` HIGHLIGHTS OF PRESCRIBING INFORMATION
` These highlights do not include all the information needed to use
`
`
`
` XULTOPHY 100/3.6 safely and effectively. See full prescribing
`information for XULTOPHY 100/3.6.
`
`XULTOPHY® 100/3.6 (insulin degludec and liraglutide injection), for
`
`
`
`
`
`subcutaneous use
`
`
`Initial U.S. Approval: 2016
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`• Liraglutide, one of the components of XULTOPHY 100/3.6, causes
`
`
`
`
`thyroid C-cell tumors at clinically relevant exposures in both
`
`genders of rats and mice. It is unknown whether XULTOPHY
`
`
`100/3.6 causes thyroid C-cell tumors, including medullary thyroid
`
`
`carcinoma (MTC), in humans, as the human relevance of
`
`
`
`liraglutide-induced rodent thyroid C-cell tumors has not been
`determined (5.1, 13.1).
`
`
`• XULTOPHY 100/3.6 is contraindicated in patients with a personal
`
`
`or family history of MTC or in patients with Multiple Endocrine
`
`
`Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the
`
`potential risk of MTC and the symptoms of thyroid tumors (4, 5.1).
`
`
`
`
`
`
`
`
`---------------------------INDICATIONS AND USAGE -----------------------­
`
`XULTOPHY 100/3.6 is a combination of insulin degludec, a long-acting
`
`
`
`
`human insulin analog, and liraglutide, a glucagon-like peptide 1 (GLP-1)
`receptor agonist, indicated as an adjunct to diet and exercise to improve
`
`glycemic control in adults with type 2 diabetes mellitus inadequately
`
`
`
`controlled on basal insulin (less than 50 units daily) or liraglutide (less than
`
`
`
`
`
`or equal to 1.8 mg daily) (1).
`
`
`Limitations of Use (1):
`
`
`• Not recommended as first-line therapy for patients inadequately
`
`
`
`controlled on diet and exercise.
`
`• Has not been studied in patients with a history of pancreatitis. Consider
`
`
`
`
`other antidiabetic therapies in patients with a history of pancreatitis.
`
`• Not recommended for use in combination with any other product
`
`
`containing liraglutide or another GLP-1 receptor agonist.
`
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`• Has not been studied in combination with prandial insulin.
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION-------------------­
`
`
`• Discontinue therapy with liraglutide or basal insulin prior to initiation of
`
`
`
`
`XULTOPHY 100/3.6 (2.1)
`
`• Recommended starting dosage is 16 units (16 units of insulin degludec
`
`
`
`
`
`
`and 0.58 mg of liraglutide) given subcutaneously once daily (2.1)
`
`
`
`• Administer once daily at same time each day with or without food (2.1)
`
`
`• Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8
`
`
`
`mg of liraglutide) (2.1)
`
`
`• XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each
`
`
`
`
`
`
`
`
`injection (2.1, 2.2); each XULTOPHY 100/3.6 dosage unit contains 1
`
`unit of insulin degludec and 0.036 mg of liraglutide (2.1).
`
`
`
`
`
`• Use alternative antidiabetic products if patients require a XULTOPHY
`
`
`100/3.6 daily dosage: (2.1)
`
`o Persistently below 16 units, or
`
`
`o Over 50 units.
`
`
`• See Full Prescribing Information for titration recommendations (2.2)
`
`
`
`• Inject subcutaneously in thigh, upper arm or abdomen (2.4)
`
`
`
`• Do not administer intravenously, intramuscularly, or by an infusion
`
`
`
`pump (2.4)
`
`
`• Do not dilute or mix with any other insulin products or solutions (2.4)
`
`
`
`
`
`
`--------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`Injection: 100 units of insulin degludec per mL and 3.6 mg of liraglutide
`
`
`
`
`per mL in a 3 mL single-patient-use pen (3).
`
`
`
`• Patients with a prior serious hypersensitivity reaction to XULTOPHY
`
`
`
`100/3.6 or either of the active substances or any of its excipients (4).
`
`
`• During episodes of hypoglycemia (4).
