CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`022341Orig1s027
`VICTOZA
`
`Trade Name:
`
`Generic or Proper
`Name:
`Sponsor:
`
`
`
`liraglutide
`
`Novo Nordisk
`
`Approval Date:
`
`August 25, 2017
`
`Indication:
`
`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;.
`
`to reduce the risk of major adverse cardiovascular
`•
`events in adults with type 2 diabetes mellitus and
`established cardiovascular disease .
`
`Limitations of Use:
`•
`Not for treatment of type 1 diabetes mellitus or
`diabetic ketoacidosis.
`•
`Has not been studied in combination with prandial
`insulin.
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`022341Orig1s027
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`
`X
`X
`
`X
`X
`
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022341Orig1s027
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`NDA 022341/S-027
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
` Novo Nordisk Inc.
`
`
` Attention: Michelle Thompson
` Senior Director, Regulatory Affairs
`
`
`
` P.O. Box 846
`
` 800 Scudders Mill Road
`
` Plainsboro, NJ 08536
`
`
`
` Dear Ms. Thompson:
`
`
` Please refer to your Supplemental New Drug Application (sNDA) dated and received
`
`
`
`
`
`
` October 25, 2016, and your amendments, submitted under section 505(b) of the Federal Food,
`
`
`
`
`
` Drug, and Cosmetic Act (FDCA) for Victoza (liraglutide) injection.
`
`
`
`
`
`
` This Prior Approval supplemental new drug application proposes the addition of an indication to
`
` reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and
`
`
`
`
`
`
`
`
`
` established cardiovascular disease, and revised labeling to reflect the results of the “Liraglutide
`
` Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results” (LEADER) trial.
`
`
`
`APPROVAL & LABELING
`
`
`We have completed our review of this supplemental application, as amended. It is approved,
`
`
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`
`
`text and with the minor editorial revisions listed below:
`
`
`
`
`
`• Brackets were removed from the dates in the Recent Major Changes section of
`
`
`
`
`
`
`Highlights.
`
`
`• The version number and date of issue were updated on the final page of the Prescribing
`
`
`
`Information.
`
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`
`
`
`
`
`automated drug registration and listing system (eLIST), as described at
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`
`
`of labeling must be identical to the enclosed labeling (text for the prescribing information,
`
`Medication Guide, and instructions for use), with the addition of any labeling changes in pending
`
`
`
`Reference ID: 4144309
`
`

`

`
`
`
`
`
`
`
`
`
`
` NDA 022341/S-027
`
` Page 2
`
`
` “Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`
`
`
`included in the enclosed labeling.
`
`
`
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`
`
`
`
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`
` Also within 14 days, amend all pending supplemental applications that include labeling changes
`
` for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
` with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`
`
` changes approved in this supplemental application, as well as annual reportable changes and
` annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`
`
` up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
` should provide appropriate annotations, including supplement number(s) and annual report
`
`
`
`
`
`
`
`date(s).
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`
`
`
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`
`
`administration are required to contain an assessment of the safety and effectiveness of the
`
`
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`
`deferred, or inapplicable.
`
`
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`
`
`FULFILLMENT OF POSTMARKETING REQUIREMENT
`
`This supplemental application contained the final report for the following postmarketing
`
`
`
`requirement listed in the January 25, 2010, approval letter for NDA 022341.
`
`
`
`
`
`
`1583-9 A randomized, double-blind, controlled trial evaluating the effect of Victoza
`
`
`
`(liraglutide [rDNA origin]) injection on the incidence of major adverse
`
`
`cardiovascular events in patients with type 2 diabetes mellitus. This trial must
`
`also assess adverse events of interest including the long-term effects of Victoza
`
`
`(liraglutide [rDNA origin]) injection on potential biomarkers of medullary thyroid
`
`carcinoma (e.g., serum calcitonin) as well as the long-term effects of Victoza
`
`
`(liraglutide [rDNA origin]) injection on pancreatitis, renal safety, serious
`
`hypoglycemia, immunological reactions, and neoplasms.
`
`
`
`
`We have reviewed your submission and conclude that the above requirement was fulfilled.
`
`
`
`Reference ID: 4144309
`
`

