HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`FARXIGA safely and effectively. See full prescribing information for
`FARXIGA.
`
`FARXIGA® (dapagliflozin) tablets, for oral use
`Initial U.S. Approval: 2014
`
`--------------------------- INDICATIONS AND USAGE --------------------------
`FARXIGA is a sodium-glucose cotransporter 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.
`
`
`(1.1)
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`The recommended starting dose is 5 mg once daily, taken in the
`
`morning, with or without food. (2.1)
`Dose can be increased to 10 mg once daily in patients tolerating
`
`FARXIGA who require additional glycemic control. (2.1)
`Assess renal function before initiating FARXIGA and periodically
`
`thereafter. (2.2)
`Initiation is not recommended in patients with an eGFR less than 60
`
`mL/min/1.73 m2. (2.2)
`Use of FARXIGA is not recommended in patients with an eGFR
`
`persistently between 30 and less than 60 mL/min/1.73 m2. (2.2)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Tablets: 5 mg and 10 mg (3)
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`History of serious hypersensitivity reaction to FARXIGA. (4)
`
`Severe renal impairment, end-stage renal disease, or dialysis. (4)
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`Hypotension: Before initiating FARXIGA, assess volume status and
`
`correct hypovolemia in the elderly, in patients with renal impairment or
`low systolic blood pressure, and in patients on diuretics. Monitor for
`signs and symptoms during therapy. (5.1, 6.1)
`Ketoacidosis: Assess patients who present with signs and symptoms of
`metabolic acidosis for ketoacidosis regardless of blood glucose level. If
`suspected, discontinue FARXIGA, evaluate and treat promptly. Before
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Limitation of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypotension
`5.2 Ketoacidosis
`5.3 Acute Kidney Injury and Impairment in Renal Function
`5.4 Urosepsis and Pyelonephritis
`5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin
`Secretagogues
`5.6 Genital Mycotic Infections
`5.7 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`5.8 Bladder Cancer
`5.9 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Positive Urine Glucose Test
`7.2 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Reference ID: 4169903
`
`
`
`initiating FARXIGA, consider risk factors for ketoacidosis. Patients on
`FARXIGA may require monitoring and temporary discontinuation of
`therapy in clinical situations known to predispose to ketoacidosis. (5.2)
`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. (5.3)
`Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of
`urinary tract infections and treat promptly, if indicated. (5.4)
`Hypoglycemia: In patients taking insulin or an insulin secretagogue with
`FARXIGA, consider a lower dose of insulin or the insulin secretagogue
`to reduce the risk of hypoglycemia. (5.5)
`Genital Mycotic Infections: Monitor and treat if indicated. (5.6)
`Increased LDL-C: Monitor and treat per standard of care. (5.7)
`Bladder Cancer: An imbalance in bladder cancers was observed in
`clinical trials. FARXIGA should not be used in patients with active
`bladder cancer and should be used with caution in patients with a prior
`history of bladder cancer. (5.8)
` Macrovascular Outcomes: There have been no clinical studies
`establishing conclusive evidence of macrovascular risk reduction with
`FARXIGA. (5.9)
`
`
`
`
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`The most common adverse reactions associated with FARXIGA (5% or
`
`greater incidence) were female genital mycotic infections,
`nasopharyngitis, and urinary tract infections. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800- 236-9933 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Pregnancy: Advise females of the potential risk to a fetus especially
`
`during the second and third trimesters. (8.1)
`Lactation: FARXIGA is not recommended when breastfeeding. (8.2)
`
`Geriatrics: Higher incidence of adverse reactions related to reduced
`
`intravascular volume. (5.1, 8.5)
`Renal Impairment: Higher incidence of adverse reactions related to
`
`reduced intravascular volume and renal function. (5.3, 6.1, 8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide
`
`Revised: 10/2017
`
`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 Overview of Clinical Studies of FARXIGA for Type 2 Diabetes
`14.2 Monotherapy
`14.3 Initial Combination Therapy with Metformin XR
`14.4 Add-On to Metformin
`14.5 Active Glipizide-Controlled Study Add-On to Metformin
`14.6 Add-On Combination Therapy with Other Antidiabetic Agents
`14.7 Use in Patients with Type 2 Diabetes and Renal Impairment
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
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`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`FARXIGA (dapagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus [see Clinical Studies (14)].
