CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` NDA 206321/S-004
`
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
` SAXENDA
`
`Liraglutide injection
`
`Novo Nordisk, Inc.
`
`April 26, 2017
`
`An adjunct to a reduced-calorie diet and increased
`physical activity for chronic weight management in adult
`patients with an initial body mass (BMI) of at least
`30kg/m² (obese) or at least 27 kg/m² (overweight) in the
`presence of at least 1 weight-related comorbid condition
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`NDA 206321/S-004
`
`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
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`APPLICATION NUMBER:
`NDA 206321/S-004
`
`NDA 206321/8-004
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
` NDA 206321/S-004
`
`NDA 206321/S-006
`
`
`
`
`
`
`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) and your amendments,
`
`
`
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`
`
`
`
`
`
`
`Saxenda (liraglutide) injection for the following Prior Approval and Changes Being Effected
`
`supplements.
`
`
`Supplement 004
`
`
`
`
`
`
`
`This “Prior Approval” sNDA, dated June 24, 2016, and received June 27, 2016, provides for
`revisions of the prescribing information (PI) to include results from 160 weeks of treatment with
`
`
`Saxenda, followed by a 12-week off-drug period in Trial NN8022-1839.
`
`
`Supplement 006
`
`
`
`
`This “Changes Being Effected” sNDA, dated and received, January 12, 2017, provides for the
`
`
`following changes to the Medication Guide, Instructions for Use, and Carton and Container
`
`
`labeling to align with the currently approved Prescribing Information:
`
`• “[rDNA origin]” removed;
`
`
`
`• Patent string replaced with URL.
`
`
`
`
`APPROVAL & LABELING
`
`We have completed our review of these supplemental applications, as amended. They are
`
`
`
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`
`We note that your April 24, 2017, submission includes final printed labeling (FPL) for your
`
`
`
`
`package insert. We have not reviewed this FPL. You are responsible for assuring that the
`
`
`
`wording in this printed labeling is identical to that of the approved content of labeling in the
`
`
`structured product labeling (SPL) format.
`
`
`Reference ID: 4089789
`
`

`

`
`
`
` NDA 206321/S-004
`
` NDA 206321/S-006
`
` Page 2
`
`
`
`
`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 package insert, Medication
`Guide, and Instructions for Use), with the addition of any labeling changes in pending “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).
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`
`We acknowledge your January 12, 2017, submission containing final printed carton and
`
`container labels.
`
`
`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.
`
`
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`

`

`
` NDA 206321/S-004
`
` NDA 206321/S-006
`
` Page 3
`
`
`
`
`
`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).
`
`
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`

`

`
` NDA 206321/S-004
`
` NDA 206321/S-006
`
` Page 4
`
`
`
` If you have any questions, call Martin White, M.S., Regulatory Project Manager, at (240) 402­
` 6018.
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`James P. Smith, M.D., M.S.
`
`Deputy Director
`
`Division of Metabolism and Endocrinology Products
`
`
`Office of Drug Evaluation II
`
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE:
`
`
`Content of Labeling
`
`
`Carton and Container Labeling
`
`
`Reference ID: 4089789
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JAMES P SMITH
`04/26/2017
`
`Reference ID: 4089789
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 206321/S-004
`NDA 206321/8-004
`
`
`LABELING
`
`APPLICA TI0N NUMBER:
`
`LABELING
`
`

