CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`203858Orig1s000
`
`
`Juxtapid
`
`Lomitapide
`
`Aegerion Pharmaceuticals, Inc
`
`12/21/2012
`
` As an adjunct to a low-fat diet and other
`lipid-lowering treatments, including LDL
`apheresis where available, to reduce low-
`density lipoprotein cholesterol (LDL-C),
`total cholesterol (TC), apolipoprotein B
`(apo-B), and non-high-density lipoprotein
`cholesterol (non-HDL-C) in patients with
`homozygous familial
`hypercholesterolemia (HoFH).
`
`Trade Name:
`
`
`Generic
`Name:
`
`Sponsor:
`
`Approval
`Date:
`
`Indications:
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`203858Orig1s000
`
`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 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
`X
`
`X
`X
`X
`X
`X
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203858Orig1s000
`APPROVAL LETTER
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`NDA 203858
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Aegerion Pharmaceuticals, Inc.
`Attention: Martha J. Carter
`Chief Regulatory Officer and Senior Vice President
`101 Main Street, Suite 1850
`Cambridge, MA 02142
`
`
`Dear Ms. Carter:
`
`Please refer to your New Drug Application (NDA) dated February 28, 2012, received
`February 29, 2012, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Juxtapid (lomitapide) capsules 5 mg, 10 mg, and 20 mg.
`
`We acknowledge receipt of your amendments dated March 1, April 16 and 19, May 3, 4, 18 (2),
`22, 23, and 30, June 15, 18, 21, and 27, July 2, 13, 18, 23, 27, and 30, August 1, 8, 17, 28, and
`31, September 7, 14, 21, 27, and 28 (2), November 20 (2), and December 4, 5, and 17, 2012. We
`also acknowledge receipt of your email dated December 21, 2012, that included the agreed-upon
`labeling and Risk Evaluation and Mitigation Strategy (REMS).
`
`
`This new drug application provides for the use of Juxtapid (lomitapide) Capsules as an adjunct
`to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available,
`to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B
`(apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous
`familial hypercholesterolemia (HoFH).
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`Sufficient stability data has been submitted to support a
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
`
`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
`
` expiration date.
`
`Reference ID: 3236196
`
`(b) (4)
`
`

`

`NDA 203858
`Page 2
`
`
`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). Information on submitting SPL files using eLIST may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`CARTON AND IMMEDIATE-CONTAINER LABELS
`Submit final printed carton and immediate-container labels that are identical to the enclosed
`carton and immediate-container labels as soon as they are available, but no more than 30 days
`after they are printed. Please submit these labels electronically according to the guidance for
`industry Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical
`Product Applications and Related Submissions Using the eCTD Specifications (June 2008).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 203858.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`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 this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk of
`hepatic transaminase elevations and hepatic steatosis, or to assess signals of a serious risk of
`small bowel and hepatic malignancies and teratogenicity, or to identify an unexpected serious
`
`Reference ID: 3236196
`
`

`

`NDA 203858
`Page 3
`
`
`risk of adverse effects on growth and neurological development in children treated with Juxtapid
`(lomitapide), or to identify an unexpected serious risk of cardiovascular adverse events.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1974-1: A juvenile animal toxicology study to evaluate the effects of lomitapide on
`neurological development (learning, memory, behavior, and coordination),
`growth, and long bone development with and without vitamin and essential fatty
`acid supplementation to determine whether any observed effects are due directly
`to lomitapide or secondarily to the inhibition of absorption of fat soluble vitamins
`and/or essential fatty acids. This study should be completed before any formal
`pediatric studies are initiated.
`
`
`
`The timetable you submitted on December 6, 2012, states that you will conduct
`this study according to the following schedule:
`
`
`
`
`
`
`
`
`Reference ID: 3236196
`
`July 15, 2013
`December 30, 2013
`June 15, 2014
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
`1974-2: An assessment and analysis of spontaneous reports of malignancy, teratogenicity,
`
`
`and hepatic abnormalities in patients treated with Juxtapid (lomitapide) for a
`
`
`period of 10 years from the date of approval. Specialized follow-up should be
`
`
`obtained on these cases to collect additional information on the reports.
`
`
`The timetable you submitted on November 20, 2012, states that you will conduct
`this study according to the following schedule:
`
`Final Protocol Submission: November 30, 2013
`Interim Report Submissions: December 31, 2014
`
`
`
`
`December 31, 2015
`
`
`
`
`December 31, 2016
`
`
`
`
`December 31, 2017
`
`
`
`
`December 31, 2018
`
`
`
`
`December 31, 2019
`
`
`
`
`December 31, 2020
`
`
`
`
`December 31, 2021
`
`
`
`
`December 31, 2022
`Study Completion:
`
`December 31, 2023
`Final Report Submission:
`June 1, 2024
`
`
`
`
`

