` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`JARDIANCE safely and effectively. See full prescribing information for
`JARDIANCE.
`
`
`JARDIANCE® (empagliflozin) tablets, for oral use
`
`Initial U.S. Approval: 2014
`
`
`---------------------------RECENT MAJOR CHANGES--------------------------­
`
`Contraindications (4)
`12/2017
`
`
`
`
`
`
`Warnings and Precautions (5)
` 12/2017
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`JARDIANCE 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,
`
`
`to reduce the risk of cardiovascular death in adult patients with type 2
`diabetes mellitus and established cardiovascular disease. (1)
`
`
`
`
`
`Limitations of Use: Not for the treatment of type 1 diabetes mellitus or
`diabetic ketoacidosis (1)
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`The recommended dose of JARDIANCE is 10 mg once daily, taken in
`
`the morning, with or without food (2.1)
`
`Dose may be increased to 25 mg once daily (2.1)
`
`Assess renal function before initiating JARDIANCE. Do not initiate
`JARDIANCE if eGFR is below 45 mL/min/1.73 m2 (2.2)
`Discontinue JARDIANCE if eGFR falls persistently below
`45 mL/min/1.73 m2 (2.2)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`Tablets: 10 mg, 25 mg (3)
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`History of serious hypersensitivity reaction to empagliflozin or any of
`
`the excipients in JARDIANCE (4)
`
`Severe renal impairment, end-stage renal disease, or dialysis (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ketoacidosis: Assess patients who present with signs and symptoms of
`metabolic acidosis for ketoacidosis, regardless of blood glucose level. If
`
`suspected, discontinue JARDIANCE, evaluate and treat promptly.
`Before initiating JARDIANCE, consider risk factors for ketoacidosis.
`Patients on JARDIANCE 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 patients for signs and symptoms
`
`of urinary tract infections and treat promptly, if indicated (5.4)
`
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or
`
`insulin to reduce the risk of hypoglycemia when initiating JARDIANCE
`(5.5)
`Genital mycotic infections: Monitor and treat as appropriate (5.6)
`Hypersensitivity reactions: Discontinue JARDIANCE, treat promptly,
`
`and monitor until signs and symptoms resolve (5.7)
`
`Increased LDL-C: Monitor and treat as appropriate (5.8)
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`The most common adverse reactions associated with JARDIANCE (5%
`
`or greater incidence) were urinary tract infections and female genital
`
`mycotic infections (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Boehringer
`
`Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906
`
`TTY, 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: JARDIANCE is not recommended when breastfeeding (8.2)
`
`Geriatric patients: Higher incidence of adverse reactions related to
`volume depletion and reduced renal function (5.1, 5.3, 8.5)
`
`Patients with renal impairment: Higher incidence of adverse reactions
`related to reduced renal function (2.2, 5.3, 8.6)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved patient labeling.
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Hypotension: Before initiating JARDIANCE assess and correct volume
`
`status in patients with renal impairment, the elderly, in patients with low
`systolic blood pressure, and in patients on diuretics. Monitor for signs
`and symptoms during therapy. (5.1)
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`
`
`Revised: 12/2017
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
` INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`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 Hypersensitivity Reactions
`
`Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`5.8
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`6.2
` Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
` Diuretics
`7.1
`
`Insulin or Insulin Secretagogues
`7.2
`7.3 Positive Urine Glucose Test
`
`Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`7.4
`
`
`
`
`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 Glycemic Control
`
`14.2 Cardiovascular Outcomes in Patients with Type 2 Diabetes
`Mellitus and Atherosclerotic Cardiovascular Disease
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`Reference ID: 4195030
`
`1
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`JARDIANCE is indicated:
`
`
` as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus,
`
`to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established
`
`
`cardiovascular disease.
`
`
`
`Limitations of Use
`
`JARDIANCE is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
`
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosage
`The recommended dose of JARDIANCE is 10 mg once daily in the morning, taken with or without food. In
`patients tolerating JARDIANCE, the dose may be increased to 25 mg [see Clinical Studies (14)].
`
`
`
`In patients with volume depletion, correcting this condition prior to initiation of JARDIANCE is recommended
`[see Warnings and Precautions (5.1), Use in Specific Populations (8.5) and Patient Counseling Information
`(17)].
