` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`
`
`
`
` Do not use in patients with a personal or family history of medullary thyroid
`
` carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4).
`
`
`
`
`Do not use if history of serious hypersensitivity to Victoza or any product
`
`
`
`
`components (4).
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Thyroid C-cell tumors in animals: Counsel patients regarding the risk of
`
`
`
`
`
`
`•
`medullary thyroid carcinoma and the symptoms of thyroid tumors (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.
`
`
`
`
`
`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
`
`
`
`
`(5.3).
`
`Serious hypoglycemia: Can occur when Victoza is used with an insulin
`
`
`
`
`
`
`secretagogue (e.g. a sulfonylurea) or insulin. Consider lowering the dose of
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.4).
`
`
`
`
`Warnings and Precautions (5.3)
`02/2015
`
`
`
`
`Renal Impairment: Has been reported postmarketing, usually in association
`
`
`
`
`
`
`•
`
`with nausea, vomiting, diarrhea, or dehydration which may sometimes
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`require hemodialysis. Use caution when initiating or escalating doses of
`
`
`
`
`Victoza is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an
`
`
`
`
`
`Victoza in patients with renal impairment (5.5).
`
`
`
`
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`
`
`
`diabetes mellitus (1).
`
`Hypersensitivity: Postmarketing reports of serious hypersensitivity
`
`
`
`reactions (e.g., anaphylactic reactions and angioedema). The patient should
`
`
`
`Important Limitations of Use (1.1):
`
`
`
`discontinue Victoza and other suspect medications and promptly seek
`
`
`medical advice (5.6).
`
`• Not recommended as first-line therapy for patients inadequately controlled
`
`
`on diet and exercise (5.1).
`
`• Macrovascular outcomes: There have been no studies establishing
`
`
`conclusive evidence of macrovascular risk reduction with Victoza or any
`
`• Has not been studied in patients with a history of pancreatitis.
`
`
`
`other antidiabetic drug (5.7).
`
`Consider other antidiabetic therapies in patients with a history of
`
`
`
`pancreatitis (5.2).
`
`• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
`
`
`
`
`
`
`• Has not been studied in combination with prandial insulin.
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Administer once daily at any time of day, independently of meals (2).
`
`
`
`
`
`
`Inject subcutaneously in the abdomen, thigh or upper arm (2).
`•
`
`
`
`
`
`• The injection site and timing can be changed without dose adjustment (2).
`
`
`
`Initiate at 0.6 mg per day for one week. This dose is intended to reduce
`•
`
`
`
`
`
`
`gastrointestinal symptoms during initial titration, and is not effective for
`
`
`
`glycemic control. After one week, increase the dose to 1.2 mg. If the 1.2 mg
`
`
`
`
`
`
`dose does not result in acceptable glycemic control, the dose can be
`
`
`increased to 1.8 mg (2).
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`The most common adverse reactions, reported in ≥5% of patients treated
`
`
`
`
`
`
`
`•
`with Victoza and more commonly than in patients treated with placebo,
`
`
`
`
`are: headache, nausea, diarrhea and anti-liraglutide antibody formation (6).
`
`
`
`
`Immunogenicity-related events, including urticaria, were more common
`
`among Victoza-treated patients (0.8%) than among comparator-treated
`
`
`
`
`patients (0.4%) in clinical trials (6).
`
`
`
`
`
`•
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or
`
`
`
`
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS----------------------------------­
`
`Victoza delays gastric emptying. May impact absorption of concomitantly
`
`
`
`
`
`•
`
`administered oral medications. Use caution (7).
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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).
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use Victoza
` safely and effectively. See full prescribing information for Victoza.
`
`
`
`
`
`Victoza® (liraglutide [rDNA origin] injection), solution for subcutaneous use
`
`
`
`
`
`
`
`
`Initial U.S. Approval: 2010
`
`
`
`
`
`
`
`
`
`
`•
`
`•
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`See full prescribing information for complete boxed warning.