`

`
`
`
`
`
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE FORMS AND STRENGTHS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙
` Injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg,
`
`
`
`
`•
`
`
`
`
` 1.8 mg, 2.4 mg or 3 mg (6 mg/mL, 3 mL) (3).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙CONTRAINDICATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`• Personal or family history of medullary thyroid carcinoma or Multiple
`
`
`
`Endocrine Neoplasia syndrome type 2 (4, 5 1).
`
`• Hypersensitivity to liraglutide or any product components (4, 5.7).
`
`
`
`• Pregnancy (4, 8.1).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙WARNINGS AND PRECAUTIONS∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙--∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`• Thyroid C-cell Tumors: See Boxed Warning (5.1).
`
`
`
`• Acute Pancreatitis: Discontinue promptly if pancreatitis is suspected. Do
`
`
`
`
`
`not restart if pancreatitis is confirmed (5.2).
`
`
`
`• Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected,
`
`
`
`
`
`gallbladder studies are indicated (5.3).
`
`
`• Serious Hypoglycemia: Can occur when Saxenda is used with an insulin
`
`
`
`
`secretagogue (e.g. a sulfonylurea). Consider lowering the dose of anti-
`
`
`diabetic drugs to reduce the risk of hypoglycemia (2, 5.4).
`
`
`• Heart Rate Increase: Monitor heart rate at regular intervals (5.5).
`
`
`
`• Renal Impairment: Has been reported postmarketing, usually in association
`
`
`
`
`
`
`with nausea, vomiting, diarrhea, or dehydration which may sometimes
`
`
`require hemodialysis. Use caution when initiating or escalating doses of
`
`
`Saxenda in patients with renal impairment (5.6).
`
`
`
`• Hypersensitivity Reactions: Postmarketing reports of serious
`
`
`
`hypersensitivity reactions (e.g., anaphylactic reactions and angioedema).
`
`Discontinue Saxenda and other suspect medications and promptly seek
`
`
`
`
`
`medical advice (5.7).
`
`• Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts.
`
`
`Discontinue Saxenda if symptoms develop (5.8).
`
`
`
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙ADVERSE REACTIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙
`
`
`• Most common adverse reactions, reported in greater than or equal to 5%
`
`
`
`
`
`are: nausea, hypoglycemia, diarrhea, constipation, vomiting, headache,
`
`
`
`decreased appetite, dyspepsia, fatigue, dizziness, abdominal pain, and
`
`
`
`
`increased lipase (6.1).
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk
`
`Inc. at 1-844-363-4448 or FDA at 1-800-FDA-1088
`
`
`
`or www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS----------------------------------­
`• Saxenda delays gastric emptying. May impact absorption of concomitantly
`
`
`
`
`administered oral medications. Use with caution (7).
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙USE IN SPECIFIC POPULATIONS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙-∙∙∙-∙∙∙∙
`
`• Pediatric Use: Safety and effectiveness not established and use not
`
`
`
`recommended (8.4).
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`
`Medication Guide.
`
`
`
`Revised: 5/2017
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` SAXENDA® safely and effectively. See full prescribing information
`
`
` for SAXENDA.
`
`
`
`SAXENDA (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 Saxenda 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).
`
`
`
`
`
`
`Saxenda 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, 13 1).
`
`
`
` ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙RECENT MAJOR CHANGES∙∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
` Boxed Warning……………………………………………………..9/2016
` Warnings and Precautions, Risk of Thyroid C-cell Tumors (5.1)....9/2016
`
`
`
`
` Warnings and Precautions, Pancreatitis (5.2)……………………...5/2017
`
`
`
`
` Warnings and Precautions, Acute Gallbladder Disease (5.3)……...5/2017
`
`
`
` Warnings and Precautions, Suicidal Behavior and Ideation (5.8)…5/2017
`
`
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙INDICATIONS AND USAGE∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
`Saxenda is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated
`
`
`
`as an adjunct to a reduced-calorie diet and increased physical activity for
`
`
`
`
`
`
`chronic weight management in adult patients with an initial body mass
`
`
`
`
`
`index (BMI) of
`
`30 kg/m2 or greater (obese) (1) or
`
`
`
`•
`27 kg/m2 or greater (overweight) in the presence of at least
`
`
`
`•
` one weight-related comorbid condition (e.g. hypertension,
`
`
`
`
` type 2 diabetes mellitus, or dyslipidemia) (1).
`
`
`
` Limitations of Use:
`
`
`
`
`
`
`
`
` • Saxenda is not indicated for the treatment of type 2 diabetes (1).
`
` • Saxenda should not be used in combination with any other GLP-1
`
`
`
`
`
`
` receptor agonist (1).
`
`
`
`
`
` • Saxenda should not be used with insulin (1, 5.4).
`
`
`
` • The effects of Saxenda on cardiovascular morbidity and mortality
`
`
`
`
` have not been established (1).
`
`
` • The safety and efficacy of coadministration with other products for
`
`
`
`
` weight loss have not been established (1).
` • Saxenda has not been studied in patients with a history of
`
`
`
`
`
` pancreatitis (1, 5.2).
`
`∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙DOSAGE AND ADMINISTRATION∙∙∙∙-∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙
`
` • Recommended dose of Saxenda is 3 mg daily. Administer at any
`
`
`
`
`
` time of day, without regard to the timing of meals (2).
`
`
`
`
`
` Initiate at 0.6 mg per day for one week. In weekly intervals,
`
`
` increase the dose until a dose of 3 mg is reached (2).
`
`
`
`
` Inject subcutaneously in the abdomen, thigh or upper arm (2).
`
`
`•
`
`• The injection site and timing can be changed without dose
`
`
` adjustment (2).
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
`
`
`
`
`Reference ID: 4089789
`
`

