`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use Victoza
`safely and effectively. See full prescribing information for Victoza.
`
`
`Victoza® (liraglutide [rDNA origin] injection), solution 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 rodents. It is unknown whether Victoza causes thyroid C-cell
`tumors, including medullary thyroid carcinoma (MTC), in humans, as
`
`human relevance could not be determined by clinical or nonclinical
`
`studies (5.1).
`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) (5.1).
`
`
`
`
`·······································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 adults with type 2
`diabetes mellitus (1).
`
`
`Important Limitations of Use (1.1):
`
`• Not recommended as first-line therapy for patients inadequately controlled
`on diet and exercise (5.1).
`
`• Has not been studied sufficiently in patients with a history of pancreatitis.
`Use caution (5.2).
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`• Has not been studied in combination with insulin.
`
`··································DOSAGE AND ADMINISTRATION·······························
`
`
`
`• Administer once daily at any time of day, independently of meals (2).
`
`
`
`Inject subcutaneously in the abdomen, thigh or upper arm (2).
`•
`
`
`• The injection site and timing can be changed without dose adjustment (2).
`
`Initiate at 0.6 mg per day for one week. This dose is intended to reduce
`•
`gastrointestinal symptoms during initial titration, and is not effective for
`
`
`
`glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg
`dose does not result in acceptable glycemic control, the dose can be
`increased to 1.8 mg (2).
`
`• When initiating Victoza, consider reducing the dose of concomitantly-
`
`administered insulin secretagogues to reduce the risk of hypoglycemia (2).
`
`
`·······························DOSAGE FORMS AND STRENGTHS······························
`
`• Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers
`
`
`
`
`doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL) (3).
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`BOXED WARNING: RISK OF THYROID C-CELL TUMORS
`
`1
`
`INDICATIONS AND USAGE
`
`Important Limitations of Use
`1.1
`DOSAGE AND ADMINISTRATION
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1 Risk of Thyroid C-cell Tumors
`
`5.2 Pancreatitis
`5.3 Use with Medications Known to Cause Hypoglycemia
`
`5.4 Macrovascular Outcomes
`
`ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`
`7.1 Oral Medications
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Gastroparesis
`
`
`2
`3
`4
`5
`
`6
`
`7
`
`8
`
`
`
`
`
`
`
`
`
`
`
`
`
`········································CONTRAINDICATIONS··············································
`Do not use in patients with a personal or family history of medullary thyroid
`carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4).
`
`··································WARNINGS AND PRECAUTIONS······························
`
`Thyroid C-cell tumors in animals: Human relevance unknown. Counsel
`•
`patients regarding the risk of medullary thyroid carcinoma and the
`
`symptoms of thyroid tumors (5.1).
`
`Pancreatitis: In clinical trials, there were more cases of pancreatitis among
`
`Victoza-treated patients than among comparator-treated patients. If
`
`pancreatitis is suspected, Victoza and other potentially suspect drugs
`should be discontinued. Victoza should not be restarted if pancreatitis is
`
`confirmed. Use with caution in patients with a history of pancreatitis (5.2).
`Serious hypoglycemia: Can occur when Victoza is used with an insulin
`
`
`secretagogue (e.g. a sulfonylurea). Consider lowering the dose of the
`
`insulin secretagogue to reduce the risk of hypoglycemia (5.3).
`
`• Macrovascular outcomes: There have been no studies establishing
`
`conclusive evidence of macrovascular risk reduction with Victoza or any
`
`other antidiabetic drug (5.4).
`
`
`•
`
`
`•
`
`
`•
`
`
`········································ADVERSE REACTIONS···········································
`
`
`The most common adverse reactions, reported in ≥5% of patients treated
`•
`with Victoza and more commonly than in patients treated with placebo,
`
`are: headache, nausea, diarrhea and anti-liraglutide antibody formation (6).
`
`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).
`
`
`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-----------------------------------
`
`
`Victoza delays gastric emptying. May impact absorption of concomitantly
`•
`
`administered oral medications. Use caution (7).