`
`
`2.2 Patients with Renal Impairment
`
`Assessment of renal function is recommended prior to initiation of JARDIANCE and periodically thereafter.
`
`JARDIANCE should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
`
`No dose adjustment is needed in patients with an eGFR greater than or equal to 45 mL/min/1.73 m2.
`
`JARDIANCE should be discontinued if eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and
`
`Precautions (5.1, 5.3) and Use in Specific Populations (8.6)].
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`JARDIANCE tablets available as:
`
` 10 mg pale yellow, round, biconvex and bevel-edged, film-coated tablets debossed with “S 10” on one
`side and the Boehringer Ingelheim company symbol on the other side.
`
`
` 25 mg pale yellow, oval, biconvex, film-coated tablets debossed with “S 25” on one side and the
`Boehringer Ingelheim company symbol on the other side.
`
`
`4
`
`CONTRAINDICATIONS
`
`
` History of serious hypersensitivity reaction to empagliflozin or any of the excipients in JARDIANCE
`[see Warnings and Precautions (5.7)].
`
`
` Severe renal impairment, end-stage renal disease, or dialysis [see Use in Specific Populations (8.6)].
`
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Hypotension
`JARDIANCE causes intravascular volume contraction. Symptomatic hypotension may occur after initiating
`JARDIANCE [see Adverse Reactions (6.1)] particularly in patients with renal impairment, the elderly, in
`patients with low systolic blood pressure, and in patients on diuretics. Before initiating JARDIANCE, assess
`
`
`2
`
`Reference ID: 4195030
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`for volume contraction and correct volume status if indicated. Monitor for signs and symptoms of hypotension
`after initiating therapy and increase monitoring in clinical situations where volume contraction is expected [see
`Use in Specific Populations (8.5)].
`
`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 co-transporter-2 (SGLT2) inhibitors, including JARDIANCE. Fatal cases of ketoacidosis have been
`reported in patients taking JARDIANCE. JARDIANCE is not indicated for the treatment of patients with type 1
`diabetes mellitus [see Indications and Usage (1)].
`
`Patients treated with JARDIANCE 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 JARDIANCE may be present even if blood glucose levels are less than 250 mg/dL. If
`ketoacidosis is suspected, JARDIANCE 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 JARDIANCE, 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 JARDIANCE consider monitoring for ketoacidosis and temporarily discontinuing JARDIANCE 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
`
`JARDIANCE causes intravascular volume contraction [see Warnings 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 SGLT2 inhibitors, including JARDIANCE;
`some reports involved patients younger than 65 years of age.
`
`Before initiating JARDIANCE, 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 JARDIANCE 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 JARDIANCE promptly and institute treatment.
`
`JARDIANCE increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more
`susceptible to these changes. Renal function abnormalities can occur after initiating JARDIANCE [see Adverse
`Reactions (6.1)]. Renal function should be evaluated prior to initiation of JARDIANCE and monitored
`periodically thereafter. More frequent renal function monitoring is recommended in patients with an eGFR
`below 60 mL/min/1.73 m2. Use of JARDIANCE is not recommended when eGFR is persistently less than 45
`
`
`3
`
`Reference ID: 4195030
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
` 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) and 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 JARDIANCE. 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)].
`
`5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased
`
` when JARDIANCE is used in combination with insulin secretagogues (e.g., sulfonylurea) or insulin [see
`Adverse Reactions (6.1)]. Therefore, a lower dose of the insulin secretagogue or insulin may be required to
`reduce the risk of hypoglycemia when used in combination with JARDIANCE.
`
`5.6 Genital Mycotic Infections
`
` JARDIANCE increases the risk for genital mycotic infections [see Adverse Reactions (6.1)]. Patients with a
`
` history of chronic or recurrent genital mycotic infections were more likely to develop genital mycotic
`
` infections. Monitor and treat as appropriate.
`
`5.7 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients
`treated with JARDIANCE. If a hypersensitivity reaction occurs, discontinue JARDIANCE; treat promptly per
`standard of care, and monitor until signs and symptoms resolve. JARDIANCE is contraindicated in patients
`
`with a previous serious hypersensitivity reaction to empagliflozin or any of the excipients in JARDIANCE [see
`Contraindications (4)].
