`
`
` These highlights do not include all the information needed to use VICTOZA
` safely and effectively. See full prescribing information for VICTOZA.
`
`
`
`VICTOZA (liraglutide) injection, for subcutaneous use
`
`
`
`
`Initial U.S. Approval: 2010
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`See full prescribing information for complete boxed warning.
`
`
`
`Liraglutide causes thyroid C-cell tumors at clinically relevant exposures
`
`
`in both genders of rats and mice. It is unknown whether VICTOZA
`
`
`causes thyroid C-cell tumors, including medullary thyroid carcinoma
`
`
`(MTC), in humans, as the human relevance of liraglutide-induced
`
`
`
`
`
`rodent thyroid C-cell tumors has not been determined (5.1, 13.1).
`
`
`VICTOZA is contraindicated in patients with a personal or family
`
`
`
`
`history of MTC or in patients with Multiple Endocrine Neoplasia
`
`
`syndrome type 2 (MEN 2). Counsel patients regarding the potential risk
`
`of MTC and the symptoms of thyroid tumors (4, 5.1).
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`
`
`VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an
`
`
`
`adjunct to diet and exercise to improve glycemic control in adults with type 2
`
`diabetes mellitus (1).
`
`
`
`Important Limitations of Use (1.1):
`
`
`• Not recommended as first-line therapy for patients inadequately controlled
`
`
`on diet and exercise (5.1).
`
`
`• Has not been studied in patients with a history of pancreatitis. 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∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`
`Inject subcutaneously in the abdomen, thigh or upper arm (2.1).
`
`•
`
`
`
`
`
`• Administer once daily at any time of day, independently of meals (2.2).
`
`
`
`
`
`
`
`Initiate at 0.6 mg per day for one week then increase to 1.2 mg. Dose can be
`
`•
`
`
`
`
`increased to 1.8 mg for additional glycemic control (2.2).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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).
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙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.
`
`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: 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 other suspect medications and promptly seek medical
`
`advice (5.6).
`
`
`• Macrovascular Outcomes: There have been no studies establishing
`
`
`
`
`
`conclusive evidence of macrovascular risk reduction with VICTOZA or
`
`any other antidiabetic drug (5.7).
`
`
`•
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`The most common adverse reactions, reported in ≥5% of patients treated
`
`•
`
`
`
`
`
`with VICTOZA are: nausea, diarrhea, headache and vomiting (6.1).
`
`
`Immunogenicity-related events, including urticaria, were more common
`
`
`
`among VICTOZA-treated patients (0.8%) than among comparator-treated
`
`
`
`
`patients (0.4%) in clinical trials (6.2).
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`
`Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`------------------------------DRUG INTERACTIONS----------------------------------
`
`
`
`
`
`VICTOZA delays gastric emptying. May impact absorption of
`
`•
`
`
`
`concomitantly administered oral medications. (7).
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`
`Renal Impairment: No dose adjustment recommended (2.3, 8.6, 12.3).
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`
`Medication Guide.
`
`
`
`
`
`
` Revised: 04/2016
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
` INDICATIONS AND USAGE
`
` 1
`
`
` 1.1 Important Limitations of Use
`
`
`
` 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
` CONTRAINDICATIONS
`
` 4
`
`
` 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 Immunogenicity
`
`
`
` 6.3 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
`
`
`
`
`14.3 Patients with Moderate Renal Impairment
`
`
`
`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
`
`listed.
`
`
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`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
`
`
`Important Administration Instructions
`2.1
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
` 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.
`
`
`General Dosing and Administration
`2.2
`
`
`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
`
`
`
`
`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.
`
`
`4
`
`
`CONTRAINDICATIONS
`
`• Medullary Thyroid Carcinoma
`
`
`
`VICTOZA is contraindicated in patients with a personal or family history of medullary thyroid
`
`
`
`
`carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
`
`
`
`
`
`
`
`
`
`
`• Hypersensitivity
`
`
`VICTOZA is contraindicated in patients with a 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
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`MTC and VICTOZA use in humans.
`
`
`
`
`
`
`VICTOZA is contraindicated in patients with a personal or family history of MTC or in patients
`
`
`
`
`
`
`
`
`
`with MEN 2. Counsel patients regarding the potential risk for MTC with the use of VICTOZA and inform
`
`
`
`
`them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
`
`
`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early
`
`
`
`
`
`
`
`detection of MTC in patients treated with VICTOZA. Such monitoring may increase the risk of
`
`
`
`
`unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence
`
`
`of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC
`
`usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the
`
`
`patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck
`
`
`
`imaging should also be further evaluated.
