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

`

`Addendum to the Primary Clinical Pharmacology Review Dated October 22, 2015
`
`
`
`Submission Date(s): July 20, 2015
`NDA: 208411
`NARCAN
`Proposed Brand Name
`Naloxone HCl Nasal Spray
`Generic Name
`Suresh B Naraharisetti, Ph.D.
`Reviewer
`Yun Xu, Ph.D.
`Team Leader
`DCPII
`OCP Division
`DAAAP
`OND division
`Adapt Pharma
`Sponsor
`IND 114704
`Relevant IND(s)
`Original Submission; 505(b)(2)
`Submission Type
`Formulation; Strength(s) Solution for Nasal Spray; 40 mg/ mL
`
`Indication
`
`NARCAN nasal spray is an opioid antagonist indicated for
`the emergency treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or central
`nervous system depression.
`
`This addendum to Primary Clinical Pharmacology review (documented in DARRTS on
`10/22/2015) is to address the recommendations made by Office of Study Integrity and
`Surveillance (OSIS) on the audited pivotal relative bioavailability study, Naloxone-Ph1a-
`002. At the time of signing-off the primary Clinical Pharmacology review for NDA
`208411, OSIS
`inspection-report
`for
`study Naloxone-Ph1a-002 was pending.
`Subsequently, OSIS finalized their report on October 30, 2015 (see review by Dr.
`Dasgupta, Arindam, Ph.D. dated 10/30/2015 for details). Overall, the OSIS inspection-
`report concluded that there were no objectionable conditions observed related to the study
`Naloxone-Ph1a-002.
`
`For study Naloxone-Ph1a-002, the clinical site where the study was conducted was at
`Vince Associates Clinical Research, KS 66212, USA; and the bio-analytical facility
`where the pharmacokinetic samples were analyzed was at
`
`, The OSIS inspection-report covered both the observations of Office of
`Regulatory Affairs (ORA) investigator’s findings for clinical site and also the
`bioanalytical facility inspection.
`
`The ORA investigator had the following two observations related to study Naloxone-
`Ph1a-002 identified at the clinical site, where a Form FDA 483 was issued to Vince &
`Associates Clinical Research. The two observations in the Form 483 were:
`
`
`
`Reference ID: 3841574
`
`1
`
`(b) (4)
`
`

`

`a) Late to transfer the collected PK samples to -20 °C freezer Within 60 minutes of
`collection (Observation 1B, OSIS Inspection report)
`b) Failure to prepare or maintain adequate and accurate case histories with respect to
`observations and data pertinent to the investigation (Observation 2A OSIS Inspection
`report)
`
`The OSIS investigator requested more data to address the two observations mentioned in
`the Form 483. After reviewing the additional data, it was concluded in the final OSIS
`report that these two observations are unlikely to impact integrity or outcome of study
`Naloxone-Phla—002. This addendum review focuses on the details of these two
`
`observations, and whether the findings impact the study Naloxone-Phla-OOZ data. The
`details are as follows.
`
`a) Late to transfer the collected PK samples to -20 0C freezer within 60 minutes of
`collection (Observation 1B, OSIS Inspection report)
`At the clinical site, the collected PK samples were not transferred to the -20 °C freezer
`within 60 minutes after the collection. To address this issue, the OSIS inspectors during
`their inspection at the bioanalytical facility requested the
`«am
`to design and conduct a benchtop stability study ofNaloxone in human whole blood up to
`60 minutes at both room temperature and 4 °C.
`The detailed description of this aspect (Observation 1B) and the conclusion of the
`conducted naloxone bench top stability experiment, copied from the OSIS inspection
`report are as below.
`
`OSIS Evaluation:
`
`The firm failed to transfer a substantial number of PK samples to
`the -20°C freezer within 60 minutes of sample collection as
`specified in the study protocol. Additionally,
`the source data did
`not document the storage condition (e.g. on ice or at room
`temperature) of the collected blood samples before they were
`centrifuged. Although bench top stability was validated for 26 hours
`during method validation study for naloxone,
`this data was generated
`from frozen plasma samples. Stability in fresh plasma or in whole
`blood for naloxone was not established during method validation.
`
`To assess the integrity of the “Late to Freezer
`analytical site for this study,
`requested to design and conduct a benchtop stability study of
`Naloxone in human whole blood up to 60 minutes at both room
`
`(LTF)” samp&fi§,
`
`the
`was
`
`temperature and 4°C. The plasma was to be transferred to the —ZO°C
`freezer after 30 minutes storage in refrigerator. The storage
`conditions in this experiment would mimic the sample handling
`procedure at the clinical site and would represent the worst—case
`scenario for these “Late to Freezer
`(LTF)” samples.
`
`The results of this study were made available to the FDA
`investigators during the inspection and revealed that naloxone was
`
`Reference ID: 3841 574
`
`