`

`NDA 203858
`Page 4
`
`
`
`1974-3: A long-term prospective observational study (product exposure registry) of
`patients with homozygous familial hypercholesterolemia (HoFH) treated with
`Juxtapid (lomitapide) to evaluate known and potential serious risks related to the
`use of Juxtapid (lomitapide), including hepatic transaminase elevations, hepatic
`steatosis, small bowel and hepatic malignancies, teratogenicity, death (including
`cause of death), and major adverse cardiovascular events (including
`cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, unstable
`angina, and revascularization procedures). The registry will continue for 10 years
`from the date of last patient enrollment.
`
`
`
`
`
`The timetable you submitted on December 2, 2012, states that you will conduct
`this study according to the following schedule:
`
`Final Protocol Submission: November 30, 2013
`Interim Report Submission: January 31, 2015
`
`
`
`
`January 31, 2016
`
`
`
`
`January 31, 2017
`
`
`
`
`January 31, 2018
`
`
`
`
`January 31, 2019
`
`
`
`
`January 31, 2020
`
`
`
`
`January 31, 2021
`
`
`
`
`January 31, 2022
`
`
`
`
`January 31, 2023
`
`
`
`
`January 31, 2024
`
`
`
`
`January 31, 2025
`
`
`
`
`January 31, 2026
`
`
`
`
`January 31, 2027
`
`
`
`
`January 31, 2028
`Study Completion:
`
`March 1, 2028
`Final Report Submission:
`September 1, 2028
`
`
`Submit the protocols to your IND 50820, with a cross-reference letter to this NDA. Submit all
`final reports to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o),” “Required Postmarketing Final Report Under
`505(o),” “Required Postmarketing Correspondence Under 505(o).”
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`
`Reference ID: 3236196
`
`

`

`NDA 203858
`Page 5
`
`
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`Section 505-1 of the 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)]. In accordance with section 505-1
`of FDCA, we have determined that a REMS is necessary for Juxtapid (lomitapide) to ensure the
`benefits of the drug outweigh the potential risk of hepatotoxicity.
`
`Pursuant to 505-1(f)(1), we have also determined that Juxtapid (lomitapide) can be approved
`only if elements necessary to assure safe use are required as part of a REMS to mitigate the risk
`of elevated liver transaminases and hepatic steatosis, a risk factor for advanced liver disease
`including steatohepatitis and cirrhosis, that are listed in the labeling. The elements to assure safe
`use will educate prescribers about the risk of hepatotoxicity associated with the use of Juxtapid
`(lomitapide), the need to monitor patients during treatment with Juxtapid (lomitapide) as per
`product labeling, and to restrict access to therapy with Juxtapid (lomitapide) to patients with a
`clinical or laboratory diagnosis consistent with homozygous familial hypercholesterolemia
`(HoFH).
`
`We remind you that section 505-1(f)(8) of the FDCA prohibits holders of an approved covered
`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
`
`Your proposed REMS, submitted on December 21, 2012, and appended to this letter, is
`approved. The REMS consists of elements to assure safe use, an implementation system, and a
`timetable for submission of assessments of the REMS.
`
`Your REMS must be fully operational before you introduce Juxtapid (lomitapide) into interstate
`commerce.
`
`The REMS assessment plan should include, but is not limited to, the following:
`
`1. A survey study to evaluate healthcare providers’ knowledge of the risk of hepatotoxicity
`associated with the use of Juxtapid (lomitapide), the need to monitor liver-related
`laboratory tests before and during treatment with Juxtapid (lomitapide) as described in
`product labeling, and prescribers’ knowledge that FDA’s determination of the safety and
`efficacy of Juxtapid (lomitapide) is limited to patients diagnosed with homozygous
`familial hypercholesterolemia.
`
`
`Reference ID: 3236196
`
`