`

`
`
`
` 10
`
` 11
`
` 12
`
`
`
`
` 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
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`
`
`16.2 Recommended Storage
`
`
`PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`listed.
`
`13
`
`
`14
`
`16
`
`
`17
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
` BOXED WARNING: RISK OF THYROID C-CELL TUMORS
`
`1
`
`2
`
`3
`
`4
`
`5
`
`
`INDICATIONS AND USAGE
`
`DOSAGE AND ADMINISTRATION
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Risk of Thyroid C-cell Tumors
`
`
`
`5.2 Acute Pancreatitis
`
`
`
`
`5.3 Acute Gallbladder Disease
`
`
`
`5.4 Risk for Hypoglycemia with Concomitant Use of
`
`
`
`Anti-Diabetic Therapy
`
`
`5.5 Heart Rate Increase
`
`
`
`5.6 Renal Impairment
`
`
`
`5.7 Hypersensitivity Reactions
`
`
`
`
`5.8 Suicidal Behavior and Ideation
`
`
`6
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Postmarketing 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
`
`
`
`
`7
`
`
`8
`
`
`
`
`Reference ID: 4089789
`
`

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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 at
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` clinically relevant exposures in both genders of rats and mice. It is unknown whether Saxenda
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` causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the
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` 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)].
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`• Saxenda is contraindicated in patients with a personal or family history of MTC and in patients
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`with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the
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`potential risk of MTC with use of Saxenda and inform them of symptoms of thyroid tumors
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`(e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of
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`serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC
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` in patients treated with Saxenda [see Contraindications (4), Warnings and Precautions (5.1)].
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`INDICATIONS AND USAGE
`1
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`Saxenda is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight
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`management in adult patients with an initial body mass index (BMI) of
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`• 30 kg/m2 or greater (obese), or
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`• 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g.,
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`hypertension, type 2 diabetes mellitus, or dyslipidemia)
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`Limitations of Use
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` Saxenda is not indicated for the treatment of type 2 diabetes mellitus.
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`  Saxenda and Victoza® both contain the same active ingredient, liraglutide, and therefore should not be used
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` together. Saxenda should not be used in combination with any other GLP-1 receptor agonist.
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`  Saxenda has not been studied in patients taking insulin. Saxenda and insulin should not be used together [see
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` Warnings and Precautions (5.4)].
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`  The effects of Saxenda on cardiovascular morbidity and mortality have not been established.
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`  The safety and effectiveness of Saxenda in combination with other products intended for weight loss,
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` including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
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` Saxenda has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)].
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`DOSAGE AND ADMINISTRATION
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`The recommended dosage of Saxenda is 3 mg daily. The dose escalation schedule in Table 1 should be used to
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`reduce the likelihood of gastrointestinal symptoms. If patients do not tolerate an increased dose during dose
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`escalation, consider delaying dose escalation for approximately one additional week. Saxenda should be
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`discontinued, however, if a patient cannot tolerate the 3 mg dose, as efficacy has not been established at lower
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`doses (0.6, 1.2, 1.8, and 2.4 mg).
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`Table 1.
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`Dose Escalation Schedule
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` Week
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` Daily Dose
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`Reference ID: 4089789
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` 1
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` 2
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` 5 and onward
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` 0.6 mg
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` 1.2 mg
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` 1.8 mg
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` 2.4 mg
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` 3 mg
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`Saxenda should be taken once daily at any time of day, without regard to the timing of meals. Saxenda can be
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`injected subcutaneously in the abdomen, thigh, or upper arm. The injection site and timing can be changed
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`without dose adjustment. Saxenda must not be administered intravenously or intramuscularly.
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`When initiating Saxenda in patients taking insulin secretagogues (such as sulfonylureas), consider reducing the
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`dose of the insulin secretagogue (for example, by one-half) to reduce the risk for hypoglycemia, and monitor
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`blood glucose. Saxenda and insulin should not be used together [see Warnings and Precautions (5.4) and
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`Adverse Reactions (6.1)]. Conversely, if discontinuing Saxenda in patients with type 2 diabetes, monitor for an
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`increase in blood glucose.