`

`Reviewer Conclusions on Observation 1B:
`Based on the conducted naloxone bench top stability experiment and the obtained results,
`we agree with OSIS conclusion that, Observation 1B is unlikely to impact the integrity of
`the naloxone concentration data.”
`
`b) Failure to prepare or maintain adequate and accurate case histories with respect
`to observations and data pertinent to the investigation (Observation 2A OSIS
`Inspection report)
`
`
`At the clinical site, discrepancies were observed between the reported protocol deviations
`and the source documents. Specifically, the protocol deviations submitted to the Agency
`do not accurately represent the information from the PK Specimen Processing Log.
`
`The detailed description of Observation 2A copied from the OSIS inspection report is as
`below.
`
`
`
`
`
`Reviewer Conclusions on Observation 2A:
`In study Naloxone-Ph1a-002, at total of 29 subjects completed the study in an open-label,
`randomized, 5-period, 5-treatment, 5-sequence, crossover design. Each participant
`received following 5 naloxone treatments during the 5 dosing periods:
`
`
`
` 
`
` Treatment A: 2 mg IN (one 0.1 mL spray of a 20 mg/mL solution in one nostril)
` Treatment B: 4 mg IN (one 0.1 mL spray of a 20 mg/mL solution in each nostril)
`
`
`
`Reference ID: 3841574
`
`3
`
`

`

` Treatment C: 4 mg IN (one 0.1 mL spray of a 40 mg/mL solution in one nostril)
` Treatment D: 8 mg IN (one 0.1 mL spray of a 40 mg/mL solution in each nostril) and
` Treatment E: 0.4 mg IM (1 mL of a 0.4 mg/mL commercial formulation, as
`reference)
`
`
`In this study, two strengths of naloxone nasal spray, 20 mg/mL and 40 mg/mL were used.
`However, sponsor plans to market only 40 mg/mL strength (4 mg in 0.1 mL). Hence the
`clinical pharmacology review for study Naloxone-Ph1a-002 focused only on the 40
`mg/mL strength and the reference IM injection treatments (Treatments C, D and E).
`
`As per OSIS review with regards to the deviations in actual sampling times, there is one
`deviation in one time point for each of the three different subjects, #2031, #2033 and
`#2045 in period 3.
`
`Out of these three deviations, two deviations, in subject #2033 and subject #2045 were
`from 20 mg/strength (2 mg dose, Treatment A), which the sponsor is not planning to
`market. Hence these two deviations need not to be considered.
`
`
`Subject # 2031 had a one-minute deviation at the 5 minute time point, which is from the
`reference treatment group of IM injection. A total of 29 subjects completed the study, and
`16 samples per subject were taken for each treatment up to 720 minutes post dose.
`Therefore, this one minute deviation at 5 minute time point in one subject, would not
`affect the calculated PK parameters and conclusion for the study.
`
`Conclusions:
`Overall, the conclusions made in the primary clinical pharmacology review dated
`October 22, 2015, will remain the same.
`
`
`
`
`Reference ID: 3841574
`
`4
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SURESH B NARAHARISETTI
`11/02/2015
`
`YUN XU
`11/02/2015
`
`Reference ID: 3841574
`
`