`
`5.8 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`Increases in LDL-C can occur with JARDIANCE [see Adverse Reactions (6.1)]. Monitor and treat as
`appropriate.
`
`
`
`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)]
`
`
`
` Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
`
`
`
`Increased Low-Density Lipoprotein Cholesterol (LDL-C) [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 practice.
`
`
`
`Reference ID: 4195030
`
`4
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
`Pool of Placebo-Controlled Trials evaluating JARDIANCE 10 and 25 mg
`The data in Table 1 are derived from a pool of four 24-week placebo-controlled trials and 18-week data from a
`
`placebo-controlled trial with insulin. JARDIANCE was used as monotherapy in one trial and as add-on therapy
`in four trials [see Clinical Studies (14)].
`
`
`These data reflect exposure of 1976 patients to JARDIANCE with a mean exposure duration of approximately
`23 weeks. Patients received placebo (N=995), JARDIANCE 10 mg (N=999), or JARDIANCE 25 mg (N=977)
`once daily. The mean age of the population was 56 years and 3% were older than 75 years of age. More than
`half (55%) of the population was male; 46% were White, 50% were Asian, and 3% were Black or African
`American. At baseline, 57% of the population had diabetes more than 5 years and had a mean hemoglobin A1c
`(HbA1c) of 8%. Established microvascular complications of diabetes at baseline included diabetic nephropathy
`(7%), retinopathy (8%), or neuropathy (16%). Baseline renal function was normal or mildly impaired in 91% of
`patients and moderately impaired in 9% of patients (mean eGFR 86.8 mL/min/1.73 m2).
`
`Table 1 shows common adverse reactions (excluding hypoglycemia) associated with the use of JARDIANCE.
`The adverse reactions were not present at baseline, occurred more commonly on JARDIANCE than on placebo
`and occurred in greater than or equal to 2% of patients treated with JARDIANCE 10 mg or JARDIANCE 25
`mg.
`
`
`Table 1
`
`
`
`Adverse Reactions Reported in 2% of Patients Treated with JARDIANCE and Greater
`than Placebo in Pooled Placebo-Controlled Clinical Studies of JARDIANCE Monotherapy
`or Combination Therapy
`
`
`
`
`
`Number (%) of Patients
`
`
`
`JARDIANCE 25 mg
`JARDIANCE 10 mg
`Placebo
`N=977
`N=999
`N=995
`Urinary tract infectiona
`
` 7.6%
`
` 9.3%
`
` 7.6%
`Female genital mycotic infectionsb
`
` 6.4%
`
` 5.4%
`
` 1.5%
`
`
`
`
`Upper respiratory tract infection
`4.0%
`3.1%
`3.8%
`Increased urinationc
`
` 3.2%
`
` 3.4%
`
` 1.0%
`
`
`
`Dyslipidemia
`2.9%
`3.9%
`3.4%
`
`
`
`Arthralgia
`2.3%
`2.4%
`2.2%
`Male genital mycotic infectionsd
`
` 1.6%
`
` 3.1%
`
` 0.4%
`
`
`
`Nausea
`1.1%
`2.3%
`1.4%
`
` aPredefined adverse event grouping, including, but not limited to, urinary tract infection, asymptomatic bacteriuria, cystitis
`
`bFemale genital mycotic infections include the following adverse reactions: vulvovaginal mycotic infection, vaginal infection, vulvitis,
`
`
`vulvovaginal candidiasis, genital infection, genital candidiasis, genital infection fungal, genitourinary tract infection, vulvovaginitis,
`
`
`
`cervicitis, urogenital infection fungal, vaginitis bacterial. Percentages calculated with the number of female subjects in each group as
`
`
`denominator: placebo (N=481), JARDIANCE 10 mg (N=443), JARDIANCE 25 mg (N=420).
`
`cPredefined adverse event grouping, including, but not limited to, polyuria, pollakiuria, and nocturia
`
`
`
`dMale genital mycotic infections include the following adverse reactions: balanoposthitis, balanitis, genital infections fungal,
`
`
`
`genitourinary tract infection, balanitis candida, scrotal abscess, penile infection. Percentages calculated with the number of male
`
`
`
`
`subjects in each group as denominator: placebo (N=514), JARDIANCE 10 mg (N=556), JARDIANCE 25 mg (N=557).