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`Evaluate the change in body weight 16 weeks after initiating Saxenda and discontinue Saxenda if the patient has
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`not lost at least 4% of baseline body weight, since it is unlikely that the patient will achieve and sustain
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`clinically meaningful weight loss with continued treatment.
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`If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An
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`extra dose or increase in dose should not be taken to make up for the missed dose. If more than 3 days have
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`elapsed since the last Saxenda dose, patients should reinitiate Saxenda at 0.6 mg daily and follow the dose
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`escalation schedule in Table 1, which may reduce the occurrence of gastrointestinal symptoms associated with
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`reinitiation of treatment.
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`Prior to initiation of Saxenda, patients should be trained by their healthcare professional on proper injection
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`technique. Training reduces the risk of administration errors such as needle sticks and incomplete dosing. Refer
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`to the accompanying Instructions for Use for complete administration instructions with illustrations.
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`Saxenda solution should be inspected prior to each injection, and the solution should be used only if it is clear,
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`colorless, and contains no particles.
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`BMI is calculated by dividing weight in (kilograms) by height (in meters) squared. A chart for determining BMI
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`based on height and weight is provided in Table 2.
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`Reference ID: 4089789
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` Table 2.
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` BMI Conversion Chart
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`DOSAGE FORMS AND STRENGTHS
`3
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`Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4
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`mg, or 3 mg (6 mg/mL, 3 mL).
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`CONTRAINDICATIONS
`4
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`Saxenda is contraindicated in:
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`• Patients with a personal or family history of medullary thyroid carcinoma (MTC) or patients with
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`Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]
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`• Patients with a prior serious hypersensitivity reaction to liraglutide or to any of the product components
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`[see Warnings and Precautions (5.7)]
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`• Pregnancy [see Use in Specific Populations (8.1)]
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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 whether
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`Saxenda will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the
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`human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
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`Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in
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`these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in
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`humans.
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`Saxenda is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2.
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`Counsel patients regarding the potential risk for MTC with the use of Saxenda and inform them of symptoms of
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`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 detection of
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`MTC in patients treated with Saxenda. Such monitoring may increase the risk of unnecessary procedures, due
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`Reference ID: 4089789
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` to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly
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` elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater
` than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.
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` Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
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`Acute Pancreatitis
`5.2
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`Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or
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`necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of Saxenda,
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`observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain,
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`sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is
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`suspected, Saxenda should promptly be discontinued and appropriate management should be initiated. If
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`pancreatitis is confirmed, Saxenda should not be restarted.
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`In Saxenda clinical trials, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 Saxenda-treated
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`patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in
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`Saxenda-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after
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`the last dose. There were 2 additional cases in Saxenda-treated patients, 1 during an off-treatment follow-up
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`period within 2 weeks of discontinuing Saxenda, and 1 that occurred in a patient who completed treatment and
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`was off-treatment for 106 days.
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`It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using
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`Saxenda, since these patients were excluded from clinical trials.
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`Acute Gallbladder Disease
`5.3
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`In Saxenda clinical trials, 2.2% of Saxenda-treated patients reported adverse events of cholelithiasis versus