`

`
`
`
`
`CLINICAL PHARMACOLOGY REVIEW
`
`Submission Date(s): July 20, 2015
`NDA: 208411
`NARCAN
`Proposed Brand Name
`Naloxone HCl Nasal Spray
`Generic Name
`Suresh B Naraharisetti, Ph.D.
`Reviewer
`Yun Xu, Ph.D.
`Team Leader
`DCPII
`OCP Division
`DAAAP
`OND division
`Adapt Pharma
`Sponsor
`IND 114704
`Relevant IND(s)
`Original Submission; 505(b)(2)
`Submission Type
`Formulation; Strength(s) Solution for Nasal Spray; 40 mg/ mL
`
`Indication
`
`NARCAN nasal spray is an opioid antagonist indicated for
`the emergency treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or central
`nervous system depression.
`
`
`Table of Contents
`1
`EXECUTIVE SUMMARY ........................................................................................................................ 2
`1.1
`RECOMMENDATION .................................................................................................................. 2
`1.2
`PHASE IV COMMITMENTS ....................................................................................................... 2
`1.3
`SUMMARY OF CLINICAL PHARMACOLOGY FINDINGS .................................................... 2
`2 QUESTION BASED REVIEW ................................................................................................................. 4
`2.1
`GENERAL ATTRIBUTES OF THE DRUG ................................................................................ 4
`2.2
`GENERAL CLINICAL PHARMACOLOGY ................................................................................ 6
`2.3
`INTRINSIC FACTORS ................................................................................................................. 7
`2.4
`GENERAL BIOPHARMACEUTICS ............................................................................................ 7
`2.5
`ANALYTICAL SECTION ............................................................................................................ 12
`LABELING RECOMMENDATIONS ..................................................................................................... 13
`3
`4 APPENDIX ........................................................................................................................................... 14
`4.1
`CLINICAL PHARMACOLOGY FILING MEMO ..................................................................... 14
`4.2
`INDIVIDUAL STUDY SYNOPSIS ............................................................................................. 17
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3837063
`
`1
`
`

`

`
`1 Executive Summary
`
`1.1 Recommendation
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology 2 (OCP/DCP-2) has
`reviewed NDA 208411 submitted on July 20, 2015 and found it acceptable from clinical
`pharmacology perspective, pending the Office of Scientific Investigation (OSI) inspection result.
`While finalizing this review, the OSI inspection report for pivotal comparative bioavailability study
`Naloxone-Ph1a-002 is still pending. An addendum will be added to the clinical pharmacology review
`based on the OSI inspection report, if necessary.
`
`1.2 Phase IV Commitments
`None.
`
`1.3 Summary of Clinical Pharmacology Findings
`
`Key clinical pharmacology findings:
`The clinical/clinical pharmacology database for this NDA consists of one pivotal comparative
`bioavailability study (Naloxone-Ph1a-002) conducted in 29 healthy volunteers. In this study
`(Naloxone-Ph1a-002), the relative bioavailability from one IN1 spray in one nostril (4 mg, 0.1 mL of
`40 mg/mL) and one IN spray in each nostril (8 mg, 0.1 mL of 40 mg/mL in each nostril) was
`compared to the reference 0.4 mg of naloxone IM2 injection. The final to be marketed product was
`used in the study.
`The NARCAN (naloxone hydrochloride) nasal spray exhibited 5.5 -fold higher Cmax and 4.7 -fold
`higher AUCt from one IN spray in one nostril (4 mg total dose, 0.1 mL of 40 mg/mL naloxone
`hydrochloride solution), and 11 -fold higher Cmax and 8.9 -fold higher AUCt from one IN spray in
`each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution) compared to the
`reference, a single dose of 0.4 mg naloxone IM injection.
`After 0.4 mg of naloxone HCl IM injection, a Cmax of 880 pg/mL was observed at Tmax of ~23
`minutes (n= 29 subjects). With IN NARCAN spray, the concentrations greater than 880 pg/mL were
`maintained for longer duration, up to 120 minutes from one IN spray in one nostril and up to 180
`minutes from one IN spray in each nostril.
`
`Relative Bioavailability of NARCAN (naloxone hydrochloride) Nasal Spray in Comparison to
`the Reference Product:
`The one NARCAN nasal spray in one nostril or one NARCAN spray in each nostril exhibited much
`higher systemic exposure of naloxone in terms of both AUC and Cmax values in comparison to the
`reference drug product, 0.4 mg naloxone IM injection (Figure 1.3). The administration of one
`NARCAN nasal spray (4 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution) in
`one nostril exhibited 555%, 469% and 462% higher geometric mean ratios (IN/IM) for Cmax, AUCt
`and AUCinf, respectively compared to the reference 0.4 mg IM injection. The corresponding 90%
`CIs for geometric mean ratios for one IN spray in comparison to IM treatment were 464-665%, 418-
`527% and 412-519%, for Cmax, AUCt and AUCinf, respectively (Table 1.3a). The administration
`of one NARCAN nasal spray in each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone
`hydrochloride solution) exhibited 1110%, 890% and 878% higher geometric mean ratios (IN/IM) for
`Cmax, AUCt and AUCinf, respectively compared to the reference 0.4 mg IM injection. The
`
`1 IN- Intranasal
`2 IM- Intramuscular
`
`
`2
`
`Reference ID: 3837063
`
`