`
`
`
`
`----------------------WARNINGS AND PRECAUTIONS---------------------­
`• Thyroid C-cell Tumors: See Boxed Warning (5.1).
`
`
`
`
`• Pancreatitis: Postmarketing reports, including fatal and non-fatal
`
`
`
`hemorrhagic or necrotizing pancreatitis have been reported for
`
`liraglutide. Discontinue promptly if pancreatitis is suspected (5.2).
`
`
`• Never share a XULTOPHY 100/3.6 pen between patients, even if the
`
`
`needle is changed (5.3).
`
`
`
`
`• Hyper- or hypoglycemia with changes in XULTOPHY 100/3.6 regimen:
`
`
`Carry out under close medical supervision and increase frequency of
`
`
`blood glucose monitoring (5.4).
`
`
`• Overdose due to medication errors: XULTOPHY 100/3.6 contains two
`
`
`drugs. Instruct patients to check label before injection since accidental
`
`
`mix-ups with insulin containing products can occur. Do not exceed the
`
`
`
`
`
`maximum dose or administer with other GLP-1 receptor agonists (5.5).
`
`• Hypoglycemia: May be life-threatening. Increase monitoring with
`
`
`
`changes to: dosage, co-administered glucose lowering medications, meal
`
`pattern, physical activity; and in patients with renal impairment or
`
`
`hepatic impairment or hypoglycemia unawareness (5.6, 6.1).
`
`
`
`
`• Acute Kidney Injury: Has been reported postmarketing for liraglutide,
`
`
`usually in association with nausea, vomiting, diarrhea, or dehydration,
`
`
`
`which may sometimes require hemodialysis. Advise patients of the
`
`potential risk of dehydration due to gastrointestinal adverse reactions
`
`
`and take precautions to avoid fluid depletion (5.7).
`
`
`
`• Hypersensitivity and Allergic Reactions: Severe, life-threatening,
`
`
`
`generalized allergy, including anaphylaxis, angioedema, bronchospasm,
`
`
`
`hypotension, and shock can occur. If a hypersensitivity reaction occurs,
`
`
`discontinue and treat per standard of care (5.8).
`
`
`• Hypokalemia: May be life-threatening. Monitor potassium levels in
`
`
`
`
`patients at risk for hypokalemia and treat if indicated (5.9).
`
`
`• Fluid retention and congestive heart failure with use of
`
`
`
`thiazolidinediones (TZDs): Observe for signs and symptoms of heart
`
`failure; consider dosage reduction or discontinuation if heart failure
`
`
`occurs (5.10).
`
`• Macrovascular Outcomes: There have been no studies establishing
`
`
`
`
`conclusive evidence of macrovascular risk reduction with XULTOPHY
`
`
`100/3.6 (5.11).
`-------------------------------ADVERSE REACTIONS--------------------------­
`The most common adverse reactions, reported in ≥5% of patients treated
`
`
`
`
`
`
`
`with XULTOPHY 100/3.6: nasopharyngitis, headache, nausea, diarrhea,
`
`
`
`
`increased lipase and upper respiratory tract infection (6).
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo
`
`
`
`Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`
`
`
`
`
`
`------------------------------DRUG INTERACTIONS---------------------------­
`
`
`• Drugs that affect glucose metabolism: Adjustment of XULTOPHY
`
`
`
`
`
`100/3.6 dosage may be needed; closely monitor blood glucose (7.1).
`
`
`• Anti-Adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and
`
`
`
`reserpine): Hypoglycemia signs and symptoms may be reduced (7.1).
`
`
`
`• Effects of delayed gastric emptying on oral medications: May impact
`
`
`
`absorption of concomitantly administered oral medications (7.2).
`
`
`---------------- USE IN SPECIFIC POPULATIONS ------------------------­
`
`
`Pregnancy: XULTOPHY 100/3.6 should be used during pregnancy only if
`
`
`the potential benefit justifies the potential risk to the fetus (8.1).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`Medication Guide
`
`
`
`
`
`
`
`
`
`Revised: 11/2016
`
`-------------------------CONTRAINDICATIONS-------------------------------­
`• Patients with a personal or family history of medullary thyroid
`
`
`
`carcinoma or in patients with Multiple Endocrine Neoplasia syndrome
`
`type 2 (4).
