CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`206321Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF DRUG EVALUATION II
`DIVISION OF METABOLISM AND ENDOCRINOLOGY PRODUCTS
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`NDA/BLA #s:
`Products:
`APPLICANT:
`FROM:
`DATE:
`
`NDA 206321
`SAXENDA (liraglutide [rDNA origin] injection), solution for subcutaneous use
`Novo Nordisk
`Jennifer Rodriguez Pippins, M.D., M.P.H.
`October 10, 2014
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such
`a strategy is necessary to ensure that the benefits of the drug outweigh the risks
`[section 505-1(a)]. Section 505-1(a)(1) provides the following factors:
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`SAXENDA (liraglutide) is a subcutaneous injection for chronic weight management in addition
`to a reduced-calorie diet and physical activity. It will be approved for use in adults with a body
`mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater (overweight)
`who have at least one weight-related condition such as hypertension, type 2 diabetes, or high
`cholesterol (dyslipidemia). Liraglutide received initial U.S. approval in 2010 at a lower dose
`(1.8 mg vs 3.0 mg) as VICTOZA, a second-line therapy for the treatment of type 2 diabetes
`mellitus. VICTOZA (liraglutide) has in place a REMS (communication plan and a timetable for
`submission of assessments) that addresses the potential risk of medullary thyroid carcinoma and
`the risk of acute pancreatitis associated with VICTOZA (liraglutide).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for SAXENDA (liraglutide) to
`ensure that the benefits of the drug outweigh:
`
` The potential risk of medullary thyroid carcinoma identified in non-clinical studies of
`SAXENDA (liraglutide) and other glucagon-like peptide (GLP)-1 receptor agonists; and
`
` The risk of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing
`pancreatitis, identified in the post-marketing reports for liraglutide. Cases of acute
`
`Reference ID: 3677216
`
`

`

`pancreatitis have also been described in association with SAXENDA (liraglutide) during
`clinical trials. In reaching this determination, we considered the following:
`
`A. In 2011-2012 the prevalence of obesity in the United States was 34.9% in adults, and more
`than two-thirds of adults are either overweight or obese.1 In 2011, approximately 2.74
`million patients used antiobesity drugs; the most commonly used product was phentermine,
`which is approved for short-term weight loss.2
`
`B. Obesity is associated with numerous co-morbidities, including dyslipidemia, coronary artery
`disease, hypertension, stroke, and type 2 diabetes mellitus.
`
`C. The benefit of SAXENDA (liraglutide) is expected based on significant weight loss over
`lifestyle modification and modest improvements in weight-related co-morbidities. The effect
`of pharmacological weight-loss on coronary heart disease morbidity and mortality and non-
`cardiovascular mortality has not been established.
`
`D. The expected duration of therapy is over a patient’s lifetime.
`
`E. In addition to the most serious risks of medullary thyroid carcinoma and acute pancreatitis,
`SAXENDA (liraglutide) also has the following risks: acute gallbladder disease, heart rate
`increase, hypoglycemia when used with an insulin secretagogue (e.g., a sulfonylurea) or
`insulin, renal impairment, and hypersensitivity.
`
`F. SAXENDA (liraglutide) is a not a new molecular entity.
`
`The REMS will consist of a communication plan and a timetable for submission of assessments
`of the REMS.
`
`
`1 Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of Childhood and Adult Obesity in the United States,
`2011-2011. JAMA. 2014; 311(8): 806-814.
`2 Hampp C, Kang EM, Borders-Hemphill V. Use of prescription antiobesity drugs in the United States.
`Pharmacotherapy. 2013; 33(12):1299-1307.
`
`2
`
`Reference ID: 3677216
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JENNIFER R PIPPINS
`12/22/2014
`
`Reference ID: 3677216
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Review
`
`
`Date:
`
`Reviewer(s):
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Subject:
`
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`December 11, 2014
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Kate Oswell, MA, Health Communications Analyst
`DRISK
`
`Naomi Redd, Pharm.D, Acting Team Leader
`DRISK
`
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`
`
`
`
`FDA’s comments to Novo Nordisk regarding their proposed
`amendment (October 10, 2014) to the Saxenda REMS
`
`Saxenda (liraglutide [rDNA] injection)
`
`Glucagon-like peptide -1 (GLP-1) receptor agonist
`
`Solution for subcutaneous injection, prefilled, multi-dose pen that
`delivers doses of 0.6 mg, 1.2 mg, 1.8 mg/ml, 2.4 mg/ml, 3 mg/ml
`(6 mg/ml 3 ml)
`
`
`Application Type/Number: NDA 206321/Amendment
`
`Submission Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`TSI #:
`
`Seq. No. 0054
`
`Novo Nordisk
`
`2014-77 and 2014-79
`
`TSI 894
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public.
`
`Reference ID: 3671302
`
`

