` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`SYNJARDY safely and effectively. See full prescribing information for
`
`SYNJARDY.
`
`
`SYNJARDY® (empagliflozin and metformin hydrochloride) tablets,
`
`for oral use
`Initial U.S. Approval: 2015
`
`
`
`
`
`
`
`
`
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`See full prescribing information for complete boxed warning.
`
`Postmarketing cases of metformin-associated lactic acidosis have
`
`resulted in death, hypothermia, hypotension, and resistant
`bradyarrhythmias. Symptoms included malaise, myalgias,
`
`
`respiratory distress, somnolence, and abdominal pain.
`Laboratory abnormalities included elevated blood lactate levels,
`
`anion gap acidosis, increased lactate/pyruvate ratio; and
`metformin plasma levels generally >5 mcg/mL. (5.1)
`Risk factors include renal impairment, concomitant use of certain
`drugs, age ≥65 years old, radiological studies with contrast,
`
`surgery and other procedures, hypoxic states, excessive alcohol
`intake, and hepatic impairment. Steps to reduce the risk of and
`manage metformin-associated lactic acidosis in these high risk
`
`groups are provided in the Full Prescribing Information. (5.1)
`
`If lactic acidosis is suspected, discontinue SYNJARDY and
`institute general supportive measures in a hospital setting.
`
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Contraindications (4)
`12/2017
`
`
`
`
`
`
`Warnings and Precautions (5)
` 12/2017
`
`
`
`
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`SYNJARDY is a combination of empagliflozin, a sodium-glucose
`
`
`co-transporter 2 (SGLT2) inhibitor and metformin hydrochloride, a biguanide,
`
`
`indicated as an adjunct to diet and exercise to improve glycemic control in
`
`adults with type 2 diabetes mellitus when treatment with both empagliflozin
`
`and metformin hydrochloride is appropriate.
`
`
`Empagliflozin is indicated to reduce the risk of cardiovascular death in adults
`
`with type 2 diabetes mellitus and established cardiovascular disease.
`
`
`However, the effectiveness of SYNJARDY on reducing the risk of
`
`
`cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular
`
`
`disease has not been established. (1)
`
`
`Limitations of Use:
`
`Not recommended for patients with type 1 diabetes or for the treatment of
`
`
`diabetic ketoacidosis (1)
`
`----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`Individualize the starting dose of SYNJARDY based on the patient’s
`
`
`current regimen (2.1)
`The maximum recommended dose is 12.5 mg empagliflozin/1000 mg
`
`
`metformin hydrochloride twice daily (2.1)
`Take twice daily with meals, with gradual dose escalation to reduce the
`gastrointestinal side effects due to metformin (2.1)
`Assess renal function before initiating. SYNJARDY is contraindicated
`in patients with an eGFR below 45 mL/min/1.73 m2 (2.2, 4)
`
`SYNJARDY may need to be discontinued at time of, or prior to,
`
`
`iodinated contrast imaging procedures (2.3)
`---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`Tablets:
`5 mg empagliflozin/500 mg metformin hydrochloride
`
`5 mg empagliflozin/1000 mg metformin hydrochloride
`
`
`
`12.5 mg empagliflozin/500 mg metformin hydrochloride
`12.5 mg empagliflozin/1000 mg metformin hydrochloride (3)
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
` Moderate to severe renal impairment (eGFR below 45 mL/min/1.73 m2),
`
`end stage renal disease, or dialysis (4, 5.1, 5.4)
`
` Metabolic acidosis, including diabetic ketoacidosis (1, 4, 5.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`Lactic acidosis: See boxed warning (5.1)
`
`
`
`Hypotension: Before initiating SYNJARDY 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. (5.2)
`
`Ketoacidosis: Assess patients who present with signs and symptoms of
`metabolic acidosis for ketoacidosis, regardless of blood glucose level. If
`
`suspected, discontinue SYNJARDY, evaluate and treat promptly. Before
`
`initiating SYNJARDY, consider risk factors for ketoacidosis. Patients on
`SYNJARDY 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)
`Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms
`
`of urinary tract infections and treat promptly, if indicated (5.5)
`
`Hypoglycemia: Consider lowering the dose of insulin secretagogue or
`
`insulin to reduce the risk of hypoglycemia when initiating SYNJARDY
`(5.6)
`Genital mycotic infections: Monitor and treat as appropriate (5.7)
`Hypersensitivity reactions: Discontinue SYNJARDY, treat promptly,
`
`
`and monitor until signs and symptoms resolve (5.8)
`Vitamin B12 deficiency: Metformin may lower vitamin B12 levels.
