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
`
`
`
`
`
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`Initial U.S. Approval: 2010
`
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`•
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`•
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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).
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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).
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`•
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`•
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`•
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`•
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`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`The most common adverse reactions, reported in ≥5% of patients treated
`•
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`
`
`
`
`
`
`with Victoza and more commonly than in patients treated with placebo,
`
`
`
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`are: headache, nausea, diarrhea and anti-liraglutide antibody formation (6).
`
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`
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`Immunogenicity-related events, including urticaria, were more common
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`among Victoza-treated patients (0.8%) than among comparator-treated
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`
`
`
`patients (0.4%) in clinical trials (6).
`
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`•
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`
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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
`•
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`
`
`administered oral medications. Use caution (7).
`
`
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Limited data in patients with renal or hepatic impairment. (8.6, 8.7).
`•
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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).
`
`•
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`
`
`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.
`
`
`
`Consider other antidiabetic therapies in patients with a history of
`
`
`
`
`pancreatitis (5.2).
`
`Never share a Victoza pen between patients, even if the needle is changed
`
`
`
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`(5.3).
`
`Serious Hypoglycemia: Can occur when Victoza is used with an insulin
`
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`
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`secretagogue (e.g. a sulfonylurea) or insulin. Consider lowering the dose of
`
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`the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.4).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Renal Impairment: Has been reported postmarketing, usually in association
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`
`
`
`
`Boxed Warning
`03/2015
`
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`with nausea, vomiting, diarrhea, or dehydration which may sometimes
`
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`Indications and Usage: Important Limitations of Use (1.1)
`03/2015
`
`
`
`require hemodialysis. Use caution when initiating or escalating doses of
`
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`Warnings and Precautions: Risk of Thyroid C-cell Tumors (5.1)
`03/2015
`
`
`
`
`Victoza in patients with renal impairment (5.5).
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`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Hypersensitivity: Postmarketing reports of serious hypersensitivity
`
`
`Victoza is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an
`
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`
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`reactions (e.g., anaphylactic reactions and angioedema). The patient should
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`adjunct to diet and exercise to improve glycemic control in adults with type 2
`
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`
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`discontinue Victoza and other suspect medications and promptly seek
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`diabetes mellitus (1).
`
`medical advice (5.6).
`
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`• Macrovascular Outcomes: There have been no studies establishing
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`
`
`
`Important Limitations of Use (1.1):
`
`
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`conclusive evidence of macrovascular risk reduction with Victoza or any
`
`• Not recommended as first-line therapy for patients inadequately controlled
`
`
`
`other antidiabetic drug (5.7).
`
`on diet and exercise (5.1).
`
`• Has not been studied in patients with a history of pancreatitis. Consider other
`
`
`
`
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`antidiabetic therapies in patients with a history of pancreatitis (5.2).
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`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
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`
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`• Has not been studied in combination with prandial insulin.
`
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`
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`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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
`•
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`
`
`
`
`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
`
`
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`
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`dose does not result in acceptable glycemic control, the dose can be
`
`
`increased to 1.8 mg (2).
`
`
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`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`
`
`Medication Guide.
`
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`
` Revised: 03/2015
`
`Reference ID: 3712555
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`
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`
`
`

`

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`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`
` 1
` INDICATIONS AND USAGE
` 1.1 Important Limitations of Use
`
`
`
`
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
` 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 Macrovascular Outcomes
`
`
` ADVERSE REACTIONS
`
`
` 6.1 Clinical Trials Experience
`
`
`
`
` 6.2 Post-Marketing Experience
`
` DRUG INTERACTIONS
`
`
`
` 7.1 Oral Medications
`
` USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
`
` 8.3 Nursing Mothers
`
`
` 8.4 Pediatric Use
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` 8.5 Geriatric Use
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` 8.6 Renal Impairment
`
`
` 8.7 Hepatic Impairment
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` 8.8 Gastroparesis
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` 6
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` 7
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` 8
`
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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 Monotherapy
`
`
`
`14.2 Combination Therapy
`
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`
`
`16.2 Recommended Storage
`
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1 FDA-Approved Medication Guide
`
`
`
`17.2 Risk of Thyroid C-cell Tumors
`
`
`
`
`17.3 Dehydration and Renal Failure
`
`
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`17.4 Pancreatitis
`
`
`
`17.5 Never Share a Victoza Pen Between Patients
`
`
`
`17.6 Hypersensitivity Reactions17.7
`Instructions
`
`
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`
`17.8 Laboratory Tests
`
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`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`
`
`Reference ID: 3712555
`
`
`
`
`
`
`
`

`

`
`
`
`
` 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), 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.
`
` Important Limitations of Use
`
`
` 1.1
`  Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on
`
`
`
` diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans.
` Prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the
`
`
`
`potential risk [see Warnings and Precautions (5.1).
`
`
`
`
`
` Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal
`
`
`hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza. Victoza has
`
`not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history
`
`of pancreatitis are at increased risk for pancreatitis while using Victoza. Other antidiabetic therapies
`
`should be considered in patients with a history of pancreatitis.
`
`
`
` 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.
`
`
`
`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
`
`
`
`
`Reference ID: 3712555
`
`