`

`INTRODUCTION
`1
`This review documents the joint decision by the Division of Risk Management (DRISK), the Division
`of Metabolism and Endocrinology Products (DMEP), and the Office of Chief Counsel to revise the
`Saxenda REMS document for the purpose of clarifying the REMS requirement involving the
`distribution of a REMS Factsheet to healthcare providers.
`The November 10, 2014 amendment (Seq. No. 0054) to the Saxenda REMS included a revised version
`of the REMS, REMS Supporting Document, REMS Letters for Healthcare Providers, REMS Letter for
`Professional Society, REMS Factsheet, REMS Website, REMS Slides, and the REMS Changes Table.
`DRISK recommended approval of the Saxenda REMS as submitted on November 10, 2014. See
`DRISK’s review dated November 14, 2014.
`Upon further discussions between DRISK, the Division of Metabolism and Endocrinology Products
`(DMEP), and the Office of Chief Counsel it has been determined there is a need to clarify a statement
`in the REMS Document addressing the distribution of the REMS Factsheet.
`
` 2
`
` MATERIALS REVIEWED
`2.1 DATA AND INFORMATION SOURCES
`• Saxenda REMS submitted in the original application, the amended REMS received August 20,
`2014, MS Word version of all REMS documents received by the FDA via email on September
`12, 2014, and amendments received by FDA on October 2, 2014, October 16, 2014, and
`November 10, 2014.
`• DRISK reviews dated September 26, 2014, October 15, 2014, November 5, 2014, and
`November 11, 2014.
`
`•
`
`
`3 CONCLUSIONS AND RECOMMENDATIONS
`As agreed upon by DRISK, DMEP, and Office of Chief Counsel representative, the Saxenda REMS
`can be approved contingent upon revision of the REMS Document, as follows:
`Communication Plan, section 2) REMS Factsheet: “A REMS Factsheet will be made
`available to healthcare providers and distributed through Novo Nordisk SAXENDA® field
`based sales or medical representatives during the initial healthcare provider discussion
`within the first 18 months after approval of this REMS.
`
`
` Novo Nordisk SAXENDA® field
`based sales or medical representatives will verbally review each risk message contained in
`the Factsheet.”
`
`The revised Saxenda REMS Document and REMS Supporting Document are appended to this review.
`DRISK request DMEP send Novo Nordisk the comment included in section 4 of this review.
`
`2
`
`
`
`Reference ID: 3671302
`
`(b) (4)
`
`(b) (4)
`
`(b) (5)
`
`

`

`4 COMMENTS FOR THE APPLICANT
`FDA determined there is a need for clarification of the requirement for a REMS Factsheet as part of the
`communication plan included in the Saxenda REMS. FDA requests Novo Nordisk revises the Saxenda
`REMS Document as follows:
`
`Communication Plan, section 2) REMS Factsheet: “A REMS Factsheet will be made
`available to healthcare providers and distributed through Novo Nordisk SAXENDA® field
`based sales or medical representatives during the initial healthcare provider discussion
`within the first 18 months after approval of this REMS
`
`
` Novo Nordisk SAXENDA® field
`based sales or medical representatives will verbally review each risk message contained in
`the Factsheet.”
`
`The revised Saxenda REMS document and REMS Supporting Document are appended.
`
`
`
`Reference ID: 3671302
`
`3
`
`20 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`12/11/2014
`
`REEMA J MEHTA
`12/11/2014
`Signed on behalf of Cynthia LaCivita
`
`Reference ID: 3671302
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Modification Review
`
`
`Date:
`
`Reviewer(s):
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Subject:
`
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`November 14, 2014
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Kate Oswell, MA, Health Communications Analyst
`DRISK
`
`Naomi Redd, Pharm.D, Acting Team Leader
`DRISK
`
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`
`
`
`
`FDA’s comments to Novo Nordisk regarding their proposed
`amendment (October 10, 2014) to the Saxenda REMS
`
`Saxenda (liraglutide [rDNA] injection)
`
`Glucagon-like peptide -1 (GLP-1) receptor agonist
`
`Solution for subcutaneous injection, prefilled, multi-dose pen that
`delivers doses of 0.6 mg, 1.2 mg, 1.8 mg/ml, 2.4 mg/ml, 3 mg/ml
`(6 mg/ml 3 ml)
`
`
`Application Type/Number: NDA 206321/Amendment
`
`Submission Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`TSI #:
`
`Seq. No. 0054
`
`Novo Nordisk
`
`2014-77 and 2014-79
`
`TSI 894
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public.
`
`Reference ID: 3658541
`
`

