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) 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∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`Dosage and Administration (2.1)------------------------------------------06/2022
`Warnings and Precautions (5.7) -------------------------------------------06/2022
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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 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:06/2022
`
`Reference ID: 4997159
`
`
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`

`

`
`
`
`
`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
`PATIENT COUNSELING INFORMATION
`17
`
`
`*Sections or subsections omitted from the full prescribing information are
`not listed.
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: RISK OF THYROID C-CELL TUMORS
`
` 1
`
`INDICATIONS AND USAGE
`
`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
`
`
`
`Reference ID: 4997159
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`
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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 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)].
`
` 1
`
`•
`
`INDICATIONS AND USAGE
`
`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.
`
`
` 2
`
`
`2.1
`•
`•
`•
`
`DOSAGE AND ADMINISTRATION
`Important Dosing and Administration Instructions
`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.
`• Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see
`Adverse Reactions (6.3)].
`• 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.
`
`•
`
`•
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`
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`Reference ID: 4997159
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`MPI EXHIBIT 1107 PAGE 3
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`•
`
`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.
`
`•
`
` 3
`
`DOSAGE FORMS AND STRENGTHS
`
`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.
`
` 4
`
`CONTRAINDICATIONS
`
`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 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)].
`
` 5
`
`WARNINGS AND PRECAUTIONS
`
`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,
`
`
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`Reference ID: 4997159
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`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.
`
`Renal Impairment
`5.5
`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.
`
`
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`Reference ID: 4997159
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`5.7 Acute Gallbladder Disease
`Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1
`receptor agonist trials and postmarketing. 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 [see Adverse Reactions (6.1)]. 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)]
`• Acute Gallbladder Disease [see Warnings and Precautions (5.7)]
`
`
`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.
`
`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
`Nausea
`5
`18
`12
`Diarrhea
`4
`10
`10
`Headache
`7
`11
`10
`Nasopharyngitis
`8
`9
`9
`Vomiting
`2
`6
`9
`Decreased appetite
`1
`10
`7
`Dyspepsia
`1
`4
`6
`Upper Respiratory Tract Infection
`6
`7
`5
`Constipation
`1
`5
`5
`Back Pain
`3
`4
`Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights.
`
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`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)
`
`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 = 175)
`(N = 355)
`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 = 114)
`(N = 230)
`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.
`
`Patient not able to self-treat
`Patient able to self-treat
`Not classified
`Add-on to
`Metformin + Glimepiride
`
`
`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
`
`
`
`
`
`
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`Reference ID: 4997159
`
`MPI EXHIBIT 1107 PAGE 7
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`MPI EXHIBIT 1107 PAGE 7
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`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. The majority of events required hospitalization or
`cholecystectomy.
`
`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.
`
`
`
`
`
`
`
`
`Reference ID: 4997159
`
`MPI EXHIBIT 1107 PAGE 8
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`MPI EXHIBIT 1107 PAGE 8
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`
`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)].
`
`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 VICTOZA-treated patients in the double-blind 52-week monotherapy trial and in
`4.8% of the VICTOZA-treated patients in the double-blind 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 double-blind 52-
`week monotherapy trial and in 1.0% of the VICTOZA-treated patients in the double-blind 26-week add-on
`combination therapy trials.
`
`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 five double-blind glycemic control 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.
`
`In the LEADER trial [see Clinical Studies (14.3)], anti-liraglutide antibodies were detected in 11 out of the
`1247 (0.9%) VICTOZA-treated patients with antibody measurements.
`
`Of the 11 VICTOZA-treated patients who developed anti-liraglutide antibodies, none were observed to develop
`neutralizing antibodies to liraglutide, and 5 patients (0.4%) developed cross-reacting antibodies against native
`GLP-1.
`
`In a clinical trial with pediatric patients 10 to 17 years [see Clinical Studies (14.2)], anti-liraglutide antibodies
`were detected in 1 (1.5%) VICTOZA treated patient at week 26 and 5 (8.5%) VICTOZA treated patients at
`week 53. None of the 5 had antibodies cross reactive to native GLP-1 or had neutralizing antibodies.
`
`
`
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`
`
`
`
`Reference ID: 4997159
`
`MPI EXHIBIT 1107 PAGE 9
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`MPI EXHIBIT 1107 PAGE 9
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`6.3 Post-Marketing Experience
`The following additional adverse reactions have been reported during post-approval use of VICTOZA. Be