HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`
`
`
`
`
`
`
`SEGLUROMET safely and effectively. See
`full prescribing
`
`
`information for SEGLUROMET.
`
`
`
`SEGLUROMET™ (ertugliflozin and metformin hydrochloride)
`
`
`
`tablets, for oral use
`
`Initial U.S. Approval: 2017
`
`
`
`
`WARNING: LACTIC ACIDOSIS
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`
`
`• Post-marketing cases of metformin-associated lactic acidosis
`
`
`
`in death, hypothermia, hypotension, and
`have resulted
`
`included malaise,
`resistant bradyarrhythmias. Symptoms
`
`
`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 SEGLUROMET and
`
`
`institute general supportive measures in a hospital setting.
`
`Prompt hemodialysis is recommended. (5.1)
`
`
`
`is 7.5 mg ertugliflozin/1,000 mg
`
`
`
`
`----------------------------INDICATIONS AND USAGE ---------------------------­
`
`
`
`
`SEGLUROMET is a combination of ertugliflozin, a sodium glucose co-
`
`
`
`
`
`transporter 2 (SGLT2) inhibitor, and metformin, a biguanide, indicated
`
`as an adjunct to diet and exercise to improve glycemic control in adults
`
`
`
`
`
`
`
`with type 2 diabetes mellitus who are not adequately controlled on a
`
`
`
`regimen containing ertugliflozin or metformin, or in patients who are
`
`already treated with both ertugliflozin and metformin. (1)
`
`
`Limitations of Use:
`
`
`• Not for the treatment of type 1 diabetes mellitus or diabetic
`
`
`
`
`
`
`
`
`
`
`ketoacidosis. (1)
`
`
`----------------------- DOSAGE AND ADMINISTRATION ----------------------­
`
`
`
`
`
`• Individualize the starting dose based on the patient’s current
`
`
`
`regimen. (2.1)
`
`• Maximum recommended dose
`
`metformin twice daily. (2.1)
`
`• Take twice daily with meals, with gradual dose escalation. (2.1)
`
`
`• Assess renal function before initiating SEGLUROMET (2.2):
`
`
`
`o Do not use in patients with an estimated glomerular filtration rate
`
`
`(eGFR) below 30 mL/minute/1.73 m2.
`
`
`
`o Initiation is not recommended in patients with an eGFR of 30 to
`
`
`less than 60 mL/minute/1.73 m2.
`
`
`
`
`o Continued use is not recommended in patients with an eGFR
`
`
`
`
`
`persistently between 30 and less than 60 mL/min/1.73 m2.
`
`
`
`• SEGLUROMET may need to be discontinued at time of, or prior to,
`
`
`
`iodinated contrast imaging procedures. (2.3)
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------­
`
`
`
`
`
`Tablets:
`
`• Ertugliflozin 2.5 mg and metformin hydrochloride 500 mg (3)
`
`
`
`
`
`• Ertugliflozin 2.5 mg and metformin hydrochloride 1,000 mg (3)
`
`
`
`
`
`• Ertugliflozin 7.5 mg and metformin hydrochloride 500 mg (3)
`
`
`
`
`
`• Ertugliflozin 7.5 mg and metformin hydrochloride 1,000 mg (3)
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`
`• Severe renal impairment, end stage renal disease, or dialysis. (4,
`
`
`5.1, 5.4)
`
`• Metabolic acidosis, including diabetic ketoacidosis. (4, 5.1)
`
`
`• History of serious hypersensitivity reaction
`to ertugliflozin or
`
`
`metformin. (4)
`
`
`
`
`
`
`Reference ID: 4197754
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`
`
`
`
`
`• Lactic Acidosis: See boxed warning. (5.1)
`
`
`
`in patients with
`renal
`• Hypotension: May occur particularly
`
`
`
`impairment, the elderly, or patients on diuretics. Before initiating,
`
`
`
`
`
`
`assess and correct volume status. 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, evaluate, and treat
`
`
`
`promptly. Before initiating, consider risk factors for ketoacidosis.
`
`
`
`Patients 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. (5.4)
`
`
`• Urosepsis and Pyelonephritis: Evaluate patients for signs and
`
`
`
`
`
`
`symptoms of urinary tract infections and treat promptly, if indicated.
