CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208411Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Summary Review for Regulatory Action
`
`Date
`
`electronic stam
`
`Sharon Hertz, MD
`From
`
`Subject
`Division Director Summary Review
`NBA #
`208411
`
`Ada t Pharma, Inc.
`A t .licant Name
`
`Date of Submission
`July 20, 2015
`PDUFA Goal Date
`Jan .
`20, 2016
`
`
`
`
`
`
`Proprietary Name /
`Established (USAN) Name
`Dosa_e Forms / Stren_ h
`
`Proposed Indication(s)
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`CDTL Review
`Pharmacology Toxicology Review
`OPQ Review
`
`CDRH Review
`CDRH 0CP
`
`Clinical Pharmacology Review
`OSI
`
`OSE/DMEPA
`
`OPDP/DCDP
`
`OMP/DMPP
`
`Pediatric Maternal Health Staff
`
`Narcan nasal spray /
`Naloxone hydrochloride
`Intranasal s ra / 40 111 ml
`
`1. Emergency treatment of known or suspected opioid
`overdose, as manifested by respiratory and/or
`central nervous system depression
`2. Intended for immediate administration as
`
`emergency therapy in settings where opioids may
`be present
`3. Not a substitute for emer ,enc medical care
`A roval
`
`Joshua Lloyd, MD
`Newton Woo, PhD, R. Daniel Mellon, PhD
`Venkat Pavuluri, PhD, Christina Capacci—Daniel,
`PhD, Erika Pfeller, PhD, _Grace McNally, PhD,
`Edwm Jao, PhD, Steve Kinsley, Julia Pmto, PhD
`Ryan McGowan, Rick Chapman
`Juandria Williams
`
`Suresh Naraharisetti, PhD, Yun Xu, PhD
`Arindam Dasgupta, PhD, Yiyue Zhang, PhD, Melkamu
`Getie-Kebtie, PhD, RPh, Charles Bonapace, PharmD
`Millie Shah, PharmD, BCPS; Vicky Borders-Hemphill,
`PharmD; Quynh Nhu Nguyen; MS, Irene Chan,
`PhannD, BCPS
`L. Shenee Toombs
`
`Nathan Caulk, MS, BSN, RN; Barbara Fuller, RN,
`
`MSN, CWOCN; LaShawn Griffiths, MSHS-PH. BSN, RN
`
`Mona Khurana, MD: Hari Cheryl Sachs, MD; Linda
`Lewis, MD
`
`CD'IIFCIoss—Disciplinc Toa- Leader
`0ND=0flice ofNew Drugs
`comm for Device and Radiological Health
`OPQ= om of Pharmaceutical Quality
`0813: Ofiice of Surveillance and Epidemiology
`OCP = Oflice ofCombination Products
`OSI=Oflice of Scientific Investigations
`DMEPA=Division ofMedication Eirors Prevention
`0PDP=0fice of Presuiption Drug Promotion, DCDP=Division of Consumer Drug Promotion
`OMP=0flice of Medical Policy Initiatives, DMPP=Division of Medical Policy Prognms
`
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`Reference ID: 3848916
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`

`

`Signatory Authority Review Template
`
`1. Introduction
`
`The current application is a 505(b)(2) application for Narcan (naloxone hydrochloride) Nasal
`Spray which cross references the efficacy and safety information from Narcan, (NDA 016636).
`This application represents the first nasal naloxone spray to meet the criteria for novel
`naloxone products described by the Agency during the public meetings held in 2012 and in
`2015. The application was accepted for rolling review and was granted priority review status
`upon submission of the final sections reflecting the importance this product from the public
`health perspective. The application relies on a relative bioavailability study in healthy
`volunteers. As the marketing of Narcan has been discontinued, the Applicant used a generic
`product, International Medicinal System’s naloxone HCl injection USP pre-filled syringe
`(ANDA 072076) for the relative bioavailability study necessary to create a scientific bridge to
`the Agency’s prior findings for Narcan. This review will focus on the pharmacokinetic
`parameters, local adverse events, and the potential for use in pediatric overdose situations.