`
`1.1 Limitation of Use
`FARXIGA is not recommended for patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`The recommended starting dose of FARXIGA is 5 mg once daily, taken in the morning, with or without food. In patients
`tolerating FARXIGA 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once
`daily.
`
`In patients with volume depletion, correcting this condition prior to initiation of FARXIGA is recommended [see
`Warnings and Precautions (5.1), Use in Specific Populations (8.5, 8.6), and Patient Counseling Information (17)].
`
`2.2 Patients with Renal Impairment
`Assessment of renal function is recommended prior to initiation of FARXIGA therapy and periodically thereafter.
`
`Initiation of FARXIGA is not recommended in patients with an eGFR less than 60 mL/min/1.73 m2.
`
`No dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).
`
`Use of FARXIGA is not recommended in patients with an eGFR persistently between 30 and less
`
`than 60 mL/min/1.73 m2 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
`
`FARXIGA is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Contraindications (4)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
` FARXIGA 5 mg tablets are yellow, biconvex, round, film-coated tablets with “5” engraved on one side and “1427”
`engraved on the other side.
` FARXIGA 10 mg tablets are yellow, biconvex, diamond-shaped, film-coated tablets with “10” engraved on one side
`and “1428” engraved on the other side.
`
`4 CONTRAINDICATIONS
`
` History of a serious hypersensitivity reaction to FARXIGA [see Adverse Reactions (6.1)].
` Severe renal impairment, (eGFR less than 30 mL/min/1.73 m2) end-stage renal disease (ESRD), or patients on dialysis
`[see Use in Specific Populations (8.6)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypotension
`FARXIGA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating FARXIGA [see
`Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2),
`elderly patients, or patients on loop diuretics. Before initiating FARXIGA in patients with one or more of these
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`

`

`characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms of hypotension after
`initiating therapy.
`
`5.2 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 cotransporter 2
`(SGLT2) inhibitors, including FARXIGA. Fatal cases of ketoacidosis have been reported in patients taking FARXIGA.
`FARXIGA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1.1)].
`
`Patients treated with FARXIGA 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 FARXIGA may
`be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, FARXIGA should be
`discontinued, the 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 the institution of treatment was delayed because the 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 FARXIGA, 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 FARXIGA
`consider monitoring for ketoacidosis and temporarily discontinuing FARXIGA in clinical situations known to predispose
`to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
`
`5.3 Acute Kidney Injury and Impairment in Renal Function
`FARXIGA causes intravascular volume contraction [see Warning and Precautions (5.1)], 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 FARXIGA; some reports involved patients younger than 65 years of age.
`
`Before initiating FARXIGA, consider factors that may predispose patients to acute kidney injury including hypovolemia,
`chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs,
`NSAIDs). Consider temporarily discontinuing FARXIGA in any setting of reduced oral intake (such as acute illness or
`fasting) or fluid losses (gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of
`acute kidney injury. If acute kidney injury occurs, discontinue FARXIGA promptly and institute treatment.
`
`FARXIGA increases serum creatinine and decreases eGFR. Elderly patients and patients with impaired renal function
`may be more susceptible to these changes. Adverse reactions related to renal function can occur after initiating FARXIGA
`[see Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiation of FARXIGA and monitored
`periodically thereafter. Use of FARXIGA is not recommended in patients with an eGFR persistently between 30 and less
`than 60 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 [see Dosage and
`Administration (2.2), Contraindications (4), Use in Specific Populations (8.6)].
`
`5.4 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 FARXIGA. Treatment with SGLT2 inhibitors increases
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`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)].