`
`
`
`
`Thirst (including polydipsia) was reported in 0%, 1.7%, and 1.5% for placebo, JARDIANCE 10 mg, and
`JARDIANCE 25 mg, respectively.
`
`Volume Depletion
`JARDIANCE causes an osmotic diuresis, which may lead to intravascular volume contraction and adverse
`reactions related to volume depletion. In the pool of five placebo-controlled clinical trials, adverse reactions
`related to volume depletion (e.g., blood pressure (ambulatory) decreased, blood pressure systolic decreased,
`dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope) were reported by 0.3%, 0.5%,
`
`
`Reference ID: 4195030
`
`5
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`and 0.3% of patients treated with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
`JARDIANCE may increase the risk of hypotension in patients at risk for volume contraction [see Warnings and
`Precautions (5.1) and Use in Specific Populations (8.5, 8.6)].
`
`Increased Urination
`
`In the pool of five placebo-controlled clinical trials, adverse reactions of increased urination (e.g., polyuria,
`pollakiuria, and nocturia) occurred more frequently on JARDIANCE than on placebo (see Table 1).
`Specifically, nocturia was reported by 0.4%, 0.3%, and 0.8% of patients treated with placebo, JARDIANCE 10
`mg, and JARDIANCE 25 mg, respectively.
`
`Acute Impairment in Renal Function
`Treatment with JARDIANCE was associated with increases in serum creatinine and decreases in eGFR (see
`Table 2). Patients with moderate renal impairment at baseline had larger mean changes [see Warnings and
`Precautions (5.3) and Use in Specific Populations (8.5, 8.6)].
`
`
`
`
`In a long-term cardiovascular outcome trial, the acute impairment in renal function was observed to reverse
`
`
`after treatment discontinuation suggesting acute hemodynamic changes play a role in the renal function changes
`
`observed with empagliflozin.
`
`
`
`
`
`Reference ID: 4195030
`
`6
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`Table 2
`
`
`
`
`
`
`Changes from Baseline in Serum Creatinine and eGFRa in the Pool of Four 24-week
`Placebo-Controlled Studies and Renal Impairment Study
`
`
`
`
`Baseline Mean
`
`
`Week 12 Change
`
`
`Week 24 Change
`
`
`
`
`Baseline Mean
`
`
`Week 12 Change
`
`
`Week 24 Change
`
`
`Week 52 Change
`
`Post-treatment Changec
`
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`N
`
`Creatinine (mg/dL)
` eGFR (mL/min/1.73 m2)
`
`
` 
`Placebo
`187
`1.49
`44.3
`176
`0.01
`0.1
`170
`0.01
`0.2
`164
`0.02
`-0.3
`
`98
`
`0.03
`
` 0.16
`
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`-­
`
`
`
`
`
`Pool of 24-Week Placebo-Controlled Studies
` 
` 
` 
`Placebo
`JARDIANCE 10 mg
`JARDIANCE 25 mg
`
`
`825
`830
`822
`
`0.84
`0.85
`0.85
`87.3
`87.1
`87.8
`771
`797
`783
`
`0.00
`0.02
`0.01
`-0.3
`-1.3
`-1.4
`708
`769
`754
`0.00
`0.01
`0.01
`-0.3
`-0.6
`-1.4
`
`Moderate Renal Impairmentb
`
` 
` JARDIANCE 25 mg
`187
`1.46
`45.4
`179
`0.12
`-3.8
`171
`0.10
`-3.2
`162
`0.11
`-2.8
`
`103
`
`0.02
`
` 1.48
`
`aObserved cases on treatment.
