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
`
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`
`
`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).
`
`
`
`
`
` •
`
`•
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`
`•
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`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Indications and Usage ( 1) ------------------------------------------------------ 8/2017
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`Contraindications (4) ------------------------------------------------------------ 8/2017
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`Warnings and Precautions (5.2, 5.6, 5.7) ------------------------------------- 8/2017
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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).
`
`to reduce the risk of major adverse cardiovascular events in adults with type
`
`
`
`
`2 diabetes mellitus and established cardiovascular disease (1).
`
`
`
`
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`
`
`Limitations of Use:
`
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
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`
`
`• Has not been studied in combination with prandial insulin.
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Inject subcutaneously in the abdomen, thigh or upper arm (2.1).
`•
`
`
`
`
`• Administer once daily at any time of day, independently of meals (2.2).
`
`
`
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`
`
`Initiate at 0.6 mg per day for one week then increase to 1.2 mg. Dose can be
`•
`
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`
`
`
`
`
`increased to 1.8 mg for additional glycemic control (2.2).
`
`
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`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Injection: 6 mg/mL solution in a pre-filled, multi-dose pen that delivers doses of
`
`
`
`
`
`0.6 mg, 1.2 mg, or 1.8 mg (3).
`
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`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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 VICTOZA or any of the product components (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
`
`
`
`
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`(5.3).
`
`• Serious Hypoglycemia: When VICTOZA is used with an insulin secretagogue
`
`
`
`
`
`
`
`(e.g. a sulfonylurea) or insulin, consider lowering the dose of the insulin
`
`
`
`
`
`secretagogue or insulin to reduce the risk of hypoglycemia (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
`
`
`
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`
`
`VICTOZA are: nausea, diarrhea, vomiting, decreased appetite, dyspepsia,
`
`
`
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`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).
`
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`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. (7).
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Renal Impairment: No dose adjustment recommended (2.4, 8.6, 12.3).
`
`
`
`
`• Pregnancy: Victoza should be used during pregnancy only if the potential
`
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`
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`benefit justifies the potential risk to the fetus (8.1).
`
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`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`
`
`Medication Guide.
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`
` Revised: 08/2017
`
`Reference ID: 4144309
`
`
`
`
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
` INDICATIONS AND USAGE
`
` 1
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Important Administration Instructions
`
`
` 2.2 General Dosing and Administration
`
`
`
`
`
` 2.3 Concomitant Use with an Insulin Secretagogue (e.g. Sulfonylurea)
`
`
`
`
` or with Insulin
`
` 2.4 Dosage in Patients with Renal Impairment
`
`
`
`
`
` 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 Use with Medications Known to Cause 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
`
` USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
`
` 8.6 Renal Impairment
`
`
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` 8.7 Hepatic Impairment
`
`
` 8.8 Gastroparesis
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`
`
`10
`
`11
`
`12
`
`
`13
`14
`
`
`16
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`
`
`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 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
`
`
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`listed.
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`
` 6
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`
`
` 7
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`
`
` 8
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`
`
`
`
`Reference ID: 4144309
`
`
`
`
`
`
`
`

`

`
`
`
`
` 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 adults 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 (14.2)].
`
`
`
`
`
`•
`
`
`
`Limitations of Use:
`
`
`
` 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.
`
`
`
` The concurrent use of VICTOZA and prandial insulin has not been studied.
`
`
` 2
`
`
` 2.1
`
`
`
` DOSAGE AND ADMINISTRATION
`
` Important Administration Instructions
`
`Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no
`
` particles.
` 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.
`
`
`
` 2.2
`
` General Dosing and Administration
` Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals.
`
`
`
`
`
`
`
`
`
`
`
` Initiate VICTOZA 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. If a dose is
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4144309
`
`

`

`
`
`
`
`
`
`
`
` missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer
`
`
` an extra dose or increase in 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.
`
`
`
`
`
`
`
`
`
`
`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`2.3
`
`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
`
`(5.4) and Adverse Reactions (6)].
`
`
`
`
`Dosage in Patients with Renal Impairment
`2.4
`
`
`No dose adjustment is recommended for patients with renal impairment.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`Injection: 6 mg/mL solution in a pre-filled, multi-dose 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 VICTOZA or to
`
`
`any of the product components. 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
`
`
`
`Reference ID: 4144309
`
`

