CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208411Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`
`CDER stamp date:
`
`Product:
`Indication:
`
`Applicant:
`Review Division:
`
`208411
`SDN 4; SDN 10; SDN 13
`July 18, 2015; September 8, 2015; October 5,
`2015
`July 20, 2015; September 8, 2015; October 5,
`2015
`NARCAN nasal spray
`Treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or
`central nervous system depression.
`Adapt Pharma Operations Limited
`Division of Anesthesia, Analgesia, and Addiction
`Products
`Newton H. Woo, PhD
`Reviewer:
`R. Daniel Mellon, PhD
`Supervisor:
`Sharon Hertz, MD
`Division Director:
`Diana L. Walker, PhD
`Project Manager:
`Template Version: September 1, 2010
`Disclaimer
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208411 are owned by Adapt Pharma Operations Limited
`or are data for which Adapt Pharma Operations Limited has obtained a written right of
`reference. Any information or data necessary for approval of NDA 208411 that Adapt
`Pharma Operations Limited does not own or have a written right to reference constitutes
`one of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 208411.
`
`Reference ID: 3841831
`
`1
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`TABLE OF CONTENTS
`
`1
`
`3
`
`EXECUTIVE SUMMARY...........................................................................................6
`1.1
`INTRODUCTION .....................................................................................................6
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................6
`1.3
`RECOMMENDATIONS .............................................................................................6
`2 DRUG INFORMATION............................................................................................11
`2.1
`DRUG ................................................................................................................11
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS..........................................................11
`2.3
`DRUG FORMULATION ..........................................................................................12
`2.4
`COMMENTS ON NOVEL EXCIPIENTS......................................................................13
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN........................................13
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.....................................20
`2.7
`REGULATORY BACKGROUND ...............................................................................21
`STUDIES SUBMITTED...........................................................................................22
`3.1
`STUDIES REVIEWED............................................................................................22
`3.2
`STUDIES NOT REVIEWED.....................................................................................23
`3.3
`PREVIOUS REVIEWS REFERENCED.......................................................................23
`PHARMACOLOGY .................................................................................................23
`4.1
`PRIMARY PHARMACOLOGY ..................................................................................23
`4.2
`SECONDARY PHARMACOLOGY .............................................................................24
`4.3
`SAFETY PHARMACOLOGY ....................................................................................24
`PHARMACOKINETICS/ADME/TOXICOKINETICS ...............................................24
`5.1
`PK/ADME .........................................................................................................24
`5.2
`TOXICOKINETICS.................................................................................................24
`6 GENERAL TOXICOLOGY......................................................................................24
`
`4
`
`5
`
`7 GENETIC TOXICOLOGY........................................................................................25
`
`8 CARCINOGENICITY...............................................................................................25
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY.................................25
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT................................................26
`9.2
`EMBRYONIC FETAL DEVELOPMENT.......................................................................27
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT..........................................................28
`10
`SPECIAL TOXICOLOGY STUDIES....................................................................37
`
`11
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................37
`
`APPENDIX/ATTACHMENTS ..............................................................................38
`12
`REFERENCE LIST...........................................................................................................38
`
`Reference ID: 3841831
`
`2
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table of Tables
`
`Table 1: Composition of NARCAN Nasal Spray.............................................................12
`Table 2: Excipients included in the drug product and qualification status ......................12
`Table 3: Applicant’s Drug Substance Specifications ......................................................13
`Table 4: Adequacy of Applicant’s Drug Substance Specifications .................................14
`Table 5: Applicant’s Drug Product Specifications..........................................................15
`Table 6: Adequacy of Applicant’s Drug Product Specifications......................................16
`Table 7: Extractables and Worst Case Estimates of Exposure ......................................17
`Table 8: Compounds Below the Toxicologic Threshold of Concern of
`/day .........19
`
`Reference ID: 3841831
`
`3
`
`(b) (4)
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table of Figures
`
`Figure 1: Naloxone Nasal Spray and How Administered ...............................................11
`Figure 2: Diagram of Naloxone Nasal Spray (not to scale) ............................................16
`
`Reference ID: 3841831
`
`4
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`The Applicant, Adapt Pharmaceuticals, has submitted a 505(b)(2) NDA for an intranasal
`naloxone hydrochloride spray for the treatment of known or suspected opioid overdose,
`as manifested by respiratory and/or central nervous system depression with the
`intention of being used by laypersons or caregivers in the out-of-hospital, non-
`healthcare setting. This application is relying upon the published literature to support
`the safety and efficacy of this intranasal product. The Applicant owns the original NDA
`for Narcan (naloxone hydrochloride) injection.