`

`
`
`
`
` 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 (5.4) and
`
`
`Adverse Reactions (6)].
`
`
`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.
`
`
`
`
`
`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.
`
`If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled
`
`
`dose. An extra dose or increase in dose should not be taken to make-up for the missed dose.
`
`
`
`
`Based on the elimination half-life, patients should be advised to reinitiate Victoza at 0.6 mg if more than
`
`
`
`3 days have elapsed since the last Victoza dose. This approach will mitigate any gastrointestinal
`
`
`
`symptoms associated with reinitiation of treatment. Upon reinitiation, Victoza should be titrated at the
`
`
`
`discretion of the prescribing healthcare provider.
`
`
`
`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).
`
`
`
`
`
`
`Victoza is contraindicated in patients with a prior serious hypersensitivity reaction to Victoza or to any of
`
`
`
`
`
`the product components.
`
`
`
`
`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).
`
`
`
`
`
`
`
`Reference ID: 3712555
`
`

`

`
`
`
`
`
`
`
`
`
`
` 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, 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. Consider antidiabetic therapies other than Victoza in patients with a history of
`
`
`
`pancreatitis.
`
`
` In clinical 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.
`
`
`
` 5.3
`
`
`
`
`
` Never Share a Victoza Pen Between Patients
` 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 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
`
`
`
`
`
`
`Reference ID: 3712555
`
`
`
`
`
`

`

`
`
`ADVERSE 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, the patient should
`
`
`
`discontinue Victoza and other suspect medications and promptly seek medical advice.
`
`
`
`
`
` Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a
` history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients
`
`will be predisposed to angioedema with Victoza.
`
`
`5.7 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`Victoza or any other antidiabetic drug.
`
`
`
`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 (5.3)]
`
` • Renal Impairment [see Warnings and Precautions (5.4)]
`
`
` • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
`
`
`
`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.
`
`
`
`The safety of Victoza has been evaluated in 8 clinical trials [see Clinical Studies (14)]:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`• A double-blind 52-week monotherapy trial compared Victoza 1.2 mg daily, Victoza 1.8 mg daily,
`
`
`
`
`
`
`
`and glimepiride 8 mg daily.
`
`
`
`• A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza
`
`
`
`
`1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily.
`
`
`
`
`
`
`• A double-blind 26 week add-on to glimepiride trial compared Victoza 0.6 mg daily, Victoza 1.2
`
`
`
`
`
`mg once-daily, Victoza 1.8 mg once-daily, placebo, and rosiglitazone 4 mg once-daily.
`
`
`
`
`
`• A 26 week add-on to metformin + glimepiride trial, compared double-blind Victoza 1.8 mg once-
`
`
`
`
`daily, double-blind placebo, and open-label insulin glargine once-daily.
`
`
`
`
`• A double-blind 26-week add-on to metformin + rosiglitazone trial compared Victoza 1.2 mg once-
`
`
`
`
`
`daily, Victoza 1.8 mg once-daily and placebo.
`
`
`
`• An open-label 26-week add-on to metformin and/or sulfonylurea trial compared Victoza 1.8 mg
`
`
`
`
`
`
`once-daily and exenatide 10 mcg twice-daily.
`
`
`• An open-label 26-week add-on to metformin trial compared Victoza 1.2 mg once-daily, Victoza
`
`
`
`
`1.8 mg once-daily, and sitagliptin 100 mg once-daily.
`
`
`• An open-label 26-week trial compared insulin detemir as add-on to Victoza 1.8 mg + metformin
`
`
`
`
`
`
`
`to continued treatment with Victoza + metformin alone.
`
`
`
`
`
`
`Withdrawals
`
`
`Reference ID: 3712555
`
`
`
`
`
`