`

`
`
`
`
` 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, 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.
`
`
`
`Use with Medications Known to Cause Hypoglycemia
`5.4
`
`
`Patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin
`
`
`may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction
`
`in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin [see
`
`
`
`
`Dosage and Administration (2.2), Adverse Reactions (6.1)].
`
`
`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
`
`
`
`
`Reference ID: 4144309
`
`
`
`
`
`

`

`
`
`
`
` 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.
`
`
`
` 5.7 Acute Gallbladder Disease
` In the LEADER trial [see Clinical Studies (14.2)], 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.
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`The following serious adverse reactions are described below or elsewhere in the prescribing information:
`
`
`
`• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
`
`
`
`
`• Pancreatitis [see Warnings and Precautions (5.2)]
`
`
`
`
`• Use with Medications Known to Cause 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 data in Table 1 are derived from 5 glycemic control, placebo-controlled trials [see Clinical Studies
`
`
`(14.1)]. These data reflect exposure of 1673 patients to VICTOZA and a mean duration of exposure to
`
`
`
`
`
`
`VICTOZA of 37.3 weeks. The mean age of 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, 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.
`
`
`
`Table 1 Adverse reactions reported in ≥ 5% of VICTOZA-treated patients
`
`
`
`
`
`
`
`
` Placebo
` Liraglutide 1.8 mg
`
`
` Liraglutide 1.2 mg
`
`
`
` N= 1024
`
` N= 645
` N=661
`
` (%)
`
` (%)
`
` (%)
` Adverse Reaction
` 20
`
`
`
` 18
`
` 5
`Nausea
`Diarrhea
`
` 12
`
` 10
`
` 4
`
`
` 10
`
` 11
`
` 7
`Headache
`
`
` 10
`
` 9
`
` 8
` Nasopharyngitis
`
` 9
`
` 6
`
` 2
`
` Vomiting
`
` 9
` 10
`
` 1
` Decreased appetite
`
`
`Reference ID: 4144309
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 7
`
` 6
`
` 5
`
` 5
`
`
`
`
`
`
`
`
`
` 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)
`
` 0
`
` 2.6 (0.17)
`
` 0
` Placebo +
`
` Metformin + Rosiglitazone
`
` (N = 175)
`
`
`
` Patient not able to self-treat
`
`
`
` Patient able to self-treat
` Not classified
`
`
`Reference ID: 4144309
`
`
`
` 0
`
`
` 4.6 (0.15)
`
` 1.1 (0.03)
`
`
` Dyspepsia
`
` 4
`
` 1
`
`
` 7
`
` 6
` Upper Respiratory Tract Infection
`
` 5
`
` 1
`
` Constipation
`
` 4
`
` 3
`
` Back Pain
` Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights
`
`
` 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
`
`Hypoglycemia requiring the assistance of another person in placebo-controlled trials
`
`
`
`
`In 5 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 Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy
`
`
`
`
`Placebo-controlled Trials
`
`
`
` Add-on to Metformin
`
`
`
` VICTOZA Treatment
`
`
`
` 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)
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` Add-on to Metformin +
`
` Glimepiride
`
` Placebo +
`
`
` VICTOZA +
`
`
` Metformin +
`
` Metformin +
`
` Glimepiride
`
` Glimepiride
`
` (N = 114)
`
` (N = 230)
` Patient not able to self-treat
`
` 2.2 (0.06)
`
`
` 0
`
`
` 27.4 (1.16)
`
`
` 16.7 (0.95)
` Patient able to self-treat
` Not classified
`
`
`
` 0
` 0
` “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment
`
`
`
`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 (14.2)], 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) n 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%.
`
`
`
`
`
`Reference ID: 4144309
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`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)].
`
`
`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 (14.2)], anti-liraglutide antibodies were detected in 11 out of
`
`
`
`
`the 1247 (0.9%) VICTOZA-treated patients with antibody measurements.
`
`
`
`
`Reference ID: 4144309
`
`
`
`
`
`

`

`
`
`
`
`
`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.
`
`
`6.3 Post-Marketing Experience
`
`
`
`The following additional adverse reactions have been reported during post-approval use of VICTOZA.
`
`
`
`Because these events are reported voluntarily from a population of uncertain size, it is generally not
`
`
`possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
`
`
`• Medullary thyroid carcinoma [see Warnings and Precautions (5.1)]
`
`
`
`
`
` • Dehydration resulting from nausea, vomiting and diarrhea. [see Warnings and Precautions (5.5)
`
`
`
` and Patient Counseling Information (17)]
`
`
`
`
`
`•
`
` Increased serum creatinine, acute renal failure or worsening of c