`

`
`
`
`
` NDA 022341/S-027
`
` Page 3
`
`
` We remind you that there are postmarketing requirements listed in the January 25, 2010,
`
` approval letter that are still open.
`
`
`
`PROMOTIONAL MATERIALS
`
` You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`
` labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
` comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`
`
`
` (3) the package insert(s) to:
`
`
`
`
`
`OPDP Regulatory Project Manager
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`
`
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`
`
`
`
`FDA 2253 is available at
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`more information about submission of promotional materials to the Office of Prescription Drug
`
`
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`If you have any questions, call Marisa Petruccelli, Regulatory Project Manager, at
`
`
`
`(240) 402-6147.
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4144309
`
`

`

`
`
` NDA 022341/S-027
`
` Page 4
`
`
`
`
`
` Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Jean-Marc Guettier, M.D.
`
`Director
`
`Division of Metabolism and Endocrinology Products
`
`
`Office of Drug Evaluation II
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`
`Prescribing Information
`
`Medication Guide
`
`
`Instructions for Use (version approved April 25, 2017)
`
`
`
`Reference ID: 4144309
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JEAN-MARC P GUETTIER
`08/25/2017
`
`Reference ID: 4144309
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`022341Orig1s027
`
`
`LABELING
`
`

`

` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use VICTOZA
` safely and effectively. See full prescribing information for VICTOZA.
`
`
`
`
`
`VICTOZA® (liraglutide) injection, for subcutaneous use
`
`
`
`
`Initial U.S. Approval: 2010
`
`
`
`
`
`
`
`WARNING: RISK OF THYROID C-CELL TUMORS
`
`See full prescribing information for complete boxed warning.
`
`
`
`
`Liraglutide causes thyroid C-cell tumors at clinically relevant exposures
`
`
`
`in both genders of rats and mice. It is unknown whether VICTOZA
`
`
`
`
`causes thyroid C-cell tumors, including medullary thyroid carcinoma
`
`(MTC), in humans, as the human relevance of liraglutide-induced
`
`rodent thyroid C-cell tumors has not been determined (5.1, 13.1).
`
`
`
`
`VICTOZA is contraindicated in patients with a personal or family
`
`
`
`
`
`
`history of MTC or in patients with Multiple Endocrine Neoplasia
`
`
`
`
`
`syndrome type 2 (MEN 2). Counsel patients regarding the potential risk
`
`
`
`
`
`of MTC and the symptoms of thyroid tumors (4, 5.1).
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`
`Indications and Usage ( 1) ------------------------------------------------------ 8/2017
`
`
`
`Contraindications (4) ------------------------------------------------------------ 8/2017
`
`
`
`Warnings and Precautions (5.2, 5.6, 5.7) ------------------------------------- 8/2017
`
`
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated:
`
`
`
`
`
`• as an adjunct to diet and exercise to improve glycemic control in adults with
`
`
`
`
`
`
`
`
`type 2 diabetes mellitus (1).
`
`to reduce the risk of major adverse cardiovascular events in adults with type
`
`
`
`
`2 diabetes mellitus and established cardiovascular disease (1).
`
`
`
`
`
`
`
`
`Limitations of Use:
`
`
`• 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 (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
`
`
`
`
`promptly seek medical advice (5.6).
`• Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
`
`
`
`
`
`
`gallbladder studies are indicated (5.7)
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• The most common adverse reactions, reported in ≥5% of patients treated with
`
`
`
`
`
`
`
`VICTOZA are: nausea, diarrhea, vomiting, decreased appetite, dyspepsia,
`
`
`
`
`constipation (6.1).
`
`
`• Immunogenicity-related events, including urticaria, were more common
`
`
`among VICTOZA-treated patients (0.8%) than among comparator-treated
`
`
`
`
`patients (0.4%) in clinical trials (6.2).
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS----------------------------------­
`VICTOZA delays gastric emptying. May impact absorption of concomitantly
`
`
`
`
`
`
`administered oral medications. (7).
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Renal Impairment: No dose adjustment recommended (2.4, 8.6, 12.3).
`
`
`
`
`• Pregnancy: Victoza should be used during pregnancy only if the potential
`
`
`
`
`
`
`
`benefit justifies the potential risk to the fetus (8.1).
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved
`
`
`Medication Guide.
`
`
`
`
`
`
` Revised: 08/2017
`
`Reference ID: 4144309
`
`
`
`
`
`
`
`