`
`1.2 Brief Discussion of Nonclinical Findings
`The Applicant did not submit any new nonclinical studies to support this marketing NDA
`as none were required. Local tolerance studies would normally be required to support a
`reformulated drug product that employs an alternate route, however, the Division
`determined that nonclinical studies would not be required given the clinical experience
`with intranasal naloxone, lack of any novel excipients, the acute use of the drug product,
`and the potentially life-saving indication.
`
`The Applicant has provided adequate data to support the safety of the drug substance,
`drug product, and drug product formulation. To support the safety of the container
`closure system, the Applicant has submitted extractables data under various extraction
`conditions. Under the most relevant solvent condition using water, no peaks were
`present indicating that there were no compounds that appeared after harsh extraction
`conditions. It is notable that a leachables assessment was not conducted but the
`Applicant has indicated that potential leachables will be evaluated in long-term stability
`samples. It is in the opinion of this Reviewer that the absence of leachables data does
`not preclude marketing approval for the following reasons: 1) the
`
`plungers is used in other FDA-approved aqueous based nasal and injectable drug
`products; 2) analysis of water extracts did not identify any substances; 3) the Applicant
`has committed to monitor for leachables during stability; 4) most importantly, this
`product is indicated for an acute, single-use indication; and 5) the drug product is a
`potentially life-saving therapy. The Applicant has committed to monitoring batches on
`stability for leachables. This should be solidified as a formal post-marketing
`commitment (PMC).
`
`1.3 Recommendations
`
`1.3.1 Approvability
`From a pharmacology toxicology perspective, NDA 208411 may be approved with a
`post-marketing commitment (PMC).
`
`Reference ID: 3841831
`
`5
`
`(b) (4)
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`1.3.2 Additional Non Clinical Recommendations
`The following nonclinical study is recommended as a post-marketing commitment
`(PMC) should this NDA be approved in the first cycle:
`
`As proposed, conduct and submit an adequate leachable safety assessment for your
`drug product and container closure system. This assessment must include leachable
`data from long-term stability studies taking into consideration the proposed shelf-life to
`determine if the specified extractables also leach into the drug product over time, and 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.
`
`Additional Comments for the Leachables Assessment
` The leachable compounds you propose to evaluate in your leachables
`assessment appear appropriate.
` In your leachables assessment, evaluate at least three batches of your drug
`product over the course of your stability studies at multiple timepoints during the
`proposed shelf-life of your 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 this 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 that include any intended secondary container closure system(s) unless
`otherwise justified.
`
`- Published literature to support the safety of a leachable rarely provides
`adequate detail of the study design and study results to permit a thorough
`independent evaluation of the data. Summary reviews, (e.g., BIBRA, CIR,
`HERA), although potentially useful to identify original source material, are
`not acceptable as the source material is not provided and the conclusions
`cannot be independently verified. Submission of any published study
`reports must be accompanied by a detailed comparison to modern
`toxicology study endpoints and any shortcomings of the study must be
`discussed and justification must be provided to support your assertion that
`these data are adequate to support the safety of your container closure
`system.
`
`- Safety justifications based on analogous compounds are also not
`acceptable unless you can provide adequate data to support your
`conclusions that a risk assessment based on one compound can be
`logically interpolated to represent an adequate safety evaluation for your
`leachable. This should include a detailed understanding of the absorption,
`distribution, metabolism, and elimination of the compounds and an
`adequate scientific bridge to interpolate a NOAEL for the leachable.
`
`Reference ID: 3841831
`
`6
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`1.3.3 Labeling
`
`The following changes to the Applicant’s proposed labeling are recommended in the
`table below. Refer to the action letter for final drug product labeling.