`

` 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 double-blind 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. In these five trials, 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.
`
`
`
`
`
`
`Common adverse reactions
`
`
`
`
`
`Tables 1, 2, 3 and 4 summarize common adverse reactions (hypoglycemia is discussed separately)
`
`
`
`
`
`
`
`
`
`reported in seven of the eight controlled trials of 26 weeks duration or longer. Most of these adverse
`
`
`
`reactions were gastrointestinal in nature.
`
`
`
`
`In the five double-blind clinical trials of 26 weeks duration or longer, gastrointestinal adverse reactions
`
`
`were reported in 41% of Victoza-treated patients and were dose-related. Gastrointestinal adverse
`
`
`
`
`reactions occurred in 17% of comparator-treated patients. Common adverse reactions that occurred at a
`higher incidence among Victoza-treated patients included nausea, vomiting, diarrhea, dyspepsia and
`
`constipation.
`
`
`
`
`In the five double-blind and three open-label clinical trials of 26 weeks duration or longer, the percentage
`
`of patients who reported nausea declined over time. In the five double-blind trials approximately 13% of
`
`Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of
`
`treatment.
`
`
`
`
`
`
`
`In the 26-week open-label trial comparing Victoza to exenatide, both in combination with metformin
`
`
`
`
`
`and/or sulfonylurea, gastrointestinal adverse reactions were reported at a similar incidence in the Victoza
`
`
`
`and exenatide treatment groups (Table 3).
`
`
`
`
`
`
`In the 26-week open-label trial comparing Victoza 1.2 mg, Victoza 1.8 mg and sitagliptin 100 mg, all in
`
`
`combination with metformin, gastrointestinal adverse reactions were reported at a higher incidence with
`
`
`Victoza than sitagliptin (Table 4).
`
`
`
`
`In the remaining 26-week trial, all patients received Victoza 1.8 mg + metformin during a 12-week run-in
`
`
`
`period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of
`
`
`
`
`
`withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of
`
`
`withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period
`
`
`
`with inadequate glycemic control were randomized to 26 weeks of add-on therapy with insulin detemir or
`
`
`
`
`continued, unchanged treatment with Victoza 1.8 mg + metformin. During this randomized 26-week
`
`
`
`
`period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with Victoza 1.8 mg +
`
`
`
`
`metformin + insulin detemir (11.7%) and greater than in patients treated with Victoza 1.8 mg and
`
`metformin alone (6.9%).
`
`
`
`
`
`
`Table 1 Adverse reactions reported in ≥5% of Victoza-treated patients in a 52-week monotherapy
`
`trial
`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
` Vomiting
`
`
`
`Reference ID: 3712555
`
`
` All Victoza
`
`
`
` N = 497
` (%)
`
`
` 28.4
`
` 17.1
`
` 10.9
`
` Glimepiride
`
`
`
`
` N = 248
` (%)
`
`
` 8.5
` 8.9
`
`
` 3.6
`
`
`
`
`
`

`

`
`
`
`
`
`
` Table 2 Adverse reactions 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
`
` All Victoza +
`Placebo +
`
` Metformin
`
`
` Metformin
` N = 724
`
`
`
`
`
`
` N = 121
`
` (%)
` (%)
`
`
` 15.2
`
` 4.1
`
` 10.9
`
` 4.1
`
`
`
` 6.6
` 9.0
`
` 6.5
`
` 0.8
` Add-on to Glimepiride Trial
`
`
`
` All Victoza +
` Placebo +
`
`
`
` Glimepiride
` Glimepiride
`
`
`
`
` N = 114
` N = 695
`
`
`
` (%)
`
`
` (%)
`
` 1.8
`
` 7.5
`
` 1.8
`
` 7.2
`
` 0.9
`
` 5.3
`
` 0.9
`
` 5.2
`
` Add-on to Metformin + Glimepiride
`
` Victoza 1.8 +
`
`
`
`
` Placebo +
`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
` 8.2
`
`
` 5.1
`
`
` 9.9
`
` 9.1
`
`
` 4.8
` 9.3
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo +
`
`Metformin +
`
` Rosiglitazone
`
`
`
` N = 175
` (%)
`
`
` 8.6
`
` 6.3
`
` 2.9
`
` 4.6
`
` 1.1
`
`
`
` 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
`
`
`
` Table 3 Adverse Reactions reported in ≥5% of Victoza-treated patients in a 26-Week Open-Label
`
` Trial versus Exenatide
`
`
`
`
`
` Constipation
`
` Headache
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Vomiting
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
` Constipation
`
` Dyspepsia
`
`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Dyspepsia
`
` Vomiting
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Vomiting
`
` Headache
` Constipation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3712555
`
`
`
`
`
`

`

`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Dyspepsia
`
` Vomiting
` Constipation
`
`
`
`
`
`Victoza
`
`
`
` 1.8 mg once daily
` + metformin and/or
`
`
` sulfonylurea
`
`
` N = 235
` (%)
`
`
` 25.5
`
` 12.3
`
` 8.9
`
` 8.9
`
` 6.0
`
` 5.1
`
` Exenatide
`
`
`
` 10 mcg twice daily
`
` + metformin and/or
`
`
` sulfonylurea
`
`
` N = 232
` (%)
`
`
` 28.0
`
` 12.1
`
` 10.3
`
` 4.7
`
` 9.9
`
` 2.6
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 4 Adverse Reactions in ≥5% of Victoza-treated patients in a 26-Week Open-Label Trial
`
` versus Sitagliptin
`
`
`
`
` Adverse Reaction
`
` Nausea
`
` Headache
`
` Diarrhea
` Vomiting
`
`
` All Victoza
`
`
` + metformin
`
` N = 439
`
` (%)
`
` 23.9
`
` 10.3
`
` 9.3
`
` 8.7
`
`
`
`
` Sitagliptin 100 mg/day
` + metformin
`
`
` N = 219
`
` (%)
`
` 4.6
`
` 10.0
`
` 4.6
`
` 4.1
`
`
`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 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. 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 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.
`
`
`
`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-
`
`
`
`
`
`
`Reference ID: 3712555
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
` negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no
` reduction in HbA1c with Victoza treatment.
`
`
`
`
`
`
`
`
`In the five double-blind 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 double-blind 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 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 p