`

`
`
`corresponding 90% CIs for geometric mean ratios for one IN spray in each nostril in comparison to
`IM treatment were 925-1320%, 793-999% and 783-985%, for Cmax, AUCt and AUCinf,
`respectively (Table 1.3a).
`
`Figure 1.3 Mean plasma concentration time profiles of naloxone from 0 to 4 hours following
`intranasal and intramuscular naloxone administration to healthy subjects (N = 29)
`
`
`Table: 1.3a. Geometric mean ratios and 90% CIs for plasma naloxone pharmacokinetic parameters
`following intranasal and intramuscular administration.
`Parameter
`Test Vs Reference
`Adjusted Geometric LS mean
`Test
`Reference
`(n=29)
`(n=29)
`4.83
`0.870
`
`
`7.90
`1.68
`
`
`1.73
`
`
`4 mg -one IN Spray
`in one nostril (Test)
`
`Vs
`
`0.4 mg IM
`(Reference)
`
`7.99
`
`
`Ratio %[Test/Reference]
` (lower , upper 90% CI of
`ratio)
`555 (464, 665)
`
`469 (418, 527)
`
`462 (412, 519)
`
`
`Cmax
`(ng/mL)
`AUC0-t
`(h*ng/mL)
`AUC0-inf
`(h*ng/mL)
`
`Cmax
`(ng/mL)
`AUC0-t
`(h*ng/mL)
`AUC0-inf
`(h*ng/mL)
`
`Since the concentrations of naloxone at early time points after the administration of naloxone
`products for reversal of opioid overdose is critical, the mean concentrations of naloxone from plasma
`concentration-time profile after administration of NARCAN (naloxone hydrochloride) nasal spray
`3
`
`8 mg -one IN Spray
`in each nostril (Test)
`
`Vs
`
`0.4 mg IM
`(Reference)
`
`9.62
`
`15.0
`
`15.2
`
`
`0.870
`
`1.68
`
`1.73
`
`
`1110 (925, 1320)
`
`890 (793, 999)
`
`878 (783, 985)
`
`
`
`
`Reference ID: 3837063
`
`