`
`
`
`Liraglutide causes thyroid C-cell tumors at clinically relevant exposures
`
`
`
`in rodents. It is unknown whether Victoza causes thyroid C-cell
`
`
`
`tumors, including medullary thyroid carcinoma (MTC), in humans, as
`
`
`human relevance could not be determined by clinical or nonclinical
`
`
`
`studies (5.1).
`
`
`Victoza is contraindicated in patients with a personal or family history
`
`
`
`of MTC or in patients with Multiple Endocrine Neoplasia syndrome
`
`
`
`
`type 2 (MEN 2) (5.1).
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Limited data in patients with renal or hepatic impairment. (8.6, 8.7).
`
`
`
`
`
`
`•
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`
`
`Medication Guide.
`
`
`
`
` Revised: 02/2015
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
` 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
`
`
`
` 8.5 Geriatric Use
`
`
`
`
` 8.6 Renal Impairment
`
`
` 8.7 Hepatic Impairment
`
`
` 8.8 Gastroparesis
`
`
`
`
`
` 6
`
`
`
` 7
`
`
`
` 8
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`14
`
`
`16
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`CLINICAL STUDIES
`
`14.1 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
`
`
`
`
`17.4 Pancreatitis
`
`
`
`17.5 Never Share a Victoza Pen Between Patients
`
`
`
`17.6 Hypersensitivity Reactions
`
`
`
`17.7
`Instructions
`
`
`
`17.8 Laboratory Tests
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`listed.
`
`
`
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`
`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at
` clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes
`
`
`
`
` thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance
` could not be ruled out by clinical or nonclinical studies. Victoza is contraindicated in patients with a
`
`
` personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2
` (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound
`
`
` was performed during clinical trials, but this may have increased the number of unnecessary thyroid
`
`
`
` surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate
`
`
` human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of
`
`
`
`
` thyroid tumors [see Contraindications (4), Warnings and Precautions (5.1) and Nonclinical
` Toxicology (13.1)].
`
`
`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
`
`
`
`  Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe
`
` Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk.
`
`
` Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on
`
` diet and exercise.
`
`
`
` 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
`
`
`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.
`
`
`
`
`
`Reference ID: 3706643
`
`

`

`
`
`
`
`
`
`
`
`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
`
`
`
`
`
`
`
`
`Do not use 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).
`
`
`
`
`
`
`
`Do not use in patients with a prior serious hypersensitivity reaction to Victoza or to any of the product
`
`components.
`
`
`5
`
`
`
`Risk of Thyroid C-cell Tumors
`5.1
`
`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas
`
`and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical
`
`
`Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically
`
`
`
`
`
`significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure
`
`
`compared to controls. It is unknown whether Victoza will cause thyroid C-cell tumors, including
`
`medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent
`thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning,
`
`Contraindications (4)].
`
`
`
`
`
`
`In the clinical trials, there have been 6 reported cases of thyroid C-cell hyperplasia among Victoza-treated
`
`
`
`
`
`patients and 2 cases in comparator-treated patients (1.3 vs. 1.0 cases per 1000 patient-years). One
`
`
`comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L
`
`
`suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was
`
`
`prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Five of
`
`the six Victoza-treated patients had elevated calcitonin concentrations at baseline and throughout the
`
`
`WARNINGS AND PRECAUTIONS
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`
`
`
`trial. One Victoza and one non-Victoza-treated patient developed elevated calcitonin concentrations
`
`while on treatment.
`
`
`
`Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The
`
`
`serum calcitonin assay used in the Victoza clinical trials had a lower limit of quantification (LLOQ) of
`
`
`
`
`0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At
`Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in
`Victoza-treated patients compared to placebo-treated patients but not compared to patients receiving
`
`
`active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just
`
`
`
`above the LLOQ with between-group differences in adjusted mean serum calcitonin values of
`approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit
`
`
` of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent
` measurements occurred most frequently among patients treated with Victoza 1.8 mg/day. In trials with
`
`
`
`
`
`on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza 1.8
`mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range
`
`compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza.