`

`INTRODUCTION
`1
`This review documents the Division of Risk Management (DRISK) evaluation of Novo Nordisk’s
`November 10, 2014 amendment (Seq. No. 0054) to the proposed risk evaluation and mitigation strategy
`(REMS) for Saxenda (liraglutide) initially received by FDA on December 20, 2013 (Seq. No. 0000)
`and amended on August 20, 2014 (Seq. No.0033), October 2, 2014 (Seq. No. 0042), and October 16
`(email submission).
`The November 10, 2014 amendment included a revised version of the REMS, REMS Supporting
`Document, REMS Letters for Healthcare Providers, REMS Letter for Professional Society, REMS
`Factsheet, REMS Website, REMS Slides, and the REMS Changes Table.
`
` 2
`
` MATERIALS REVIEWED
`2.1 DATA AND INFORMATION SOURCES
`• Saxenda REMS submitted in the original application, the amended REMS received August 20,
`2014, MS Word version of all REMS documents received by the FDA via email on September
`12, 2014, and amendments received by FDA on October 2, 2014, October 16, 2014, and
`November 10, 2014.
`• DRISK reviews dated September 26, 2014, October 15, 2014, and November 5, 2014.
`
`3 REVIEW RESULTS
`The Saxenda REMS documents received by FDA on November 10, 2014 include all the revisions to
`the REMS materials recommended by DRISK.
`
` 4
`
` CONCLUSIONS AND RECOMMENDATIONS
`Novo Nordisk revised the Saxenda REMS as recommended by DRISK.
`DRISK recommends approval of the Saxenda REMS.
`The Saxenda REMS document and REMS materials are appended to this review.
`
`
`
`
`
`
`APPENDED MATERIALS:
`
`• REMS Document
`• REMS Letter to Healthcare Providers
`• REMS Letter for Professional Societies
`• REMS Factsheet
`• REMS Slides
`• REMS Website (landing page)
`• REMS Supporting Document
`
`
`
`Reference ID: 3658541
`
`2
`
`33 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`11/14/2014
`
`CYNTHIA L LACIVITA
`11/14/2014
`Concur
`
`Reference ID: 3658541
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Modification Review
`
`
`Date:
`
`Reviewer(s):
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Subject:
`
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`November 5, 2014
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Kate Oswell, MA, Health Communications Analyst
`DRISK
`
`Naomi Redd, Pharm.D, Acting Team Leader
`DRISK
`
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`
`
`
`
`FDA’s comments to Novo Nordisk regarding their proposed
`amendment (October 10, 2014) to the Saxenda REMS
`
`Saxenda (liraglutide [rDNA] injection)
`
`Glucagon-like peptide -1 (GLP-1) receptor agonist
`
`Solution for subcutaneous injection, prefilled, multi-dose pen that
`delivers doses of 0.6 mg, 1.2 mg, 1.8 mg/ml, 2.4 mg/ml, 3 mg/ml
`(6 mg/ml 3 ml)
`
`
`Application Type/Number: NDA 206321/Amendment
`
`Submission Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`TSI #:
`
`Seq. No. 0042 and Email submission from October 16, 2014
`
`Novo Nordisk
`
`2014-77 and 2014-79
`
`TSI 894
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public.
`
`Reference ID: 3654567
`
`

