INVOKANA 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 INVOKANA may be present even if blood glucose levels
`
`
`
`are less than 250 mg/dL. If ketoacidosis is suspected, INVOKANA 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 INVOKANA, 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 INVOKANA consider monitoring for ketoacidosis and
`
`
`
`
`
`temporarily discontinuing INVOKANA
`in clinical situations known
`to
`to predispose
`
`
`ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
`
`
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`
`
`INVOKANA causes intravascular volume contraction [see Warnings and Precautions (5.2)] and
`
`
`
`
`
`
`can cause renal impairment [see Adverse Reactions (6.1)]. There have been postmarketing
`
`reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving
`
`
`INVOKANA; some reports involved patients younger than 65 years of age.
`
`
`
`
`
`Before initiating INVOKANA, consider factors that may predispose patients to acute kidney
`
`
`
`injury including hypovolemia, chronic renal insufficiency, congestive heart failure and
`
`
`
`
`
`
`
`
` 6
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`
`
` concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily
`
` discontinuing INVOKANA in any setting of reduced oral intake (such as acute illness or fasting)
`
`
`
` or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for
`
`
` signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue
`
`
`
`
`
` INVOKANA promptly and institute treatment.
`
` INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be
`
`
`
`more susceptible to these changes. Renal function abnormalities can occur after initiating
` INVOKANA [see Adverse Reactions (6.1)]. Renal function should be evaluated prior to
`
`
` initiation of INVOKANA and monitored periodically thereafter. Dosage adjustment and more
`
` frequent renal function monitoring are recommended in patients with an eGFR below
`
`
` 60 mL/min/1.73 m2. Use of INVOKANA is not recommended when eGFR is persistently less
`
`
`
`than 45 mL/min/1.73 m2 and
`than
`in patients with an eGFR
`is contraindicated
`less
`
`
`
`30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4) and Use in
`
`
`
`
`
`
`Specific Populations (8.6)].
`
`
`5.5 Hyperkalemia
`
`
`INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking
`
`
`medications that interfere with potassium excretion, such as potassium-sparing diuretics, or
`
`medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk
`
`
`of developing hyperkalemia [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
`
`
`
`
`Monitor serum potassium levels periodically after initiating INVOKANA in patients with
`
`
`
`impaired renal function and in patients predisposed to hyperkalemia due to medications or other
`
`medical conditions.
`
`
`5.6 Urosepsis and Pyelonephritis
`
`
`There have been postmarketing reports of serious urinary tract infections including urosepsis and
`
`
`
`
`pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including
`
`
`INVOKANA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections.
`
`
`Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if
`
`
`
`
`indicated [see Adverse Reactions (6)].
`
`
`
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`
`
`
`Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase
`
`
`
`the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse
`
`
`Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to
`
`
`minimize the risk of hypoglycemia when used in combination with INVOKANA.
`
`
`
`
` 7
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`5.8 Genital Mycotic Infections
`
`
`INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital
`
`
`
`mycotic infections and uncircumcised males were more likely to develop genital mycotic
`
`
`infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
`
`
`
`
`5.9 Hypersensitivity Reactions
`
`
`Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with
`
`INVOKANA. These reactions generally occurred within hours to days after initiating
`
`
`INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and
`
`
`monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions
`
`
`
`(6.1, 6.2)].
`
`
`5.10 Bone Fracture
`
`
`An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was
`
`
`
`
`observed in patients using INVOKANA. Consider factors that contribute to fracture risk prior to
`
`
`initiating INVOKANA [see Adverse Reactions (6.1)].
`
`
`
`5.11 Increases in Low-Density Lipoprotein (LDL-C)
`
`
`Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions (6.1)].
`
`
`
`Monitor LDL-C and treat if appropriate after initiating INVOKANA.
`
`
`
`
`5.12 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`
`
`reduction with INVOKANA [see Adverse Reactions (6.1)].
`
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`The following important adverse reactions are described below and elsewhere in the labeling:
`
`
`
`
`
`
`
`
` • Lower Limb Amputation [see Boxed Warning and Warnings and Precautions (5.1)]
`
` • Hypotension [see Warnings and Precautions (5.2)]
`
`
`
`
` • Ketoacidosis [see Warnings and Precautions (5.3)]
`
`
`
`
`
` in Renal Function [see Warnings and
`
`
`
`
`
` • Acute Kidney Injury and Impairment
`
`
`
` Precautions (5.4)]
`
`
` • Hyperkalemia [see Warnings and Precautions (5.5)]
`
`
`
`
` • Urosepsis and Pyelonephritis [see Warnings and Precautions (5.6)]
`
`
`
`
` • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see
`
`
`
`
` Warnings and Precautions (5.7)]
`
` • Genital Mycotic Infections [see Warnings and Precautions (5.8)]
`
`
`
`
`
`
`
`Reference ID: 4129174
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
`
`
`
`
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.9)]
`
` • Bone Fracture [see Warnings and Precautions (5.10)]
`
`
`
`
`
` Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.11)]
`
`
`
`
`•
` 6.1 Clinical Studies Experience
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`
` observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical
`
` trials of another drug and may not reflect the rates observed in clinical practice.
`
`
`
`
`
`
`
`
` Pool of Placebo-Controlled Trials
`
`
`The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial
`
`
`
`
`
`INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on
`
`therapy [see Clinical Studies (14)]. These data reflect exposure of 1667 patients to INVOKANA
`
`
`
`
`
`
`and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA
`
`
`
`
`
`100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age
`
`
`
`
`
`of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of
`
`
`
`
`
`the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or
`
`
`African American. At baseline the population had diabetes for an average of 7.3 years, had a
`mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes.
