Reference ID: 5269279
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SYNJARDY and SYNJARDY XR safely and effectively. See full
`prescribing information for SYNJARDY and SYNJARDY XR.
`
`SYNJARDY® (empagliflozin and metformin hydrochloride tablets), for
`oral use
`SYNJARDY® XR (empagliflozin and metformin hydrochloride extended-
`release 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 or
`SYNJARDY XR and institute general supportive measures in a
`hospital setting. Prompt hemodialysis is recommended. (5.1)
`
`
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage (1)
`
`
`
` 6/2023
`Dosage and Administration (2.2)
`
`
` 2/2023
`Dosage and Administration (2.3, 2.7)
`
`
` 6/2023
`Dosage and Administration (2.6)
`
`
` 10/2023
`Warnings and Precautions (5.2, 5.8)
`
`
` 10/2023
`Warnings and Precautions (5.5)
`
`
`
` 6/2023
`----------------------------INDICATIONS AND USAGE---------------------------
`SYNJARDY
`SYNJARDY is a combination of empagliflozin, a sodium-glucose co-
`transporter 2 (SGLT2) inhibitor and metformin hydrochloride (HCl), a
`biguanide, indicated as an adjunct to diet and exercise to improve glycemic
`control in adults and pediatric patients aged 10 years and older with type 2
`diabetes mellitus.
`
`SYNJARDY XR
`SYNJARDY XR is a combination of empagliflozin, a SGLT2 inhibitor and
`metformin HCl, a biguanide, indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus.
`
`Empagliflozin
`Empagliflozin, when used as a component of SYNJARDY or SYNJARDY
`XR, is indicated in adults with type 2 diabetes mellitus to reduce the risk of:
`• Cardiovascular death in adults with established cardiovascular disease. (1)
`• Cardiovascular death and hospitalization for heart failure in adults with
`heart failure. (1)
`
`
`Limitations of Use:
`• Not recommended for use to improve glycemic control in patients with
`type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis
`in these patients. (1)
`• Because of the metformin component, the use of SYNJARDY or
`SYNJARDY XR is limited to patients with type 2 diabetes mellitus for all
`indications. (1)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`• Assess renal function before initiating and as clinically indicated. Assess
`volume status and correct volume depletion before initiating. (2.1)
`• Individualize the starting dosage based on the patient’s current regimen and
`renal function. (2.2, 2.3, 2.4)
`• The maximum recommended dosage is 25 mg/day of empagliflozin and
`2,000 mg/day of metformin HCl. (2.2, 2.3)
`
`
`
`• Initiation of SYNJARDY or SYNJARDY XR is not recommended in
`patients with an eGFR less than 45 mL/min/1.73 m2, due to the metformin
`component. (2.4)
`• SYNJARDY: take orally twice daily with meals, with gradual dosage
`escalation to reduce the gastrointestinal side effects due to metformin. (2.2,
`2.3)
`• SYNJARDY XR: take orally once daily with a meal in the morning, with
`gradual dosage escalation to reduce the gastrointestinal side effects due to
`metformin. Swallow whole; do not split, crush, dissolve, or chew. (2.2)
`• SYNJARDY or SYNJARDY XR may need to be discontinued at time of,
`or prior to, iodinated contrast imaging procedures. (2.5)
`• Withhold SYNJARDY or SYNJARDY XR at least 3 days, if possible,
`prior to major surgery or procedures associated with prolonged fasting.
`(2.6)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`SYNJARDY Tablets:
`• 5 mg empagliflozin/500 mg metformin HCl (3)
`• 5 mg empagliflozin/1,000 mg metformin HCl (3)
`• 12.5 mg empagliflozin/500 mg metformin HCl (3)
`• 12.5 mg empagliflozin/1,000 mg metformin HCl (3)
`
`SYNJARDY XR Tablets:
`• 5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
`• 10 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
`• 12.5 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
`• 25 mg empagliflozin/1,000 mg metformin HCl extended-release (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`• Severe renal impairment (eGFR below 30 mL/min/1.73 m2), end stage
`renal disease, or on dialysis (4)
`• Metabolic acidosis, including diabetic ketoacidosis (4)
`• Hypersensitivity to empagliflozin, metformin or any of the excipients in
`SYNJARDY or SYNJARDY XR (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other
`Ketoacidosis: Consider monitoring in patients at risk of ketoacidosis, as
`indicated. Assess for ketoacidosis regardless of presenting blood glucose
`levels and discontinue SYNJARDY or SYNJARDY XR if ketoacidosis is
`suspected. Monitor patients for resolution of ketoacidosis before restarting.