`

`INTRODUCTION
`1
`This review documents the Division of Risk Management (DRISK) evaluation of Novo Nordisk’s
`October 2, 2014 amendment (Seq. No. 0042) to the proposed risk evaluation and mitigation strategy
`(REMS) for Saxenda (liraglutide) initially received by FDA on December 20, 2013 (Seq. No. 0000)
`and amended on August 20, 2014 (Seq. No.0033), October 2, 2014 (Seq. No. 0042), and October 16
`(email submission).
`The October 16, 2014 amendment included a revised version of the REMS, REMS Supporting
`Document, REMS Letters for Healthcare Providers, REMS Letter for Professional Society, REMS
`Factsheet, REMS Website, REMS Slides, and the REMS Changes Table.
`
` 2
`
` MATERIALS REVIEWED
`2.1 DATA AND INFORMATION SOURCES
`• Saxenda REMS submitted in the original application, the amended REMS received August 20,
`2014, MS Word version of all REMS documents received by the FDA via email on September
`12, 2014, and amendment received by FDA on October 2, 2014.
`• DRISK reviews dated September 26, 2014 and October 15, 2014.
`
`3 REVIEW RESULTS
`The Saxenda REMS documents received by FDA on October 16, 2014 reflects the most recent changes
`to the Saxenda label (as of October 16, 2014) and revisions to the REMS materials as recommended by
`DRISK.
`A table included in section 5 of this review includes DRISK’s comments to Novo Nordisk’s proposed
`revisions to the REMS.
`
` 4
`
` CONCLUSIONS AND RECOMMENDATIONS
`Additional revisions to the Saxenda® REMS and REMS appended materials are still required.
`DRISK requests that the Division of Metabolism and Endocrinology Products (DMEP) sends Novo
`Nordisk the comments included in section 5 below and the appended REMS documents with tracked
`changes.
`
` 5
`
` COMMENTS FOR THE APPLICANT
`The comments included in the following table address Novo Nordisk’s amendment of the Saxenda®
`REMS (liraglutide, NDA 206321, Submission Number: 0042 and email submission from October 16,
`2014). Appended is the revised version of the REMS document, REMS appended material, and REMS
`Supporting Document.
`
`
`
`Reference ID: 3654567
`
`2
`
`44 Page(s) have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`APPENDED MATERIALS:
`
`• REMS Document
`• REMS Letter to Healthcare Providers
`• REMS Letter for Professional Societies
`• REMS Factsheet
`• REMS Slides
`• REMS Website (landing page)
`• REMS Supporting Document
`
`
`
`Reference ID: 3654567
`
`47
`
`34 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`11/06/2014
`
`CYNTHIA L LACIVITA
`11/07/2014
`Concur
`
`Reference ID: 3654567
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Modification Review
`
`
`Date:
`
`Reviewer(s):
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Subject:
`
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`October 15, 2014
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Kate Oswell, MA, Health Communications Analyst
`DRISK
`
`Naomi Redd, Pharm.D, Acting Team Leader
`DRISK
`
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`
`
`
`
`FDA’s comments to Novo Nordisk regarding their proposed
`amendment (October 10, 2014) to the Saxenda REMS
`
`Saxenda (liraglutide [rDNA] injection)
`
`Glucagon-like peptide -1 (GLP-1) receptor agonist
`
`Solution for subcutaneous injection, prefilled, multi-dose pen that
`delivers doses of 0.6 mg, 1.2 mg, 1.8 mg/ml, 2.4 mg/ml, 3 mg/ml
`(6 mg/ml 3 ml)
`
`
`Application Type/Number: NDA 206321/Amendment
`
`Submission Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`TSI #:
`
`0042
`
`Novo Nordisk
`
`2014-77 and 2014-79
`
`TSI 894
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public.
`
`Reference ID: 3644162
`
`