`
`2. Background
`
`Naloxone HCl was first approved in 1971(Narcan, NDA 016636), for intravenous,
`intramuscular, and subcutaneous administration. The current labeling of Narcan recommends
`an initial dose of 0.4 mg to 2 mg, followed by repeated doses up to 10 mg in the setting of
`suspected opioid overdose. The off-label use of commercially available naloxone
`hydrochloride by the intranasal route of administration using a nasal atomizer is growing in
`popularity as many programs and communities seek to address the public health problem of
`prescription and illicit opioid abuse and the overdoses that occur in these settings. The need
`for a naloxone product for use outside of a controlled medical setting extends beyond the
`setting of abuse. As the management of chronic pain in the US relies heavily on the use of
`chronic opioid treatment, there is risk for overdose for patients and household contacts. The
`first product approved to address the risk of opioid overdose in all settings was Evzio
`(naloxone HCl injection), approved on April 3, 2014. Evzio is an autoinjector with audible
`and written instructions for use, and delivers 0.4 mg of naloxone in 0.4 mL to the
`subcutaneous or intramuscular space.
`
`There is evidence that the off-label use of naloxone by the intranasal route has been effective
`in reversing opioid overdose in many cases. However, there are no data that specifically
`quantitate the success rate, leaving the question of whether there are situations that could have
`benefited from a higher dose of naloxone. Unpublished pharmacokinetic data suggest that
`naloxone levels following off-label use by the intranasal route are lower than by the approved
`routes of administration. The lowest effective dose of naloxone is unclear, and is likely
`dependent on a number of factors, including dose, route of administration, and the amount and
`
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`type of opioid involved in the overdose. In discussion with the Applicant during product
`development, it was determined that designing an efficacy study to define an effective range of
`naloxone use in the proposed setting would be difficult to justify as it would require
`administration of opioids to create an overdose, albeit in a controlled setting. The use of
`pharmacodynamic measurements such as pupil dilation or response to inhaled carbon dioxide
`may demonstrate an effect of naloxone, however, because the relationship between
`experimental opioid effects and reversal of a clinically meaningful overdose is not well
`defined, could not be relied upon for dose selection. Furthermore, there is an approved dosing
`regimen for naloxone. Therefore, the approach required by the division was to match the
`naloxone exposure achieved by administration of naloxone using an approved dose and route.
`This is done by conducting a relative bioavailability study that demonstrates the new product
`matches or exceeds the pharmacokinetic parameters of Cmax and Tmax for naloxone by an
`approved route, intramuscular, intravenous, or subcutaneous injection. The first few minutes
`are of particular importance, because if the overdose has led to apnea, time is of the essence if
`the brain is to be spared permanent hypoxic injury. Therefore, in addition to Cmax and Tmax,
`it is necessary to demonstrate that the naloxone levels are comparable to the approved route
`during the first minutes after dosing. Given the known safety profile of naloxone, the relative
`bioavailability study can be conducted in a normal healthy volunteer population without risk to
`the study participants. This approach has been discussed at two public meetings hosted by
`FDA.1,2
`
`In patients managed with opioid analgesics, an opioid overdose leading to death can occur in a
`variety of settings. Patients may inadvertently take too much trying to better manage pain, or
`through errors in dose or frequency. Initiating a new concomitant medication that inhibits the
`metabolic pathway of an opioid, or discontinuation of a concomitant medication that induces
`the metabolic pathway can result in overdose in a patient who has used their opioid analgesic
`according to instructions. Addition of a new medication with the adverse effect of central
`nervous system depression, or an error in judgment surrounding the use of alcohol can also
`create a situation of over sedation in a patient previously stable on an opioid. Overdose can
`occur in household contacts of a patient prescribed opioids by accidental exposure or through
`intentional misuse or abuse. Individuals abusing prescription opioid analgesics or illicit
`opioids can also inadvertently overdose. With the range of potency of available opioids, death
`from overdose can occur with the first attempt at abuse. Death due to overdose from most
`opioids may be preventable with the immediate administration of an opioid antagonist such as
`naloxone. However, there are limitations in the prevention of death in this setting. The effects
`of some opioids such as buprenorphine may be difficult to antagonize. Larger doses of
`antagonist may be necessary than are available and the opioid overdose must be reversed
`before hypoxia results in irreversible injury. Also, it is important to realize that the duration of
`antagonists such as naloxone are generally shorter than the duration of action of most opioids.
`Therefore, even when an antagonist is available, it is no substitute for seeking emergency
`medical help.
`
`1Exploring Naloxone Uptake and Use – A Public Meeting, July 1 and 2, 2015.
`http://www fda.gov/Drugs/NewsEvents/ucm442236.htm
`2 Role of Naloxone in Opioid Overdose Fatality Prevention; Request for Comments; Public Workshop, April 12,
`2012. http://www fda.gov/Drugs/NewsEvents/ucm277119.htm
`
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`3. OPQIDevice
`
`Narcan Nasal Spray consists of the formulated drug product filled into a unit—dose vial which
`is stoppered and placed within a Unit-dose Delivery Device produced by (we)
`. This unit-dose
`device is then placed into a single blister pack. The container closure—spray device is a single-
`entity combination (drug/device) product. The device contains 100 microliters of a 40 mg/mL
`solution of naloxone hydrochloride, and is intended to deliver a dose of 4 mg with one spray.