`
`Monitor hematologic parameters annually. (5.9)
`
`
`
`Increased LDL-C: Monitor and treat as appropriate (5.10)
`
`
`
`
` Macrovascular outcomes: There have been no clinical studies
`
`establishing conclusive evidence of macrovascular risk reduction with
`SYNJARDY. (5.11)
`------------------------------ADVERSE REACTIONS------------------------------­
`
` Most common adverse reactions associated with empagliflozin (5% or
`greater incidence) were urinary tract infection and female genital
`
`mycotic infections. (6.1)
`
` Most common adverse reactions associated with metformin (>5%) are
`diarrhea, nausea/vomiting, flatulence, abdominal discomfort,
`
`indigestion, asthenia, and headache. (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.
`------------------------------DRUG INTERACTIONS------------------------------­
`
`Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
`
`
`
`Consider more frequent monitoring. (7.2)
`
`
`Drugs that reduce metformin clearance (such as ranolazine, vandetanib,
`
`dolutegravir, and cimetidine) may increase the accumulation of
`
`metformin. Consider the benefits and risks of concomitant use. (7.2)
`
`Alcohol can potentiate the effect of metformin on lactate metabolism.
`
`
`Warn patients against excessive alcohol intake. (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: SYNJARDY is not recommended when breastfeeding. (8.2)
`
`Females and Males of Reproductive Potential: Advise premenopausal
`females of the potential for an unintended pregnancy (8.3).
`
`Geriatric patients: Higher incidence of adverse reactions related to
`volume depletion and reduced renal function. Assess renal function
`more frequently (5.2, 5.4, 8.5)
`Patients with renal impairment: Higher incidence of adverse reactions
`related to reduced renal function (2.2, 5.4, 8.6)
`Hepatic Impairment: Avoid use in patients with hepatic impairment.
`(8.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
`
`
`
`Revised: 12/2017
`
`
`
`
`Reference ID: 4195013
`
`1
`
`
`
`
`History of serious hypersensitivity reaction to empagliflozin, metformin
`or any of the excipients in SYNJARDY (4)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`_______________________________________________________________________________________________________________________________________
`
`
`7.2 Drug Interactions with Metformin Hydrochloride
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`8.6 Renal Impairment
`
`
`8.7 Hepatic Impairment
`
`
`
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 SYNJARDY Glycemic Control Studies
`
`14.2 Empagliflozin Cardiovascular Outcome Study 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.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
`
`
`
`
` INDICATIONS AND USAGE
`1
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosage
`
`
`2.2 Recommended Dosage in Patients with Renal Impairment
`
`
`2.3
` Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Lactic Acidosis
`
`
`
`5.2 Hypotension
`
`
`5.3 Ketoacidosis
`
`
`
`5.4 Acute Kidney Injury and Impairment in Renal Function
`
`
`
`5.5 Urosepsis and Pyelonephritis
`
`
`5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin
`
`Secretagogues
`
`
`
`5.7 Genital Mycotic Infections
`
`
`5.8 Hypersensitivity Reactions
`
`
`
`5.9 Vitamin B12 Levels
`
`
`
`5.10 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`
`
`
`5.11 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`6.2
` Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`7.1 Drug Interactions with Empagliflozin
`
`
`
`
`
`
`Reference ID: 4195013
`
`2
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`
`Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia,
`
`hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often
`subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress,
`somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated
`blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia),
`an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings
`and Precautions (5.1)].
`Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of
`certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater,
`having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute
`congestive heart failure), excessive alcohol intake, and hepatic impairment.
`
`Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups
`are provided in the full prescribing information [see Dosage and Administration (2.2), Contraindications
`(4), Warnings and Precautions (5.1), Drug Interactions (7.2), and Use in Specific Populations (8.6, 8.7)].
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY and institute
`general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings
`and Precautions (5.1)].
`
`
`
`1
`INDICATIONS AND USAGE
`SYNJARDY is a combination of empagliflozin and metformin hydrochloride indicated as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both
`empagliflozin and metformin hydrochloride is appropriate.
`
`
`
`Empagliflozin is indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and
`established cardiovascular disease [see Clinical Studies (14.2)]. However, the effectiveness of SYNJARDY on
`
`reducing the risk of cardiovascular death in adults with type 2 diabetes mellitus and cardiovascular disease has
`not been established.
`
`
`Limitations of Use
`SYNJARDY is not recommended for patients with type 1 diabetes or for the treatment of diabetic ketoacidosis
`[see Warnings and Precautions (5.3)].
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosage
`
`In patients with volume depletion not previously treated with empagliflozin, correct this condition before
`
`initiating SYNJARDY [see Warnings and Precautions (5.2)].