`

`
`
`Reference
`
`IM injection
`(0.4 mg)
`
`
`Test
`
`One IN spray
`in one nostril
`(4mg)
`
`
`Test
`
`One IN spray
`in each
`nostril (8mg)
`
`
`2.5
`5
`10
`15
`20
`30
`45
`60
`
`0.079 (168)
`0.306 (108)
`0.578 (55)
`0.696 (46)
`0.754 (36)
`0.749 (25)
`0.684 (25)
`0.604 (24)
`
`
`The median naloxone Tmax after IN administration was not significantly different compared to the
`IM administration. The median naloxone Tmax after single NARCAN nasal spray (4 mg) in one
`nostril and one NARCAN nasal spray in each nostril (8 mg) was 0.50 h (range, 0.17 to 1.00 h) and
`0.33 h (range, 0.17 to 1.00 h), respectively. The median naloxone Tmax after IM injection was 0.38h
`and has relatively high variability with the range of 0.08 to 2.05h compared to the IN route. The IN
`route has slightly longer half-life of 2.1 h compared to 1.2 h for IM route.
`
`
`and reference IM injection were compared (Table 1.3b). Compared to the reference IM injection, the
`naloxone concentrations were higher in the range of 3.5 to 6.0 fold after one IN spray in one nostril,
`and 9.7 to 13.3 fold after one IN spray in each nostril, respectively, from 2.5 minutes to 60 minutes
`post dose.
`
`Table 1.3b. Comparison of mean naloxone concentrations between IM injection and NARCAN one
`spray in one nostril or one spray in each nostril from 2.5 to 60 minutes post dose.
`Time post-dose
`Mean Concentration (ng/mL) (% CV) N=29
`Fold higher
`Fold higher
`after naloxone
`
`naloxone
`naloxone
`drug product
`concentration:
`concentration:
`administration
`
`
`(minutes)
`One IN spray
`One IN spray
`(4mg) Vs. IM
`in each nostril
`injection (0.4
`(8mg) Vs. IM
`mg)
`injection
`(0.4mg)
`11.8
`12.3
`13.3
`11.6
`10.8
`10.6
`10.0
`9.7
`
`0.28 (151)
`1.48 (117)
`3.24 (67)
`3.97 (56)
`4.53 (50)
`4.43 (43)
`3.95 (41)
`3.28 (37)
`
`0.93(131)
`3.78 (105)
`7.66 (68)
`8.10 (44)
`8.14 (31)
`7.92 (25)
`6.83 (24)
`5.87 (23)
`
`3.5
`4.8
`5.6
`5.7
`6.0
`5.9
`5.8
`5.4
`
` 2
`
` Question Based Review
`
`
`2.1 General Attributes of the Drug
`
`2.1.1. What pertinent regulatory background or history contributes to the current assessment of
`the clinical pharmacology of this drug product?
`Naloxone HCl is approved for intravenous (IV), intramuscular (IM), and subcutaneous (SC)
`administration. According to Narcan’s labeling, Narcan may be administered intravenously,
`intramuscularly, or subcutaneously. In adults with opioid overdose, an initial dose of 0.4 mg to 2 mg
`of Narcan may be administered intravenously. Intramuscular or subcutaneous administration may be
`necessary if the intravenous route is not available.
`
`The proposed naloxone hydrochloride nasal spray is an aqueous solution presented in a Type I glass
`vial closed with a
` plunger which in turn is mounted into a unit-dose nasal spray
`device. The device is a non-pressurized dispenser delivering a spray containing a unit dose of the
`active ingredient. Each delivered dose contains 100 μL.
`
`
`
`
`Reference ID: 3837063
`
`4
`
`(b) (4)
`
`