`
` bSubset of patients from renal impairment study with eGFR 30 to less than 60 mL/min/1.73 m2
`
`
`cApproximately 3 weeks after end of treatment.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4195030
`
`7
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`
`
` Monotherapy
`
` (24 weeks)
`
`Overall (%)
`
`Severe (%)
`In Combination with
`
`Metformin
`
`(24 weeks)
`
`Overall (%)
`
`Severe (%)
`In Combination with
`Metformin + Sulfonylurea
`
`(24 weeks)
`
`
`Overall (%)
`
`Severe (%)
`In Combination with
`
`Pioglitazone +/- Metformin
`
`(24 weeks)
`
`Placebo
` (n=229)
`
`
`0.4%
`0%
`Placebo + Metformin
`
`(n=206)
`
`
`0.5%
`0%
`Placebo
`
`(n=225)
`
`
`8.4%
`0%
`Placebo
`
`(n=165)
`
`
`
` JARDIANCE 10 mg
`
` (n=224)
`
`0.4%
`
`0%
`JARDIANCE 10 mg +
`
`Metformin
`
`(n=217)
`
`1.8%
`
`0%
`JARDIANCE 10 mg +
`Metformin +
`Sulfonylurea
`
`(n=224)
`16.1%
`
`0%
`JARDIANCE 10 mg +
`Pioglitazone +/-
`
`Metformin
`
`(n=165)
`
`1.2%
`
`0%
`
`
`JARDIANCE 10 mg
`
`(n=169)
`
`19.5%
`0%
`
`
`JARDIANCE 10 mg
`(n=186)
`
`
`
`
`
`
` JARDIANCE 25 mg
`
` (n=223)
`
`0.4%
`
`0%
`JARDIANCE 25 mg +
`
`Metformin
`
`(n=214)
`
`1.4%
`
`0%
`JARDIANCE 25 mg +
`Metformin +
`Sulfonylurea
`
`(n=217)
`
`11.5%
`
`0%
`JARDIANCE 25 mg +
`Pioglitazone +/-
`
`Metformin
`
` (n=168)
`
`2.4%
`
`0%
`
`JARDIANCE 25 mg
`
`(n=155)
`
`
`28.4%
`
`1.3%
`
`JARDIANCE 25 mg
`(n=189)
`
`
`41.3%
`
`0.5%
`
`
`1.8%
`0%
`Placebo
`
`(n=170)
`
`20.6%
`0%
`Placebo
`(n=188)
`
`
`
`Hypoglycemia
`The incidence of hypoglycemia by study is shown in Table 3. The incidence of hypoglycemia increased when
`JARDIANCE was administered with insulin or sulfonylurea [see Warnings and Precautions (5.5)].
`
`Table 3
`
`Incidence of Overalla and Severeb Hypoglycemic Events in Placebo-Controlled Clinical
`Studiesc
`
`
`
`Overall (%)
`
`Severe (%)
`In Combination with Basal Insulin +/-
`
`Metformin
`(18 weeksd)
`Overall (%)
`
`Severe (%)
`
`In Combination with MDI Insulin +/-
`
`Metformin
`(18 weeksd)
`
`39.8%
`37.2%
`Overall (%)
`
`
`
`0.5%
`0.5%
`Severe (%)
` aOverall hypoglycemic events: plasma or capillary glucose of less than or equal to 70 mg/dL
`
`
`bSevere hypoglycemic events: requiring assistance regardless of blood glucose
`
`
`cTreated set (patients who had received at least one dose of study drug)
`
`
`
`
`dInsulin dose could not be adjusted during the initial 18 week treatment period
`
`Genital Mycotic Infections
`In the pool of five placebo-controlled clinical trials, the incidence of genital mycotic infections (e.g., vaginal
`mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis, and vulvitis) was
`increased in patients treated with JARDIANCE compared to placebo, occurring in 0.9%, 4.1%, and 3.7% of
`patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively. Discontinuation
`from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with
`either JARDIANCE 10 or 25 mg.
`
`Genital mycotic infections occurred more frequently in female than male patients (see Table 1).
`
`
`Phimosis occurred more frequently in male patients treated with JARDIANCE 10 mg (less than 0.1%) and
`JARDIANCE 25 mg (0.1%) than placebo (0%).