`Individualize the starting dose of SYNJARDY based on the patient’s current regimen:
` In patients on metformin hydrochloride, switch to SYNJARDY containing empagliflozin 5 mg with a
`
`similar total daily dose of metformin hydrochloride;
` In patients on empagliflozin, switch to SYNJARDY containing metformin hydrochloride 500 mg with a
`
`similar total daily dose of empagliflozin;
` In patients already treated with empagliflozin and metformin hydrochloride, switch to SYNJARDY
`
`containing the same total daily doses of each component.
`
`
`
`
`
`Reference ID: 4195013
`
`3
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
` Take SYNJARDY twice daily with meals; with gradual dose escalation to reduce the gastrointestinal side
`
` effects due to metformin [see Dosage Forms and Strengths (3)].
`
` Adjust dosing based on effectiveness and tolerability while not exceeding the maximum recommended daily
`
` dose of metformin hydrochloride 2000 mg and empagliflozin 25 mg [see Dosage and Administration (2.2)].
`
`
`
`2.2 Recommended Dosage in Patients with Renal Impairment
`
` Assess renal function prior to initiation of SYNJARDY and periodically, thereafter.
`
` SYNJARDY is contraindicated in patients with an eGFR less than 45 mL/min/1.73 m2 [see
`Contraindications (4) and Warnings and Precautions (5.1, 5.4)].
`
`
`2.3 Discontinuation for Iodinate d Contrast Imaging Procedures
`Discontinue SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an
`eGFR between 45 and 60 mL/min/1.73 m2; in patients with a history of liver disease, alcoholism or heart
`failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours
`after the imaging procedure; restart SYNJARDY if renal function is stable [see Warnings and Precautions
`
`(5.1)].
`
`DOSAGE FORMS AND STRENGTHS
`3
`SYNJARDY is a combination of empagliflozin and metformin hydrochloride. SYNJARDY is available in the
`following dosage forms and strengths:
`
` 5 mg empagliflozin/500 mg metformin hydrochloride tablets are orange yellow, oval, biconvex, film-coated
`tablets. One side is debossed with the Boehringer Ingelheim company symbol and “S5”; the other side is
`debossed with “500”.
`
` 5 mg empagliflozin/1000 mg metformin hydrochloride tablets are brownish yellow, oval, biconvex, film-
`coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and “S5”; the other
`
`side is debossed with “1000”.
`
` 12.5 mg empagliflozin/500 mg metformin hydrochloride tablets are pale brownish purple, oval, biconvex,
`film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and “S12”; the
`other side is debossed with “500”.
`
` 12.5 mg empagliflozin/1000 mg metformin hydrochloride tablets are dark brownish purple, oval, biconvex,
`film-coated tablets. One side is debossed with the Boehringer Ingelheim company symbol and “S12”; the
`other side is debossed with “1000”.
`
`
`4
`CONTRAINDICATIONS
`
`SYNJARDY is contraindicated in patients with:
`
` Moderate to severe renal impairment (eGFR less than 45 mL/min/1.73 m2), end stage renal disease, or
`dialysis [see Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
`
`
` Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be
`treated with insulin [see Warnings and Precautions (5.1)].
`
`
` History of serious hypersensitivity reaction to empagliflozin, metformin or any of the excipients in
`SYNJARDY.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases
`had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain,
`respiratory distress, or increased somnolence; however, hypothermia, hypotension, and resistant
`bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized
`by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or
`4
`
`
`Reference ID: 4195013
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin
`decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis,
`
`especially in patients at risk.
`
`If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly
`in a hospital setting, along with immediate discontinuation of SYNJARDY. In SYNJARDY-treated patients
`with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the
`acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to
`170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of
`symptoms and recovery.
`
`
`Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct
`
`them to discontinue SYNJARDY and report these symptoms to their healthcare provider.
`
`For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to
`
`reduce the risk of and manage metformin-associated lactic acidosis are provided below:
`
`Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients
`with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis
`increases with the severity of renal impairment because metformin is substantially excreted by the kidney.
`Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration
`(2.2), Clinical Pharmacology (12.3)].
`
`
` Before initiating SYNJARDY, obtain an estimated glomerular filtration rate (eGFR).
`
` SYNJARDY is contraindicated in patients with an eGFR below 45 mL/min/1.73 m2 [see
`
`Contraindications (4)].
`
` Obtain an eGFR at least annually in all patients taking SYNJARDY. In patients at increased risk
`
`for the development of renal impairment (e.g., the elderly), renal function should be assessed more
`frequently.
`
`
`Drug Interactions: The concomitant use of SYNJARDY with specific drugs may increase the risk of
`metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic
`change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7.2)].
`Therefore, consider more frequent monitoring of patients.
`
`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age because
`
`elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.
`Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
`
`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in metformin­
`treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop
`SYNJARDY at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR
`between 45 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart
`failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours
`after the imaging procedure, and restart SYNJARDY if renal function is stable.