`
`
`····································USE IN SPECIFIC POPULATIONS·····························
`
`
`There are no data in patients below 18 years of age (8.4).
`•
`
`Use with caution in patients with renal or hepatic impairment. Limited data
`•
`(8.6, 8.7).
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`Medication Guide.
`
`Revised: 1/2010
`
`
`
`
`
`
`
`10
`11
`12
`
`
`13
`14
`
`16
`
`17
`
`
`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 Monotherapy
`
`14.2 Combination Therapy
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Recommended Storage
`PATIENT COUNSELING INFORMATION
`17.1 Risk of Thyroid C-cell Tumors
`
`
`17.2 Pancreatitis
`
`
`17.3 Never Share a Victoza Pen Between Patients
`
`17.4 Instructions
`
`17.5 Laboratory Tests
`17.6 FDA-Approved Medication Guide
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
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`

`

`
`
`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 human relevance
`could not be ruled out by clinical or nonclinical studies. 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). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound
`was performed during clinical trials, but this may have increased the number of unnecessary thyroid
`surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate
`human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of
`thyroid tumors [see Contraindications (4), Warnings and Precautions (5.1) and Nonclinical
`Toxicology (13.1)].
`
`INDICATIONS AND USAGE
`1
`Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2
`diabetes mellitus.
`
`Important Limitations of Use
`1.1
`
`ƒ Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe
`Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk.
`Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on
`diet and exercise.
`
`
`
`ƒ In clinical trials of Victoza, there were more cases of pancreatitis with Victoza than with comparators.
`Victoza has not been studied sufficiently in patients with a history of pancreatitis to determine whether
`these patients are at increased risk for pancreatitis while using Victoza. Use with caution in patients
`with a history of pancreatitis.
`
`
`
`ƒ Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes
`mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
`
`
`
`ƒ The concurrent use of Victoza and insulin has not been studied.
`
`DOSAGE AND ADMINISTRATION
`2
`
`Victoza can be administered once daily at any time of day, independently of meals, and can be injected
`subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed
`without dose adjustment.
`
`For all patients, Victoza should be initiated with a dose of 0.6 mg per day 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. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the
`1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg.
`
`When initiating Victoza, consider reducing the dose of concomitantly administered insulin secretagogues
`(such as sulfonylureas) to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3) and
`Adverse Reactions (6)].
`
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
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`

`
`
`Victoza solution should be inspected prior to each injection, and the solution should be used only if it is
`clear, colorless, and contains no particles.
`
`DOSAGE FORMS AND STRENGTHS
`3
`Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or
`1.8 mg (6 mg/mL, 3 mL).
`
`CONTRAINDICATIONS
`4
`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).
`
`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. A statistically
`significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure
`compared to controls. 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 could not be determined by clinical or nonclinical studies [see Boxed Warning,
`Contraindications (4)].
`
`In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza-treated
`patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One
`additional case of thyroid C-cell hyperplasia in a Victoza-treated patient and 1 case of MTC in a
`comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC
`had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of
`these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine,
`protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had
`elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non­
`liraglutide-treated patient developed elevated calcitonin concentrations while on treatment.
`
`Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The
`serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of
`0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At
`Weeks 26 and 52 in the clinical 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. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just
`above the LLOQ with between-group differences in adjusted mean serum calcitonin values of
`approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit
`of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent
`measurements occurred most frequently among patients treated with Victoza 1.8 mg/day. In trials with
`on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza 1.8
`mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range
`compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza.
`In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with
`Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference
`range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated
`
`
`
`
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`IPR2023-00724
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`

`
`
`with Victoza 1.2 mg, placebo and active control, respectively. Otherwise, Victoza did not produce
`consistent dose-dependent or time-dependent increases in serum calcitonin.
`
`Patients with MTC usually have calcitonin values >50 ng/L. In Victoza clinical trials, among patients
`with pre-treatment serum calcitonin <50 ng/L, one Victoza-treated patient and no comparator-treated
`patients developed serum calcitonin >50 ng/L. The Victoza-treated patient who developed serum
`calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7
`ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L
`more than 2.5 years after the last dose of Victoza. The largest increase in serum calcitonin in a
`comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from
`
`19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began
`with serum 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, with an
`
`incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these
`findings is unknown.