`
`
`
`
`
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`Important Dosage Information
`
`2.1
`
`
`2.2 Titration of XULTOPHY 100/3.6
`
`
`
`2.3 Missed Doses
`
`
`
`2.4
`Important Administration Instructions
`
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Risk of Thyroid C-cell Tumors
`
`
`
`5.2 Pancreatitis
`
`
`
`
`
`5.3 Never Share a XULTOPHY 100/3.6 Pen Between Patients
`
`
`
`
`
`5.4 Hyperglycemia or Hypoglycemia with Changes in XULTOPHY
`
`
`
`
`100/3.6 Regimen
`
`
`5.5 Overdose due to Medication Errors
`
`
`
`5.6 Hypoglycemia
`
`
`
`5.7 Acute Kidney Injury
`
`
`
`5.8 Hypersensitivity and Allergic Reactions
`
`
`
`5.9 Hypokalemia
`
`
`5.10 Fluid Retention and Congestive Heart Failure with Concomitant
`
`
`
`
`Use of a PPAR Gamma Agonist
`
`
`5.11 Macrovascular Outcomes
`
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Trial Experience
`
`
`
`6.2
`Immunogenicity
`
`
`
`6.3 Post-Marketing Experience
`
`
`
`6
`
`
`
`
`
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Medications that Can Affect Glucose Metabolism
`
`
`
`
`7.2 Effects of Delayed Gastric Emptying on Oral Medications
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Renal Impairment
`
`
`
`8.7 Hepatic Impairment
`
`
`
`8.8 Gastroparesis
`
`
`
`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
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`
`16.2 Recommended Storage
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are
`..
`
`not listed.
`
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`• Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment­
`
`
`
`
`duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats
`
`
`
`and mice. It is unknown whether XULTOPHY 100/3.6 causes thyroid C-cell tumors, including
`
`medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced
`rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and
`
`Nonclinical Toxicology (13)].
`
`
`
`
`• XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC and
`
`
`
`
`in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients
`
`
`
`regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of
`
`symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early
`detection of MTC in patients treated with XULTOPHY 100/3.6 [see Contraindications (4),
`
`
`
`
`Warnings and Precautions (5.1)].
`
`
`
`1 INDICATIONS AND USAGE
`
`
`
`
`
`
`
`
`XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to
`
`
`
`diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled
`
`
`
`
`
`
`
`on basal insulin (less than 50 units daily) or liraglutide (less than or equal to 1.8 mg daily).
`
`
`
`Limitations of Use:
`• XULTOPHY 100/3.6 is not recommended as first-line therapy for patients who have inadequate
`
`
`
`glycemic control on diet and exercise because of the uncertain relevance of the rodent C-cell tumor
`
`findings to humans [see Warnings and Precautions (5.1)].
`
`
`• XULTOPHY 100/3.6 has not been studied in patients with a history of pancreatitis [see Warnings and
`
`
`
`
`
`Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis.
`
`• XULTOPHY 100/3.6 is not recommended for use in combination with any other product containing
`
`liraglutide or another GLP-1 receptor agonist [see Warnings and Precautions (5.5)].
`
`
`
`• XULTOPHY 100/3.6 is not indicated for use in patients with type 1 diabetes mellitus or for the treatment
`
`
`
`
`
`
`
`of diabetic ketoacidosis.
`
`• XULTOPHY 100/3.6 has not been studied in combination with prandial insulin.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`Important Dosage Information
`2.1
`
`
`
`The following are important dosing information for XULTOPHY 100/3.6, a combination of insulin degludec
`
`
`
`
`and liraglutide:
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` • Discontinue therapy with liraglutide or basal insulin prior to initiation of XULTOPHY 100/3.6.
`
` • The recommended starting dosage of XULTOPHY 100/3.6 is 16 units (16 units of insulin degludec
`
`
`
`
`
` and 0.58 mg of liraglutide) given subcutaneously once daily.
`
`
`
`
` • Administer XULTOPHY 100/3.6 once-daily at the same time each day with or without food.
