CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`
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`APPLICATION NUMBER:
`208411Orig1s000
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`MEDICAL REVIEW(S)
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
`
`Food and Drug Administration
`Office of Drug Evaluation IV
`Division of Pediatric and Maternal Health
`Silver Spring, MD 20993
`Telephone 301-796-2200
`FAX 301-796-9744
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`
`
`M E M O R A N D U M
`
`Mona Khurana, M.D., Medical Officer
`Division of Pediatric and Maternal Health
`Office of Drug Evaluation IV
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`
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`Hari Cheryl Sachs, M.D., Team Leader
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`Linda Lewis, M.D., Acting Deputy Director
`
`Division of Anesthesia, Analgesia, and Addiction Products
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`Naloxone
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`Opioid antagonist
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`NDA 208411 (IND 114704)
`
`Adequacy of Pediatric Assessment
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`Adapt Pharma Limited
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`From:
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`Through:
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`To:
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`Drug:
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`Therapeutic Category:
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`Application number:
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`Subject:
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`Applicant:
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`Proposed Indication:
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`Emergency treatment of known or suspected opioid overdose as
`manifested by respiratory and/or central nervous system
`depression
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`Formulation:
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`Materials Reviewed
`• Modules 1.9.6, 2.2 (Introduction) and 2.5 (Clinical Overview) of NDA 208411
`1
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`Single 4 mg dose of naloxone hydrochloride in a 0.1 milliliter
`intranasal spray delivered via
`Unit-Dose Nasal Device
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`Reference ID: 3844432
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`(b) (4)
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`

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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`• Orange Book (accessed 10/14/15; Rx active ingredient search term: “naloxone”)
`• Drugs@FDA (accessed 10/14/15; search term: “Narcan”)
`• UptoDate (accessed 10/15/15; search term: “naloxone”)
`• PubMed (accessed 10/15/15; search terms: “nasal” AND “”airway” AND “anatomy” OR
`“development”; “intranasal” AND “drug” AND “delivery” with limits: human, English,
`pediatric age [birth to 18 years], review; “intranasal drug” AND “neonates”)
`• Retrieval and review of referenced publications in pediatric assessment (10/16/15)
`• DARRTS for IND 114704 Application History (accessed 10/19/15)
`
`
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`Consult Request
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`The Division of Anesthesia, Analgesia, and Addiction Products (DAAAP) consulted the
`Division of Pediatric and Maternal Health (DPMH) to comment on the following:
`• The adequacy of the pediatric assessment submitted with new drug application (NDA)
`208411
`• Recommend which pediatric age ranges, if any, for whom naloxone should be approved
`based on the pediatric assessment
`• Recommend what additional studies could be done to fulfill the Pediatric Research
`Equity Act (PREA) requirements for those pediatric age ranges in which the pediatric
`assessment is inadequate
`
`Intranasal Drug Delivery
`
`I.
`A. Anatomical Considerations
`The goal of intranasal (IN) drug delivery is to maximize drug deposition in the portion of the
`nasal cavity primarily responsible for systemic drug entry while minimizing runoff of the drug
`into the pharynx and lungs.1 The main site of systemic entry of IN drugs is a highly vascularized
`region near the inferior turbinate, known as the respiratory zone, which has a large surface area
`of 120-150 squared centimeters (cm2) in adults (see Figure 1).2 Residual drug that is not
`absorbed after 30 minutes may be cleared by ciliary cells.1 The olfactory epithelium is an
`appealing site for delivery of central nervous system (CNS)-acting drugs because the blood-brain
`barrier is bypassed allowing direct CNS access.3 However, the olfactory epithelium does not
`
`1 Del Pizzo J and Callahan JM. Intranasal Medications in Pediatric Emergency Medicine. Pediatric Emergency care
`30: 496-504, 2014.
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`2 Grassin-Delyle, Buenestado A, Naline E, et al. Intranasal Drug Delivery: An Efficient and Non-Invasive Route for
`Systemic Administration. Focus on Opioids. Pharmacology & Therapeutics 134: 366-379, 2012.