`(5.2)
`• Volume Depletion: Before initiating SYNJARDY or SYNJARDY XR,
`assess volume status and renal function in patients with impaired renal
`function, elderly patients, or patients on loop diuretics. Monitor for signs
`and symptoms 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: Adult patients taking an insulin secretagogue or insulin
`may have an increased risk of hypoglycemia. In pediatric patients 10 years
`of age and older, the risk of hypoglycemia was higher regardless of insulin
`use. Consider lowering the dosage of insulin secretagogue or insulin to
`reduce the risk of hypoglycemia when initiating SYNJARDY or
`SYNJARDY XR. (5.5)
`• Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-
`threatening cases have occurred in both females and males. Assess patients
`presenting with pain or tenderness, erythema, or swelling in the genital or
`perineal area, along with fever or malaise. If suspected, institute prompt
`treatment. (5.6)
`• Genital Mycotic Infections: Monitor and treat as appropriate. (5.7)
`• Lower Limb Amputation: Monitor patients for infections or ulcers of lower
`limbs, and institute appropriate treatment. (5.8)
`• Hypersensitivity Reactions: Serious hypersensitivity reactions (e.g.,
`angioedema) have occurred with empagliflozin. If hypersensitivity
`reactions occur, discontinue SYNJARDY or SYNJARDY XR, treat
`promptly, and monitor until signs and symptoms resolve. (5.9)
`• Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure
`hematologic parameters annually and vitamin B12 at 2 to 3 year intervals
`and manage any abnormalities. (5.10)
`------------------------------ADVERSE REACTIONS-------------------------------
`• Most common adverse reactions associated with empagliflozin (5% or
`greater incidence) were urinary tract infections and female genital mycotic
`infections. (6.1)
`
`1
`
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`IPR2023-00724
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`

`Reference ID: 5269279
`
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Pregnancy: Advise females of the potential risk to a fetus especially during
`the second and third trimesters. (8.1)
`• Lactation: 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. (8.5)
`• Renal Impairment: Higher incidence of adverse reactions related to reduced
`renal function. (8.6)
`• Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7)
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`
`
`
`
`
`
`
` Revised: 10/2023
`
`• 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 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)
`• Drugs that Reduce Metformin Clearance: May increase risk of lactic
`acidosis. Consider benefits and risks of concomitant use. (7)
`• See full prescribing information for additional drug interactions and
`information on interference of SYNJARDY or SYNJARDY XR with
`laboratory tests. (7)
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: LACTIC ACIDOSIS
` INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR
`2.2 Recommended Dosage and Administration of SYNJARDY or
`SYNJARDY XR in Adults
`2.3 Recommended Dosage and Administration of SYNJARDY in
`Pediatric Patients Aged 10 Years and Older
`2.4 Dosage Recommendations in Patients with Renal Impairment
`2.5 Discontinuation for Iodinated Contrast Imaging Procedures
`2.6 Temporary Interruption for Surgery
`2.7 Recommendations Regarding Missed Dose
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Lactic Acidosis
`5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus
`and Other Ketoacidosis
`5.3 Volume Depletion
`5.4 Urosepsis and Pyelonephritis
`5.5 Hypoglycemia
`5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`5.7 Genital Mycotic Infections
`5.8 Lower Limb Amputation
`5.9 Hypersensitivity Reactions
`5.10 Vitamin B12 Deficiency
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`
`
`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 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus
`14.2 Glycemic Control Trials in Pediatric Patients with Type 2 Diabetes
`Mellitus
`14.3 Empagliflozin Cardiovascular Outcome Trial in Adult Patients
`with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular
`Disease
`14.4 Empagliflozin Heart Failure Trials, Including Adult Patients with
`Type 2 Diabetes Mellitus
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`2
`
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`IPR2023-00724
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`

`Reference ID: 5269279
`
`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 (2.1),
`Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific
`Populations (8.6, 8.7)].