`
`
`
` • The maximum daily dosage of XULTOPHY 100/3.6 is 50 units (50 units of insulin degludec and 1.8
`
`
`
`
`
` mg of liraglutide) [see Warnings and Precautions (5.5)].
`
`
` • The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection (see Table 1)
`
`
`
`
`
` [see Dosage and Administration (2.2)]
`
`
` • Use alternative antidiabetic products if patients require a XULTOPHY 100/3.6 daily dosage:
`
`
`o Persistently below 16 units [Dosage and Administration (2.2)], or
`
`
`
`
`
`
`o Over 50 units.
`
`
`
` Table 1 presents the units of insulin degludec and the milligrams of liraglutide in each dosage of
`
` XULTOPHY 100/3.6.
`
`Table 1: Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY
`
`100/3.6
`
`
`
`
`XULTOPHY 100/3.6
`
`
`(dose counter display)*
`
`
`
`▪▪ ─
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`
`insulin degludec
`
`component dose
`
`
`--­
`
`
`10 units
`
`
`11 units
`
`
`12 units
`
`13 units
`
`
`
`14 units
`
`
`15 units
`
`
`16 units
`
`
`17 units
`
`
`18 units
`
`
`19 units
`
`
`20 units
`
`
`21 units
`
`
`22 units
`
`23 units
`
`
`
`24 units
`
`
`25 units
`
`
`26 units
`
`
`27 units
`
`
`28 units
`
`
`29 units
`
`
`30 units
`
`
`31 units
`
`
`32 units
`
`
`33 units
`
`
`34 units
`
`
`35 units
`
`
`36 units
`
`
`37 units
`
`
`38 units
`
`
`liraglutide
`
`component dose
`
`
`--­
`
`0.36 mg
`
`
`0.4 mg
`
`
`0.43 mg
`
`
`0.47 mg
`
`
`
`0.5 mg
`
`
`0.54 mg
`
`
`0.58 mg
`
`
`0.61 mg
`
`
`0.65 mg
`
`
`0.68 mg
`
`
`0.72 mg
`
`
`0.76 mg
`
`
`0.79 mg
`
`
`0.83 mg
`
`
`0.86 mg
`
`
`0.9 mg
`
`
`0.94 mg
`
`
`0.97 mg
`
`
`1.01 mg
`
`
`1.04 mg
`
`
`1.08 mg
`
`
`1.12 mg
`
`
`1.15 mg
`
`
`1.19 mg
`
`
`1.22 mg
`
`
`1.26 mg
`
`
`1.3 mg
`
`
`1.33 mg
`
`
`1.37 mg
`
`
`
`
` Comment
`Priming symbol
`
`Temporary dose for down titration
`
`
`
`
`Temporary dose for down titration
`
`
`
`
`Temporary dose for down titration
`
`
`
`
`Temporary dose for down titration
`
`
`
`
`Temporary dose for down titration
`
`
`
`
`Temporary dose for down titration
`
`
`
`
`
`Recommended starting dosage
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`

`

`
`
`
`
` 1.4 mg
`
` 39 units
`
` 39
`
`
`
`
` 1.44 mg
`
` 40 units
`
` 40
`
`
`
`
` 1.48 mg
` 41 units
`
`
` 41
`
`
`
` 1.51 mg
`
` 42 units
`
`
` 42
`
`
`
` 1.55 mg
`
` 43 units
`
`
` 43
`
`
`
` 1.58 mg
`
` 44 units
`
`
` 44
`
`
`
` 1.62 mg
`
` 45 units
`
`
` 45
`
`
`
` 1.66 mg
`
` 46 units
`
`
` 46
`
`
`
` 1.69 mg
`
` 47 units
`
`
` 47
`
`
`
` 1.73 mg
`
` 48 units
`
`
` 48
`
`
`
` 1.76 mg
`
` 49 units
`
`
` 49
`Maximum daily dosage [see
`
`
`
`
` 1.8 mg
`
` 50 units
`
`
` 50
`Warnings and Precautions (5.5)]
`
`
` * The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the
`
`
`
`
`
`
`
`
`
`
` odd units.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`2.2 Titration of XULTOPHY 100/3.6
`
`
`
`
`• After starting with 16 units of XULTOPHY 100/3.6 (16 units of insulin degludec and 0.58 mg of
`
`liraglutide), titrate the dosage upwards or downwards by two units (see Table 2) every three to four
`
`
`
`
`
`
`
`days based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control
`
`
`
`
`
`goal until the desired fasting plasma glucose is achieved. The dosage of XULTOPHY 100/3.6 is
`
`between 16 to 50 units (see Table 1).