`
`
`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may
`increase the risk for volume depletion, hypotension and renal impairment. SYNJARDY should be temporarily
`discontinued while patients have restricted food and fluid intake.
`
`
`
`Reference ID: 4195013
`
`5
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the
`setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
`Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with
`hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events
`occur, discontinue SYNJARDY.
`
`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this may
`increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while
`
`receiving SYNJARDY.
`
`Hepatic Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic
`acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid
`
`use of SYNJARDY in patients with clinical or laboratory evidence of hepatic disease.
`
`5.2 Hypotension
`Empagliflozin causes intravascular volume contraction. Symptomatic hypotension may occur after initiating
`empagliflozin [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 SYNJARDY, assess 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)].
`
`5.3 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 empagliflozin. Fatal cases of ketoacidosis have been
`reported in patients taking empagliflozin. SYNJARDY is not indicated for the treatment of patients with type 1
`diabetes mellitus [see Indications and Usage (1)].
`
`Patients treated with SYNJARDY 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 SYNJARDY may be present even if blood glucose levels are less than 250 mg/dL. If
`ketoacidosis is suspected, SYNJARDY 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 SYNJARDY, 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 SYNJARDY consider monitoring for ketoacidosis and temporarily discontinuing SYNJARDY in clinical
`situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
`
`
`
`Reference ID: 4195013
`
`6
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
` 5.4 Acute Kidney Injury and Impairment in Renal Function
`
`Empagliflozin 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 SGLT2 inhibitors, including empagliflozin;
`some reports involved patients younger than 65 years of age.
`
`Before initiating SYNJARDY, 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 SYNJARDY 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 SYNJARDY promptly and institute treatment.
`
`Empagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more
`susceptible to these changes. Renal function abnormalities can occur after initiating SYNJARDY [see Adverse
`Reactions (6.1)]. Renal function should be evaluated prior to initiation of SYNJARDY 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 SYNJARDY is contraindicated in patients with an eGFR less than 45
`mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4) and Use in Specific Populations
`
`(8.6)].
`
`5.5 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 empagliflozin. 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)].
`
`5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
`Empagliflozin
`Insulin and insulin secretagogues are known to cause hypoglycemia. The risk of hypoglycemia is increased
`when empagliflozin 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 SYNJARDY.
`
`Metformin
`
`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could
`occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation,
`or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly,
`debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication
`are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly,
`and in people who are taking β-adrenergic blocking drugs. Monitor for a need to lower the dose of
`
`SYNJARDY to minimize the risk of hypoglycemia in these patients.
`
`5.7 Genital Mycotic Infections
`Empagliflozin 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.
`
`
`
`
`Reference ID: 4195013
`
`7
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`5.8 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions, (e.g., angioedema) in patients
`treated with empagliflozin, one of the components of SYNJARDY. If a hypersensitivity reaction occurs,
`discontinue SYNJARDY; treat promptly per standard of care, and monitor until signs and symptoms resolve.
`SYNJARDY is contraindicated in patients with a previous serious hypersensitivity reaction to empagliflozin or
`any of the excipients in SYNJARDY [see Contraindications (4)].
`
`5.9 Vitamin B12 Levels
`
`In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum
`vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated
`patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex,
`is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year)
`of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin,
`and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin
`B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
`Measurement of hematologic parameters on an annual basis is advised in patients on SYNJARDY and any
`apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with
`inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal
`vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be
`useful.
`
`5.10 Increased Low-Density Lipoprotein Cholesterol (LDL-C)
`
`Increases in LDL-C can occur with empagliflozin. Monitor and treat as appropriate.
`
`
`5.11 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`SYNJARDY.
`
`6
`ADVERSE REACTIONS
`
`
`The following important adverse reactions are described below and elsewhere in the labeling:
`
`
`
` Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
`
`
` Hypotension [see Warnings and Precautions (5.2)]
`
`
` Ketoacidosis [see Warnings and Precautions (5.3)]
`
`
` Acute Kidney Injury and Impairment in Renal Function [see Warnings and Precautions (5.4)]
`
`
` Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
`
`
` Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and
`Precautions (5.6)]
`
`
` Genital Mycotic Infections [see Warnings and Precautions (5.7)]
`
`
` Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
`
`
` Vitamin B12 Deficiency [see Warnings and Precautions (5.9)]
`
`
`Increased Low-Density Lipoprotein Cholesterol (LDL-C) [see Warnings and Precautions (5.10)]
`
`
`
`
`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: 4195013
`
`8
`
`Novo Nordisk Exhibit 2452
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`
`The safety of concomitantly administered empagliflozin (daily dose 10 mg and 25 mg) and metformin
`hydrochloride (mean daily dose of approximately 1800 mg) has been evaluated in 3456 patients with type 2
`diabetes mellitus treated for 16 to 24 weeks,