`The device is displayed in the following figures:
`
`After Use
`
`Before Use
`
`(It) (4)
`
`NOZZLE
`
`PLUNGER
`
`
`From the Office of Pharmaceutical Quality review:
`
`(m4) The drug product is formulated in
`The naloxone API is supplied by
`mm comprising the following excipients: Sodium chloride,
`M“)
`and benzalkonilnn chloride, in a concentration of 40mg/ml. The container
`closure system is a glass vial with a
`M“) stopper which is then encased within
`a nasal actuator and container holder. The nasal spray device is by
`(I'm, under
`DMF
`(5x4), and has been reviewed by CDRH and OPQ, for use with the naloxone
`drug product. Each unit dose device, formulated to deliver one dose of naloxone, is
`placed within a blister package. Two units or blister packages are then stored per
`carton. Adequate data to assess the device delivery of the drug product and to assure
`the identity, strength, purity, and quality of the drug product is provided. The drug
`product is granted an expiry of 24 months, when stored at room temperature.
`Further, the Office of Process and Facilities, has made an overall recommendation of
`adequate for all facilities related to this application. Therefore,
`from a quality
`perspective, this NDA is recommended for approval.
`
`Mr. McGowan performed an evaluation of the design of the device constituent parts of the
`combination product and covered the intended design and design control information for the
`subject device constituent part. From Mr. McGowan’s review:
`
`The device consultant authoring this review memorandum has performed a design review of
`submission materials intended to support the safety and functionality of the of the device
`constituent parts of the subject combination product. After examination of the original new drug
`application (NDA), cross-referenced drug master files (DMF), and responses to information
`requests, the consulting reviewer has determined that the device constituent parts of the
`
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`combination product have been designed appropriately for the product’s intended use and
`essential performance requirements have been verified with a reasonable degree of certainty
`at a time period shortly after manufacture.
`
`The reviewer was not able to locate information which assures that the combination product is
`free from unacceptable risk with respect to the potential for under-dose or failure-to-dose
`events. Specifically, the sponsor has not demonstrated that a population of manufactured
`product is able to activate reliability after conditioning to applicable environmental or physical
`effects.
`
`The consulting reviewer discussed the lack of reliability information available within the
`submission record with CDERIOND/ODEII/DAAAP within a September 23, 2015 mid-cycle
`meeting and an October 22, 2015 wrap-up meeting. The review division agreed with the
`consulting reviewer’s assessment that additional information is needed regarding combination
`product reliability, however given the benefits of the product; the review division determined
`that this information could be requested within a post-market commitment or post-market
`requirement. Please see the final section of this review memorandum for recommended post-
`market commitment/requirement language regarding combination product reliability.
`
`Therefore, the consulting review finds this submission to be approvable for device constituent
`part design considerations and requests commitment from the sponsor to engage in post-
`market activities to verify combination product reliability.
`
`As discussed by Dr. Lloyd in his review:
`
`Mr. McGowan determined that “the device constituent parts of the combination
`product have been designed appropriately for the product’s intended use and essential
`performance requirements have been verified with a reasonable degree of certainty at a
`time period shortly after manufacture.” However, Mr. McGowan notes that the
`application contains inadequate information to demonstrate that the manufactured
`product is able to activate reliably after exposure to a variety of real-world conditions.
`There is a potential for under—dose or failure-to-dose events leading to undertreated,
`life-threatening CNS and respiratory depression as a consequence of a device failure
`under these conditions.
`
`Also noted by Dr. Lloyd in his review:
`
`Mr. McGowan found the device-related product specifications acceptable with the
`exception of dose content uniformity, which allowed for relatively wide batch release
`specifications. This specification requires that
`(m4)
`
`Given the relatively wide
`safety margin with naloxone, there is little concern for the upper limits of these release
`specifications, particularly since Narcan is labeled with dosing recommendations 11p to
`a total of 10 mg of naloxone. In general, the greatest concern would be for releasing a
`batch that might not deliver an adequate dose of naloxone in an immediately life-
`threatening situation. However, given the pharmacokinetic profile of this product
`(refer to Section 5 below), which achieves much higher systemic exposures to
`naloxone than the approved comparator dose of naloxone (i.e., 0.4 mg IM), the lower
`
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`limit of these specifications are also acceptable. Additionally, Narcan nasal spray
`should only be made available in a two-pack configuration,
` (refer to Section 12 below for additional discussion),
`ensuring that a second dose is available in the event of an inadequate response.