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`0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in Saxenda-treated patients versus
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`0.4% in placebo-treated patients. The majority of Saxenda-treated patients with adverse events of cholelithiasis
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`and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of
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`cholelithiasis; however, the incidence of acute gallbladder disease was greater in Saxenda-treated patients than
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`in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected,
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`gallbladder studies and appropriate clinical follow-up are indicated.
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`Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy
`5.4
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`The risk for serious hypoglycemia is increased when Saxenda is used in combination with insulin secretagogues
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`(for example, sulfonylureas) in patients with type 2 diabetes mellitus. Therefore, patients may require a lower
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`dose of sulfonylurea (or other concomitantly administered insulin secretagogues) in this setting [see Dosage
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`and Administration (2) and Adverse Reactions (6.1)]. Saxenda should not be used in patients taking insulin.
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`Saxenda can lower blood glucose [see Clinical Pharmacology (12.2)]. Monitor blood glucose parameters prior
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`to starting Saxenda and during Saxenda treatment in patients with type 2 diabetes. If needed, adjust co­
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`administered anti-diabetic drugs based on glucose monitoring results and risk of hypoglycemia.
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`Heart Rate Increase
`5.5
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`Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical
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`monitoring in Saxenda-treated patients compared to placebo in clinical trials. More patients treated with
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`Saxenda, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm
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`(34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate
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`exceeding 100 bpm was recorded for 6% of Saxenda-treated patients compared with 4% of placebo-treated
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`patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was
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`reported as an adverse reaction in 0.6% of Saxenda-treated patients and in 0.1% of placebo-treated patients.
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`Reference ID: 4089789
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` In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, Saxenda treatment was
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` associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo.
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`The clinical significance of the heart rate elevation with Saxenda treatment is unclear, especially for patients
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`with cardiac and cerebrovascular disease as a result of limited exposure in these patients in clinical trials.
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`Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform
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`health care providers of palpitations or feelings of a racing heartbeat while at rest during Saxenda treatment. For
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`patients who experience a sustained increase in resting heart rate while taking Saxenda, Saxenda should be
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`discontinued.
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`Renal Impairment
`5.6
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`In patients treated with GLP-1 receptor agonists, including Saxenda, there have been reports of acute renal
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`failure and worsening of chronic renal failure, sometimes requiring hemodialysis [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, or diarrhea leading to volume
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`depletion. Some of the reported events occurred in patients receiving one or more medications known to affect
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`renal function or volume status. Altered renal function has been reversed in many of the reported cases with
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`supportive treatment and discontinuation of potentially causative agents, including liraglutide. Use caution
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`when initiating or escalating doses of Saxenda in patients with renal impairment [see Use in Specific
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`Populations (8.6)].
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`5.7 Hypersensitivity Reactions
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`There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in
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`patients treated with liraglutide [see Adverse Reactions (6.1, 6.2)]. If a hypersensitivity reaction occurs, the
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`patient should discontinue Saxenda and other suspect medications and promptly seek medical advice.
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`Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a
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`history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients
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`will be predisposed to angioedema with Saxenda.
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`Suicidal Behavior and Ideation
`5.8
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`In Saxenda clinical trials, 9 (0.3%) of 3384 Saxenda-treated patients and 2 (0.1%) of the 1941 placebo-treated
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`patients reported suicidal ideation; one of these Saxenda-treated patients attempted suicide. Patients treated with
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`Saxenda should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior,
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`and/or any unusual changes in mood or behavior. Discontinue Saxenda in patients who experience suicidal
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`thoughts or behaviors. Avoid Saxenda in patients with a history of suicidal attempts or a