`
`
`(5.5)
`
`• Lower Limb Amputation: Before initiating, consider factors that may
`
`
`
`increase risk of amputation. Monitor patients for infections or ulcers
`
`
`of lower limbs, and discontinue if these occur. (5.6)
`
`
`insulin
`lower dose of
`insulin or
`• Hypoglycemia: Consider a
`
`
`
`
`
`
`secretagogue to reduce risk of hypoglycemia when used in
`
`combination. (5.7)
`
`• Genital Mycotic Infections: Monitor and treat if indicated. (5.8)
`
`
`
`
`
`
`• Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels.
`
`
`
`
`
`
`Measure hematological parameters annually. (5.9)
`
`• Increased LDL-C: Monitor and treat as appropriate. (5.10)
`
`
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------­
`
`
`
`
`• The most common adverse reactions associated with ertugliflozin
`
`
`
`
`(incidence ≥5%) were female genital mycotic infections. (6.1)
`
`
`
`
`• Most common adverse
`reactions associated with metformin
`
`(incidence ≥5%): diarrhea, nausea, vomiting, flatulence, abdominal
`
`
`
`discomfort, indigestion, asthenia, and headache. (6.1)
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`
`
`
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877­
`
`
`
`
`
`
`
`
`
`888-4231 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,
`
`
`the
`vandetanib, dolutegravir, and cimetidine) may
`increase
`
`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: Breastfeeding not recommended. (8.2)
`
`
`
`
`• Females and Males of Reproductive Potential: Advise
`
`
`for an unintended
`premenopausal
`females of
`the potential
`
`pregnancy. (8.3)
`
`• Geriatrics: Higher incidence of adverse reactions related to reduced
`
`
`
`
`
`intravascular volume. (5.2, 8.5)
`
`
`
`• Renal impairment: Higher incidence of adverse reactions related to
`
`
`
`reduced intravascular volume and renal function. (5.1, 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
`
`
`
`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: LACTIC ACIDOSIS
`
`INDICATIONS AND USAGE
`1
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosage
`
`
`
`2.2 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 Lower Limb Amputation
`
`
`
`5.7 Hypoglycemia with Concomitant Use with Insulin and
`
`
`
`Insulin Secretagogues
`
`
`5.8 Genital Mycotic Infections
`
`
`
`5.9 Vitamin B12 Levels
`
`
`
`5.10 Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
`
`
`
`
`5.11 Macrovascular Outcomes
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Drug Interactions with Ertugliflozin
`
`
`
`
`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 Overview of Clinical Studies in Patients with Type 2
`
`
`
`Diabetes Mellitus
`
`
`14.2 Ertugliflozin as Add-on Combination Therapy with
`
`Metformin
`
`
`14.3 In Combination with Sitagliptin versus Ertugliflozin Alone
`
`
`
`
`and Sitagliptin Alone, as Add-on to Metformin
`
`
`
`14.4 Ertugliflozin as Add-on Combination Therapy with
`
`Metformin and Sitagliptin
`
`
`14.5 Active Controlled Study of Ertugliflozin Versus Glimepiride
`
`
`
`as Add-on Combination Therapy with Metformin
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed.
`
`
`
`
`
`Reference ID: 4197754
`
`
`
`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: LACTIC ACIDOSIS
`
`
`
`
`•
`
`Post-marketing 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), and Use in Specific
`
`Populations (8.6, 8.7)].
`immediately discontinue
`is suspected,
`lactic acidosis
`If metformin-associated
`
`
`
`
`
`
`
`
`
`
`SEGLUROMET and
`institute general supportive measures
`in a hospital setting. Prompt
`
`
`
`
`hemodialysis is recommended [see Warnings and Precautions (5.1)].
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`
`SEGLUROMET™ is indicated as an adjunct to diet and exercise to improve glycemic control in
`
`
`
`adults with type 2 diabetes mellitus who are not adequately controlled on a regimen containing
`
`
`
`
`
`ertugliflozin or metformin, or in patients who are already treated with both ertugliflozin and metformin.
`
`
`
`Limitations of Use
`
`
`
`
`
`
`
`
`
`• SEGLUROMET is not recommended in patients with type 1 diabetes mellitus or for the
`
`treatment of diabetic ketoacidosis.