`

`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
` WARNING: RISK OF THYROID C-CELL TUMORS
`
`
` 1
`INDICATIONS AND USAGE
`
`
` 2
` DOSAGE AND ADMINISTRATION
`
`
`
` 2.1 Important Administration Instructions
`
`
` 2.2 General Dosing and Administration
`
`
`
`
`
` 2.3 Concomitant Use with an Insulin Secretagogue (e.g. Sulfonylurea)
`
`
`
`
` or with Insulin
`
`
` 2.4 Dosage in Patients with Renal Impairment
`
`
`
`
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
` 4
`
` CONTRAINDICATIONS
`
`
` 5
` WARNINGS AND PRECAUTIONS
`
`
`
`
` 5.1 Risk of Thyroid C-cell Tumors
`
`
` 5.2 Pancreatitis
`
`
`
`
`
`
` 5.3 Never Share a VICTOZA Pen Between Patients
`
`
` 5.4 Use with Medications Known to Cause Hypoglycemia
`
`
`
` 5.5 Renal Impairment
`
`
`
`
`
` 5.6 Hypersensitivity Reactions
`
`
`
`
` 5.7 Acute Gallbladder Disease
`
` ADVERSE REACTIONS
`
` 6.1 Clinical Trials Experience
`
`
`
`
` 6.2 Immunogenicity
`
`
` 6.3 Post-Marketing Experience
`
`
` DRUG INTERACTIONS
`
`
`
` 7.1 Oral Medications
`
` USE IN SPECIFIC POPULATIONS
`
`
` 8.1 Pregnancy
`
`
` 8.2 Lactation
`
`
`
`
` 8.4 Pediatric Use
`
`
`
` 8.5 Geriatric Use
`
`
`
` 8.6 Renal Impairment
`
`
`
` 8.7 Hepatic Impairment
`
`
` 8.8 Gastroparesis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`14
`
`
`16
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`
`CLINICAL STUDIES
`
`14.1 Glycemic Control Trials in Adults with Type 2 Diabetes
`
`
`
`
`
`Mellitus
`
`
`
`14.2 Cardiovascular Outcomes Trial in Patients with Type 2
`
`
`
`
`Diabetes Mellitus and Atherosclerotic Cardiovascular Disease
`
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
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`16.2 Recommended Storage
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`17
`PATIENT COUNSELING INFORMATION
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`*Sections or subsections omitted from the full prescribing information are not
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`listed.
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`Reference ID: 4144309
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` FULL PRESCRIBING INFORMATION
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` WARNING: RISK OF THYROID C-CELL TUMORS
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` • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors
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` at clinically relevant exposures in both genders of rats and mice. It is unknown whether
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` 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
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` been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
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`• VICTOZA is contraindicated in patients with a personal or family history of MTC and in
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`patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients
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`regarding the potential risk for MTC with the use of VICTOZA and inform them of
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`symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent
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`hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of
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`uncertain value for early detection of MTC in patients treated with VICTOZA [see
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` Contraindications (4) and Warnings and Precautions (5.1)].
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`INDICATIONS AND USAGE
`1
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`VICTOZA is indicated:
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`• as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
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`mellitus,
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`to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal
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`myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established
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`cardiovascular disease [see Clinical Studies (14.2)].
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`•
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`Limitations of Use:
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` VICTOZA is not a substitute for insulin. VICTOZA should not be used in patients with type 1 diabetes
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`mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
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` The concurrent use of VICTOZA and prandial insulin has not been studied.
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`2
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` 2.1
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` DOSAGE AND ADMINISTRATION
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` Important Administration Instructions
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`Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no
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` particles.
` Inject VICTOZA subcutaneously in the abdomen, thigh or upper arm. No dose adjustment is needed
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` if changing the injection site and/or timing.
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`  When using VICTOZA with insulin, administer as separate injections. Never mix.
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` It is acceptable to inject VICTOZA and insulin in the same body region but the injections should not
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` be adjacent to each other.
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` 2.2
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` General Dosing and Administration
` Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals.
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` Initiate VICTOZA with a dose of 0.6 mg per day for one week. The 0.6 mg dose is a starting dose
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` intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic
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` 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
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` does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. If a dose is
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`Reference ID: 4144309
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` missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer
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` an extra dose or increase in dose to make up for the missed dose.
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` 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,
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` VICTOZA should be titrated at the discretion of the prescriber.
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`Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`2.3
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`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
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`(5.4) and Adverse Reactions (6)].
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`Dosage in Patients with Renal Impairment
`2.4
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`No dose adjustment is recommended for patients with renal impairment.
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`DOSAGE FORMS AND STRENGTHS
`3
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`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
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`mg.
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`CONTRAINDICATIONS
`4
`Medullary Thyroid Carcinoma
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`•
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`VICTOZA is contraindicated in patients with a personal or family history of medullary thyroid carcinoma