`
`• The XULTOPHY 100/3.6 dosage may be temporarily down titrated to below 16 units (i.e., 10 to 15
`
`
`units). However, if patients require persistent dosages below 16 units of XULTOPHY 100/3.6,
`
`
`
`discontinue and use alternative therapy (see Table 1).
`
`
`• To minimize the risk of hypoglycemia or hyperglycemia, additional titration may be needed with
`
`
`
`
`changes in physical activity, meal patterns (i.e., macronutrient content or timing of food intake), or
`renal or hepatic function; during acute illness; or when used with other medications [see Warnings
`
`
`
`
`
`and Precautions (5.4) and Drug Interactions (7)].
`
`Table 2: Recommended Titration of XULTOPHY 100/3.6 (Every Three to Four Days)1
`
`
`
`
`Self-Monitored Fasting
`
`
` XULTOPHY 100/3.6 Dosage Adjustment
`
`
`Plasma Glucose
`
`Above target range
`
`+ 2 units (2 units of insulin degludec and 0.072 mg of liraglutide)
`
`
`
`Within target range
`
`
`0 units
`
`
`
`Below target range
`
`- 2 units (2 units of insulin degludec and 0.072 mg of liraglutide)
`
`
`
`
` 1 The recommended XULTOPHY 100/3.6 dosage is between 16 to 50 units (see Table 1)
`
`
`
`
`
`
`
`
`
`
`
` 2.3 Missed Doses
`
` Instruct patients who miss a dose of XULTOPHY 100/3.6 to resume the once-daily regimen as
`
`
`•
`
`
` prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up
`for the missed dose.
`
`
` If more than three days have elapsed since the last XULTOPHY 100/3.6 dose, reinitiate XULTOPHY
`
` 100/3.6 at the starting dose (i.e., 16 units) to mitigate any gastrointestinal symptoms associated with
`
`
`
`
` reinitiation of treatment [see Dosage and Administration (2.1, 2.2)].
`
`
`
`
`
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`

`

`
`•
`
`
`
`
`
`
`
` Important Administration Instructions
`
`
`2.4
`
` • The XULTOPHY 100/3.6 pen is for single-patient-use only [see Warnings and Precautions (5.3)].
`
`
`
`
` • Train patients on proper use and injection technique before initiating XULTOPHY 100/3.6.
`
`
`
` • Always check the label on the XULTOPHY 100/3.6 pen before administration [see Warnings and
`
`
`
`Precautions (5.5)].
`
` Inspect visually for particulate matter and discoloration prior to administration. Only use XULTOPHY
`
` 100/3.6 if the solution appears clear and colorless.
`
` Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen.
`
`
`•
`
` • Rotate injection sites within the same region from one injection to the next to reduce the risk of
`
` lipodystrophy [see Adverse Reactions (6.1)].
`
`
`
` • Do not administer XULTOPHY 100/3.6 intravenously, intramuscularly, or in an insulin infusion pump.
`
`
`
` • Do not dilute or mix XULTOPHY 100/3.6 with any other insulin products or solutions.
`
`
`
`
`
`
` • Do not split the dose of XULTOPHY 100/3.6.
`
`
`
`
`
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`XULTOPHY 100/3.6 injection: 100 units insulin degludec per mL and 3.6 mg liraglutide per mL available
`
`
`as a clear, colorless solution in a 3 mL pre-filled, disposable, single-patient-use pen injector.
`
`
`
`CONTRAINDICATIONS
`4
`
`
`XULTOPHY 100/3.6 is contraindicated:
`
`
`
`
`•
`
`In patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with
`
`
`Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)].
`
`
`
`• During episodes of hypoglycemia [see Warnings and Precautions (5.6)].