`
`5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin and insulin secretagogues are known to cause hypoglycemia. FARXIGA 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 these agents are used in combination
`with FARXIGA.
`
`5.6 Genital Mycotic Infections
`FARXIGA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections were more
`likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
`
`5.7 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`Increases in LDL-C occur with FARXIGA [see Adverse Reactions (6.1)]. Monitor LDL-C and treat per standard of care
`after initiating FARXIGA.
`
`5.8 Bladder Cancer
`Across 22 clinical studies, newly diagnosed cases of bladder cancer were reported in 10/6045 patients (0.17%) treated
`with FARXIGA and 1/3512 patient (0.03%) treated with placebo/comparator. After excluding patients in whom exposure
`to study drug was less than one year at the time of diagnosis of bladder cancer, there were 4 cases with FARXIGA and no
`cases with placebo/comparator. Bladder cancer risk factors and hematuria (a potential indicator of pre-existing tumors)
`were balanced between treatment arms at baseline. There were too few cases to determine whether the emergence of these
`events is related to FARXIGA.
`
`There are insufficient data to determine whether FARXIGA has an effect on pre-existing bladder tumors. Consequently,
`FARXIGA should not be used in patients with active bladder cancer. In patients with prior history of bladder cancer, the
`benefits of glycemic control versus unknown risks for cancer recurrence with FARXIGA should be considered.
`
`5.9 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with FARXIGA.
`
`6 ADVERSE REACTIONS
`
`The following important adverse reactions are described below and elsewhere in the labeling:
`
` Hypotension [see Warnings and Precautions (5.1)]
`
` Ketoacidosis [see Warnings and Precautions (5.2)]
`
` Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)]
`
` Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
`
` Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.5)]
`
` Genital Mycotic Infections [see Warnings and Precautions (5.6)]
`
`Increases in Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.7)]
`
`
` Bladder Cancer [see Warnings and Precautions (5.8)]
`
`6.1 Clinical Trials 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 rates in the clinical trials of another drug and may not reflect the rates observed
`in clinical practice.
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`Pool of 12 Placebo-Controlled Studies for FARXIGA 5 and 10 mg
`The data in Table 1 is derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies FARXIGA
`was used as monotherapy, and in 8 studies FARXIGA was used as add-on to background antidiabetic therapy or as
`combination therapy with metformin [see Clinical Studies (14)].
`
`These data reflect exposure of 2338 patients to FARXIGA with a mean exposure duration of 21 weeks. Patients received
`placebo (N=1393), FARXIGA 5 mg (N=1145), or FARXIGA 10 mg (N=1193) once daily. The mean age of the
`population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81%
`were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an
`average of 6 years, had a mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications
`of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of
`patients (mean eGFR 86 mL/min/1.73 m2).
`
`Table 1 shows common adverse reactions associated with the use of FARXIGA. These adverse reactions were not present
`at baseline, occurred more commonly on FARXIGA than on placebo, and occurred in at least 2% of patients treated with
`either FARXIGA 5 mg or FARXIGA 10 mg.
`
`Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with FARXIGA
`
`Adverse Reaction
`
`Female genital mycotic infections*
`
`Nasopharyngitis
`
`Urinary tract infections†
`
`Back pain
`
`Increased urination‡
`
`Male genital mycotic infections§
`
`Nausea
`
`Influenza
`
`Dyslipidemia
`
`Constipation
`
`Discomfort with urination
`
`% of Patients
`
`Pool of 12 Placebo-Controlled Studies
`
`Placebo
`N=1393
`
`FARXIGA 5 mg
`N=1145
`
`FARXIGA 10 mg
`N=1193
`
`1.5
`
`6.2
`
`3.7
`
`3.2
`
`1.7
`
`0.3
`
`2.4
`
`2.3
`
`1.5
`
`1.5
`
`0.7
`
`8.4
`
`6.6
`
`5.7
`
`3.1
`
`2.9
`
`2.8
`
`2.8
`
`2.7
`
`2.1
`
`2.2
`
`1.6
`
`6.9
`
`6.3
`
`4.3
`
`4.2
`
`3.8
`
`2.7
`
`2.5
`
`2.3
`
`2.5
`
`1.9
`
`2.1
`
`1.7
`2.0
`1.4
`Pain in extremity
`
` * Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal
`mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital
`infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, FARXIGA 5
`mg=581, FARXIGA 10 mg=598).