`
`In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with
`
`Victoza 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference
`
`range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated
`
`
`with Victoza 1.2 mg, placebo and active control, respectively. Otherwise, Victoza did not produce
`
`consistent dose-dependent or time-dependent increases in serum calcitonin.
`
`
`
`Patients with MTC usually have calcitonin values >50 ng/L. In Victoza clinical trials, among patients
`
`
`
`with pre-treatment serum calcitonin <50 ng/L, one Victoza-treated patient and no comparator-treated
`
`
`
`
`patients developed serum calcitonin >50 ng/L. The Victoza-treated patient who developed serum
`
`
`
`
`
`
`calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7
`
`
`ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L
`
`
`
`more than 2.5 years after the last dose of Victoza. The largest increase in serum calcitonin in a
`
`
`comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from
`
`
`19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began
`
`with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza-treated
`
`
`patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an
`
`
`incidence of 1.1% among patients treated with 1.8 mg/day of Victoza. The clinical significance of these
`
`
`
`findings is unknown.
`
`
`
`Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck,
`
`
`
`
`
`
`
`dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or
`
`
`thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of
`
`
`
`unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence
`
`
`
`
`of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained
`
`
`for other reasons should be referred to an endocrinologist for further evaluation. Although routine
`
`
`
`monitoring of serum calcitonin is of uncertain value in patients treated with Victoza, if serum calcitonin is
`
`
`measured and found to be elevated, the patient should be referred to an endocrinologist for further
`
`
`
`evaluation.
`
`
`
`
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`
`
` 5.2
` Pancreatitis
`
`
`
`
`
`
` 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.
`
`
` 5.4
`
`
`Use with Medications Known to Cause Hypoglycemia
` 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
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`5.7 Macrovascular Outcomes
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with
`
`Victoza or any other antidiabetic drug.
`
`
`
`ADVERSE REACTIONS
`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.
`
`
`
`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
`
`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.
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`
`
` 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
`
`
`
` All Victoza
`
`
`
` N = 497
` (%)
`
`
` 28.4
`
` 17.1
`
` 10.9
`
` 9.9
`
` 9.1
`
` Glimepiride
`
`
`
`
` N = 248
` (%)
`
`
` 8.5
` 8.9
`
`
` 3.6
`
` 4.8
` 9.3
`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
` Vomiting
`
` Constipation
`
` Headache
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Vomiting
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
` Constipation
`
` Dyspepsia
`
`
`
`
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Dyspepsia
`
` Vomiting
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
` Table 3 Adverse Reactions reported in ≥5% of Victoza-treated patients in a 26-Week Open-Label
`
` Trial versus Exenatide
`
`
`
`
` Glimepiride +
` Metformin
`
`
`
`
`
` N = 242
` (%)
`
`
` 3.3
` 3.7
`
`
` 9.5
`
` 0.4
`
`
` Rosiglitazone +
`
` Glimepiride
`
`
`
` N = 231
` (%)
`
`
` 2.6
`
` 2.2
`
` 1.7
`
` 2.6
`
`
`
` Glargine +
`
`
`Metformin +
`
` Glimepiride
`
`
`
` N = 232
` (%)
`
`
` 1.3
`
` 1.3
`
` 5.6
`
` 1.7
`
` 0.4
`
` Placebo +
`
`Metformin +
`
` Rosiglitazone
`
`
`
` N = 175
` (%)
`
`
` 8.6
`
` 6.3
`
` 2.9
`
` 4.6
`
` 1.1
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Vomiting
`
` Headache
` 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
`
`
`
` Adverse Reaction
`
` Nausea
` Diarrhea
`
`
` Headache
`
` Dyspepsia
`
` Vomiting
` Constipation
`
`
`
`
`
`
`Reference ID: 3706643
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
` 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