`
`Applicant’s Proposed labeling
`
`Reviewer’s proposed changes
`
`Rationale for changes
`
`8 USE IN SPECIFIC POPULATIONS
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Risk Summam
`
`8.1 Pregnancy
`
`Risk Summam
`
`m” w” °°‘°"°“‘*e"'a'“““”°‘m-
`
`in
`
`adrug-
`
`r
`pregnan women
`associated risk. In animal
`reproduction studies
`u
`
`in
`
`r
`pregnan women
`associated risk. In animal
`reproduction studieF
`no embryotoxic or tera genrc
`
`adrug-
`
`Defer to Maternal Health Team.
`
`Changes were made to
`maintain consistency with other
`emergency use naloxone drug
`products and also update
`margins with a human dose of 8
`mglday (two NARCAN nasal
`sprays) based on body surface
`area and a 60 k human.
`9
`
`naloxone hydrochloride during the
`period of organogenesis at doses
`equivalent to
`12-
`times. re
`
`e .
`a uman use of
`RCAN nasal
`
`0
`
`m ay
`
`-ba on
`compariso .
`
`ysurface area
`
`a .
`
`groun n
`m
`e
`major birth defects and
`miscarriage in clinically recognized
`pregnancies is 2% to 4% and 15%
`to 20%, respectively.
`
`of
`
`e
`
`major
`groun n
`e
`birth defects and miscarriage in
`clinically recognized pregnancies is
`2% to 4% and 15% to 20%.
`respectively.
`
`Reference ID: 3841831
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`
`(b) (4)
`
`Animal Data
`
`Animal Data
`
`No significant changes
`recommended. The data are
`
`from the original NARCAN
`labeling. HED were based on a
`human dose of 8 mglday (two
`NARCAN intranasal sprays)
`and 60 kg human.
`
`
`
`Naloxone hydrochloride occurs as
`a white to sli . ht off-white
`
`Naloxone hydrochloride. an opioid
`anta . onist. occurs as a white to
`
`Reference ID: 3841831
`
`
`
`Naloxone hydrochloride was
`administered during
`organogenesis to mice and rats at
`doses
`(5) “’times,
`respectively,
`
`(5) (0
`ose of flmglday
`(b) (4)
`
`based on body surface area ('9(4)
`
`(5) ‘4) studies
`). These
`demonstrated no embryotoxic or
`teratogenic effects due to
`naloxone hydrochloride (”X9
`
`1 1 DESCRIP'I10N
`
`NARCAN (naloxone
`hydrochloride) nasal spray is a
`pre-tilled. single dose intranasal
`spray.
`(m4)
`
`Chemically. naloxone
`hydrochloride is the hydrochloride
`salt of 17-AIIyI-4,5a-epoxy-3,14—
`dihydroxymorphinan—G—one
`hydrochloride with the following
`structure:
`
`H
`
`,
`
`in“
`,
`
`x <\
`,
`\ HO-ZT\
`,
`x
`,
`->
`,
`>
`1
`\
`z
`
`,7
`\
`\
`<1
`\
`
`\=(“.H2
`
`-
`
`HLI
`
`H()
`
`‘0
`
`l)
`
`C19H21N04' HCl
`M.W. 363.84
`
`
`
`Naloxone hydrochloride was
`administered during organogenesis
`to mice and rats at subcutaneous
`
`doses up to 10 mglkg/day
`(equivalent to
`‘5’ (4’ 12-
`times, respectively,
`(5)“)
`a human dose of
`
`:28 mglday (two NARCAN nasal
`sprays)
`(5)“)
`based on body surface area
`(b)
`(4) comparison). These
`(”W’studies demonstrated no
`embryotoxic or teratogenic effects
`due to naloxone hydrochloride 0"“)
`
`Pregnant female rats were
`administered 2 or 10 mg/kg
`naloxone subcutaneously from
`Gestation Day 15 to Postnatal day
`21. There were no adverse effects
`
`on the offspring (up to 12-times a
`human dose of 8 mglday (two
`NARCAN nasal sprays) based on
`bod surface area com-arison .