`
`† Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection,
`cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection,
`and prostatitis.
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`
`Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine
`‡
`output increased.
`§ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis,
`
`fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis,
`balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, FARXIGA 5 mg=564, FARXIGA 10 mg=595).
`
`Pool of 13 Placebo-Controlled Studies for FARXIGA 10 mg
`The safety and tolerability of FARXIGA 10 mg was also evaluated in a larger placebo-controlled study pool. This pool
`combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy
`studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily
`with FARXIGA 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and
`4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian,
`and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean
`HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired
`in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).
`
`Volume Depletion
`FARXIGA causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to
`volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in
`Table 2 for the 12-study and 13-study, short-term, placebo-controlled pools [see Warnings and Precautions (5.1)].
`
`Table 2: Adverse Reactions of Volume Depletion* in Clinical Studies with FARXIGA
`
`Pool of 12 Placebo-Controlled
`Studies
`
`Placebo FARXIGA
`5 mg
`N=1145
`7 (0.6%)
`
`N=1393
`5
`(0.4%)
`
`FARXIGA
`10 mg
`N=1193
`9 (0.8%)
`
`Pool of 13 Placebo-
`Controlled
`Studies
`Placebo
`FARXIGA
`10 mg
`N=2360
`27 (1.1%)
`
`N=2295
`17 (0.7%)
`
`n=40
`0
`
`n=107
`1 (0.9%)
`
`n=216
`1 (0.5%)
`
`n=31
`3 (9.7%)
`
`n=89
`1 (1.1%)
`
`n=204
`3 (1.5%)
`
`n=267
`4 (1.5%)
`
`n=268
`4 (1.5%)
`
`n=711
`6 (0.8%)
`
`n=236
`6 (2.5%)
`
`n=265
`5 (1.9%)
`
`n=665
`11 (1.7%)
`
`Overall population N (%)
`
`Patient Subgroup n (%)
`Patients on loop diuretics
`
`Patients with moderate renal impairment with
`eGFR ≥30 and <60 mL/min/1.73 m2
`
`Patients ≥65 years of age
`
`n=55
`1
`(1.8%)
`n=107
`2
`(1.9%)
`n=276
`1
`(0.4%)
`* Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension.
`
`Impairment of Renal Function
`Use of FARXIGA was associated with increases in serum creatinine and decreases in eGFR (see Table 3). In patients with
`normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24.
`Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients
`treated with FARXIGA (see Table 4). Elderly patients and patients with impaired renal function were more susceptible to
`these adverse reactions (see Table 4). Sustained decreases in eGFR were seen in patients with moderate renal impairment
`(eGFR 30 to less than 60 mL/min/1.73 m2).