`
`Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck,
`dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or
`thyroid ultrasound will mitigate the potential risk of MTC, and 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. Patients with thyroid nodules noted on physical examination or neck imaging obtained
`for other reasons should be referred to an endocrinologist for further evaluation. Although routine
`monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is
`measured and found to be elevated, the patient should be referred to an endocrinologist for further
`evaluation.
`
`5.2
`Pancreatitis
`
`In clinical trials of Victoza, there were 7 cases of pancreatitis among Victoza-treated patients and 1 case
`among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza
`were reported as acute pancreatitis and two cases with Victoza 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. One additional case of pancreatitis has subsequently been
`
`reported in a Victoza-treated patient. Some patients had other risk factors for pancreatitis, such as a
`history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis
`with Victoza treatment. After initiation of Victoza, and after dose increases, 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, Victoza
`and other potentially suspect medications should be discontinued promptly, confirmatory tests should be
`performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should
`not be restarted. Use with caution in patients with a history of pancreatitis.
`
`Use with Medications Known to Cause Hypoglycemia
`5.3
`Patients receiving Victoza in combination with an insulin secretagogue (e.g., sulfonylurea) may have an
`increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia
`requiring the assistance of another person for treatment occurred in 7 Victoza-treated patients and in no
`comparator-treated patients. Six of these 7 patients treated with Victoza were also taking a sulfonylurea.
`The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin
`secretagogues [see Adverse Reactions (6.1)].
`
`
`
`
`
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`

`
`
`
`5.4 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`Victoza or any other antidiabetic drug.
`
`6
` ADVERSE REACTIONS
`
`6.1
`Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`
`The safety of Victoza was evaluated in a 52-week monotherapy trial and in four 26-week, add-on
`combination therapy trials. In the monotherapy trial, patients were treated with Victoza 1.2 mg daily,
`Victoza 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated
`with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to
`glimepiride trial, patients were treated with Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or
`rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza 1.8
`mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated
`with Victoza 1.2 mg, Victoza 1.8 mg or placebo [see Clinical Studies (14)].
`
`Withdrawals
`The incidence of withdrawal due to adverse events was 7.8% for Victoza-treated patients and 3.4% for
`comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference
`was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza­
`treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to
`withdrawal for Victoza-treated patients were nausea (2.8% versus 0% for comparator) and vomiting
`(1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred
`during the first 2-3 months of the trials.
`
`Tables 1 and 2 summarize the adverse events reported in ≥5% of Victoza-treated patients in the five
`controlled trials of 26 weeks duration or longer.
`
`Table 1 Adverse events reported in ≥ 5% of Victoza-treated patients or ≥5% of glimepiride-treated
`
`patients: 52-week monotherapy trial
`
`
`Adverse Event Term
`Nausea
`Diarrhea
` Vomiting
`
` Constipation
`
`Upper Respiratory Tract Infection
`Headache
`Influenza
`Urinary Tract Infection
`Dizziness
`Sinusitis
`Nasopharyngitis
`
` Back Pain
` Hypertension
`
`
`
`All Victoza
`N = 497
`(%)
`28.4
`17.1
`10.9
`9.9
`9.5
`9.1
`7.4
`6.0
`5.8
`5.6
`5.2
`5.0
`3.0
`
`
`
`Glimepiride
`N = 248
`(%)
`8.5
`8.9
`3.6
`4.8
`5.6
`9.3
`3.6
`4.0
`5.2
`6.0
`5.2
`4.4
`6.0
`
`
`
`
`
`
`
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`IPR2023-00724
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`

`
`
`
`
`Adverse Event Term
`Nausea
`Diarrhea
`Headache
`Vomiting
`
`
`
`Adverse Event Term
`Nausea
`Diarrhea
`Constipation
`Dyspepsia
`
`
`
`Adverse Event Term
`Nausea
`Diarrhea
`Headache
`Dyspepsia