`
`3 Wolfe TR and Braud DA. Intranasal Medication Delivery for Children: A Brief Review and Update. Pediatrics
`126(3): 532-537, 2010.
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`2
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`appear to be significantly involved in systemic absorption of IN drugs since the small surface
`area (1-5 cm2) in adults accounts for only 3-5% of the total surface area of the nasal cavity and is
`difficult to reach via IN delivery.1 Venous drainage of the nasal cavity occurs directly into the
`superior vena cava and then into the systemic circulation via the internal jugular veins, thereby
`avoiding first-pass hepatic metabolism.1
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`Figure 1. Different anatomical regions of the nasal cavity2
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`B. Factors Affecting Intranasal Delivery
`Optimizing delivery of IN drugs requires interactions between the formulation, the device, the
`mode of administration, and patient technique.4 The highest IN absorption occurs with drugs
`that are characterized by low molecular weight, high lipophilicity, and no net charge at
`physiologic pH.1 Additional factors affecting IN drug absorption include the following:1
`• Amount of time the drug is in contact with the nasal mucosa. For example, epistaxis or a
`large amount of nasal secretions will reduce contact of the drug with the mucosal surface
`and reduce the mucosal surface area available for absorption.
`• Deposition of the drug in the wrong part of the nasal cavity may result in not only
`reduced absorption but also increased runoff into the posterior pharynx with subsequent
`entry into the lungs.
`• Due to the low surface area of the nasal mucosa, IN administration of volumes greater
`than 200 microliters (µL) may be associated with increased runoff into the pharynx.2
`Individual variations in the structure and function of the nasal cavity may prevent the
`same IN dose from having a uniform effect in all individuals.5 For example, underlying
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`4 Foo MY, Cheng Y, Su w, et al. The Influence of Spray Properties on Intranasal Deposition. Journal of Aerosol
`Medicine 20(4): 495-508, 2007.
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`•
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`5 Mygind N and Dahl R. Anatomy, Physiology and Function of the Nasal Cavities in Health and Disease. Advanced
`Drug Delivery Reviews 29: 3-12, 1998.
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`Reference ID: 3844432
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`3
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`COPYRIGHT MATERIAL WITHHELD
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`co-morbidities that affect ciliary function (i.e. cystic fibrosis) or nasal anatomy (i.e. nasal
`polyps) may reduce absorption of intranasally administered drugs.
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`C. Intranasal Drug Products Approved for Pediatric Use
`Multiple IN drug products are approved for pediatric use in the United States. None are
`approved for use down to birth and only one is approved for use within the first year of life (see
`Table 1). Additionally, the intranasal influenza vaccines, FluMist Quadrivalent and the trivalent
`FluMist, are biologic drug products approved for use in pediatric patients’ only down to age 2
`years.6 Both IN influenza vaccines products were tested in patients less than 2 years of age and
`were not approved in this age group because of an increased risk of wheezing and
`hospitalization.
`
`DPMH Comments: Multiple drugs are also currently being used intranasally off-label in
`pediatric patients for the following reasons:1
`• Pediatric sedation as an anxiolytic or amnestic (e.g. midazolam)
`• Pain associated with orthopedic injuries (e.g. fentanyl citrate)
`• Status epilepticus or febrile seizure (e.g. midazolam, lorazepam)
`• Pre-operative sedation (e.g. ketamine, sufentanil)
`The extent of this off-label use and the age ranges of the treated pediatric patients are difficult to
`determine.