`

`INTRODUCTION
`1
`This review documents the Division of Risk Management (DRISK) evaluation of Novo Nordisk’s
`October 2, 2014 amendment (Seq. No. 0042) to the proposed risk evaluation and mitigation strategy
`(REMS) for Saxenda (liraglutide) initially received by FDA on December 20, 2013 (Seq. No. 0000)
`and amended on August 20, 2014 (Seq. No.0033).
`The October 2, 2014 amendment included a revised version of the REMS, REMS Supporting
`Document, REMS Letters for Healthcare Providers, REMS Letter for Professional Society, REMS
`Factsheet, REMS Website, REMS Slides, and the REMS Changes Table.
`
` 2
`
` MATERIALS REVIEWED
`2.1 DATA AND INFORMATION SOURCES
`• Saxenda REMS submitted in the original application, the amended REMS received August 20,
`2014, MS Word version of all REMS documents received by the FDA via email on September
`12, 2014, and amendment received by FDA on October 2, 2014.
`• DRISK review dated September 26, 2014.
`
`
`3 REVIEW RESULTS
`The Saxenda REMS documents received by FDA on October 2, 2014 do not reflect the most recent
`changes to the Saxenda label. Revisions to the Saxenda label have resulted in several modifications to
`the Saxenda REMS Message Map (see Table 1). Also, after further internal discussions, DRISK and
`Division of Metabolism and Endocrinology Products (DMEP) determined that the risk of duplicative
`therapy does not need to be included in the REMS and can be communicated via the label.
`
`
`TABLE 1: REVISED SAXENDA® REMS MESSAGE MAP FOR HEALTHCARE
`PROVIDERS
`
`
`Message 1
`Potential 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 SAXENDA®
`causes thyroid C-cell tumors,
`including medullary thyroid
`carcinoma (MTC), in humans, as
`human relevance of liraglutide-
`induced rodent thyroid C-cell tumors
`has not been determined.
`• SAXENDA® is contraindicated in
`patients with a personal or family
`
`Message 2
`Risk of Acute Pancreatitis
`
`• Based on spontaneous postmarketing
`reports, acute pancreatitis, including
`fatal and nonfatal hemorrhagic or
`necrotizing pancreatitis, has been
`observed in patients treated with
`liraglutide.
`• In clinical trials studying
`SAXENDA®, there were more cases
`of pancreatitis in patients treated with
`SAXENDA® than in patients treated
`with comparators.
`
`• SAXENDA® has not been studied
`sufficiently in patients with a history
`
`2
`
`Key
`Message
`
`Supporting
`Detail 1
`
`
`
`Reference ID: 3644162
`
`

`

`TABLE 1: REVISED SAXENDA® REMS MESSAGE MAP FOR HEALTHCARE
`PROVIDERS
`
`
`Message 2
`Risk of Acute Pancreatitis
`
`of pancreatitis.
`
`• After initiation of SAXENDA®, and
`after dose increases, 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,
`SAXENDA® should promptly be
`discontinued and appropriate
`management should be initiated.
`• If pancreatitis is confirmed,
`SAXENDA® should not be restarted.
`
`
`Appropriate
`Patient
`Selection
`Supporting
`Detail 2
`HCP Action
`
`Message 1
`Potential Risk of
`Thyroid C-cell Tumors
`history of MTC and in patients with
`Multiple Endocrine Neoplasia
`syndrome type 2 (MEN2).
`• Counsel patients regarding the risk
`of MTC with use of SAXENDA®
`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 SAXENDA®.
`• 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 be further evaluated.
`
`Table 2 in section 6 of this review includes DRISK’s comments to Novo Nordisk’s proposed revisions
`to the REMS.
`
`4 REMS ASSESSMENT PLAN
`Below is a revised version of the REMS assessments plan.
`a. An evaluation of the implementation of REMS Communication Plan activities:
`i. Product launch date
`ii. Number of healthcare providers and professional societies targeted by the REMS.
`iii. REMS Letter: Number of REMS letters sent to healthcare providers and Professional
`Societies via US mail (or email if this method is added) and the dates the letters were sent.
`Number of letters that were undeliverable will be included. Provide a list of names of
`professional societies with date of confirmed REMS letter receipt, along with any actions
`taken (e.g., posting on societies website, other outreach to members regarding REMS
`letters).
`iv. REMS Factsheet: number of healthcare providers detailed and provided the REMS
`Factsheet through the detail.
`v. REMS Slides: number of presentations employing the REMS Slides during the reporting
`period and cumulatively and number of attendees (including targeted physicians).
`
`3
`
`
`
`Reference ID: 3644162
`
`

