`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` 208411Orig1s000
`
`
`Narcan Nasal Spray, 4 mg.
`
`naloxone hydrochloride
`
`Adapt Pharma Operations Limited
`
`November 18, 2015
`
`For the emergency treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or central
`nervous system depression.
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`208411Orig1s000
`
`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
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208411Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 208411
`
`
`
`
`
`Food and Drug Administration
`Silver Spring, MD 20993
`
`NDA APPROVAL
`
`
`Adapt Pharma Operations Limited
`c/o Pacific-Link Consulting
`8195 Run of the Knolls Court
`San Diego, CA 92127
`
`Attention: Richard E. Lowenthal, MS, MBA
` President, Pacific-Link Consulting,
`Adapt Pharma Regulatory Representative
`
`
`
`Dear Mr. Lowenthal:
`
`Please refer to your New Drug Application (NDA) dated July 17, 2015, received July 20, 2015,
`and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act (FDCA), for Narcan Nasal Spray (naloxone hydrochloride), 4 mg.
`
`This new drug application provides for the use of Narcan Nasal Spray (naloxone hydrochloride),
`for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory
`and/or central nervous system depression.
`
`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.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`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
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`patient package insert, Instructions for Use, and Quick Start 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
`
`Reference ID: 3848912
`
`

`

`NDA 208411
`Page 2
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`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 208411.” 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.
`
`MARKET PACKAGE
`
`Please submit one market package of the drug product when it is available to the following
`address:
`
`
`Diana L. Walker, PhD, Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`White Oak Building 22, Room: 3240
`10903 New Hampshire Avenue
`Silver Spring, Maryland
`Use zip code 20903 if shipping via United States Postal Service (USPS).
`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
`
`
`
`
`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.
`
`This product is appropriately labeled for use in all relevant pediatric populations. Therefore, no
`additional pediatric studies are required at this time.
`
`
`Reference ID: 3848912
`
`

`

`NDA 208411
`Page 3
`
`
`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 identify an unexpected serious
`risk of untreated respiratory arrest that may result from device failure and subsequent loss (i.e.,
`failure) of the expected pharmacologic action of Narcan Nasal Spray (naloxone hydrochloride).
`
`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:
`
`2990-1 Establish reliability requirements for the combination product Narcan Nasal Spray
`(naloxone hydrochloride), and complete testing which verifies the combination
`product reliability.
`
`
`The timetable you submitted on November 17, 2105, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
`Please note the following considerations regarding the postmarketing requirement described
`above:
`
`02/2016
`09/2016
`11/2016
`
`a. Establish reliability requirements for your combination product. It is recommended
`that reliability be directly specified as R(t) = x%, where t = time and x% = probability
`of meeting essential performance requirements. These requirements should be
`objective and relate to the ability of a population of devices to meet essential
`performance requirements after pre-conditioning to elements outlined within c,
`below. The reliability requirements should be verified with a high degree of statistical
`confidence.
`
`b. Provide rationale and justification supporting the clinical acceptability of the
`established reliability requirements.
`
`c. Perform a test to verify the reliability requirements specified above.
`
`d. Devices assessed within the reliability test should be preconditioned to reasonably
`foreseeable worst-case conditions. We recommend the following preconditioning
`activities. However, you should provide rationale supporting the final precondition
`
`
`
`
`
`Reference ID: 3848912
`
`