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`6 https://www.flumistquadrivalent.com/consumer/; accessed 10/19/15
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`4
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 20841 1
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`Division of Pediatric and Maternal Health Review
`November 9. 2015
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`Table 1. Examples of intranasal drug products approved in the United States with pediatric ages
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`specified in labeling
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`Drug
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`Prescri 3 tion
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`Nasal
`Formulation
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`Pediatric Indication
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`Pediatric Age Range
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`Metered Spray:
`100 ill/actuation
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`Antidiuretic therapy in
`central diabetes insipidus
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`3 months to 12 years
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`Metered spray:
`100 uL/actuation
`
`Nasal symptoms of allergic
`rhinitis, nasal congestion
`associated with seasonal
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`2 years and older
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`Qnasl
`(beclomethasone)
`N202 8 13
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`Aerosol spray:
`Volume/actuation
`
`unspecified
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`2 years and older
`
`(desmopressin
`acetate)
`N02 1333
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`Nasonex
`
`(mometasone
`furoate
`
`monohydrate)
`N020762
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`Atrovent
`
`(ipratropium
`bromide)
`N020393
`Rhinocort
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`(budesonide)
`N020746
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`Beconase AQ
`(beclomethasone
`dipropioante
`monohydrate)
`N0 193 89
`Patanase
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`(olapatadine HCl)
`N02 1 861
`Over-the-Counter
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`allergic rhinitis,
`prophylaxis of seasonal
`aller ‘, 'c rhinitis
`Treatment of nasal
`
`symptoms associated with
`seasonal and perennial
`aller ic rhinitis
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`Symptomatic relief of
`rhinorrhea associated with
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`allergic and non-allergic
`erennial rhinitis
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`Temporary relief of hay
`fever or other upper
`res .irato
`aller ‘ es
`Relief of seasonal or
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`perennial allergic and
`nonallergic rhinitis
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`4 years and older
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`6 years and older
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`6 years and older
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`6 years and older
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`Metered spray:
`70 ill/actuation
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`Metered spray:
`Volume/actuation
`uns oecified
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`Metered spray:
`Volmne/actuation
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`unspecified
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`Metered spray:
`100 [IL/actuation
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`Relief of symptoms of
`seasonal allergic rhinitis
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`6 years and older
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`Nasacort Allergy 24 Metered spray:
`Hour
`Volume/actuation
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`(triamcinolone
`acetonide)
`N020468
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`unspecified
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`Temporary relief of hay
`fever or other upper
`respiratory allergies
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`(Source: created by this reviewer)
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`DPMH Comments: These approved IN drug products administer volumes per actuation ranging
`from 75 to 125 µL and appear to be well-tolerated. The applicant is proposing a 100 µL volume
`per actuation that is within the volumes per actuation of these currently approved drug products.
`
`IN drugs, particularly those given chronically, have the potential for causing local toxicity such
`as anosmia, epistaxis, and numbness depending on their active ingredient and excipient contents.
`For example, over-the-counter (OTC) IN drugs containing zinc for treatment of common cold
`symptoms have been associated with reports of anosmia while oral zinc tablets and lozenges
`have not been implicated in these reports.7 Many affected consumers stated that the loss of sense
`of smell occurred with the first dose of IN zinc products, although some report anosmia after
`later doses. Some OTC IN antihistamines contain labeling cautioning consumers to stop product
`use and ask a doctor if they have severe or frequent nosebleeds.8 Approved prescription IN
`steroids contain labeling language cautioning about the potential for local nasal effects such as
`epistaxis and nasal ulceration.9
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`No local nasal effects were observed in the pilot pharmacokinetic (PK) study conducted by the
`applicant, but 12 adult subjects in the pivotal PK study experienced at least one adverse event
`(AE) thought to be at least possibly related to naloxone. The most frequent naloxone-related
`AEs were local effects including nasal erythema (n=5) and nasal edema (n=4). The occurrence
`of these AEs in pediatric patients may be of greater concern than in adults if the proposed
`product were to be used chronically rather than as intended for single use in an emergency
`setting.