`
`
`Pancreatitis
`5.2
`
`
`
`
`Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal
`
`
`hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with VICTOZA. After
`
`
`initiation of VICTOZA, observe patients carefully for signs and symptoms of pancreatitis (including
`
`
`persistent severe abdominal pain, 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
`
`
` 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
`
`
`
`
`
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`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
`
`
`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 placebo-controlled clinical trials [see Clinical Studies (14)]. 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= 645
`
` N= 1024
`
` N=661
`
`
` (%)
` (%)
`
` (%)
` Adverse Reaction
`
` 18
`
` 20
`
`
` Nausea
` 5
`
`
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Diarrhea
`
`
` 12
`
` 10
`
` 4
` Headache
`
` 10
`
` 11
`
` 7
`
`
` 10
`
` 9
`
` 8
` Nasopharyngitis
`
` 9
`
` 6
`
` 2
`
`Vomiting
`
` 9
`
` 10
`
` 1
` Decreased appetite
`
` 7
`
` 4
`
` 1
`
` Dyspepsia
`
` 6
`
` 7
`
` 6
` Upper Respiratory Tract Infection
`
` 5
`
` 5
`
` 1
`
` Constipation
`
` 5
`
` 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 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 clinical 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 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
`
`
`
`
` 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
`
`Reference ID: 3920460
`
`
`
` 0
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Patient able to self-treat
`
` Not classified
` Add-on to Metformin +
`
` Glimepiride
`
`
` 4.6 (0.15)
`
` 7.9 (0.49)
`
` 1.1 (0.03)
`
` 0.6 (0.01)
` 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
`
`
`
` 0
` 0
` Not classified
`
`
` “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment
`
`
`
`
` Malignancy
`
` In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms
`
` (based on investigator-reported events, medical history, pathology reports, and surgical reports from both
`
` blinded and open-label study periods) was 10.9 for VICTOZA, 6.3 for placebo, and 7.2 for active
`
`
` comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions (6.1)], no
`
` particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year
`
`of exposure to study medication, six events among VICTOZA-treated patients (4 colon, 1 prostate and 1
`
` nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not
`
` been established.
`
` 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 pathology specimens after thyroidectomy prompted by findings on protocol-specified screening
`
`
`
` with serum calcitonin or thyroid ultrasound.
`
` Cholelithiasis and cholecystitis
`
` In clinical trials of Saxenda (liraglutide at doses up to 3 mg), 1.5% and 0.6% of Saxenda-treated patients
`
`
`
`
` reported adverse events of cholelithiasis and cholecystitis versus 0.5% and 0.2% of placebo-treated
` patients. The majority of Saxenda-treated patients with adverse events of cholelithiasis and cholecystitis
`
`
`
`
` required cholecystectomy. In clinical 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.
`
`
`
` Laboratory Tests
`
` Bilirubin
`
`
`
` In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations
`
` (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of VICTOZA-
`
`
` treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This
`
`
`
` finding was not accompanied by abnormalities in other liver tests. The significance of this isolated
`
`
`
`
`finding is unknown.
`
`
`Calcitonin
`
`
`
`Calcitonin, a biological marker of MTC, was measured throughout the clinical development
`
`
`program. At the end of 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
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`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 placebo-controlled 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%.The clinical significance of these
`
`
`
`changes is unknown.
`
`
`
`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. The long-term clinical
`
`effects of the increase in pulse rate have not been established [see Warnings and Precautions (5.7)].
`
`
`
`Immunogenicity
`6.2
`
`
`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 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-negative patients. However, the 3 patients with the highest titers of anti-liraglutide
`
`
`
`
`antibodies had no reduction in HbA1c with VICTOZA treatment.
`
`
`
`Reference ID: 3920460
`
`
`
`
`
`
`
`
`
`
`
`
`In 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.
`
`
`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 (17.3)]
`
`
`
`
`•
`
`Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes
`
`
`
`requiring hemodialysis. [see Warnings and Precautions (5.5) and Patient Counseling Information
`
`
`
`
`(17.3)]
`
`
`• Angioedema and anaphylactic reactions. [see