`
`
`
`
` In patients with hypersensitivity to XULTOPHY 100/3.6, either of the active drug substances (insulin
`
`
`•
` degludec or liraglutide), or any of its excipients [see Warnings and Precautions (5.8)].
`
`
`
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1
`
`
`
`
`Risk of Thyroid C-cell Tumors
`
`
`Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration­
`
`
`
`dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both
`
`
`genders of rats and mice [see Nonclinical Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were
`
`
`
`
`
`detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors,
`including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced
`
`rodent thyroid C-cell tumors has not been determined.
`
`
`
`
`Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in
`
`
`these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in
`
`humans.
`
`
`
`
`XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients
`
`
`with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and
`
`inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent
`
`hoarseness).
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection
`of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary
`
`
`procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid
`
`disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have
`
`calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be
`
`further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also
`
`be further evaluated.
`
`Pancreatitis
`5.2
`
`
`Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or
`
`
`necrotizing pancreatitis, has been observed in patients treated with liraglutide, one of the components of
`
`XULTOPHY 100/3.6. In clinical trials of liraglutide, there have been 13 cases of pancreatitis among
`
`
`
`
`liraglutide-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1000
`
`patient-years). Nine of the 13 cases with liraglutide were reported as acute pancreatitis and four were
`
`
`
`reported as chronic pancreatitis. In one case in a liraglutide-treated patient, pancreatitis, with necrosis, was
`
`
`observed and led to death; however clinical causality could not be established. Some patients had other risk
`
`
`
`factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse.
`
`
`
`After initiation of XULTOPHY 100/3.6, observe patients carefully for signs and symptoms of pancreatitis
`
`
`(including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be
`
`
`
`accompanied by vomiting). If pancreatitis is suspected, XULTOPHY 100/3.6 should promptly be
`
`discontinued and appropriate management should be initiated. If pancreatitis is confirmed, restarting
`
`
`
`XULTOPHY 100/3.6 is not recommended. Consider antidiabetic therapies other than XULTOPHY 100/3.6
`
`
`in patients with a history of pancreatitis.
`5.3
`
`
`
`
`
`Never Share a XULTOPHY 100/3.6 Pen Between Patients
`
`
`
`
`XULTOPHY 100/3.6 pen must never be shared between patients, even if the needle is changed. Sharing of
`
`
`
`the pen poses a risk for transmission of blood-borne pathogens.
`5.4
`
`
`
`
`
`
`
`
`Hyperglycemia or Hypoglycemia with Changes in XULTOPHY 100/3.6 Regimen
`
`
`
`
`Changes in XULTOPHY 100/3.6 regimen may affect glycemic control and predispose to hypoglycemia or
`
`
`hyperglycemia [see Warnings and Precautions (5.5)]. These changes should be made cautiously and only
`
`
`under medical supervision and the frequency of blood glucose monitoring should be increased. Adjustments
`
`
`
`
`
`in concomitant oral anti-diabetic treatment may be needed. When converting from basal insulin therapies or
`
`liraglutide to XULTOPHY 100/3.6 follow dosing recommendations [see Dosage and Administration (2.1,
`
`
`
`
`2.2)].
`
`
`
`
`
`
`Overdose due to Medication Errors
`5.5
`
`
`XULTOPHY 100/3.6 contains two drugs: insulin degludec and liraglutide. Administration of more than 50
`
`
`units of XULTOPHY 100/3.6 daily can result in overdose of the liraglutide component. Do not exceed the
`
`1.8 mg maximum recommended dose of liraglutide or use with other glucagon-like peptide-1 receptor
`
`agonists.
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`Accidental mix-ups between insulin products have been reported. To avoid medication errors between
`XULTOPHY 100/3.6 (an insulin containing product) and other insulin products, instruct patients to always
`
`
`
`
`
`
`check the label before each injection.
`
`
`Hypoglycemia
`5.6
`
`
`Hypoglycemia is the most common adverse reaction of insulin containing products, including XULTOPHY
`
`
`
`
`
`100/3.6 [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or
`
`
`cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual
`
`
`and others at risk in situations where these abilities are important (e.g., driving or operating other
`
`
`
`
`machinery). XULTOPHY 100/3.6 (an insulin-containing product) or any insulin, should not be used during
`
`
`
`episodes of hypoglycemia [see Contraindications (4)].
`
`
`
`
`
`Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the
`
`
`
`same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with
`longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the
`
`
`
`sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7.1)], or in patients who experience
`
`
`
`recurrent hypoglycemia.
`
`
`Risk Factors for Hypoglycemia
`
`
`The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia
`
`
`after an injection is related to the duration of action of the insulin [see Clinical Pharmacology (12.2)] and, in
`
`
`
`general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin containing
`
`
`products, the glucose lowering effect time course of XULTOPHY 100/3.6 may vary among different
`
`
`
`
`individuals or at different times in the same individual and depends on many conditions, including the area
`
`
`of injection as well as the injection site blood supply and temperature.
`
`
`
`Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g.,
`macronutrient content or timing of meals), changes in level of physical activity, or changes to co­
`
`administered medication [see Drug Interactions (7.1)]. Patients with renal or hepatic impairment may be at
`
`
`higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
`
`
`
`
`Risk Mitigation Strategies for Hypoglycemia
`
`
`Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood
`
`
`glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk
`
`
`for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased
`frequency of blood glucose monitoring is recommended.
`
`
`Acute Kidney Injury
`5.7
`
`
`There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which
`
`
`may sometimes require hemodialysis in patients treated with liraglutide, one of the components of
`
`
`
`
`XULTOPHY 100/3.6 [see Adverse Reactions (6.3)]. Some of these events were reported in patients without
`
`
`known underlying renal disease. A majority of the reported events occurred in patients who had experienced
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`

`

`nausea, vomiting, diarrhea, or dehydration. Some of the reported events occurred in patients receiving one or
`
`
`more medications known to affect renal function or hydration status. Altered renal function has been
`reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative
`
`
`agents, including liraglutide. Advise patients of the potential risk of dehydration due to gastrointestinal
`
`
`adverse reactions and take precautions to avoid fluid depletion.
`
`
`Hypersensitivity and Allergic Reactions
`5.8
`
`
`Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm,
`hypotension, and shock can occur with XULTOPHY 100/3.6. Allergic reactions (manifested with signs and
`
`
`
`
`symptoms such as urticaria, rash, pruritus) have been reported with XULTOPHY 100/3.6. There have been
`
`
`postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in
`
`
`patients treated with liraglutide, one of the components of XULTOPHY 100/3.6 [see Adverse Reactions
`
`
`
`(6.3)]. If a hypersensitivity reaction occurs, discontinue XULTOPHY 100/3.6; treat per standard of care and
`
`
`monitor until symptoms and signs resolve.
`
`
`
`Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a
`history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will
`
`
`
`
`be predisposed to angioedema with XULTOPHY 100/3.6. XULTOPHY 100/3.6 is contraindicated in
`
`
`
`patients who have had hypersensitivity reactions to insulin degludec, liraglutide or one of the excipients of
`
`
`these products [see Contraindications (4)].
`
`
`
`
`5.9
` Hypokalemia
`
` All insulin-containing products, including XULTOPHY 100/3.6, cause a shift in potassium from the
`
`
` extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
`
`
` respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for
`
`hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications
`
`
`
` sensitive to serum potassium concentrations).
`
`
`
`
`
`
`
`
`
`5.10
`
`
`
`
` Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma
`
` Agonist
` Peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention,
`
`particularly when used in combination with insulin containing products, including XULTOPHY 100/3.6.
`Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin containing
`
` products, including XULTOPHY 100/3.6 and a PPAR-gamma agonist should be observed for signs and
` symptoms of congestive heart failure. If congestive heart failure develops, it should be managed according to
`
`
`current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be
`
`considered.
`
`
`
`
`5.11 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`
`
`XULTOPHY 100/3.6 or any other antidiabetic drug.
`
`
`
`
`Reference ID: 4016640
`
`Novo Nordisk Exhibit 2459
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
`
`

`

`
`
` ADVERSE REACTIONS
`
`6
`
` The following serious adverse reactions are described below or elsewhere in the prescribing information:
` • Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]