`II. Clinical Pharmacology
`A. Naloxone Hydrochloride
`Naloxone is essentially a pure opioid antagonist that lacks intrinsic agonist properties.10
`Naloxone has not been shown to produce tolerance or cause physical or psychological
`dependence but will produce acute withdrawal symptoms in adults who are physically dependent
`
`
`7 http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm166931.htm; accessed 10/29/15
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`8 http://www.accessdata.fda.gov/drugsatfda docs/label/2015/020468Orig1s040lbl.pdf; accessed at Drugs@FDA
`10/29/15
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`9 http://www.accessdata.fda.gov/drugsatfda docs/label/2013/022004s013lbl.pdf; accessed at Drugs@FDA
`10/29/15
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`10 http://www.accessdata.fda.gov/drugsatfda docs/label/2002/016636s052s054lbl.pdf; accessed at Drugs@FDA
`10/21/15
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`6
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 20841 1
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`on opioids,” including neonates born to opioid-dependent mothers. 11 Withdrawal symptoms
`may appear within minutes of naloxone administration and persist for two hours.13 The
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`intravenous (IV) onset of action is generally apparent within two minutes but is slightly less
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`rapid when given intramuscularly (IM) or subcutaneously (SC).13 The duration of action
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`depends on both the dose and route of naloxone administration with the IM route producing a
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`more prolonged efiect than the IV route. Repeated naloxone doses may be needed to reverse the
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`effects of some opioids which have longer duration of action than naloxone.
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`B. Composition of Proposed Intranasal Formulation
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`Component
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`Sodium chloride
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`Concentration
`
`
`40 mg/mL
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`Quantity per unit
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`
`
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`Quantity per mL
`dose (100 FL)
`
`
`Naloxone HCl dihydrate
`USPr‘Ph. Eur
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`(corresponding to naloxone l-IC'l)
`(I!) (4)
`(m4)
`.
`_
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`Benzalkomum chloride
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`(5) (4) P11. Eur USP NF
`
`USPDisodium edemte
`
`
`MULTI-
`COMPENDIAL:
`
`USP. BP. Ph. Eur.
`JP
`
`
`Ph. Eur USP
`
`Hydrochloric acid
`(5)(4)
`USPr‘Ph. Eur
`
`
`
`USP = United States Pharmacopeia
`q.s_ ad = a sufiicient quantity to make
`
`(Source: Table 2.2-1 page 11 of Module 2.2 Introduction to Summaries for NDA 208411)
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`The drug product solution will be filled into 0.1 mL (100 uL) Type I glass vials which are closed
`with
`(we) plungers. The vials are mounted into an monasal spray device
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`designed to deliver 100 uL with each actuation. The device is a non-pressurized dispenser
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`delivering a single 100 [1L spray containing a metered dose (4 milligrams [mg]) of the active
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`ingredient.
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`DPMH Comments: The excipients at the proposed concentrations do not appear to raise safety
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`concernsfrom DPMH’s perspective, but we defer to Chemistry, Manufacturing, and Control
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`(CMC) colleagues in DAAAP. Disodium edetate is the disodium saltform ofedetate, which is a
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`11 American Academy of Pediatrics Committee on Drugs. Naloxone Use in Newborns. Pediatrics 65: 667-669,
`1980.
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`.12 While the
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`amount of edetate in other development programs has raised safety concerns
`the relatively lower concentration present in the
`proposed IN formulation does not appear to raise similar safety concerns. A single actuation of
`the proposed product will deliver a 100 µL volume containing
` of edetate disodium.
`Approved drugs contain edetate in amounts ranging from 0.05 mg to 2.5 mg per dose.
`III. Regulatory History of this Application
`The program was developed under investigational new drug (IND) 114704, and the proposed IN
`naloxone formulation received Fast Track designation on January 26, 2015.
`
`
`
`The applicant submitted a 505(b)(2) NDA for IN naloxone for emergency treatment of known or
`suspected opioid overdose as manifested by respiratory and/or central nervous system
`depression. The proposed drug is intended for use in community settings. This NDA relies on
`previous findings of safety and efficacy submitted in NDA 016636 for the reference listed drug
`(RLD), Narcan® (naloxone hydrochloride) for injection, and on relevant clinical data published
`since Narcan’s 1971 approval. The RLD is approved for IV, IM, or SC use in pediatric patients
`of all ages, including neonates, to reverse the effects of opiates.13 Importantly, an auto-injector
`containing naloxone (Evzio Auto-Injector, NDA 205787) was approved in adults and pediatric
`patients of all ages on April 3, 2014 for IM or SC use for emergency treatment of known or
`suspected opioid overdose, as manifested by respiratory and/or central nervous system
`depression, and for immediate administration as emergency therapy in settings where opioids
`may be present.14 The Evzio labeling contains no limitations of use but does caution that IM or
`SC absorption of naloxone in pediatric patients may be delayed or erratic (Section 8.4 Pediatric
`Use).