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`(MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
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`Hypersensitivity
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`VICTOZA is contraindicated in patients with a prior serious hypersensitivity reaction to VICTOZA or to
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`any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and
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`angioedema have been reported with VICTOZA [see Warnings and Precautions (5.6)].
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`WARNINGS AND PRECAUTIONS
`5
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`Risk of Thyroid C-cell Tumors
`5.1
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`Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas
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`and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical
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`Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown
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`whether VICTOZA will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in
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`humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been
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`determined.
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`Cases of MTC in patients treated with VICTOZA have been reported in the postmarketing period;
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`the data in these reports are insufficient to establish or exclude a causal relationship between
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`MTC and VICTOZA use in humans.
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`VICTOZA is contraindicated in patients with a personal or family history of MTC or in patients with
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`MEN 2. Counsel patients regarding the potential risk for MTC with the use of VICTOZA and inform
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`them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
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`Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early
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`detection of MTC in patients treated with VICTOZA. Such monitoring may increase the risk of
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`unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence
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`of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC
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`Reference ID: 4144309
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` usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the
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` patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck
` imaging should also be further evaluated.
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`Pancreatitis
`5.2
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`Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal
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`hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with VICTOZA. After
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`initiation of VICTOZA, observe patients carefully for signs and symptoms of pancreatitis (including
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`persistent severe abdominal pain, sometimes radiating to the back and which may or may not be
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`accompanied by vomiting). If pancreatitis is suspected, VICTOZA should promptly be discontinued and
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`appropriate management should be initiated. If pancreatitis is confirmed, VICTOZA should not be
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`restarted.
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` In glycemic control trials of VICTOZA, there have been 13 cases of pancreatitis among VICTOZA-treated
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`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
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`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.
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`VICTOZA has been studied in a limited number of patients with a history of pancreatitis. It is unknown if
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`patients with a history of pancreatitis are at higher risk for development of pancreatitis on VICTOZA.
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` Never Share a VICTOZA Pen Between Patients
` 5.3
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` 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.
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`Use with Medications Known to Cause Hypoglycemia
`5.4
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`Patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin
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`may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction
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`in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin [see
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`Dosage and Administration (2.2), Adverse Reactions (6.1)].
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`Renal Impairment
`5.5
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`VICTOZA has not been found to be directly nephrotoxic in animal studies or clinical trials.
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`There have been postmarketing reports of acute renal failure and worsening of chronic renal failure,
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`which may sometimes require hemodialysis in VICTOZA-treated patients [see Adverse Reactions (6.2)].
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`Some of these events were reported in patients without known underlying renal disease. A majority of the
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`reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration [see
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`Adverse Reactions (6.1)]. Some of the reported events occurred in patients receiving one or more
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`medications known to affect renal function or hydration status. Altered renal function has been reversed
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`in many of the reported cases with supportive treatment and discontinuation of potentially causative
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`agents, including VICTOZA. Use caution when initiating or escalating doses of VICTOZA in patients
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`with renal impairment [see Use in Specific Populations (8.6)].
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` 5.6 Hypersensitivity Reactions
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` There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions
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` and angioedema) in patients treated with VICTOZA. If a hypersensitivity reaction occurs, discontinue
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`Reference ID: 4144309
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` VICTOZA; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not
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` use in patients with a previous hypersensitivity reaction to VICTOZA [see Contraindications (4)].
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`Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a
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`patient with a history of anaphylaxis or angioedema with another GLP-receptor agonist because it is
`unknown whether such patients will be predisposed to these reactions with VICTOZA.
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` 5.7 Acute Gallbladder Disease