`

`vi. Scientific meetings: list of scientific meetings where Novo Nordisk Medical Information
`has a presence (e.g., booth) in which the SAXENDA® REMS Factsheet was made available.
`vii. REMS website: Date when the REMS website went live and number of unique site visits
`during the assessment period and cumulative.
`b. Evaluation of healthcare providers’ knowledge:
`i. An evaluation of healthcare providers’ knowledge of the potential risk for medullary thyroid
`carcinoma and the risk of acute pancreatitis (including necrotizing pancreatitis). Stratify
`results by type of healthcare provider.
`ii. An evaluation of healthcare providers’ awareness of REMS materials.
`iii. An evaluation of healthcare providers’ sources of knowledge about the risks associated with
`SAXENDA®.
`c. Safety Surveillance and Utilization Data for the reporting period and cumulatively:
`i. SAXENDA® total prescription data by healthcare providers target in SAXENDA® call plan.
`ii. A summary and analysis of all SAXENDA® postmarketing case reports of (a) pancreatitis
`and b) medullary thyroid carcinoma.
`d. Evaluation of the extent to which the elements of the REMS are meeting the goals and
`objectives of the REMS and whether modifications to the elements or goals and objectives are
`needed.
`
` 5
`
` CONCLUSIONS AND RECOMMENDATIONS
`Additional revisions to the Saxenda® REMS and REMS appended materials are still required to include
`the most recent changes to the product label and to remove from the REMS the risk of duplicative
`therapy.
`DRISK requests DMEP sends Novo Nordisk the comments included in section 6 below and the
`appended REMS documents with tracked changes.
`
` 6
`
` COMMENTS FOR THE APPLICANT
`The comments included in the following table address Novo Nordisk’s amendment of the Saxenda®
`REMS (liraglutide, NDA 206321, Submission Number: 0042). Appended is the revised version of the
`REMS document and REMS Supporting Document.
`
`
`
`
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`Reference ID: 3644162
`
`4
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`APPENDED DOCUMENTS:
`
`• REMS Document
`
`• REMS Supporting Document
`
`
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`Reference ID: 3644162
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMARILYS VEGA
`10/15/2014
`
`CYNTHIA L LACIVITA
`10/16/2014
`Concur
`
`Reference ID: 3644162
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Risk Evaluation and Mitigation Strategy (REMS) Modification Review
`
`
`Date:
`
`Reviewer(s):
`
`
`
`
`Team Leader:
`
`
`Division Director
`
`
`Subject:
`
`
`Drug Name(s):
`
`Therapeutic Class:
`
`Dosage and Route:
`
`September 26, 2014
`
`Amarilys Vega, M.D., M.P.H, Medical Officer
`Division of Risk Management (DRISK)
`Kate Oswell, MA, Health Communications Analyst
`DRISK
`
`Doris Auth, Pharm D, Team Leader
`DRISK
`
`Cynthia LaCivita, Pharm.D, Acting Director
`DRISK
`
`
`
`
`FDA’s comments to Novo Nordisk regarding their proposed
`REMS for Saxenda
`
`Saxenda (liraglutide [rDNA] injection)
`
`Glucagon-like peptide -1 (GLP-1) receptor agonist
`
`Solution for subcutaneous injection, prefilled, multi-dose pen that
`delivers doses of 0.6 mg, 1.2 mg, 1.8 mg/ml, 2.4 mg/ml, 3 mg/ml
`(6 mg/ml 3 ml)
`
`
`Application Type/Number: NDA 206321/Amendment
`
`Submission Number:
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`TSI #:
`
`0033
`
`Novo Nordisk
`
`2014-77 and 2014-79
`
`TSI 894
`
`
`*** This document contains proprietary and confidential information ***
`that should not be released to the public.
`
`Reference ID: 3635994
`
`

`

`INTRODUCTION
`1
`This review documents DRISK’s evaluation of Novo Nordisk’s proposed risk evaluation and
`mitigation strategy (REMS) for Saxenda (liraglutide) initially received by FDA on December 20, 2013
`(Seq. No. 0000) and amended on August 20, 2014 (Seq. No.0033). In this submission, the Sponsor
`included a revised version of the REMS and REMS Supporting Document to reflect revisions made to
`the Victoza REMS on July 31, 2014. In addition, at FDA’s request, the Sponsor submitted MS Word
`version of the REMS, REMS appended materials, and REMS Supporting Document via email on
`September 12, 2014.
`Novo Nordisk is seeking approval for liraglutide 3.0 mg for once daily subcutaneous administration,
`for chronic weight management as an adjunct to a reduced calorie diet and increased physical activity
`in adults with an initial body mass index (BMI) of ≥30 kg/m2 (obese) or ≥27 kg/m2 (overweight) with
`at least one weight-related co-morbidity such as hypertension, dysglycemia (pre-diabetes and type 2
`diabetes mellitus), dyslipidemia or obstructive sleep apnea.
`Liraglutide is marketed worldwide as Victoza with an estimated number of patient years of exposure of
`over 3.3 million.
`1.1 BACKGROUND
`Obesity. Obesity is a major public health problem which affects adults and children in the United
`States. According to a recent publication by the CDC, since 1960, the prevalence of adult obesity in the
`United States has nearly tripled (13% in 1960–1962 to 36% 2009–2010) and more than tripled among
`children (5% in 1971–1974 to 17% in 2009–2010).1 Obesity is associated with major comorbidities,
`including hypertension, hyperglycemia, type 2 diabe