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`2.1 Recommended Dosage
`
`
`
`
`Individualize the starting dose of SEGLUROMET (ertugliflozin and metformin hydrochloride)
`•
`
`
`
`
`
`
`
`
`based on the patient’s current regimen, while not exceeding the maximum recommended daily
`
`
`
`dose of 15 mg ertugliflozin and 2,000 mg metformin HCl:
`o
`
`
`
`
`
`
`In patients on metformin, switch to SEGLUROMET tablets containing 2.5 mg ertugliflozin,
`
`
`with a similar total daily dose of metformin.
`o
`
`
`
`
`
`
`
`
`In patients on ertugliflozin, switch to SEGLUROMET tablets containing 500 mg metformin,
`
`
`with a similar total daily dose of ertugliflozin.
`o
`
`
`
`
`
`
`
`In patients already treated with ertugliflozin and metformin, switch to SEGLUROMET
`
`tablets containing the same total daily dose of ertugliflozin and a similar daily dose of
`
`metformin.
`
`
`
`
`• Take SEGLUROMET twice daily with meals, with gradual dose escalation for those initiating
`
`
`
`metformin to reduce the gastrointestinal side effects due to metformin [see Adverse Reactions
`
`
`(6.1)].
`
`
`
`
`
`
`
`In patients with volume depletion not previously treated with ertugliflozin, correct this condition
`
`
`
`prior to initiation of SEGLUROMET [see Warnings and Precautions (5.2)].
`
`
`
`• Dosing may be adjusted based on effectiveness and tolerability.
`
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`• Assess renal function prior to initiation of SEGLUROMET and periodically thereafter [see
`
`
`Warnings and Precautions (5.4)].
`
`
`
`
`• Use of SEGLUROMET
`is contraindicated
`30 mL/minute/1.73 m2 [see Contraindications (4)].
`
`
`
`
`
`
`in patients with an eGFR
`
`less
`
`
`than
`
`Reference ID: 4197754
`
`3
`
`
`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
`•
`
`
`4
`
`recommended
`is not
`in patients with an eGFR of
`Initiation of SEGLUROMET
`
`
`
`
`30 mL/minute/1.73 m2 to less than 60 mL/minute/1.73 m2 [see Warnings and Precautions (5.4)
`
`
`
`
`
`
`
`
`
`
`
`and Use in Specific Populations (8.6)].
`
`• Continued use of SEGLUROMET is not recommended when eGFR is persistently between 30
`
`
`
`
`
`
`
`
`and less than 60 mL/min/1.73 m2.
`
`
`
`• No dose adjustment is needed in patients with mild renal impairment.
`
`
`
`
`
`2.3 Discontinuation for Iodinated Contrast Imaging Procedures
`
`
`
`Discontinue SEGLUROMET 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 SEGLUROMET if renal function is stable [see Warnings and
`
`
`Precautions (5.1)].
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`
`
`• Tablets: ertugliflozin 2.5 mg and metformin hydrochloride 500 mg, pink, oval, debossed with
`
`“2.5/500” on one side and plain on the other side.
`
`
`
`
`
`
`• Tablets: ertugliflozin 2.5 mg and metformin hydrochloride 1000 mg, pink, oval, debossed with
`
`“2.5/1000” on one side and plain on the other side.
`
`
`
`
`
`
`• Tablets: ertugliflozin 7.5 mg and metformin hydrochloride 500 mg, red, oval, debossed with
`
`“7.5/500” on one side and plain on the other side.
`
`
`
`
`
`• Tablets: ertugliflozin 7.5 mg and metformin hydrochloride 1000 mg, red, oval, debossed with
`
`“7.5/1000” on one side and plain on the other side.
`
`CONTRAINDICATIONS
`
`
`
`
`
`
`
`• Severe renal impairment, end stage renal disease (ESRD), or patients on dialysis [see
`
`
`Warnings and Precautions (5.1, 5.4) and Use in Specific Populations (8.6)].
`
`
`
`
`
`
`
`• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
`
`
`
`• History of a serious hypersensitivity reaction to SEGLUROMET, ertugliflozin, or metformin
`
`hydrochloride.
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Lactic Acidosis
`
`
`
`There have been post-marketing 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 were 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 SEGLUROMET. In
`
`
`
`SEGLUROMET-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 SEGLUROMET 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:
`
`
`Reference ID: 4197754
`
`
`4
`
`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
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`Renal Impairment: The postmarketing metformin-associated lactic acidosis cases primarily occurred in
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`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
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`by the kidney [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].
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`• Before initiating SEGLUROMET, obtain an eGFR.