`11 DESCRIP110N
`
`NARCAN (naloxone hydrochloride)
`nasal spray is a pre-tilled, single
`dose intranasal spray. NARCAN
`does not contain any natural
`rubber latex. Chemically, naloxone
`hydrochloride is the hydrochloride
`salt of 17-Allyl-4.50-epoxy-3,14-
`dihydroxymorphinan—G-one
`hydrochloride with the following
`structure:
`
`H. Na
`',
`‘/<
`’
`‘
`x,
`\
`{I
`1
`,/—\‘ H0t\
`‘
`.
`(-
`I
`/
`I
`\
`\
`,
`\
`./
`\’
`x
`,
`a.
`
`\
`
`\—(‘H.
`—
`‘
`\
`,
`
`'
`
`HLI
`
`H()
`
`‘O
`
`l)
`
`C 19H21N04' HCl
`M.W. 363.84
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`
`
`powder, and is soluble in water, in
`dilute acids, and in strong alkali;
`slightly soluble in alcohol;
`practically insoluble in ether and in
`chloroform.
`
`slightly off-white powder, and is
`soluble in water, in dilute acids,
`and in strong alkali; slightly soluble
`in alcohol; practically insoluble in
`ether and in chloroform.
`
`The established
`
`pharmacological class should
`be included in this section.
`
`
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`Naloxone hydrochloride is an
`Naloxone hydrochloride is an
`opioid antagonist that antagonizes
`opioid antagonist that antagonizes
`opioid effects by competing for the
`opioid effects by competing for the
`same receptor sites.
`same receptor sites.
`Naloxone hydrochloride reverses
`Naloxone hydrochloride reverses
`the effects of opioids, including
`the effects of opioids, including
`respiratory depression. sedation,
`respiratory depression. sedation,
`and hypotension "9 (0 it can
`and hypotension.
`"9 (0 it can
`reverse the psychotomimetic and
`reverse the psychotomimetic and
`dysphoric effects of agonist-
`dysphoric effects of agonist-
`antagonists such as pentazocine.
`antagonists such as pentazocine.
`
`
`No changes recommended.
`
`13.1 Carcinogenesis, Mutagenesis,
`lmpairrnent of Fertility
`
`Carcinogenesis
`Long-tenn animal studies to evaluate the
`carcinogenic potential of naloxone have not
`been completed.
`
`Mutagenesis
`Naloxone was weakly positive in the Ames
`mutagenicity and in the in vitro human
`lymphocyte chromosome aberration test but
`was negative in the in vitro Chinese hamster
`V79 cell HGPRT mutagenicity assay and in
`the in vivo rat bone marrow chromosome
`
`No changes recommended.
`
`No changes recommended.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis,
`lmpairrnent of Fertility
`
`Carcinogenesis
`Long-tenn animal studies to evaluate the
`carcinogenic potential of naloxone have not
`been completed.
`
`Mutagenesis
`Naloxone was weakly positive in the Ames
`mutagenicity and in the in vitro human
`lymphocyte chromosome aberration test but
`was negative in the in vitro Chinese
`hamster V79 cell HGPRT mutagenicity
`assay and in the in vivo rat bone marrow
`chromosome aberration study.
`
`Impairment of Fertilig
`
`(5X4)
`
` 13 NONCLINICAL TOXICOLOGY
`
`aberration study.
`
`Impairment of Fertilig
`
`(5X4)
`
`(5) (4)
`
`HED were based on a
`
`Male rats were treated with 2 or 10 mg/kg
`naloxone for 60 days prior to mating.
`Female rats treated for 14-days prior to
`mating and throughout gestation with the
`same doses of naloxone (up to 12-times a
`human dose of 8 mg/day (two NARCAN
`nasal sprays) based on body surface area
`comparison). There was no adverse effect
`on fertility.
`
`
`human dose of 8 mg/day (two
`NARCAN intranasal sprays)
`and 60 kg human.