`Vomiting
`
`
`
`
`Table 2 Adverse events reported in ≥ 5% of Victoza-treated patients and occurring more frequently
`
`with Victoza compared to placebo: 26-week combination therapy trials
`
` Add-on to Metformin Trial
`
`Placebo +
`All Victoza +
`Metformin
`Metformin
`N = 121
`N = 724
`(%)
`(%)
`15.2
`4.1
`10.9
`4.1
`9.0
`6.6
`6.5
`0.8
`
`
` Add-on to Glimepiride Trial
`
`Placebo +
`All Victoza +
`Glimepiride
`Glimepiride
`N=114
`N=695
`(%)
`(%)
`7.5
`1.8
`7.2
`1.8
`5.3
`0.9
`5.2
`0.9
`Add-on to Metformin + Glimepiride
`
`
`Placebo +
` Victoza 1.8+
`Metformin +
`Metformin +
`Glimepiride
`Glimepiride
`N = 230
`N = 114
`(%)
`(%)
`13.9
`3.5
`10.0
`5.3
`9.6
`7.9
`6.5
`0.9
`6.5
`3.5
`Add-on to Metformin + Rosiglitazone
`
`
`All Victoza +
`Metformin +
`Rosiglitazone
`N = 355
`(%)
`34.6
`14.1
`12.4
`9.3
`9.0
`8.2
`5.1
`5.1
`
`Adverse Event Term
`Nausea
`Diarrhea
`Vomiting
`Decreased Appetite
`Anorexia
`Headache
`Constipation
`Fatigue
`
`
`Glimepiride +
` Metformin
`N = 242
`(%)
`3.3
`3.7
`9.5
`0.4
`
`
`Rosiglitazone +
`Glimepiride
`N=231
`(%)
`2.6
`2.2
`1.7
`2.6
`
`Glargine +
`Metformin +
`Glimepiride
`N = 232
`(%)
`1.3
`1.3
`5.6
`1.7
`0.4
`
`Placebo +
`Metformin +
`
`Rosiglitazone
`N = 175
`(%)
`8.6
`6.3
`2.9
`1.1
`0.0
`4.6
`1.1
`1.7
`
`
`Gastrointestinal adverse events
`In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in
`41% of Victoza-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17%
`of comparator-treated patients. Events that occurred more commonly among Victoza-treated patients
`included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or
`longer, the percentage of patients who reported nausea declined over time. Approximately 13% of
`Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of
`treatment.
`
`
`
`
`
`
`
`
`
`
`Novo Nordisk Exhibit 2068
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

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`Immunogenicity
`Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients
`treated with Victoza may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza-treated
`patients in the five 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. Sampling was not
`performed uniformly across all patients in the clinical trials, and this may have resulted in an
`underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti­
`liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza-treated
`patients in the 52-week monotherapy trial and in 4.8% of the Victoza-treated patients in the 26-week add-
`on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect
`against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was
`not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3%
`of the Victoza-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza-treated
`patients in the 26-week add-on combination therapy trials.
`
`Among Victoza-treated patients who developed anti-liraglutide antibodies, the most common category of
`adverse events was that of infections, which occurred among 40% of these patients compared to 36%,
`34% and 35% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients,
`respectively. The specific infections which occurred with greater frequency among Victoza-treated
`antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred
`among 11% of Victoza-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-
`negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Among
`Victoza-treated antibody-negative patients, the most common category of adverse events was that of
`gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza-treated,
`placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated
`with reduced efficacy of Victoza when comparing mean HbA1c of all antibody-positive and all antibody-
`negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no
`reduction in HbA1c with Victoza treatment.
`
`In clinical trials of Victoza, events from a composite of adverse events potentially related to
`immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza-treated patients and among
`0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this
`composite for Victoza-treated patients. Patients who developed anti-liraglutide antibodies were not more
`likely to develop events from the immunogenicity events composite than were patients who did not
`develop anti-liraglutide antibodies.
`
`Injection site reactions
`Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza­
`treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza-treated
`patients discontinued due to injection site reactions.