`
`
`
`
`
`Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2).
`
`
`
`
`
`
`Table 1 shows common adverse reactions associated with the use of INVOKANA. These
`
`
`
`adverse reactions were not present at baseline, occurred more commonly on INVOKANA than
`
`
`on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or
`
`
`
`INVOKANA 300 mg.
`
`
`
`
`
`
`Reference ID: 4129174
`
`
`
` 9
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
`
`
` Table 1:
`
`
`
`
`
` Adverse Reactions From Pool of Four 26−Week Placebo-Controlled Studies Reported in ≥ 2%
`
`
`
`
`
` of INVOKANA-Treated Patients*
`
`
`
`
`
`INVOKANA
`INVOKANA
`
`
`
` Placebo
`
`
` 300 mg
`
`
` 100 mg
`Adverse Reaction
`N=834
`N=833
`N=646
`
`
`
`
`Urinary tract infections‡
`4.4%
`5.9%
`3.8%
`
`
`
`
`Increased urination§
`
`4.6%
`5.1%
`0.7%
`
`
`
`Thirst#
`
`2.4%
`2.8%
`0.1%
`
`
`
`2.4%
`1.8%
`0.9%
`Constipation
`
`
`
`
`2.3%
`2.1%
`1.6%
`Nausea
`
`
`
`
`
`N=430
`N=425
`N=312
`
`
`
`Female genital mycotic infections†
`11.6%
`10.6%
`2.8%
`
`
`
`
`3.2%
`1.6%
`0.0%
`Vulvovaginal pruritus
`
`
`
`
`
`N=404
`N=408
`N=334
`
`
`
`Male genital mycotic infections¶
`3.8%
`4.2%
`0.7%
`
`
`
`
`
` * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and
`
`
`
`
` sulfonylurea, or metformin and pioglitazone.
`
`
`
`
`† Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection,
`
`
`
`
`
`
`
`Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal.
`‡ Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.
`
`
`
`
`§
`
`
`
`
`
`Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.
`¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection
`
`
`
`
`
`
`
`fungal.
`# Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.
`
`
`
`
`
`
`Note: Percentages were weighted by studies. Study weights were proportional to the harmonic mean of the three treatment sample sizes.
`
`
`
`
`
`
`
`
`
`
`Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg
`
`(1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).
`
`
`
`Pool of Placebo- and Active-Controlled Trials
`
`
`
`
`The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients
`
`
`participating in placebo- and active-controlled trials.
`
`
`The data combined eight clinical trials [see Clinical Studies (14)] and reflect exposure of
`
`
`
`
`
`
`
`
`6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks
`
`
`
`
`with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received
`
`
`
`
`INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once
`
`
`
`
`
`daily. The mean age of the population was 60 years and 5% were older than 75 years of age.
`
`
`
`
`
`Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian,
`
`
`
`
`
`and 4% were Black or African American. At baseline, the population had diabetes for an average
`of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications
`
`
`
`
`
`
`of diabetes. Baseline renal function was normal or mildly
`impaired (mean eGFR
`
`
`81 mL/min/1.73 m2).
`
`
`
`
`The types and frequency of common adverse reactions observed in the pool of eight clinical
`
`
`
`trials 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,
`
`
`
`
`
` 10
`
`
`
`Reference ID: 4129174
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00010
`
`

`

`
`
`
`
` INVOKANA was also associated with the adverse reactions of fatigue (1.8% with comparator,
`
` 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or
`
`
`
`
` energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with
`
`
`
`
` INVOKANA 300 mg).
`
` In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%,
`
`
`
`
`
`
`
` 0.2%, and 0.1% receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg,
`
` respectively.
`
`
`
`
` In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema,
`
` rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving
`
` comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients
`
`
`
`
` experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4
`
`
`
` patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of
`
`
` exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One
`
`
`
` patient with urticaria had recurrence when INVOKANA was re-initiated.
`
`
`
`
` Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light
`
` eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator,
`
`
`
`
` INVOKANA 100 mg, and INVOKANA 300 mg, respectively.
`
`
`
` Other adverse reactions occurring more frequently on INVOKANA than on comparator were:
`
`
`
`
`
` Lower Limb Amputation
`
`
`
`An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA
`
`use was observed in CANVAS and CANVAS-R, two large, randomized, placebo-controlled
`
`
`
`trials evaluating patients with type 2 diabetes who had either established cardiovascular disease
`
`
`or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed
`
`
`
`for an average of 5.7 and 2.1 years, respectively. The amputation data for CANVAS and
`
`CANVAS-R are shown in Tables 2 and 3, respectively [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
` Table 2:
`
`
`
`
` CANVAS AMPUTATIONS
`
`
`
`
`Patients with an amputation, n (%)
`
`
`
`Total amputations
`
`Amputation incidence rate
`
` (per 1000 patient-years)
`
`
`Hazard Ratio (95% CI)
`
`
`
`
`Reference ID: 4129174
`
`Placebo
`
`N=1441
`
`22 (1.5)
`
`33
`
`
`
`2.8
`
`-­
`
`
`
`INVOKANA
`
`
`
` 100 mg
` N=1445
`
`50 (3.5)
`
`83
`
`
`INVOKANA
`
`
`
` 300 mg
` N=1441
`
`45 (3.1)
`
`79
`
`
`INVOKANA
`
`
` (Pooled)
`
` N=2886
`95 (3.3)
`
`162
`
`
`
`6.2
`
`
`5.5
`
`
`5.9
`
`2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38)
`
`
`
`
`
`
`
`
`
` 11
`
`Novo Nordisk Exhibit 2432
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023