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
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`

`

`Table 3: Changes in Serum Creatinine and eGFR Associated with FARXIGA in the Pool of 12 Placebo-Controlled
`Studies and Moderate Renal Impairment Study
`
`Baseline Mean
`
`Week 1 Change
`
`Week 24 Change
`
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`
`Baseline Mean
`
`Week 1 Change
`
`Week 24 Change
`
`Week 52 Change
`
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`Serum Creatinine (mg/dL)
`eGFR (mL/min/1.73 m2)
`
`Placebo
`N=1393
`0.853
`86.0
`−0.003
`0.4
`−0.005
`0.8
`
`Placebo
`N=84
`1.46
`45.6
`0.01
`0.5
`0.02
`0.03
`0.10
`−2.6
`
`Pool of 12 Placebo-Controlled Studies
`FARXIGA 5 mg
`FARXIGA 10 mg
`N=1145
`N=1193
`0.860
`0.847
`85.3
`86.7
`0.029
`0.041
`−2.9
`−4.1
`−0.001
`0.001
`0.8
`0.3
`Moderate Renal Impairment Study
`FARXIGA 5 mg
`FARXIGA 10 mg
`N=83
`N=85
`1.53
`1.52
`44.2
`43.9
`0.13
`0.18
`−3.8
`−5.5
`0.08
`0.16
`−4.0
`−7.4
`0.06
`0.15
`−4.2
`−7.3
`
`Table 4: Proportion of Patients with at Least One Renal Impairment-Related Adverse Reaction
`
`Pool of 6 Placebo-Controlled
`Studies
`(up to 104 weeks)*
`Placebo FARXIGA
`FARXIGA
`5 mg
`10 mg
`
`Baseline Characteristic
`
`Overall population
`Patients (%) with at least one event
`
`n=785
`13
`(1.7%)
`n=190
`4 (2.1%)
`n=77
`5 (6.5%)
`n=41
`
`65 years of age and older
`Patients (%) with at least one event
`eGFR ≥30 and <60 mL/min/1.73 m2
`Patients (%) with at least one event
`65 years of age and older and eGFR ≥30 and
`<60 mL/min/1.73 m2
`4 (11.4%)
`3 (7.0%)
`2 (4.9%)
`Patients (%) with at least one event
` * Subset of patients from the pool of 12 placebo-controlled studies with long-term extensions.
`
`
`† Subset of patients from the pool of 13 placebo-controlled studies with long-term extensions.
`
`n=767
`14 (1.8%)
`n=162
`5 (3.1%)
`n=88
`7 (8.0%)
`n=43
`
`n=859
`16 (1.9%)
`n=159
`6 (3.8%)
`n=75
`9 (12.0%)
`n=35
`
`Pool of 9 Placebo-Controlled
`Studies
`(up to 104 weeks)†
`Placebo
`FARXIGA
`10 mg
`n=2026
`136 (6.7%)
`
`n=1956
`82 (4.2%)
`
`n=655
`52 (7.9%)
`n=249
`40 (16.1%)
`n=141
`
`n=620
`87 (14.0%)
`n=251
`71 (28.3%)
`n=134
`
`27 (19.1%)
`
`47 (35.1%)
`
`The safety of FARXIGA was evaluated in a study of patients with moderate renal impairment (eGFR 30 to less than 60
`mL/min/1.73 m2) [see Clinical Studies (14)]. In this study 13 patients experienced bone fractures for treatment durations
`up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the FARXIGA 5 mg group, and 8 occurred in
`the FARXIGA 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to
`45 mL/min/1.73 m2. Eleven of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern
`with respect to the anatomic site of fracture.
`
`Reference ID: 4169903
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`Hypoglycemia
`The frequency of hypoglycemia by study [see Clinical Studies (14)] is shown in Table 5. Hypoglycemia was more
`frequent when FARXIGA was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)].
`
`Table 5: Incidence of Major* and Minor† Hypoglycemia in Controlled Clinical Studies
`
`FARXIGA 5 mg FARXIGA 10 mg
`
`Placebo/Active
`Control
`N=75
`0
`0
`N=137
`0
`0
`N=408
`
`3 (0.7)
`147 (36.0)
`N=146
`0
`3 (2.1)
`N=109
`0
`4 (3.7)
`N=139
`0
`0
`N=226
`0
`3 (1.3)
`N=197
`
`Reference ID: 4169903
`
`N=64
`0
`0
`N=137
`0
`2 (1.5)
`–
`
`–
`–
`N=145
`0
`8 (5.5)
`-
`-
`-
`N=141
`0
`3 (2.1)
`–
`–
`–
`N=212
`
`N=70
`0
`0
`N=135
`0
`1 (0.7)
`N=406
`
`0
`7 (1.7)
`N=151
`0
`9 (6.0)
`N=109
`0
`14 (12.8)
`N=140
`0
`0
`N=225
`1 (0.4)
`4 (1.8)
`N=196
`
`Monotherapy* (24 weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to Metformin* (24 weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Active Control Add-on to Metformin versus Glipizide
`(52 weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to Glimepiride* (24 weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to Metformin and a Sulfonylurea (24 Weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to Pioglitazone* (24 weeks)
`
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to DPP4 inhibitor (24 weeks)
`Major [n (%)]
`
`Minor [n (%)]
`
`Add-on to Insulin with or without other OADs‡ (24
`weeks)
`1 (0.5)
`1 (0.5)
`1 (0.5)
`Major [n (%)]
`
`79 (40.3)
`92 (43.4)
`67 (34.0)
`Minor [n (%)]
`
`* Major episodes of hypoglycemia were defined as symptomatic episodes requiring external (third party) assistance due to severe
`
`impairment in consciousness or behavior with a capillary or plasma glucose value <54 mg/dL and prompt recovery after glucose
`or glucagon administration.