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`• SEGLUROMET is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2.
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`•
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`recommended
`is not
`Initiation of SEGLUROMET
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`30 mL/minute/1.73 m2 to less than 60 mL/min/1.73 m2.
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`in patients with an eGFR of
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`• Continued use of SEGLUROMET is not recommended when eGFR is persistently between
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`30 and less than 60 mL/min/1.73 m2.
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`• Renal function should be evaluated prior to initiating SEGLUROMET and periodically thereafter.
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`In patients at increased risk for the development of renal impairment (e.g., the elderly), renal
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`function should be assessed more frequently.
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`Drug Interactions: The concomitant use of SEGLUROMET with specific drugs may increase the risk of
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`metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic
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`change, interfere with acid-base balance or increase metformin accumulation (e.g., cationic drugs) [see
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`Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
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`Age 65 or Greater: The risk of metformin-associated lactic acidosis increases with the patient’s age
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`because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than
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`younger patients. Assess renal function more frequently in elderly patients [see Use in Specific
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`Populations (8.5)].
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`Radiological Studies with Contrast: Administration of intravascular iodinated contrast agents in
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`metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic
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`acidosis. Stop SEGLUROMET at the time of, or prior to, an iodinated contrast imaging procedure in
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`patients with an eGFR less than 60 mL/min/1.73 m2; in patients with a history of hepatic impairment,
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`alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re­
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`evaluate eGFR 48 hours after the imaging procedure, and restart SEGLUROMET if renal function is
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`stable.
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`Surgery and Other Procedures: Withholding of food and fluids during surgical or other procedures may
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`increase the risk for volume depletion, hypotension and renal impairment. SEGLUROMET should be
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`temporarily discontinued while patients have restricted food and fluid intake.
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`Hypoxic States: Several of the postmarketing cases of metformin-associated lactic acidosis occurred in
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`the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and
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`hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions
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`associated with hypoxemia have been associated with lactic acidosis and may also cause pre-renal
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`azotemia. When such events occur, discontinue SEGLUROMET.
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`Excessive Alcohol Intake: Alcohol potentiates the effect of metformin on lactate metabolism and this
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`may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol
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`intake while receiving SEGLUROMET.
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`Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic
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`acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore,
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`avoid use of SEGLUROMET in patients with clinical or laboratory evidence of hepatic disease.
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`Reference ID: 4197754
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`5
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`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
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`5.2 Hypotension
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`Ertugliflozin, a component of SEGLUROMET, causes intravascular volume contraction. Therefore,
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`symptomatic hypotension may occur after initiating SEGLUROMET [see Adverse Reactions (6.1)]
`particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2) [see Use in
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`Specific Populations (8.6)], elderly patients (≥65 years), in patients with low systolic blood pressure, and
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`in patients on diuretics. Before initiating SEGLUROMET, volume status should be assessed and
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`corrected if indicated. Monitor for signs and symptoms of hypotension after initiating therapy.
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`5.3 Ketoacidosis
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`Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, have
`been identified in clinical trials and postmarketing surveillance in patients with type 1 and type 2 diabetes
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`mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors and cases have been reported in
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`ertugliflozin-treated patients in clinical trials. Across the clinical program, ketoacidosis was identified in 3
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`of 3,409 (0.1%) of ertugliflozin-treated patients and 0% of comparator-treated patients. Fatal cases of
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`ketoacidosis have been
`taking medicines containing SGLT2
`inhibitors.
`reported
`in patients
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`SEGLUROMET is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications
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`and Usage (1)].
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`Patients treated with SEGLUROMET who present with signs and symptoms consistent with severe
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`metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as
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`ketoacidosis associated with SEGLUROMET may be present even if blood glucose levels are less than
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`250 mg/dL. If ketoacidosis is suspected, SEGLUROMET should be discontinued, patient should be
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`evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid,
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`and carbohydrate replacement.
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`In many of the reported cases, and particularly in patients with type 1 diabetes, the presence of
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`ketoacidosis was not immediately recognized and institution of treatment was delayed because
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`presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less
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`than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe
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`metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of
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`breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction,
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`acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting
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`insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse
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`were identified.