`
`
`
`Reference ID: 3841831
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`2
`
`Drug Information
`
`2.1 Drug
`CAS Registry Number
`51481-60-8
`
`Generic Name
`Naloxone hydrochloride
`
`Code Name
`N/A
`
`Chemical Name
`Morphinan-6-one,4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)-,hydrochloride,(5 )-,
`dihydrate 17-Allyl-4,5-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride
`dihydrate
`
`Molecular Formula/Molecular Weight
`C19H21NO4 • HCl
`
`Structure
`
`Pharmacologic Class
`Opioid antagonist (Established Pharmacological Class)
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`Strength
`Marketing
`AP
`(route)
`Status
`Date
`
`Drug Name Division
`
`NDA
`
`16636
`
`Narcan
`(Naloxone
`HCl) Injection
`
`DAAAP
`
`1 mg/mL
`(IV, IM,
`SC)
`
`Withdrawn
`FR Effective
`
`August
`20,
`2010
`
`Indication
`The complete and partial
`reversal of opioid depression,
`including respiratory
`depression, induced by natural
`and synthetic opioids and
`diagnosis of suspected or
`known acute opioid overdosage.
`
`Sponsor
`
`Adapt
`Pharma
`(formerly
`Endo)
`
`IND
`
`114704
`
`Drug Name
`Naloxone HCl
`Nasal Spray
`
`Division
`
`Status
`
`DAAAP
`
`Active
`
`Indication
`For the complete or partial reversal of opioid
`depression, including respiratory depression
`induced by natural and synthetic opioids
`
`Sponsor
`Adapt
`Pharma
`
`Reference ID: 3841831
`
`10
`
`(b) (4)
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`DMF
`
`Subject of DMF
`
`Holder
`
`Status and
`Submit Date
`
`Active since January
`25, 1972
`
`Active since August
`20, 2010
`
`Active since October
`31, 2007
`
`Active since April
`24, 2007
`
`Active since January
`5, 2004
`
`Reviewer’s Comment
`
`LOA provided. Referenced by
`FDA approved drug products.
`Adequate.
`LOA provided. Referenced by
`FDA approved drug products.
`Adequate.
`LOA provided. Referenced by
`FDA approved drug products.
`Adequate.
`LOA provided. Referenced by
`FDA approved drug products.
`Adequate.
`LOA provided. Referenced by
`FDA approved drug products.
`Adequate.
`
`2.3 Drug Formulation
`The drug product is a non-pressurized unit-dose nasal spray dispenser designed to
`deliver
` (or 0.1 mL) in a single spray. The drug product solution is filled into
`
`125 mcL glass vials closed with rubber plungers. The vials are mounted into an
`unit-dose spray device that is commercially available. This unit-dose spray device does
`not require priming before use and the device can be used in any orientation. When the
`device is actuated the cannula of the actuator punctures the septum on the vial and
`delivers a
` (or 0.1 mL) spray of naloxone intranasal solution.
`
`Figure 1: Naloxone Nasal Spray and How Administered
`
`Composition of the naloxone hydrochloride 40 mg/mL nasal spray solution is presented
`in Table provided by the Sponsor below.
`
`Reference ID: 3841831
`
`11
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table 1: Composition of NARCAN Nasal Spray
`
`QuaIItIty
`per ImIt dose
`(I 00 Ill-«l
`per m
`4.4 mg
`44.0 mg
`Naloxone HCI dihydrate
`(4.0mm
`(41) (1 mg)
`(cm'lcw/mnding In nulmnm' H( I)
`
`
`
`Benzalkonium chloride . (b) (4)
`Disodium edetate
`
`Quantih
`L
`
`
`
`
`(omponent
`
`Grade
`
`
`
`
`
`Sodium chloride
`
`
`Hydrochloric acid.
`Purified water
`
`[I SP : United States Pharmacopeia
`q.s. ad = a sufiicicm quantity to make
`
`2.4 Comments on Novel Excipients
`
`There are no novel excipients in the NARCAN nasal spray formulation. All of the
`excipients are listed in the FDA Inactive Ingredients Database (IID) and are present at
`lower levels1 than contained in several FDA-approved nasal drug products.