`

`
`
`Adapt Pharma submitted a 505(b)(2) NDA for NARCAN (naloxone hydrochloride) Nasal Spray and
`proposed to rely on the Agency’s previous finding of the safety and efficacy of the listed drug,
`Narcan (NDA 016636). As indicated in the Agency’s comments to regulatory Question #6 at the Pre-
`IND meeting, for a 505(b)(2) application, the listed drug relied upon for approval must be a product
`approved under section 505(b) (NDA) of the Food, Drug, and Cosmetic Act. When an ANDA
`product must be used for a bio-bridging study because the NDA product is no longer available in the
`market, the Sponsor must identify an NDA product as the listed drug and do a patent certification
`against that NDA product. Because the NDA product Narcan is not available, in the pivotal
`comparative bioavailability study Naloxone-Ph1a-002, sponsor used an ANDA product to Narcan
`NDA (016636), sourced from a commercial supplier and is manufactured by
`
` to establish the PK bridge. This approach was deemed acceptable per the Agency’s
`Pre-IND meeting minutes dated May 18, 2012.
`
`After the NDA is submitted, the Sponsor acquired NDA 016636. However, this NDA remains as a
`505(b)(2) application since Sponsor still relies on literature data for pediatric assessment to support
`pediatric labeling. Considering this product is life-saving and will only be used during opioid
`overdose, no additional clinical pharmacology studies will be required.
`
`
`2.1.2 What are the highlights of the chemistry and physico-chemical properties of the drug
`substances, and the formulation of the drug product?
`
`Table 2.1.2a Physical-Chemical Properties of Naloxone Hydrochloride
`Drug Name
`Naloxone Hydrochloride
`Chemical Name
`17-Allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6 hydrochloride
`Structure
`
`C19H21NO4HCl2H2O
`
`
`
`Molecular Weight
`Appearance
`Solubility
`
`
`White to off-white powder
`Soluble in water, in dilute acids, and in strong alkali; slightly
`soluble in alcohol, and practically insoluble in ether and in
`chloroform
`
`
`The components and compositions of NARCAN (naloxone hydrochloride) Nasal Spray formulation
`are listed in Table 2.1.2b. The NARCAN (naloxone hydrochloride) nasal spray is an aqueous
`solution (40 mg/mL) presented in a Type I glass vial closed with a
` plunger which
`in turn is mounted into a unit-dose nasal spray device. The device is a non-pressurized dispenser
`
`
`
`Reference ID: 3837063
`
`5
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`delivering a spray containing a unit dose of the active ingredient. Each delivered dose contains 100
`uL.
`
`Table 2.1.2b Components and Composition of NARCAN (naloxone hydrochloride) Nasal Spray
`Concentration
`
`40 mg.~’mL
`
`
`
`_
`
`‘
`
`‘
`
`Quantity per unit
`
`
`
`44.0 mg
`
`
`
`
`
`
`Naloxone HCl dihydrate
`(corresponding to naloxone HCl)
`
`Bammom‘m‘ Chlg‘ge
` Disodium edetate
`
`Component
`
`Grade
`
`.
`USP’Ph‘ Eur
`
`Ph. EuerSPfNF
`
`
`
`
`
` Hydrochloric acid
`Ph. EurfUSP (b) (4)
`
`MULTI-
`
`COMPENDIAL;
`USP. BP. Ph. Eur.
`
`2.1.3. What are theproposed mechanism(s) ofaction and therapeutic indication(5)?
`
`While the mechanism of action of naloxone is not fully understood, evidence suggests that naloxone
`antagonizes the opioid effects by competing for the same receptor sites. The NARCAN nasal spray is
`an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose,
`as manifested by respiratory and/or central nervous system depression.
`
`2.1.4 What are the proposed dosage(s) and roate(s) ofadministration?
`A single 4 mg (40 mg/mL) spray of NARCAN nasal spray may be administered nasally into one
`nostril
`to adults or pediatric patients. The repeated doses of NARCAN nasal spray may be
`administered if the patient is not adequately responding or responds and then relapses back into
`respiratory depression, until emergency medical assistance arrives
`
`2.2 General Clinical Pharmacology
`
`2.2.1. What is known about the PK characteristics ofnaloxonefor the listed drug, Narcan?
`Following parenteral administration naloxone hydrochloride is rapidly distributed in the body. It is
`metabolized in the liver, primarily by glucuronide conjugation, and excreted in urine. In one study
`the serum half-life in adults ranged from 30 to 81 minutes (mean 64 1r 12 minutes). In a neonatal
`
`study the mean plasma half-life was observed to be 3.1 i 0.5 hours.
`
`2.2.2. What moieties in the plasma appropriately identified and measured to assess the
`pharmacokinetics?
`Naloxone was measured in the pivotal PK study.
`
`Reference ID: 3837063
`
`