`
`If metformin-associated lactic acidosis is suspected, immediately discontinue SYNJARDY or
`SYNJARDY XR and institute general supportive measures in a hospital setting. Prompt
`hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`INDICATIONS AND USAGE
`1
`SYNJARDY
`SYNJARDY is a combination of empagliflozin and metformin hydrochloride (HCl) indicated as an adjunct to
`diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type
`2 diabetes mellitus.
`
`SYNJARDY XR
`SYNJARDY XR is a combination of empagliflozin and metformin HCl indicated as an adjunct to diet and
`exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`
`Empagliflozin
`Empagliflozin, when used as a component of SYNJARDY or SYNJARDY XR, is indicated in adults with type
`2 diabetes mellitus to reduce the risk of:
`• Cardiovascular death in adults with established cardiovascular disease.
`• Cardiovascular death and hospitalization for heart failure in adults with heart failure.
`
`
`Limitations of Use
`• SYNJARDY and SYNJARDY XR are not recommended for use to improve glycemic control in patients
`with type 1 diabetes mellitus. It may increase the risk of diabetic ketoacidosis in these patients [see
`Warnings and Precautions (5.2)].
`• Because of the metformin component, the use of SYNJARDY or SYNJARDY XR is limited to patients
`with type 2 diabetes mellitus for all indications.
`
`
`
`
`
`3
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`

`Reference ID: 5269279
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Testing Prior to Initiation of SYNJARDY or SYNJARDY XR
`• Assess renal function before initiating SYNJARDY or SYNJARDY XR and as clinically indicated [see
`Warnings and Precautions (5.1, 5.3)].
`• Assess volume status. In patients with volume depletion, correct this condition before initiating
`SYNJARDY or SYNJARDY XR [see Warnings and Precautions (5.3) and Use in Specific Populations
`(8.5, 8.6)].
`
`
`2.2 Recommended Dosage and Administration of SYNJARDY or SYNJARDY XR in Adults
`• When switching to SYNJARDY or SYNJARDY XR from:
`o Metformin HCl: initiate SYNJARDY or SYNJARDY XR at a similar total daily dosage of metformin
`HCl and a total daily empagliflozin dosage of 10 mg.
`o Empagliflozin: initiate SYNJARDY or SYNJARDY XR at the same total daily dosage of empagliflozin
`and a total daily metformin HCl dosage of 1,000 mg.
`o Empagliflozin and metformin HCl: initiate SYNJARDY or SYNJARDY XR at the same total daily
`dosages of each component.
`• Recommended dosage of SYNJARDY or SYNJARDY XR:
`o The recommended total daily dosage of empagliflozin is 10 mg.
`o For additional glycemic control, empagliflozin may be increased to a maximum total daily dosage of 25
`mg in patients tolerating 10 mg daily and metformin may be increased to a maximum total daily dosage
`of 2,000 mg, with gradual escalation to reduce gastrointestinal adverse reactions with metformin [see
`Adverse Reactions (6.1)].
`• Take SYNJARDY orally twice daily with meals.
`• Take SYNJARDY XR orally once daily with a meal in the morning. Swallow each tablet whole. Do not
`split, crush, dissolve, or chew.
`
`
`2.3 Recommended Dosage and Administration of SYNJARDY in Pediatric Patients Aged 10 Years and
`Older
`Individualize the dosage of SYNJARDY based on the patient’s current regimen.
`•
`• Monitor effectiveness and tolerability, and adjust dosage as appropriate, not to exceed the maximum total
`daily dosage of empagliflozin 25 mg and metformin HCl 2,000 mg.
`• Take SYNJARDY orally twice daily with meals; with gradual dose escalation to reduce gastrointestinal
`adverse reactions with metformin [see Adverse Reactions (6.1)].
`
`
`2.4 Dosage Recommendations in Patients with Renal Impairment
`Initiation of SYNJARDY or SYNJARDY XR is not recommended in patients with an eGFR less than
`•
`45 mL/min/1.73 m2, due to the metformin component.
`• SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR less than
`30 mL/min/1.73 m2 or in patients on dialysis [see Contraindications (4), Warnings and Precautions (5.1),
`and Use in Specific Populations (8.6)].