`
`Table 2: Excipients included in the drug product and qualification status
` Function Ingredients
`
` Maximum
`
`
`Acceptable? (Rationale)
`exposure of
`
`two sprays
`
`
`
`lmaldavl
`(b))(4)
`
`Benzalkonium chloride
`Y_ES
`(5)“)
`Disodium edetate
`Y—ES
`
`YES
`Sodium Chloride
`
`
`
`
`IID: FDA Inactive Ingredients Database
`
`2.5 Comments on Impurities/Degradants of Concern
`
`Drug Substance Impurities
`Adapt Pharma submitted specifications for naloxone hydrochloride substance (as
`shown below) that complies with the requirements of the United States Pharmacopeia
`(USP) and European Pharmacopoeia (EP) monographs:
`
`1 taking into consideration the concentration and daily intake associated with the designated maximum
`daily dose of 8 mg
`
`Reference ID: 3841831
`
`12
`
`

`

`NDA 208411
`
`Newton H. W00, PhD
`
`Table 3: Applicant’s Drug Substance Specifications
`
`Acceptance criteria
`Related substances EP
`
`Unknown related substances (each)
`Total related substances
`
`Assay (HPLC)
`
`Naloxone
`
`Reference is made to tn” DMF
`
`for details regarding the justification of
`
`It Is no ed that me Sponsor has submitted two
`the specifications of the rug su s nce.
`separate specifications that appear to conform to EP and USP guidelines but this
`Reviewer denotes the lowest specificafion below for review purposes and comments on
`me acceptability of the dmg substance specification.
`
`The identification flireshold according to ICH Q3A(R2) for a maximum daily dose of a
`drug substance that is 5 2 glday is 0.10% or 1.0 mg intake, whichever is lower. The
`qualification threshold according to ICH Q3A(R2) for a MDD of a drug substance that is
`s 2 glday is 0.15% or 1.0 mg total daily intake, whichever is lower.
`
`The following Table illustrates me drug substance specifications (adapted from the
`Applicant’s submission) and adequacy of the specifications.
`
`Reference ID: 3841831
`
`1 3
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table 4: Adequacy of Applicant’s Drug Substance Specifications
`
`Criteria %wlw
`
`Applicant’s Acceptance mmAcceptable?
`
`ICH Q3A(R2)
`0.15% or 1 mg,
`whichever is lower
`
`substance
`
`Not detected; no
`specification
`
`
`
`ICH M7
`NMT than 120
`
`mcglday
`
`0.10%
`
`ICH Q3A(R2)
`0.15% or 1 mg,
`whichever is lower
`
`Exceeds ICH
`Q3A(R2)
`0.15% or 1 mg,
`whichever is lower
`
`Exceeds ICH
`Q3A(R2)
`0.15% or 1 mg,
`whichever is lower
`
`lower than 120
`mcg/day as per ICH
`M7.
`
`Yes
`
`Yes; Although the
`specification is above
`the ICH qualification
`threshold, at this
`specification the daily
`intake would be
`
`P The DMF as
`
`een deemed
`
`acceptable for other
`FDA-approved
`naloxone drug
`- rcducts.
`
`Yes; Although the
`specification is above
`the ICH qualification
`threshold, at this
`specification the daily
`intake would be
`
`P The DMF as
`
`een deemed
`
`acceptable for other
`FDA-approved
`naloxone drug
`
`Residual Solvents
`
`
`The A licant notes that naloxone h drochloride final
`
`
`
` evera a C es were screene O
`
`
`Reference ID: 3841831
`
`14
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`levels were significantly below ICH solvent Option 1 guidelines and therefore has not
`proposed to test for these residual solvents. The acceptability of this justification is
`deferred to the CMC reviewer.
`
`Drug Product
`The Applicant has submitted the following drug product specifications for naloxone (see
`Table below provided by the Applicant).
`
`Table 5: Applicant’s Drug Product Specifications
`
`.
`.
`.»'\ppcarancc ol contamcr
`
`A ) acarancc ofcontainer —
`I 1
`.
`devrce
`
`.
`.
`F1llcd V1111
`
`Clear glass \‘ial with black lunger.
`*
`.
`.
`p
`‘
`No usual detects.
`
`73.7320
`
`Assembled llnit
`
`Vl'll with lunacr 11101111th in unit-
`‘
`.
`p.
`‘
`.
`.
`dose deuce. No \‘lSllal detect.