` In the LEADER trial [see Clinical Studies (14.2)], 3.1% of Victoza-treated patients versus 1.9% of placebo-
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`treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. The
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`majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder
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`studies and appropriate clinical follow-up are indicated.
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`ADVERSE REACTIONS
`6
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`The following serious adverse reactions are described below or elsewhere in the prescribing information:
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`• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
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`• Pancreatitis [see Warnings and Precautions (5.2)]
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`• Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.4)]
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`• Renal Impairment [see Warnings and Precautions (5.5)]
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`• Hypersensitivity Reactions [see Warnings and Precautions (5.6)]
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`Clinical Trials Experience
`6.1
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`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
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`the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
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`may not reflect the rates observed in practice.
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`Common Adverse Reactions
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`The data in Table 1 are derived from 5 glycemic control, placebo-controlled trials [see Clinical Studies
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`(14.1)]. These data reflect exposure of 1673 patients to VICTOZA and a mean duration of exposure to
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`VICTOZA of 37.3 weeks. The mean age of patients was 58 years, 4% were 75 years or older and 54%
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`were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of
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`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
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`moderately impaired in 11.9% of the pooled population.
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`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of
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`VICTOZA. These adverse reactions occurred more commonly on VICTOZA than on placebo and
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`occurred in at least 5% of patients treated with VICTOZA.
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`Table 1 Adverse reactions reported in ≥ 5% of VICTOZA-treated patients
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` Placebo
` Liraglutide 1.8 mg
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` Liraglutide 1.2 mg
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` N= 1024
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` N= 645
` N=661
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` (%)
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` (%)
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` (%)
` Adverse Reaction
` 20
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` 18
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` 5
`Nausea
`Diarrhea
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` 12
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` 10
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` 4
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` 10
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` 11
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` 7
`Headache
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` 10
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` 9
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` 8
` Nasopharyngitis
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` 9
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` 6
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` 2
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` Vomiting
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` 9
` 10
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` 1
` Decreased appetite
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`Reference ID: 4144309
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` 7
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` 6
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` 5
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` 5
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` Patient not able to self-treat
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` Patient able to self-treat
` Add-on to Glimepiride
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` Patient not able to self-treat
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` Patient able to self-treat
` Not classified
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` Add-on to Metformin +
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` Rosiglitazone
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` Placebo Comparator
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` Placebo +
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` Metformin
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`(N = 121)
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` 0
` 2.5 (0.06)
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` Placebo +
`Glimepiride
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`(N = 114)
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` 0
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` 2.6 (0.17)
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` 0
` Placebo +
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` Metformin + Rosiglitazone
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`(N = 175)
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` Patient not able to self-treat
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` Patient able to self-treat
` Not classified
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`Reference ID: 4144309
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` 0
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` 4.6 (0.15)
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` 1.1 (0.03)
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` Dyspepsia
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` 4
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` 1
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` 7
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` 6
` Upper Respiratory Tract Infection
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` 5
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` 1
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` Constipation
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` 4
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` 3
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` Back Pain
` Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights
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` In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse
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` reactions, excluding hypoglycemia, were similar to those listed in Table 1.
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`Other Adverse Reactions
`Gastrointestinal Adverse Reactions
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`In the pool of 5 glycemic control, placebo-controlled clinical trials, withdrawals due to gastrointestinal
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`adverse reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients.
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`Withdrawal due to gastrointestinal adverse events mainly o