`
`NDA 208411 is supported by two PK bridging studies conducted to compare the bioavailability
`of the proposed IN formulation to IM naloxone, the generic form of the RLD. The bridging
`studies consist of a pilot PK study (Naloxone-Ph1a-001) and a pivotal PK study (Naloxone-
`Ph1a-002) which used the to-be-marketed IN formulation. The applicant has not conducted any
`additional non-clinical or clinical studies. DAAAP had previously conveyed to the applicant that
`additional clinical efficacy studies would not be required if the bioavailability of the proposed IN
`
`12 http://pubchem.ncbi.nlm.nih.gov/compound/8759; accessed 10/21/15
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`13 http://www.accessdata.fda.gov/drugsatfda docs/label/2002/016636s052s054lbl.pdf; accessed at Drugs@FDA
`10/21/15
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`14 http://www.accessdata.fda.gov/drugsatfda docs/appletter/2014/205787Orig1s000ltr.pdf; accessed at
`Drugs@FDA 10/29/15
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`8
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`Reference ID: 3844432
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`formulation is the same or greater than a parenteral naloxone comparator at an approved labeled
`dose (0.4 mg to 2 mg).15 DAAAP also conveyed that additional safety data may be needed
`depending on how much the PK profile of the proposed IN formulation differs from that of
`parenteral naloxone.
`
`
`Pediatric Development Program
`
`IV.
`The initial pediatric study plan (iPSP) was presented to the Pediatric Review Committee (PeRC)
`on May 6, 2015. At the meeting, DAAAP clarified that the applicant has proposed not to
`conduct any clinical studies and plans to rely upon demonstration of relative bioavailability.
`DAAAP concurred with the applicant that non-clinical juvenile animal studies would not be
`warranted based on the indication and significant safety margin for acute naloxone use. The
`PeRC agreed that a 2 mg IN dose could be acceptable if DAAAP is satisfied with the data
`provided in the NDA submission. However, PeRC was not convinced there was sufficient data
`to show that the proposed dosage volume and method of administration via a nasal spray device
`would consistently deliver a 2 mg dose to younger pediatric patients and opined that, without
`these data, pediatric studies may need to be deferred. PeRC stated the applicant must provide
`justification that a 2 mg dose would be safe for all pediatric patients and that, if adequate safety
`data are provided, then no clinical safety studies would be needed. PeRC also recommended the
`following:
`
`• The applicant should provide information about whether the proposed device can be used
`to administer the drug to all pediatric patients including neonates.
`
`• The applicant must demonstrate that the volume administered via the proposed device
`will have the same absorption characteristics in pediatric patients as in adults.
`
`The PeRC’s recommendations were conveyed to the applicant on May 13, 2015. FDA
`subsequently issued an Agreed iPSP Agreement to the applicant on June 22, 2015.