`
`Appearance ot‘fbrmulation
`
`Filled Vial
`
`Identity (UV)
`
`73.7868
`
`Filled Vial
`
`Identity (HPI.C)
`
`73.7822
`
`Filled Vial
`
`A clear and colorless or slightly
`.
`.
`.
`yello“ ltqu1d.
`
`The standard and sample spectra must
`be essentially iacuuwgmu
`0"“)
`
`Retention time of peak due to
`naloxone in the assay corresponds to
`that of the standard.
`
`
`
`‘
`IlPIL‘ lor N'aloxone
`
`._
`I‘lllcd Vial
`
`_
`‘
`(5X4)
`"h (ol label claim)
`
`HPI.C for Benzalkonium
`chloride
`
`73.7820
`
`l-‘illed le
`
`lIPI.C for Disodium cdctatc
`
`73.4011
`
`Filled Vial
`
`.
`
`~ V
`
`l l" 'r ‘
`,«_x
`“"““.‘“.‘E-‘ MAO“? units (as
`1 mlonmty 01 mass)
`
`USP"905>
`\
`current ed.
`
`.
`'\.~semhled Umt
`
`3.
`
`- '.
`
`Per USP
`
`It was noted in early development studies with naloxone solution that yellow
`discoloration occurred. Formation of this discoloration was confirmed to be independent
`0
`(mo formation. However the Applicant eliminated this discoloration by the
`addition of EDTA and also noted that
`“""formation was absent.
`
`As the maximum daily intake of intranasal naloxone is designated to be 8 mg, the
`identification threshold according to ICH Q3B(R2) for a maximum daily dose of a drug
`product that is 1 mg — 10 mg is 0.5% or 20 mcg intake, whichever is lower. The
`qualification threshold according to ICH Q3B(R2) for a MDD of a drug product
`administered per day between < 10 mg is 1% or 50 mcg total daily intake, whichever is
`lower.
`
`Reference ID: 3841831
`
`1 5
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table 6: Adequacy of Applicant’s Drug Product Specifications
`
`Degradant
`
`Applicant’s Acceptance
`Criteria (%wlw)
`
`ICH threshold
`
`Acceptable?
`
`
`
`
`W" ICH Q3B(R2)
`
`
`on 1%
`
`ICH Q3B(R2) 0.5%
`(”"9 Not detected; no
`
`
`specification
`
`Unknown impurity
`
`Container Closure System
`NARCAN nasal spray consists of an
`rubber stopper attached to the actuator.
`primary container closure system.
`
`"Munit dose actuator, with a glass vial and
`“m unit dose actuator is not part of the
`
`As seen in the Figure below, the vial/stopper provides a fully enclosed container-closure
`system. The Applicant submitted results from only an extractables study to support the
`safety of the container closure system.
`
`Figure 2: Diagram of Naloxone Nasal Spray (not to scale)
`
`Nasal Actuator orifice
`
`k."
`
`Nasalactuator plunger
`piercer/driver
`(b) (4)
`
`-
`
`ed-
`
`PlungerStopper
`(0(4)
`.
`Vlal
`
`’
`
`‘
`
`* Formulated Solution
`
`Q ‘ ‘ ~ Container holder
`
`(I!) (4)
`
`Extractables Study (Report 2014001844 rev. 1)
`plungers and glass vials was
`An extractables evaluation of
`conducted to determine the extractable profile of the container closure system in direct
`contact with the drug solution. Extraction was performed on one lot of stoppers and one
`lot of vials in solvents of varying polarities that included, water,
`"m
`. The stopper extracts were analyzed in duplicates by Liquid
`Chromatography/Mass Spectrometry (LC/MS), Gas Chromatography/Mass
`Spectrometry (GC/MS) direct injection and headspace, Ion Chromatography (IC) and
`Inductively Coupled Plasma/Optical Emission Spectroscopy (lCP/OES). Following were
`the extraction procedures utilized for this study (excerpt from Applicant’s submission):
`
`Extraction Procedure for LC/MS (nonvolatile organic compounds) and GC/MS (semi-
`volatile organic compounds) Direct Injection
`About
`
`0:) (4)
`
`Reference ID: 3841831
`
`1 6
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`prepared by refluxing the same volume of each solvent at the same conditions. After
`extraction,
`"M" before being
`transferred to glass vials for storage until analysis.