`

`NDA 208411
`Page 4
`
`
`
`elements chosen and the order in which the products are conditioned. Your
`assessment of the preconditioning parameters should be based on your own failure
`analyses (e.g., fault tree analysis) in order to assure that the scope of preconditions
`and their boundary values are adequately correct and complete.
`• Shipping
`• Aging
`• Storage orientation and conditions
`• Vibration handling
`• Shock handling (e.g., resistance to random impacts, such as being dropped)
`
`e. Devices assessed within the reliability analysis should be activated under reasonably
`foreseeable worst-case conditions. We recommend the following circumstances of
`activation. However, you should provide rationale supporting the final circumstances
`of activation chosen.
`
`
`• Activation orientation
`• Environmental temperature
`
`
`2990-2 Establish procedures for monitoring reports of failure of the combination product
`Narcan Nasal Spray (naloxone hydrochloride) to activate or failure of the
`combination product to deliver the full-labeled dose. Provide interim and final reports
`to the NDA, which contain a detailed analysis of reported device failures (including
`reported malfunctions that did, as well as did not result in patient harm), full event
`narratives of the failure and any subsequent adverse events, and the results of root
`cause analysis performed for the reported failure.
`
`
`The timetable you submitted on November 17, 2015, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission: 02/2016
`Interim Report Submission: 01/2017
`Final Report Submission:
`01/2018
`
`
`Submit the protocol(s) to your IND 114704, with a cross-reference letter to this NDA. Submit all
`final report(s) 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.
`
`Reference ID: 3848912
`
`

`

`NDA 208411
`Page 5
`
`
`
`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
`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.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`2990-3
`
`
`
`Conduct an adequate leachable safety assessment for the
`plunger used in your container closure system. This assessment must include
`leachable data from long-term stability studies testing at least three batches
`(taking into consideration the proposed shelf-life) to determine if the identified
`extractables leach into the drug product over time. Using this information,
`conduct a toxicological risk assessment justifying the safety of the leachables,
`taking into consideration the maximum daily dose of the identified materials for
`this drug product. Submit a toxicological risk assessment for any leachable that
`exceeds 5 mcg/day. From a genetic toxicology perspective, any leachable that
`contains a structural alert for mutagenicity must not exceed 120 mcg/day for an
`acute indication, or be adequately qualified for safety. The risk assessment should
`be based on the maximum level of each leachable detected in long-term stability
`samples.
`
`
`The timetable you submitted on November 17, 2015, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission: 02/2016
`Interim Report Submission: 01/2017
`Final Report Submission:
`11/2017
`
`
`2990-4
`
`
`
`Conduct a long-term stability evaluation placing at least three (3) manufactured
`lots of NARCAN Nasal Spray, 40 mg/mL, on long-term stability evaluation at the
`following temperatures:
`
`a. 2 to 8°C
`b. 40°C/75% RH - to extend the time points out to 24 months
`
`
`The timetable you submitted on November 17, 2015, states that you will conduct this study
`according to the following schedule:
`
`
`Reference ID: 3848912
`
`(b) (4)
`
`

`

`NDA 208411
`Page 6
`
`
`
`Final Protocol Submission: 02/2016
`Interim Report Submission: 06/2017
`Final Report Submission:
`06/2018
`
`
`Submit clinical protocols to your IND 114704 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`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,
`Medication Guide, and patient PI (as applicable) to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`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 ).
`
`
`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. 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.
`
`
`
`
`Reference ID: 3848912
`
`

`

`NDA 208411
`Page 7
`
`
`EXPIRY DATING PERIOD
`
` A
`
` 24-month expiry dating period is granted for Narcan Nasal Spray, when stored at 59°F to 77°F
`(15°C to 25°C). Excursions permitted between 4°C to 40°C (39°F to 104°F).
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`SPECIAL REPORTING REQUESTS
`
` •
`
` Submit both serious and non-serious outcomes as expedited reports within 15 days of receipt
`for the following:
`o All reports in patients less than one year of age
`
`Include a summary evaluation of each of these reports requested in the submission of the
`periodic reports for each reporting period, with an analysis of treatment failures and adverse
`events of airway obstruction, respiratory distress, or respiratory arrest; in addition to a
`summary of these events in the context of all similar events reported for Narcan Nasal Spray.
`
`•
`
`
`
`If you have any questions, call Diana L. Walker, PhD, Regulatory Project Manager, at (301) 796-
`4029.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Sharon Hertz, MD
`Director
`Division of Anesthesia, Analgesia, and
` Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`
`
`
`
`Reference ID: 3848912
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`11/18/2015
`
`Reference ID: 3848912
`
`