`

`Intrinsic Factors
`
`
`2.3
`
`2.3.1. What is the pediatric plan?
`
`The reference listed product for Naloxone Hydrochloride Intranasal is Narcan, which was approved
`for use in pediatric patients of all ages experiencing opioid overdose. There have been some clinical
`studies in pediatric patients with naloxone injection or other dosage forms. Primarily, the safety,
`efficacy and dose have been extrapolated from adult use or from case studies published in the
`literature and the Narcan labeling. A literature review and reference to the Narcan labeling has been
`provided in the NDA.
`
`The Applicant provided a complete literature review and summary of data that is available on the use
`of naloxone in children by injection (IM or IV), as well as intranasal administration as part of the
`NDA for Narcan (naloxone hydrochloride) Nasal Spray. The Applicant addressed the following:
`a. The safety and effectiveness of the proposed dose of naloxone for all pediatric age ranges,
`including neonates
`b. Justification for the proposed dosing volume in all pediatric patients, including neonates
`c. Justification for why the absorption of drugs through the nasal mucosa will not be different in
`pediatric patients, including neonates, compared to adults
`d. A device (e.g., nasal tip) that can appropriately deliver the correct volume to all pediatric
`patients, including neonates
`
`
`The Applicant proposed labeling that allows use of a single 4 mg intranasal dose in persons of all
`ages from infants to adults. The Applicant acknowledged that additional clinical or nonclinical
`information may be required at a later time to address concerns about the ability to consistently
`administer the proposed product intranasally to neonates. The Applicant included information that
`supports the consistent delivery of the proposed product with the proposed intranasal delivery system
`in neonates with the pediatric assessment in the NDA.
`
`For the proposed product, the Clinical team and PeRC were discussing the pediatric concerns
`regarding the ability of the product to deliver a consistent dose in neonates who are obligate nasal
`breathers, and how to address them in the labeling without requiring additional studies.
`
`2.4 General Biopharmaceutics
`
` 2.4.1 What is the relative bioavailability of naloxone following the administration of NARCAN
`(naloxone hydrochloride) Nasal Spray in comparison to the reference, intramuscular injection via
`standard syringe?
`
`The relative bioavailability of naloxone following the administration of NARCAN (naloxone
`hydrochloride) Nasal Spray in comparison to the reference drug naloxone IM injection were
`evaluated in an inpatient open-label, randomized, 5-period, 5-treatment, 5-sequence, crossover study
`involving approximately 29 healthy volunteers. Each participant received 5 naloxone treatments
`during the 5 dosing periods:
`
`
`
`
`
`
`
`7
`
`Reference ID: 3837063
`
`