`† Minor episodes of hypoglycemia were defined as either a symptomatic episode with a capillary or plasma glucose measurement
`<63 mg/dL regardless of need for external assistance, or an asymptomatic capillary or plasma glucose measurement <63 mg/dL
`that does not qualify as a major episode.
`‡ OAD = oral antidiabetic therapy.
`Genital Mycotic Infections
`Genital mycotic infections were more frequent with FARXIGA treatment. Genital mycotic infections were reported in
`0.9% of patients on placebo, 5.7% on FARXIGA 5 mg, and 4.8% on FARXIGA 10 mg, in the 12-study placebo-
`controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2%
`of patients treated with FARXIGA 10 mg. Infections were more frequently reported in females than in males (see Table
`1). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis
`in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during
`the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, FARXIGA
`5 mg, and FARXIGA 10 mg, respectively).
`
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`IPR2023-00724
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`

`

`Hypersensitivity Reactions
`Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with FARXIGA treatment. Across
`the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported
`in 0.2% of comparator-treated patients and 0.3% of FARXIGA-treated patients. If hypersensitivity reactions occur,
`discontinue use of FARXIGA; treat per standard of care and monitor until signs and symptoms resolve.
`
`Laboratory Tests
`
`Increase in Hematocrit
`In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in
`FARXIGA-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from
`baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and
`2.30% in the FARXIGA 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated
`patients and 1.3% of FARXIGA 10 mg-treated patients.
`
`Increase in Serum Inorganic Phosphorus
`In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at
`Week 24 in FARXIGA-treated patients compared with placebo-treated patients (mean increase of 0.13 versus −0.04
`mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6
`mg/dL for age 17-65 years or ≥5.1 mg/dL for age ≥66 years) were reported on FARXIGA at Week 24 (0.9% versus 1.7%
`for placebo and FARXIGA 10 mg, respectively).
`
`Increase in Low-Density Lipoprotein Cholesterol
`In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in FARXIGA-
`treated patients compared to placebo-treated patients. Mean percent changes from baseline at Week 24, were 0.0% versus
`2.5% for total cholesterol and −1.0% versus 2.9% for LDL cholesterol, in the placebo and FARXIGA 10 mg groups,
`respectively.
`
`Decrease in Serum Bicarbonate
`
`In a study of concomitant therapy of FARXIGA 10 mg with exenatide extended-release (on a background of metformin),
`four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to
`one each (0.4%) in the FARXIGA and exenatide-extended release treatment groups [see Warnings and Precautions
`(5.2)].
`
`6.2 Postmarketing Experience
`Additional adverse reactions have been identified during postapproval use of FARXIGA. Because these reactions are
`reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or
`establish a causal relationship to drug exposure.
`
` Ketoacidosis [see Warnings and Precautions (5.2)]
`
` Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.3)]
`
` Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4)]
`
` Rash
`
`7 DRUG INTERACTIONS
`
`7.1 Positive Urine Glucose Test
`
`Reference ID: 4169903
`
`Novo Nordisk Exhibit 2434
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2
`inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternativ