`
`
` These highlights do not include all the information needed to use
` VICTOZA safely and effectively. See full prescribing information for
`
`
`
` VICTOZA.
`
`
`VICTOZA® (liraglutide) injection, for subcutaneous use
`
`
`
`Initial U.S. Approval: 2010
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
` See full prescribing information for complete boxed warning.
`
`
` Liraglutide causes thyroid C-cell tumors at clinically relevant
`
`
`
`
` exposures in both genders of rats and mice. It is unknown
` whether VICTOZA 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).
`
`
`
`
` VICTOZA 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).
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`
` Indications and Usage, Limitations of Use (1)-------------- Removed 11/2020
`
`
` Warnings and Precautions (5.4) -------------------------------------------11/2020
`
`
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist
`
`
`
` indicated:
` • as an adjunct to diet and exercise to improve glycemic control in
`
`
`
`
`
`
`
`
` patients 10 years and older with type 2 diabetes mellitus (1).
` to reduce the risk of major adverse cardiovascular events in adults with
`
`
`
`
`
`
`
` type 2 diabetes mellitus and established cardiovascular disease (1).
`
`
`Limitations of Use:
`
`• Not for treatment of type 1 diabetes mellitus.
`
`
`
`• Should not be coadministered with other liraglutide-containing
`
`
`products
`
`
`
`•
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Inspect visually prior to each injection. Only use if solution is clear,
`
`
`•
`colorless, and contains no particles (2.1).
`
`
`
`Inject VICTOZA subcutaneously once-daily at any time of day,
`
`
`independently of meals, in the abdomen, thigh or upper arm (2.1).
`
`
`
`• When using VICTOZA with insulin, administer as separate injections.
`
`
`Never mix. (2.1).
`
`
`• Adult Dosage: Initiate at 0.6 mg daily for one week then increase to
`
`
`
`
`
`
`
`
`
`1.2 mg daily. If additional glycemic control is required, increase the
`
`
`
`
`dose to 1.8 mg daily after one week of treatment with the 1.2 mg daily
`
`
`
`
`dose (2.2).
`
`
`• Pediatric Dosage: Initiate at 0.6 mg daily for at least one week. If
`
`
`
`
`
`
`
`additional glycemic control is required increase the dose to 1.2 mg
`
`
`
`daily and if additional glycemic control is still required, increase the
`
`
`dose to 1.8 mg daily after at least one week of treatment with the 1.2
`
`
`
`
`mg daily dose (2.3).
`
`
`
`
`•
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Injection: 6 mg/mL solution in a pre-filled, single-patient-use pen that
`
`
`
`
`delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (3).
`
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`VICTOZA is contraindicated in patients with a personal or family history of
`
`
`
`
`
`
`medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia
`
`
`
`syndrome type 2 (4).
`
`
`VICTOZA is contraindicated in patients with a prior serious hypersensitivity
`
`
`
`reaction to liraglutide or any of the excipients in VICTOZA (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. Discontinue promptly if pancreatitis is suspected.
`
`
`
`Do not restart if pancreatitis is confirmed (5.2).
`
`
`• Never share a VICTOZA pen between patients, even if the needle is changed
`
`
`
`
`(5.3).
`
`• Hypoglycemia: Adult patients taking an insulin secretagogue or insulin may
`
`
`
`have an increased risk of hypoglycemia, including severe hypoglycemia. In
`
`
`
`pediatric patients 10 years of age and older, the risk of hypoglycemia was
`
`higher with VICTOZA regardless of insulin and/or metformin use. Reduction
`
`
`
`in the dose of insulin secretagogues or insulin may be necessary (5.4).
`
`
`
`• Renal Impairment: Postmarketing, usually in association with nausea,
`
`
`
`
`
`vomiting, diarrhea, or dehydration which may sometimes require
`
`
`
`hemodialysis. Use caution when initiating or escalating doses of VICTOZA in
`
`
`
`
`
`patients with renal impairment (5.5).
`
`
`• Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions
`
`
`
`
`
`(e.g., anaphylactic reactions and angioedema). Discontinue VICTOZA and
`
`
`
`
`
`promptly seek medical advice (5.6).
`
`• Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
`
`
`
`
`gallbladder studies are indicated (5.7)
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`• The most common adverse reactions, reported in ≥5% of patients treated with
`
`
`
`
`VICTOZA are: nausea, diarrhea, vomiting, decreased appetite, dyspepsia,
`
`
`
`
`constipation (6.1).
`
`
`• Immunogenicity-related events, including urticaria, were more common
`
`
`among VICTOZA-treated patients (0.8%) than among comparator-treated
`
`
`
`patients (0.4%) in clinical trials (6.2).
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or
`
`
`www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS----------------------------------
`
`Oral Medications: VICTOZA delays gastric emptying and may impact
`
`
`
`
`
`
`absorption of concomitantly administered oral medications (7).
`
`
`
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with
`
`Insulin: when initiating, consider reducing the dose of concomitantly
`
`
`administered insulin secretagogues (such as sulfonylureas) or insulin to reduce
`
`the risk of hypoglycemia (7).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Pregnancy: VICTOZA 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 FDA-Approved
`
`Medication Guide.
`
`
`
`
`
`
`
`
`
`
`Revised: 11/2020
`
`
`
`Reference ID: 4705241
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
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`
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`
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`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`INDICATIONS AND USAGE
`
` 1
`
`
` DOSAGE AND ADMINISTRATION
`
`
` 2
` 2.1 Important Dosing and Administration Instructions
`
`
`
`
` 2.2 Adult Dosage
`
`
`
`
`
` 2.3 Pediatric Dosage
`
`
`
` 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 VICTOZA Pen Between Patients
`
`
` 5.4 Hypoglycemia
`
`
` 5.5 Renal Impairment
`
`
`
`
` 5.6 Hypersensitivity Reactions
`
`
`
` 5.7 Acute Gallbladder Disease
`
`
` ADVERSE REACTIONS
`
` 6.1 Clinical Trials Experience
`
`
`
` 6.2 Immunogenicity
`
`
` 6.3 Post-Marketing Experience
`
`
` DRUG INTERACTIONS
`
`
`
` 7.1 Oral Medications
`
` 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea)
`
`
` or with Insulin
`
` 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
`
`
`
`
` 6
`
`
`
` 7
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`14
`
`
`16
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`CLINICAL STUDIES
`
`14.1 Glycemic Control Trials in Adults with Type 2 Diabetes
`
`
`
`
`Mellitus
`
`
`14.2 Glycemic Control Trial in Pediatric Patients 10 Years of
`
`
`
`Age and Older with Type 2 Diabetes Mellitus
`
`
`
`
`
`14.3 Cardiovascular Outcomes Trial in Patients with Type 2
`
`
`
`
`
`Diabetes Mellitus and Atherosclerotic Cardiovascular Disease
`
`
`
`
`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: 4705241
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`• Liraglutide 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 VICTOZA
`
`
`
`
`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 (13.1)].
`
`
`
`
`
`• VICTOZA 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 VICTOZA 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 VICTOZA [see Contraindications (4) and Warnings and Precautions (5.1)].
`
`
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`VICTOZA is indicated:
`
`
`
`
`• as an adjunct to diet and exercise to improve glycemic control in patients 10 years and older with type 2
`
`diabetes mellitus,
`
`
`
`to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial
`
`
`
`
`infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease
`
`[see Clinical Studies (14.3)].
`
`
`•
`
`
`
`Limitations of Use:
`
`
`VICTOZA should not be used in patients with type 1 diabetes mellitus.
`
`
`
`VICTOZA contains liraglutide and should not be coadministered with other liraglutide-containing products.
`
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Important Dosing and Administration Instructions
`2.1
`
`
`
`Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles.
`
`
`
`
`•
`Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals.
`
`
`•
`Inject VICTOZA subcutaneously in the abdomen, thigh or upper arm. No dose adjustment is needed if
`
`
`
`
`
`•
`changing the injection site and/or timing.
`
`
`
`• When using VICTOZA with insulin, administer as separate injections. Never mix.
`
`
`
`
`It is acceptable to inject VICTOZA and insulin in the same body region but the injections should not be
`
`
`
`
`
`•
`adjacent to each other.
`
`If a dose is missed, 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 3 days have elapsed since the last VICTOZA dose, reinitiate VICTOZA at 0.6 mg to mitigate
`
`
`
`any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, VICTOZA should
`
`
`
`
`be titrated at the discretion of the prescriber.
`
`
`2.2
`Adult Dosage
`
`
`Initiate VICTOZA with a dose of 0.6 mg daily for one week. The 0.6 mg dose is a starting dose intended to
`
`
`
`
`•
`reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control in adults.
`
`
`
`
`After one week at 0.6 mg per day, increase the dose to 1.2 mg daily.
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`
`
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`If additional glycemic control is required, increase the dose to 1.8 mg daily after at least one week of
`
`treatment with the 1.2 mg daily dose.
`
`
`
`2.3
`Pediatric Dosage
`
`
`
`
`
`Initiate VICTOZA with a dose of 0.6 mg daily.
`•
`
`
`
`
`• After at least one week at 0.6 mg daily, the dose may be increased to 1.2 mg daily if additional glycemic
`
`
`control is required.
`
`
`
`
`
`If additional glycemic control is required, increase the dose to 1.8 mg daily after at least one week of
`
`treatment with the 1.2 mg daily dose.
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`
`
`Injection: 18 mg/3 mL (6 mg/mL) clear, colorless solution in a pre-filled, single-patient-use pen that delivers
`
`doses of 0.6 mg, 1.2 mg, or 1.8 mg.
`
`
`
`CONTRAINDICATIONS
`4
`
`Medullary Thyroid Carcinoma
`
`
`•
`
`
`
`
`
`VICTOZA 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).
`
`
`Hypersensitivity
`
`
`•
`
`
`
`
`
`
`VICTOZA is contraindicated in patients with a prior serious hypersensitivity reaction to liraglutide or to any of
`
`
`
`
`the excipients in VICTOZA. Serious hypersensitivity reactions including anaphylactic reactions and
`
`
`angioedema have been reported with VICTOZA [see Warnings and Precautions (5.6)].
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`Risk of Thyroid C-cell Tumors
`5.1
`
`Liraglutide 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
`
`
`
`VICTOZA 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 VICTOZA have been reported in the postmarketing period;
`
`
`the data in these reports are insufficient to establish or exclude a causal relationship between
`
`
`
`MTC and VICTOZA use in humans.
`
`
`
`
`
`
`
`VICTOZA 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 VICTOZA 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 VICTOZA. 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 VICTOZA. After initiation of VICTOZA,
`
`
`
`observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain,
`
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
`
`
`
`
`
`
`
`
`
`
`
`
`sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is
`
`suspected, VICTOZA should promptly be discontinued and appropriate management should be initiated. If
`
`
`
`
`pancreatitis is confirmed, VICTOZA should not be restarted.
`
`
`
`
`
` In glycemic control trials of VICTOZA, there have been 13 cases of pancreatitis among VICTOZA-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 VICTOZA were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case
`
` in a VICTOZA-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.
`
`
` VICTOZA has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients
`
`
` with a history of pancreatitis are at higher risk for development of pancreatitis on VICTOZA.
`
` Never Share a VICTOZA Pen Between Patients
` 5.3
`
`
`
`
`
`
` VICTOZA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk
` for transmission of blood-borne pathogens.
`
`
`
`5.4 Hypoglycemia
`
`
`Adult patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin
`
`
`
`may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of
`
`
`age and older, the risk of hypoglycemia was higher with VICTOZA regardless of insulin and/or metformin use.
`
`
`[see Adverse Reactions (6.1), Drug Interactions (7.2)].
`
`
`
`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.
`
`
`
`
` 5.5
` Renal Impairment
`
`
`
`
`
`
` VICTOZA has not been found to be directly nephrotoxic in animal studies or clinical trials.
`
` There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may
`
`
`
`
` sometimes require hemodialysis in VICTOZA-treated patients [see Adverse Reactions (6.2)]. 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 nausea, vomiting, diarrhea, or dehydration [see Adverse Reactions
`
`
` (6.1)]. 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 VICTOZA. Use caution
`
`
` when initiating or escalating doses of VICTOZA in patients with renal impairment [see Use in Specific
`
`
`
`Populations (8.6)].
`
`
` 5.6 Hypersensitivity Reactions
`
`
`
`
` There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and
` angioedema) in patients treated with VICTOZA. If a hypersensitivity reaction occurs, discontinue VICTOZA;
`
`
`
`
` treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a
`
` previous hypersensitivity reaction to VICTOZA [see Contraindications (4)].
`
`
` Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient
`
`
`
` with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is unknown whether
`such patients will be predisposed to these reactions with VICTOZA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
`
`
`
`
`5.7 Acute Gallbladder Disease
`
`
`
` In the LEADER trial [see Clinical Studies (14.3)], 3.1% of VICTOZA-treated patients versus 1.9% of placebo-
`
` treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. The
`
`
`
`
`
` majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder studies
`
`
` and appropriate clinical follow-up are indicated.
`
`6
` ADVERSE REACTIONS
`
`
` 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)]
`
` • Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
` • Hypoglycemia [see Warnings and Precautions (5.4)]
`
`
`
`
` • Renal Impairment [see Warnings and Precautions (5.5)]
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
`
`
`
`
`
` Clinical Trials Experience
` 6.1
`
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
`
` clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not
`
` reflect the rates observed in practice.
`
`
`
` Common Adverse Reactions
`
`
`
`
`
`
`The safety of VICTOZA in subjects with type 2 diabetes was evaluated in 5 glycemic control, placebo-
`
`
`
`
`
`controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see
`
`
`
`
`
`
`Clinical Studies (14.1)]. The data in Table 1 reflect exposure of 1673 adult patients to VICTOZA and a mean
`
`
`
`
`
`
`
`duration of exposure to VICTOZA of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75
`
`
`
`
`years or older and 54% were male. The population was 79% White, 6% Black or African American, 13%
`
`
`
`
`
`Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9.1
`years and a mean HbA1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88.1%
`
`
`
`
`and moderately impaired in 11.9% of the pooled population.
`
`
`
`
`Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of
`
`
`
`
`VICTOZA. These adverse reactions occurred more commonly on VICTOZA than on placebo and occurred in at
`
`
`
`
`
`least 5% of patients treated with VICTOZA. Overall, the type, and severity of adverse reactions in adolescents
`
`
`
`
`
`and children aged 10 years and above were comparable to that observed in the adult population.
`
`
`
`
`Table 1 Adverse reactions reported in ≥ 5% of VICTOZA-treated patients
`
`
`
`
`
`
`
`Liraglutide 1.8 mg
`Placebo
`Liraglutide 1.2 mg
`
`
`
`
`
`
`
`
`N= 1024
`N=661
`N= 645
`
`
`
`Adverse Reaction
`
`(%)
`(%)
`(%)
`
`
`
`20
`18
`Nausea
`5
`
`
`
`
`12
`Diarrhea
`4
`10
`
`
`
`
`10
`Headache
`7
`11
`
`
`
`
`10
`Nasopharyngitis
`8
`9
`
`
`
`
`9
`2
`6
`Vomiting
`
`
`
`
`9
`Decreased appetite
`1
`10
`
`
`
`
`
`7
`Dyspepsia
`1
`4
`
`
`
`
`6
`Upper Respiratory Tract Infection
`6
`7
`
`
`
`
`
`
`
`5
`Constipation
`1
`5
`
`
`
`
`5
`3
`4
`Back Pain
`
`
`
`
`
` Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`
`
`
`
`In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions,
`
`excluding hypoglycemia, were similar to those listed in Table 1.
`
`
`
`
`Other Adverse Reactions
`
`Gastrointestinal Adverse Reactions
`
`In the pool of 5 glycemic control, placebo-controlled clinical trials, withdrawals due to gastrointestinal adverse
`
`
`
`reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients. Withdrawal due
`
`
`
`to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials.
`
`
`
`
`Injection site reactions
`
`Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of VICTOZA-
`
`
`
`
`treated patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of
`
`
`
`
`
`
`
`VICTOZA-treated patients discontinued due to injection site reactions.
`
`
`
`
`Hypoglycemia
`
`In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia
`
`
`
`
`requiring the assistance of another person for treatment occurred in 8 VICTOZA-treated patients (7.5 events per
`
`
`
`
`1000 patient-years). Of these 8 VICTOZA-treated patients, 7 patients were concomitantly using a sulfonylurea.
`
`
`
`
`
`
`
` Table 2 Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy
`
`
`
`
` Placebo- controlled Trials
`
`Add-on to
`
`Metformin
`
`Patient not able to self-treat
`
`Patient able to self-treat
`
`Add-on to
`
` Glimepiride
`
`Patient not able to self-treat
`
`Patient able to self-treat
`
`
`Not classified
`
`Add-on to
`
` Metformin + Rosiglitazone
`
`
`
`
`
`Placebo Comparator
`
`Placebo + Metformin
`
`
`
`(N = 121)
`0
`
`2.5 (0.06)
`
`Placebo + Glimepiride
`
`
`(N = 114)
`
`VICTOZA Treatment
`
`
`VICTOZA + Metformin
`
`
`
`
`(N = 724)
`0.1 (0.001)
`
`3.6 (0.05)
`
`VICTOZA + Glimepiride
`
`
` (N = 695)
`
`
`
`
`
`
`Patient not able to self-treat
`
`Patient able to self-treat
`
`
`Not classified
`
`Add-on to
`
` Metformin + Glimepiride
`
`
`
`0.1 (0.003)
`0
`
`
`7.5 (0.38)
`2.6 (0.17)
`
`
`0.9 (0.05)
`0
`
`
`VICTOZA + Metformin +
`Placebo + Metformin +
`
`
`
`
`
` Rosiglitazone
`
` Rosiglitazone
`
`
`(N = 355)
`(N = 175)
`
`0
`0
`
`
`7.9 (0.49)
`4.6 (0.15)
`
`
`0.6 (0.01)
`1.1 (0.03)
`
`
`VICTOZA + Metformin +
`Placebo + Metformin +
`
`
`
`
`
` Glimepiride
`
` Glimepiride
`
`
`(N = 230)
`(N = 114)
`
`2.2 (0.06)
`0
`Patient not able to self-treat
`
`
`
`27.4 (1.16)
`16.7 (0.95)
`Patient able to self-treat
`
`
`
`0
`0
`Not classified
`
`
`
` “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In a 26-week pediatric placebo-controlled clinical trial with a 26-week open-label extension, 21.2% of
`
`
`
`
`VICTOZA treated patients (mean age 14.6 years) with type 2 diabetes, had hypoglycemia with a blood glucose
`
`
`
`
`
`
`<54 mg/dL with or without symptoms (335 events per 1000 patient years). No severe hypoglycemic episodes
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`
`
`
`
`occurred in the VICTOZA treatment group (severe hypoglycemia was defined as an episode requiring
`
`
`assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions).
`
`
`Papillary thyroid carcinoma
` In glycemic control trials of VICTOZA, there were 7 reported cases of papillary thyroid carcinoma in patients
`
`
`
`
`
`treated with VICTOZA and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1000 patient-years).
` Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical
`
`
`
`
`
`pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum
`
` calcitonin or thyroid ultrasound.
`
` Cholelithiasis and cholecystitis
`
`
`
` In glycemic control trials of VICTOZA, the incidence of cholelithiasis was 0.3% in both VICTOZA-treated and
` placebo-treated patients. The incidence of cholecystitis was 0.2% in both VICTOZA-treated and placebo-treated
`
`
`
`
`
`
` patients.
`
`In the LEADER trial [see Clinical Studies (14.3)], the incidence of cholelithiasis was 1.5% (3.9 cases per 1000
`
`
`
` patient years of observation) in VICTOZA-treated and 1.1% (2.8 cases per 1000 patient years of observation) in
`
`
`
`
`placebo-treated patients, both on a background of standard of care. The incidence of acute cholecystitis was
`
` 1.1% (2.9 cases per 1000 patient years of observation) in VICTOZA-treated and 0.7% (1.9 cases per 1000
`
`
`
`patient years of observation) in placebo-treated patients.
`
`
`Laboratory Tests
`
`Bilirubin
`
`In the five glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations
`
`
`
`
`
`(elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of VICTOZA-treated
`
`
`
`
`patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not
`
`
`accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown.
`
`
`
`
` Calcitonin
`
` Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the
`
`
`
`
`
`
`
`
` end of the glycemic control trials, adjusted mean serum calcitonin concentrations were higher in VICTOZA-
` treated patients compared to placebo-treated patients but not compared to patients receiving active comparator.
`
`
` Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less.
`
` Among patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of
`
` VICTOZA-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients.
`
`
`
` The clinical significance of these findings is unknown.
`
`
`
`Lipase and Amylase
`
`
`
`
`
`In one glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for
`
`amylase from baseline was observed for VICTOZA-treated patients while placebo-treated patients had a mean
`
`
`
`
`
`decrease in lipase of 3% and a mean increase in amylase of 1%.
`
`
`
`In the LEADER trial, serum lipase and amylase were routinely measured. Among VICTOZA-treated patients,
`
`
`
`
`
`7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of
`
`normal compared with 4.5% of placebo-treated patients, and 1% of VICTOZA-treated patients had an amylase
`
`
`
`
`
`
`value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of
`
`placebo-treated patients.
`
`
`
`
`
`The clinical significance of elevations in lipase or amylase with VICTOZA is unknown in the absence of other
`
`signs and symptoms of pancreatitis [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`Reference ID: 4705241
`
`Novo Nordisk Exhibit 2407
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
`
`
`
`
`
`
`Vital signs
`
`
`
`VICTOZA did not have adverse effects on blood pressure. Mean increases from baseline in heart rate of 2 to 3
`
`
`beats per minute have been observed with VICTOZA compared to placebo.
`
`
`
`Immunogenicity
`6.2
`
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated
` with VICTOZA may develop anti-liraglutide antibodies. The detection of antibody formation is highly
`
`
`
`
`
`dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody
` (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay
`
`methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
`
`
`
`
`For these reasons, the incidence of antibodies to liraglutide cannot be directly compared with the incidence of
`
`antibodies of other products.
`
` Approximately 50-70% of VICTOZA-treated patients in five double-blind clinical trials of 26 weeks duration or
`
`
`
`longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers
`(concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these
`
`VICTOZA-treated patients. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP
`
`
`1) occurred in 6.9% of the VICT