`

`
`
`
`
`A. 2 mg IN (one 0.1 mL spray of a 20 mg/mL3 solution in one nostril)
`B. 4 mg IN (one 0.1 mL spray of a 20 mg/mL3 solution in each nostril)
`C. 4 mg IN (one 0.1 mL spray of a 40 mg/mL solution in one nostril)
`D. 8 mg IN (one 0.1 mL spray of a 40 mg/mL solution in each nostril) and
`E. 0.4 mg IM (1 mL of a 0.4 mg/mL commercial formulation)
`
`
`On the day after clinic admission, participants were administered the study drug in randomized order
`with a 4-day washout period between doses until all 5 treatments were administered. Blood was
`collected for naloxone PK prior to dosing and approximately 2.5, 5, 10, 15, 20, 30, 45, 60, 120, 180,
`240, 300, 360, 480, and 720 minutes after the start of study drug administration.
`
`Drug Administration:
`
`
` single dose device
`IN naloxone was administered using an
` with the subject in a fully supine position. The left nostril was used for all single dose
`IN administrations (Treatments A and C); when two IN sprays were given, one spray was
`administered into each nostril (Treatments B and D). The participant remained fully supine
`for approximately one hour postdose. Participants were instructed not to breathe through the
`nose during administration of the nasal spray into the nose.
`IM naloxone was administered at a dose of 0.4 mg in 1.0 mL with a 23-gauge needle as a
`single injection in the gluteus maximus muscle. For the IM injection, 1 mL of naloxone was
`withdrawn from one vial (0.4 mg/mL in a 1 mL vial) into a syringe at bedside.
`
`
`
`
`Lot and Formulation Identification:
` Naloxone Nasal Spray: Naloxone hydrochloride for IN administration was provided by
` at a concentration of either 20
`
`mg/mL or 40 mg/mL.
`Lot Code Manufacture Date
`Naloxone Nasal Spray Batch Number
`02 Sep 2014
`20 mg/mL
`29 Aug 2014
`40 mg/mL
`IM injection: Naloxone hydrochloride for IM injection, an ANDA product to Narcan NDA
`(016636), was sourced from a commercial supplier and is manufactured by
`
`.
`
`
`
`
`The naloxone plasma concentration-time profiles from 0 to 4 h following intranasal and
`intramuscular naloxone administration to healthy subjects are shown in Figure 2.4.1a. The naloxone
`plasma concentration-time profiles with and without error bars from 0 to 12 h are shown in Figure
`2.4.1b.
`
`After 0.4 mg of naloxone HCl IM injection, a Cmax of 880 pg/mL was observed at Tmax of ~23
`minutes (n= 29 subjects). With IN NARCAN spray, the concentrations greater than 880 pg/mL were
`maintained for longer duration, up to 120 minutes from one IN spray in one nostril (4 mg) and up to
`180 minutes from one IN spray in each nostril (8 mg).
`
`
`3 Although both 20 mg/mL and 40 mg/mL strengths of Naloxone Nasal Spray were used in this study,
`sponsor plans to market only 40 mg/mL strength (4 mg in 0.1 mL).
`
`
`
`8
`
`Reference ID: 3837063
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`The initial time concentrations of naloxone after the administration of naloxone drug products for
`reversal of opioid overdose are critical. Hence the mean concentrations of naloxone from plasma
`concentration time profile after administration of NARCAN (naloxone hydrochloride) nasal spray
`and IM injection were compared (Table 2.4.1a). Compared to the reference IM injection, the
`naloxone concentrations were higher in the range of 3.5 to 6.0 fold after one IN spray in one nostril
`and 9.7 to 13.3 fold after one IN spray in each nostril from 2.5 minutes to 60 minutes post-dose.
`
`The PK parameters and statistical analysis for the assessment of relative bioavailability following
`intranasal and intramuscular naloxone administration to healthy subjects’ results are presented in the
`Table 2.4.1b and Table 2.4.1c. The PK parameters of only 40 mg/mL strength of Naloxone Nasal
`Spray, which the sponsor plans to market, were included in the Tables.
`
`The one NARCAN nasal spray in one nostril or one NARCAN spray in each nostril exhibited much
`higher systemic exposure of naloxone in terms of both AUC and Cmax values in comparison to the
`reference drug product, 0.4 mg naloxone IM injection. The administration of one NARCAN nasal
`spray (4 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution) in one nostril
`exhibited 555%, 469% and 462% higher geometric mean ratios (IN/IM) for Cmax, AUCt and
`AUCinf, respectively compared to the reference 0.4 mg IM injection. The corresponding 90% CIs for
`geometric mean ratios for one IN spray in comparison to IM treatment were 464-665%, 418-527%
`and 412-519%, for Cmax, AUCt and AUCinf, respectively. The administration of one NARCAN
`nasal spray in each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution)
`exhibited 1110%, 890% and 878% higher geometric mean ratios for Cmax, AUCt and AUCinf,
`respectively compared to the reference 0.4 mg IM injection. The corresponding 90% CIs for
`geometric mean ratios for one IN spray in each nostril in comparison to IM treatment were 925-
`1320%, 793-999% and 783-985%, for Cmax, AUCt and AUCinf, respectively.
`
`The median naloxone Tmax after single NARCAN nasal spray (4 mg) in one nostril and one
`NARCAN nasal spray in each nostril (8 mg) was 0.50 h (range, 0.17 to 1.00 h) and 0.33 h (range,
`0.17 to 1.00 h), respectively. The median naloxone Tmax after IM injection was 0.38h and has
`relatively high variability with the range of 0.08 to 2.05h compared to the IN route. The IN route has
`slightly longer half-life of 2.1 h compared to 1.2 h for IM route.
`
`
`
`
`
`Reference ID: 3837063
`
`9
`
`

`

`
`
`Figure 2.4.1a Mean plasma concentration time profiles from 0 to 4 hours of naloxone following
`intranasal and intramuscular naloxone administration to healthy subjects (N = 29)
`
`
`Figure 2.4.1b Mean plasma concentration time profiles of naloxone following intranasal and
`intramuscular naloxone administration to healthy subjects (N = 29)
`
`
`A. Without error bars
`
`B. With error bars
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3837063
`
`10
`
`

`

`
`
`Table: 2.4.1a.The comparison of mean naloxone concentrations between IM injection and NARCAN
`one or two IN sprays from 2.5 to 60 minutes post dose.
`Time post-dose
`Mean Concentration (ng/mL) (% CV) N=29
`after naloxone
`Reference
`Test
`Test
`drug product
`
`
`
`administration
`IM injection
`One IN spray
`One IN spray
`(minutes)
`(0.4 mg)
`in one nostril
`in each
`
`(4mg)
`nostril (8mg)
`
`
`
`Fold higher
`naloxone
`concentration:
`
`One IN spray
`(4mg) Vs. IM
`injection (0.4
`mg)
`
`2.5
`5
`10
`15
`20
`30
`45
`60
`
`0.0