`
`
`2.5 Discontinuation for Iodinated Contrast Imaging Procedures
`Discontinue SYNJARDY or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging
`procedure in patients with an eGFR less than 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 or SYNJARDY XR if renal function is stable
`[see Warnings and Precautions (5.1)].
`
`2.6 Temporary Interruption for Surgery
`
`
`
`4
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`Reference ID: 5269279
`
`Withhold SYNJARDY or SYNJARDY XR for at least 3 days, if possible, prior to major surgery or procedures
`associated with prolonged fasting. Resume SYNJARDY or SYNJARDY XR when the patient is clinically
`stable and has resumed oral intake [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].
`
`2.7 Recommendations Regarding Missed Dose
`If a dose is missed, instruct patients to take the dose as soon as possible.
`•
`• Do not double up the next dose.
`
` 3
`
`Color/Shape
`
`Tablet Markings
`
`DOSAGE FORMS AND STRENGTHS
`
`SYNJARDY Tablets:
`Empagliflozin
`Strength
`5 mg
`
`Metformin HCl
`Strength
`500 mg
`
`orange yellow, oval,
`biconvex, film-coated tablet
`
`5 mg
`
`1,000 mg
`
`12.5 mg
`
`500 mg
`
`12.5 mg
`
`1,000 mg
`
`brownish yellow, oval,
`biconvex, film-coated tablet
`
`pale brownish purple, oval,
`biconvex, film-coated tablet
`
`dark brownish purple, oval,
`biconvex, film-coated tablet
`
`Boehringer Ingelheim company symbol
`and “S5” debossed on one side; the other
`side is debossed with “500”.
`Boehringer Ingelheim company symbol
`and “S5” debossed on one side; the other
`side is debossed with “1000”.
`Boehringer Ingelheim company symbol
`and “S12” debossed on one side; the other
`side is debossed with “500”.
`Boehringer Ingelheim company symbol
`and “S12” debossed on one side; the other
`side is debossed with “1000”.
`
`
`SYNJARDY XR Tablets:
`Empagliflozin
`Metformin HCl
`Strength
`Extended - Release
`Strength
`1,000 mg
`
`5 mg
`
`10 mg
`
`1,000 mg
`
`12.5 mg
`
`1,000 mg
`
`Color/Shape
`
`Tablet Markings
`
`olive green, oval, biconvex,
`film-coated tablet
`
`orange, oval, biconvex,
`film-coated tablet
`
`blue, oval, biconvex,
`film-coated tablet
`
`Printed on one side in black ink with the
`Boehringer Ingelheim company symbol
`and “S5” on the top line and “1000 M” on
`the bottom line.
`Printed on one side in black ink with the
`Boehringer Ingelheim company symbol
`and “S10” on the top line and “1000 M” on
`the bottom line.
`Printed on one side in black ink with the
`Boehringer Ingelheim company symbol
`and “S12” on the top line and “1000 M” on
`the bottom line.
`Printed on one side in black ink with the
`Boehringer Ingelheim company symbol
`and “S25” on the top line and “1000 M” on
`the bottom line.
`
`25 mg
`
`1,000 mg
`
`light green, oval, biconvex,
`film-coated tablet
`
`CONTRAINDICATIONS
`
`SYNJARDY and SYNJARDY XR are contraindicated in patients with:
`• severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease, or dialysis [see
`Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].
`• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1)].
`• hypersensitivity to empagliflozin, metformin or any of the excipients in SYNJARDY or SYNJARDY XR,
`reactions such as angioedema have occurred [see Warnings and Precautions (5.9)].
`
` WARNINGS AND PRECAUTIONS
`
`5
`
` 4
`
` 5
`
`
`
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`

`Reference ID: 5269279
`
`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
`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 or SYNJARDY XR. In SYNJARDY
`or SYNJARDY XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis
`is recommended to correct the acidosis and remove accumulated metformin (metformin 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 or SYNJARDY XR 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 (2.4)
`and Clinical Pharmacology (12.3)]:
`
`
`•
`
`• Before initiating SYNJARDY or SYNJARDY XR, obtain an estimated glomerular filtration rate
`(eGFR).
`SYNJARDY and SYNJARDY XR are contraindicated in patients with an eGFR below
`30 mL/min/1.73 m2 [see Contraindications (4)].