`
`V. Considerations for Pediatric Approval
`A. PK and Dosing Considerations
`The applicant conducted two bridging PK studies in adults that consisted of a pilot study
`(Naloxone-Ph1a-001) and a pivotal study (Naloxone-Ph1a-002) which used the to-be-marketed
`IN formulation. Pilot study Naloxone-Ph1a-001 was designed as an inpatient three-treatment
`crossover study to compare the PK parameters of 2 mg and 4 mg IN doses to the approved 0.4
`
`15 June 18, 2012 Meeting Minutes for Pre-Investigational New Drug (IND) Type B Meeting (DARRTS Reference ID
`3146923)
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`Reference ID: 3844432
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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`mg IM dose in order to find an appropriate IN dose that could achieve systemic exposure
`comparable to an approved parenteral dose. Per the applicant, both the 2 mg and 4 mg IN doses
`produced naloxone plasma concentrations and exposures that were significantly higher than that
`produced by the 0.4 mg IM dose in the same subjects. The applicant also noted that the time
`from obtaining the IN device to administration of the first IN dose was less than one-third the
`time needed to prepare the IM injection. The pivotal study Naloxone-Ph1a-002 was designed as
`an inpatient, open-label, randomized, 5-period, 5-treatment, 5-sequence, crossover study in 28
`healthy adult volunteers to determine the PK of four IN doses (2 mg, 4 mg [2 nostrils], 4 mg [1
`nostril], 8 mg [2 nostrils]) compared to the approved 0.4 mg IM dose; the study’s goal was to
`determine an appropriate IN dose that could achieve systemic exposure comparable to a 2 mg IM
`dose. Results suggested that, based on dose-normalized values, the relative bioavailability of the
`intranasally administered naloxone compared to the IM naloxone ranged from 43.9% to 53.6%.
`
`Based on these PK data, the applicant is proposing a non-weight based dose of 4 mg IN naloxone
`for all age groups from birth to adults. The applicant asserts this dose will provide immediate
`rescue with onset that would be just as rapid as with an IM dose and will achieve plasma
`concentrations and exposures that approximates a 2 mg IM dose. The applicant contends that 2
`mg is the most often used and the most effective out-of-hospital naloxone dose given IV or IM.
`The applicant states the PK data suggest a single 4 mg IN dose would provide effective levels for
`at least 120-180 minutes, allowing emergency medical services up to 120 minutes to arrive after
`a caregiver has administered the IN dose. The applicant proposes a second 4 mg IN dose could
`be given if the patient remains unresponsive.
`
`DPMH Comments:
`
`A standard, non-weight based 4 mg IN dose for low birth weight neonates will potentially result
`in the delivery of a naloxone dose per body weight that is nearly 100-fold higher than the
`pediatric dose currently recommended in the RLD labeling and ten-fold higher than the
`recommendations by the American Academy of Pediatrics’ (AAP) Committee on Drugs (COD).
`Based on the assumption that 50% of the proposed 4 mg IN dose is absorbed, then neonates at
`the second percentile for weight (2 kilogram [kg]) who receive a 4 mg IN naloxone dose may
`receive up to 1 mg/kg of naloxone.16 The RLD labeling recommends an initial pediatric dose of
`0.01 mg/kg body weight IV. The AAP COD recommends a parenteral naloxone dose of 0.1
`
`
`16 http://www.cdc.gov/growthcharts/who charts.htm; accessed 10/15/15
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`10
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`Reference ID: 3844432
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`

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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`mg/kg for pediatric patients from birth to age 5 years or 20 kg of body weight and a dose of 2 mg
`for pediatric patients older than age 5 years or weighing more than 20 kg.17
`
`The applicant conducted a review of the published literature since the 1971 approval of the RLD
`to identify any new clinical data relevant to this NDA. The applicant retrieved seven
`publications describing PK studies of naloxone which the applicant says did not reveal any
`pharmacological issues that impact labeling.
`
`DPMH Comments:
`
`Two retrieved publications were PK studies examining IV and IM naloxone delivery in
`newborns18 and IV naloxone delivery in very low birth weight (VLBW) infants19. The authors
`who conducted the PK study in newborns concluded the IM route (200 µg) resulted in higher
`plasma concentrations and longer time to reach peak plasma levels than either of two IV doses
`(35 µg and 70 µg) administered to term newborns. Notably, the plasma half-life of naloxone in
`the newborns was two to three times longer than that reported for adults. The authors
`attributed the longer half-life to decreased ability of the newborns to eliminate naloxone via
`glucuronide conjugation. Results from the PK study in 10 VLBW infants suggested the mean
`(range) serum half-life of IV naloxone was 70.8 (26 to 122) minutes which the authors stated is
`comparable to IV naloxone’s reported half-life of 64 + 12 minutes in adults.20
`
`A third retrieved publication describing the PK of naloxone administered IV and orally on
`separate occasions to the same adult male subject showed that oral naloxone has a significant
`first-pass effect and is 1/50th as potent as IV administered naloxone.21 Oral naloxone’s poor
`bioavailability due to the first-pass effect may have clinical efficacy implications for the
`proposed IN formulation if the delivered dose is inadvertently swallowed.