`

`NDA 203858
`Page 6
`
`
`
`a. The target level of healthcare provider knowledge for each educational goal of the
`REMS.
`
`
`b. If the target levels for healthcare provider knowledge are not met, provide
`possible causes for the deficiencies and proposed measures to improve
`knowledge.
`
`
`
`
`
`
`
`1. An assessment of enrollment in the Juxtapid REMS Program, including the following:
`
`
`a. Number of healthcare providers certified during the reporting period and
`cumulatively.
`
`
`
`i. Prescriber information, including degree, specialty, and practice setting
`(i.e., type of practice, geographic location)
`ii. Volume of prescriptions for each prescriber and each specialty
`
`b. Number of pharmacies certified during the reporting period and cumulatively.
`
`c. Number of healthcare providers and pharmacies that had their certification
`revoked during the reporting period and cumulatively and the reason for the
`revocation.
`
`2. Metrics regarding Juxtapid (lomitapide) distribution and dispensing to assess pharmacy
`compliance with the Juxtapid REMS:
`
`
`
`a. The number of Juxtapid (lomitapide) orders shipped to pharmacies during the
`reporting period and cumulatively, including number of bottles, bottle size, and
`dosage strength.
`
`
`b. Pharmacy compliance with Juxtapid REMS Program requirements (e.g., shipped
`to a Juxtapid REMS certified pharmacy versus a non-certified pharmacy).
`
`
`c. The number of prescriptions dispensed for Juxtapid (lomitapide), including
`quantity of tablets (mean, minimum, maximum) and dosage strength during the
`reporting period and cumulatively, overall and subset by compliance with the
`Juxtapid REMS Program requirements (e.g., received from Juxtapid REMS
`certified versus non-certified healthcare providers, number of initial prescriptions
`dispensed without a signed attestation on the Juxtapid Prescription Authorization
`Form). Dispensing details are to be obtained from the pharmacies.
`
`
`d. The number and demographics (e.g., gender, age, geographic location) of patients
`who received Juxtapid (lomitapide) during the reporting period and annually. The
`number is to be calculated by reconciling orders dispensed to unique patients.
`
`e. Duration of therapy for patients (mean, median, range).
`
`
`Reference ID: 3236196
`
`

`

`NDA 203858
`Page 7
`
`
`
`f. Report of number, length, and reasons for shipment delays to patients.
`
`g. Detailed description of root cause of noncompliance with Juxtapid REMS
`Program-required dispensing and any corrective and/or preventive actions taken
`to address noncompliance during the reporting period and cumulatively.
`
`
`
`3. Summary of issues and complaints received by Juxtapid REMS call center; summary of
`resolution of the issues and complaints.
`
`
`The requirements for assessments of an approved REMS under section 505-1(g)(3) include with
`respect to each goal included in the strategy, an assessment of the extent to which the approved
`strategy, including each element of the strategy, is meeting the goal or whether one or more such
`goals or such elements should be modified.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of the FDCA.
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
`
`NDA 203858 REMS CORRESPONDENCE
`(insert concise description of content in bold capital letters, e.g.,
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`METHODOLOGY)
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`
`NDA 203858 REMS ASSESSMENT
`
`NEW SUPPLEMENT FOR NDA 203858
`
`Reference ID: 3236196
`
`

`

`NDA 203858
`Page 8
`
`
`
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 203858
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`
`If you do not submit electronically, please send five copies of REMS-related submissions.
`
`PROMOTIONAL MATERIALS
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. 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.
`
`METHODS VALIDATION
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`REPORTING REQUIREMENTS
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST-ACTION FEEDBACK MEETING
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`
`Reference ID: 3236196
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Christine P. Nguyen, M.D.
`Acting Deputy Director
`Office of Drug Evaluation II
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`NDA 203858
`Page 9
`
`
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Kati Johnson, Regulatory Project Manager, at (301) 796-1234.
`
`
`
`
`
`
`
`
`
`
`
`Enclosures:
`Content of Labeling
`Medication Guide
`Carton and Container Labeling
`
`5 mg-28 capsules
`
`10 mg-28 capsules
`
`20 mg-28 capsules
`REMS
`
`Prescriber Training Module
`
`Prescriber Enrollment Form
` Dear Healthcare Provider letter
` Dear Professional Society letter
`
`Prescription Authorization Form
` Web site screen shot
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3236196
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTINE P NGUYEN
`12/21/2012
`
`Reference ID: 3236196
`
`