`
`
`Reference ID: 4195030
`
`8
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`
`Urinary Tract Infections
`In the pool of five placebo-controlled clinical trials, the incidence of urinary tract infections (e.g., urinary tract
`infection, asymptomatic bacteriuria, and cystitis) was increased in patients treated with JARDIANCE compared
`to placebo (see Table 1). Patients with a history of chronic or recurrent urinary tract infections were more likely
`to experience a urinary tract infection. The rate of treatment discontinuation due to urinary tract infections was
`0.1%, 0.2%, and 0.1% for placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
`
`Urinary tract infections occurred more frequently in female patients. The incidence of urinary tract infections in
`female patients randomized to placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg was 16.6%, 18.4%, and
`17.0%, respectively. The incidence of urinary tract infections in male patients randomized to placebo,
`JARDIANCE 10 mg, and JARDIANCE 25 mg was 3.2%, 3.6%, and 4.1%, respectively [see Warnings and
`
`Precautions (5.4) and Use in Specific Populations (8.5)].
`
`Laboratory Tests
`Increase in Low-Density Lipoprotein Cholesterol (LDL-C)
`Dose-related increases in low-density lipoprotein cholesterol (LDL-C) were observed in patients treated with
`JARDIANCE. LDL-C increased by 2.3%, 4.6%, and 6.5% in patients treated with placebo, JARDIANCE 10
`mg, and JARDIANCE 25 mg, respectively [see Warnings and Precautions (5.8)]. The range of mean baseline
`LDL-C levels was 90.3 to 90.6 mg/dL across treatment groups.
`
`Increase in Hematocrit
`In a pool of four placebo-controlled studies, median hematocrit decreased by 1.3% in placebo and increased by
`2.8% in JARDIANCE 10 mg and 2.8% in JARDIANCE 25 mg treated patients. At the end of treatment, 0.6%,
`2.7%, and 3.5% of patients with hematocrits initially within the reference range had values above the upper
`limit of the reference range with placebo, JARDIANCE 10 mg, and JARDIANCE 25 mg, respectively.
`
`6.2 Postmarketing Experience
`Additional adverse reactions have been identified during postapproval use of JARDIANCE. 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)]
`
`
` Urosepsis and pyelonephritis [see Warnings and Precautions (5.4)]
`
`
` Angioedema [see Warnings and Precautions (5.7)]
`
`
`
` Skin reactions (e.g., rash, urticaria)
`
`
`
`DRUG INTERACTIONS
`7
`7.1 Diuretics
`Coadministration of empagliflozin with diuretics resulted in increased urine volume and frequency of voids,
`which might enhance the potential for volume depletion [see Warnings and Precautions (5.1)].
`
`7.2 Insulin or Insulin Secretagogues
`Coadministration of empagliflozin with insulin or insulin secretagogues increases the risk for hypoglycemia
`
`[see Warnings and Precautions (5.5)].
`
`7.3 Positive Urine Glucose Test
`
`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
`alternative methods to monitor glycemic control.
`
`
`9
`
`Reference ID: 4195030
`
`Novo Nordisk Exhibit 2439
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
`7.4 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
`
`Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable
`in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic
`control.
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Risk Summary
`Based on animal data showing adverse renal effects, JARDIANCE is not recommended during the second and
`third trimesters of pregnancy.
`
`Limited data available with JARDIANCE in pregnant women are not sufficient to determine a drug-associated
`risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly
`controlled diabetes in pregnancy [see Clinical Considerations].
`
`In animal studies, adverse renal changes were observed in rats when empagliflozin was administered during a
`period of renal development corresponding to the late second and third trimesters of human pregnancy. Doses
`approximately 13-times the maximum clinical dose caused renal pelvic and tubule dilatations that were
`reversible. Empagliflozin was not teratogenic in rats and rabbits up to 300 mg/kg/day, which approximates 48­
`times and 128-times, respectively, the maximum clinical dose of 25 mg when administered during
`organogenesis [see Data].
`
`The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a
`HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated
`background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the
`estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4%
`and 15-20%, respectively.
`
`Clinical Considerations
`
`Disease-associated maternal and/or embryo/fetal risk: Poorly controlled diabetes in pregnancy increases the
`maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth, and
`delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and
`
`macrosomia related morbidity.
`
`Data
`Animal Data
`Empagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 10, 30
`and 100 mg/kg/day caused increased kidney weights and renal tubular and pelvic dilatation at 100 mg/kg/day,
`which approximates 13-times the maximum clinical dose of 25 mg, based on AUC. These findings were not
`observed after a 13 week drug-free recovery period. These outcomes occurre