`
`Papillary thyroid carcinoma
`In clinical trials of Victoza, there were 6 reported cases of papillary thyroid carcinoma in patients treated
`with Victoza and 1 case in a comparator-treated patient (1.9 vs. 0.6 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.
`
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`Novo Nordisk Exhibit 2068
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

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`Hypoglycemia
`In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another
`person for treatment occurred in 7 Victoza-treated patients (2.6 cases per 1000 patient-years) and in no
`comparator-treated patients. Six of these 7 patients treated with Victoza were also taking a sulfonylurea.
`One other patient was taking Victoza in combination with metformin but had another likely explanation
`for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3).
`Two additional cases of hypoglycemia requiring the assistance of another person for treatment have
`subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients
`were receiving Victoza, one as monotherapy and the other in combination with metformin. Both patients
`had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled
`intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake).
`
`Table 3 Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial
`and in the 26-Week Combination Therapy Trials
`
`Victoza Treatment
`Victoza (N = 497)
`Monotherapy
`Patient not able to self-treat
`0
`Patient able to self-treat
`9.7 (0.24)
`Not classified
`1.2 (0.03)
`
`Add-on to Metformin
`Victoza +
`Metformin
`
`(N = 724)
`0.1 (0.001)
`3.6 (0.05)
`Victoza +
`Glimepiride
`(N = 695)
`0.1 (0.003)
`7.5 (0.38)
`0.9 (0.05)
`Victoza +
`Metformin +
`Rosiglitazone
`(N = 355)
`0
`7.9 (0.49)
`0.6 (0.01)
`Victoza +
`Metformin +
`Glimepiride
`(N = 230)
`2.2 (0.06)
`27.4 (1.16)
`0
`
`Placebo Comparator
`None
`-
`-
`-
`Placebo +
`Metformin
`
`(N = 121)
`0
`2.5 (0.06)
`Placebo +
`Glimepiride
`
`(N = 114)
`0
`2.6 (0.17)
`0
`Placebo +
`Metformin +
`Rosiglitazone
`(N = 175)
`0
`4.6 (0.15)
`1.1 (0.03)
`Placebo +
`Metformin +
`Glimepiride
`(N = 114)
`0
`16.7 (0.95)
`0
`
`Active Comparator
`Glimepiride (N = 248)
`
`0
`25.0 (1.66)
`2.4 (0.04)
`Glimepiride +
`Metformin
`
`
`(N = 242)
`0
`22.3 (0.87)
`Rosiglitazone +
`Glimepiride
`(N = 231)
`0
`4.3 (0.12)
`0.9 (0.02)
`
`None
`
`-
`-
`-
`Insulin glargine +
`Metformin +
`Glimepiride
`(N = 232)
`0
`28.9 (1.29)
`1.7 (0.04)
`
`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
`
`Patient not able to self-treat
`Patient able to self-treat
`Not classified
`
`Add-on to Metformin +
`Glimepiride
`
`Patient not able to self-treat
`Patient able to self-treat
`Not classified
`
`
`
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`
`Novo Nordisk Exhibit 2068
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
`
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`In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms
`(based on investigator-reported events, medical history, pathology reports, and surgical reports from both
`blinded and open-label study periods) was 10.9 for Victoza, 6.3 for placebo, and 7.2 for active
`comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions (6.1)], no
`particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year
`of exposure to study medication, six events among Victoza-treated patients (4 colon, 1 prostate and 1
`nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not
`been established.
`
`Laboratory Tests
`In the five clinical 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.
`
`DRUG INTERACTIONS
`7
`7.1 Oral Medications
`Victoza causes a delay of gastric emptying, and thereby has the potential to impact the absorption of
`concomitantly administered oral medications. In clinical pharmacology trials, Victoza did not affect the
`absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless,
`caution should be exercised when oral medications are concomitantly administered with Victoza.
`
`USE IN SPECIFIC POPULATIONS
`8
`Pregnancy
`8.1
`Pregnancy Category C.
`There are no adequate and well-controlled studies of Victoza in pregnant women. Victoza should be used
`during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been
`shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the
`maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-
`concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total
`
`major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on