`
`GC/MS Headspace (volatile compounds)
`"M" was put into GC headspace vials,
`About
`W" prior to injection. A blank was
`in duplicate, and incubated at
`prepared by incubating an empty GC headspace vial at the same conditions.
`
`Extraction Procedure for ICP/OES (extractable metals)
`About
`
`were extracted, in duplicate, in
`
`conditions. After extraction, the extracts were stored in
`analysis.
`
`"M"
`W"
`was extracted at the same
`
`“"9 tubes until
`
`Extraction Procedure for IC (extractable anions)
`About
`
`"M”
`
`W" tubes until analysis.
`
`After extraction, the extracts were stored in
`
`Extraction conducted with M" was considered by the Applicant to represent a “worst
`case scenario” and formed the basis of the risk assessment with respect to GC-MS and
`LC-MS results that were submitted to the NDA.
`It was noted in the submission by the
`Applicant that the extraction conditions with
`(W) do not likely reflect real-life
`leaching due to the differences in the polarities, solvent strength, and temperature
`conditions. The Applicant reported the highest levels under any extraction conditions
`and created a summary table indicating the maximum theoretical exposure levels (see
`Table below).
`
`Table 7: Extractables and Worst Case Estimates of Exposure
`
`Genotoxic
`
`
`
`Exposure
`Compound
`(mcg per 2
`(Yes/No)
`
`
`
`sprays)
`
`
`based on
`
`data from
`
`(M)
`
`
`
`
`extracts
`
`(mo
`(”W/WHO has indicated an
`
`acceptable ADI of 0.3 mg/kg bw
`or 18 m da for 60 kg human}
`
`Common rubber
`“"9.
`Search in TOXNET did not reveal
`
`an information.
`
`“"9.
`Common rubber
`
`
`Search in TOXNET did not reveal
`
`
`
`
`any information.
`(but)
`
`
`
`Reference ID: 3841831
`
`1 7
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Selected as a leachable
`
`compound to be monitored
`over stability.
`
`Selected as a leachable
`
`compound to be monitored
`over stabili
`.
`Selected as a leachable
`
`compound to be monitored
`over stabili
`.
`
`13-week repeat-dose inhalational
`rat study noted clinical signs of
`salivafion and rubbing and
`increased kidney and liver
`weights; NOAEL was considered
`to be 1300 ppm/6h/da-
`
`. mglkg bw/day
`daily intakeIs
`(or 67 mglday for 60 kg human),
`which derives mainly from roots
`
`compound to be monitored
`over stability.
`
`m cay for a 60 kg human
`
`carcinogen
`
`Below FDA "D as an exci . ient
`
`— Below FDA "D as an exci cient
`Below FDA "D as an excipient
`
`E estimates typical dietary
`In a e of 20 to 50 mglday-
`
`has set a PDI of 18-
`
`*Potential Ieachables that will be monitored on long term stability samples
`
`Reference ID: 3841831
`
`18
`
`

`

`NDA 208411
`
`Newton H. Woo, PhD
`
`Table 8: Compounds Below the Toxicologic Threshold of Concern of 5 mcglday
`
`(5)“)
`
`Given that NARCAN nasal spray formulation is aqueous based, water extraction data
`appear to provide the most relevant representation of potential leachables. No peaks
`were detected in the water extracts analyzed by GC-MS or LC-MS. A potential
`confound is that the pH of the water was not specified in the extraction study report and
`that different results may be obtained in acid conditions, which is the case of NARCAN
`nasal spray that has a pH of 3.5 to 5.5. Other considerations are that extraction
`conditions are much harsher (i.e., temperature) than storage conditions and that the
`extraction study utilized whole stoppers in which the whole surface area of the rubber
`stopper is exposed to the solvent whereas in the case of the actual drug product only
`the base of the stopper under capped conditions is exposed to the aqueous drug
`solution.
`
`0""
`To justify the safety of the container closure system, the Applicant notes that the
`plungers is utilized in a number of FDA-approved products and has
`also committed to conducting a leachables