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`Before initiating SEGLUROMET, consider factors in the patient history that may predispose to
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`ketoacidosis, including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol
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`abuse. In patients treated with SEGLUROMET consider monitoring for ketoacidosis and temporarily
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`discontinuing SEGLUROMET in clinical situations known to predispose to ketoacidosis (e.g., prolonged
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`fasting due to acute illness or surgery).
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`5.4 Acute Kidney Injury and Impairment in Renal Function
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`SEGLUROMET causes intravascular volume contraction and can cause renal impairment [see
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`Adverse Reactions (6.1)]. There have been postmarketing reports of acute kidney injury some requiring
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`hospitalization and dialysis in patients receiving SGLT2 inhibitors.
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`Before initiating SEGLUROMET, consider factors that may predispose patients to acute kidney
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`injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant
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`temporarily discontinuing
`medications
`(diuretics, ACE
`inhibitors, ARBs, NSAIDs). Consider
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`SEGLUROMET in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such
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`as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute
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`kidney injury. If acute kidney injury occurs, discontinue SEGLUROMET promptly and institute treatment.
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`Ertugliflozin, a component of SEGLUROMET, increases serum creatinine and decreases eGFR.
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`Patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) may be more
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`susceptible to these changes. Renal function abnormalities can occur after initiating SEGLUROMET [see
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`Adverse Reactions (6.1)]. Renal function should be evaluated prior to initiating SEGLUROMET and
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`periodically thereafter. Use of SEGLUROMET is not recommended when eGFR is persistently between
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`30 mL/min/1.73 m2 and less than 60 mL/min/1.73 m2 and is contraindicated in patients with an eGFR less
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`than 30 mL/min/1.73 m2 [see Dosage and Administration (2.2), Contraindications (4), Use in Specific
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`Populations (8.6)].
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`Reference ID: 4197754
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`6
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`Novo Nordisk Exhibit 2468
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
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`5.5 Urosepsis and Pyelonephritis
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`There have been postmarketing reports of serious urinary tract infections, including urosepsis and
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`pyelonephritis, requiring hospitalization in patients receiving medicines containing SGLT2 inhibitors.
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`Cases of pyelonephritis also have been reported in ertugliflozin-treated patients in clinical trials.
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`Treatment with medicines containing SGLT2 inhibitors increases the risk for urinary tract infections.
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`Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see
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`Adverse Reactions (6.1)].
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`5.6 Lower Limb Amputation
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`An increased risk for lower limb amputation (primarily of the toe) has been observed in clinical
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`studies with another SGLT2 inhibitor. Across seven Phase 3 clinical trials in the ertugliflozin development
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`program, non-traumatic lower limb amputations were reported in 1 (0.1%) patient in the comparator
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`group, 3 (0.2%) patients in the ertugliflozin 5 mg group, and 8 (0.5%) patients in the ertugliflozin 15 mg
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`group. A causal association between ertugliflozin and lower limb amputation has not been definitively
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`established.
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`Before initiating SEGLUROMET, consider factors in the patient history that may predispose them to
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`the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy
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`and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor
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`patients receiving SEGLUROMET for signs and symptoms of infection (including osteomyelitis), new pain
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`or tenderness, sores or ulcers involving the lower limbs, and discontinue SEGLUROMET if these
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`complications occur.
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`5.7 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
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`Ertugliflozin
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`Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia.
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`Ertugliflozin, a component of SEGLUROMET, may increase the risk of hypoglycemia when used in
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`combination with insulin and/or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower
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`dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used
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`in combination with SEGLUROMET.
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`Metformin
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`Hypoglycemia does not occur in patients receiving metformin, a component of SEGLUROMET,
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`alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous
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`exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-
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`lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished
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`patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly
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`susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in
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`people who are taking β-adrenergic blocking drugs.
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`5.8 Genital Mycotic Infections
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`Ertugliflozin, a component of SEGLUROMET, increases the risk of genital mycotic infections.
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`Patients who have a history of genital mycotic infections or who are uncircumcised are more likely to
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`develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
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`5.9 Vitamin B12 Levels
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`In controlled clinical trials of metformin, a component of SEGLUROMET, of 29 weeks duration, a
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`levels, without clinical
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`decrease to subnormal levels of previously normal serum vitamin B12
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`manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to
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`interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated
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`with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12
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`supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on
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`SEGLUROMET and any apparent abnormalities should be appropriately investigated and managed.
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`Certain individuals (those with inadequate vitamin B12 or calc