`
`
`17 Committee on Drugs Naloxone Dosage and Route of Administration for Infants and Children: Addendum to
`Emergency Drug Doses for Infants and Children. Pediatrics 86(3): 484-485, 1990.
`
`18 Moreland TA, Brice JE, Walker CH, et al. Naloxone Pharmacokinetics in the Newborn. British Journal of Clinical
`Pharmacology 9(6): 609-612, 1980.
`
`19 Stile IL, Fort M, Wurzburger RJ, et al. The Pharmacokinetics of Naloxone in the Premature Newborn.
`Developmental Pharmacology and Therapeutics 10(6): 454-459, 1987.
`
`20 Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of Naloxone in Rats and in Man: Basis for its Potency
`and Short Duration of Action. Anesthesiology 44(5): 398-401, 1976.
`
`21 Fishman J, Roffwarg H, Hellman L. Disposition of Naloxone-7,8-3H in Normal and Narcotic-Dependent Men. The
`Journal of Pharmacology and Experimental Therapeutics 187(3): 575-580.
`
`11
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`Reference ID: 3844432
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`

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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
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`B. Efficacy Considerations
`The applicant relied upon adult naloxone use, published case studies, and RLD labeling for
`pediatrics to support the safety, efficacy, and dose of IN naloxone for use in pediatric patients.
`According to the applicant,22 naloxone’s 1971 approval for use in pediatric patients was
`supported by evidence from adequate and well-controlled studies in adults with additional data
`from 15 clinical studies (controlled and uncontrolled) in which neonates and older pediatric
`patients received parenteral naloxone in doses ranging from 0.005 mg/kg to 0.01 mg/kg.
`
`DPMH Comments: The applicant cited six additional published efficacy studies to support their
`conclusions that 2 mg is the most effective and most often used out-of-hospital dose given IV or
`IM and that the IN route will achieve the same beneficial effects as IM or IV naloxone. None of
`these studies enrolled young pediatric patients. Four studies were conducted in patients’ age 13
`years or older. 23,24,25,26 Subjects’ ages were not specified in one study. 27 Although a sixth study
`did enroll pediatric patients as young as age 3 years, the age range of the study population was
`very broad (3 to 96 years) and the total number of enrolled pediatric patients was not
`specified.28
`C. Safety Considerations
`1. Safety Considerations Related to Non-Weight Based IN Dose of 4 mg
`
`
`22 Page 24 in Section 2.5 Clinical Overview NDA 208411
`
`23 Kerr D, Kelly A, Dietze P, et al. Randomized Controlled Trial Comparing the Effectiveness and Safety of Intranasal
`and Intramuscular Naloxone for the Treatment of Suspected Heroin Overdose. Addiction 104: 2067-2074, 2009.
`
`24 Merlin MA, Saybolt M, Kapitanyan R, et al. Intranasal Naloxone Delivery is an Alternative to Intravenous
`Naloxone for Opioid Overdoses. The American Journal of Emergency Medicine 28: 296-303, 2010.
`
`25 Kelly A, Kerr D, Dietze P, et al. Randomised Trial of Intranasal Versus Intramuscular Naloxone in Prehospital
`Treatment for Suspected Opioid Overdose. Medical Journal of Australia 182(1): 24-27, 2005.
`
`26 Barton ED, Colwell C, Wolfe T, et al. Efficacy of Intranasal Naloxone as a Needleless Alternative for Treatment of
`Opioid Overdose in the Prehospital Setting. The Journal of Emergency Medicine 29(3): 265-271, 2005.