`• Obtain an eGFR at least annually in all patients taking SYNJARDY or SYNJARDY XR. 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 or SYNJARDY XR 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)]. 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 or SYNJARDY XR at the time of, or prior to, an iodinated contrast imaging procedure in patients
`with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or
`
`
`
`6
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
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`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 or SYNJARDY XR 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 or SYNJARDY XR
`should be temporarily discontinued while patients have restricted food and fluid intake.
`
`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the
`setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
`Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with
`hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events
`occur, discontinue SYNJARDY or SYNJARDY XR.
`
`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 or SYNJARDY XR.
`
`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 or SYNJARDY XR in patients with clinical or laboratory evidence of hepatic disease.
`
`5.2 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis
`In patients with type 1 diabetes mellitus, empagliflozin, a component of SYNJARDY or SYNJARDY XR,
`significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In
`placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly
`increased in patients who received sodium glucose co-transporter 2 (SGLT2) inhibitors compared to patients
`who received placebo and fatal ketoacidosis has occurred with empagliflozin. SYNJARDY and SYNJARDY
`XR are not indicated for glycemic control in patients with type 1 diabetes mellitus.
`
`Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also
`risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients
`with type 2 diabetes mellitus using SGLT2 inhibitors, including SYNJARDY or SYNJARDY XR.
`
`Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to
`insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet,
`surgery, volume depletion, and alcohol abuse.
`
`Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea,
`vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation
`may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and
`glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after
`discontinuing SYNJARDY or SYNJARDY XR [see Clinical Pharmacology (12.2)]; however, there have been
`postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after
`discontinuation of SGLT2 inhibitors.
`
`Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for
`ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms
`consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue SYNJARDY or
`SYNJARDY XR, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of
`ketoacidosis before restarting SYNJARDY or SYNJARDY XR.
`
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`Novo Nordisk Exhibit 2532
`Mylan Pharms. Inc. v. Novo Nordisk A/S
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`Reference ID: 5269279
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`Withhold SYNJARDY or SYNJARDY XR, if possible, in temporary clinical situations that could predispose
`patients to ketoacidosis. Resume SYNJARDY or SYNJARDY XR when the patient is clinically stable and has
`resumed oral intake [see Dosage and Administration (2.6)].
`
`Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue SYNJARDY
`or SYNJARDY XR and seek medical attention immediately if signs and symptoms occur.
`
`5.3 Volume Depletion
`Empagliflozin can cause intravascular volume depletion which may sometimes manifest as symptomatic
`hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1)]. There have been post-
`marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2
`diabetes mellitus receiving SGLT2 inhibitors, including empagliflozin. Patients with impaired renal function
`(eGFR less than 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for
`volume depletion or hypotension. Before initiating SYNJARDY or SYNJARDY XR in patients with one or
`more of these characteristics, assess volume status and renal function. In patients with volume depletion, correct
`this condition before initiating SYNJARDY or SYNJARDY XR. Monitor for signs and symptoms of volume
`depletion, and renal function after initiating therapy.
`
`5.4 Urosepsis and Pyelonephritis
`There have been reports of serious urinary tract infections including urosepsis and pyelonephritis requiring
`hospitalization in patients receiving empagliflozin. Treatment with empagliflozin 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
`Insulin and insulin secretagogues are known to cause hypoglycemia. In adult patients, the risk of hypoglycemia
`may be increased when SYNJARDY or SYNJARDY XR is used in combination with insulin secretagogues
`(e.g., sulfonylurea) or insulin. In pediatric patients aged 10 years and older, the risk of hypoglycemia was higher
`with empagliflozin regardless of insulin use [see Adverse Reactions (6.1)].
`
`The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly
`administered insulin secretagogues) or insulin. Inform patients using these concomitant medications and
`pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
`
`5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
`Reports of necrotizing fasciitis of the perineum (Fournier’s gangrene), a rare but serious and life-threatening
`necrotizing infection requiring urgent surgical intervention, have been identified in patients with diabetes
`mellitus receiving SGLT2 inhibitors, including empagliflozin. Cases have been reported in both females and
`males. Serious outcomes have included hospitalization, multiple surgeries, and death.
`
`Patients treated with SYNJARDY or SYNJARDY XR presenting with pain or tenderness, erythema, or swelling
`in the genital or perineal area, along with fever or malaise, sho