`
`27 Barton ED, Ramos J, Colwell C, et al. Intranasal Administration of Naloxone by Paramedics. Prehospital
`Emergency Care 6(1): 54-58, 2002.
`
`28 Robertson TM, Hendey GW, Stroh G, et al. Intranasal Naloxone is a Viable Alternative to Intravenous Naloxone
`for Prehospital Narcotic Overdose. Prehospital Emergency Care 13(4): 512-515, 2009.
`
`12
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`Reference ID: 3844432
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`

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`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 20841 1
`
`Division of Pediatric and Maternal Health Review
`November 9, 2015
`
`The applicant states the safety of naloxone is well-established in pediatric patients and concluded
`
`there was no significant new information regarding the safety of naloxone following their review
`
`of the published clinical literature.
`
`DPMH Comments: This reviewer ’s search ofthe PnbMed database retrieved severalpublished
`
`case reports, also referenced by the applicant, that do describe youngpediatric patients in the
`
`firstfive years oflife who received IV naloxone to reverse opioid eflects without adverse events.
`
`However, only two patients received a single dose, the remainingpatients received doses over
`
`time periods exceeding one hour (see Table 2).
`
`Table 2. Published case reports of pediatric patients in first five years of life who received the recommended
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`IV naloxone dose or higher without adverse events.
`
`Publication
`
`Patient
`
`Total Naloxone Dose
`
`Total Naloxone Dose
`
`Time Period
`
`' Ae
`Simons 1973 l
`Rumack 1974 '
`Sesso 1975
`
`2.48 mg
`
`1.04 mg
`
`
`
`PerBod Wei_ t
`0.3 mg/kg
`Weight mreported
`0.1 mg/kg
`
`Over 40 hours
`
`Over 5.5 hours
`
`(Source: created by this reviewer)
`
`29 Simons P. The Treatment of Methadone Poisoning with Naloxone (Narcan). The Journal of Pediatrics 83(5): 846-
`847, 1973.
`
`so Rumack BH and Temple AR. Lomotil Poisoning. Pediatrics 53(4): 495—500, 1974.
`
`31 Sesso AM and Rodzvilla JP. Naloxone Therapy in a Seven—Month—Old with Methadone Poisoning. Clinical
`
`Pediatrics 14(4): 388-389, 1975.
`
`32 Gober AE, Kearns GL, Yokel RA, et aI. Repeated Naloxone Administration for Morphine Overdose in a l-Month-
`Old Infant. Pediatrics 63(4): 606—608, 1979.
`
`33 Moore RA and Rumack BH. Naloxone Underdosage after Narcotic Poisoning. American Journal of Diseases in
`Children 134:156—158, 1980.
`
`3‘ Lewis JM, Klein—Schwartz W, Benson BE, et al. Continuous Naloxone Infusion in Pediatric Narcotic Overdose.
`American Journal of Diseases in Children 138: 944—946, 1984.
`
`35 Glatstein M, Finkelstein Y, Scolnik D. Accidental Methadone Ingestion in an Infant. Pediatric Emergency Care 25:
`109-111, 2009.
`
`13
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`Reference ID: 3844432
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`

`

`Narcan Nasal Spray (Naloxone Hydrochloride)
`NDA 208411
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`Division of Pediatric and Maternal Health Review
`November 9, 2015
`
`Notably, two published case reports in neonates have described serious adverse events with
`parenteral naloxone use. One case report describes a female newborn born to an opioid-
`dependent mother who developed a generalized seizure two minutes after receiving 0.2 mg IM
`naloxone for no spontaneous respiratory effort by four minutes of life.36 Her seizure failed to
`respond to three anticonvulsants but, after 30 minutes, resolved with a morphine bolus which
`was then continued as an infusion. The other case report describes a 27 week female newborn
`with a birth weight of 485 grams who developed cardiac arrest immediately after receiving 0.1
`mg/kg of IV naloxone for suspected morphine overdose