`
`The postmarket requirement recommended by Mr. McGowan is as follows:
`
`1. Establish reliability requirements for the combination product and complete testing which
`verifies combination product reliability as described in detail below:
`
`
`
`
`
`
`
`Establish reliability requirements for your combination product. It is recommended that
`reliability be directly specified as R(t) = x%, where t = time and x% = probability of meeting
`essential performance requirements. These requirements should be objective and relate to
`the ability of a population of devices to meet essential performance requirements after pre-
`conditioning to elements outlined within c, below. The reliability requirements should be
`verified with a high degree of statistical confidence.
`
`Provide rationale and justification supporting the clinical acceptability of the established
`reliability requirements.
`
`Perform a test to verify the reliability requirements specified in above.
`
` Devices assessed within the reliability test should be preconditioned to worst-case
`reasonably foreseeable conditions. The Agency has conceived the following recommended
`preconditioning activities, however you should provide rationale supporting the final
`precondition elements chosen, and the order in which the products are conditioned. Your
`assessment of the preconditioning parameters should be based on your own failure
`analyses (e.g., fault tree analysis) in order to assure that the scope of preconditions and
`their boundary values are adequately correct and complete.
`o Shipping
`o Aging
`o Storage orientation and conditions
`o Vibration handling
`o Shock handling (e.g., resistance to random impacts, such as being dropped)
`
` Devices assessed within the reliability analysis should be activated under worst-case
`reasonably foreseeable conditions. The Agency has conceived the following recommended
`circumstances of activation; however you should provide rationale supporting the final
`circumstances of activation chosen.
`o Activation orientation
`o Environmental temperature
`
`2. Establish a post-market monitoring program for detection and evaluation of under-dose and
`failure-to-dose events, regardless of cause, and provide periodic reports to the Agency which
`contain descriptions of each reported event along with results of root-cause and contributing-
`cause analyses.
`
`I concur with the conclusions reached by the OPQ review team and the CDRH reviewer
`regarding the acceptability of the manufacturing of the drug product, drug substance, and
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`(b) (4)
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`device. While Mr. McGowan has found that the reliability has not been formally documented,
`leading to the PMR, there is considerable experience with the nasal spray device by
`
`leading to a low suspicion that there will be a problem with reliability. Further, Mr. McGowan
`noted wide batch release specifications for the dose content uniformity. As will be discussed
`in the Clinical Pharmacology Section, the amount of naloxone and resultant exposure in each
`dose of the Narcan Nasal Spray are large enough to assure that even at the low end of the
`specifications, a large enough dose of naloxone will be delivered to expect efficacy. Further,
`as noted by Dr. Lloyd, the product will be available only in two-pack configurations so that a
`second dose will be available if needed.
`
`Manufacturing site inspections were acceptable. Stability testing supports an expiry of 24
`months. There are no outstanding issues that preclude approval. I concur with the
`recommended PMR.
`
`4. Nonclinical Pharmacology/Toxicology
`
`From Dr. Woo’s review:
`
`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).
`
`The PMC recommended by Dr. Woo is:
`
`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.
`
`I concur with the conclusions reached by the pharmacology/toxicology reviewer that there are
`no outstanding pharm/tox issues that preclude approval and with the PMC described.
`
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`(b) (4)
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`(b) (4)
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`

`5. Clinical Pharmacology/Biopharmaceutics
`
`The basis for efficacy for Narcan Nasal Spray cross reference to the efficacy and safety
`information from Narcan and the relative pharmacokinetic profile of naloxone from this new
`Nasal Spray. The key study as described by Dr. Lloyd:
`
`The Applicant conducted study Naloxone-Ph1a-002 (also referred to as study 002, in
`this review), a pivotal relative bioavailability study, in support of this application to
`establish a scientific bridge to their NDA for Narcan (NDA 16636) in order to establish
`the safety and efficacy of Narcan nasal spray.
`
`Study 002 was an open-label, randomized, 5-period, 5-treatment, 5-sequence, crossover
`study conducted in 30 adult male and female healthy volunteers in an inpatient setting
`to evaluate the pharmacokinetics of two doses of Narcan nasal spray (i.e., 4 mg [one
`spray in one nostril] and 8 mg [one spray in each nostril) in comparison to an approved
`generic version of naloxone given intramuscularly (i.e., 0.4 mg). Two doses of another
`formulation of intranasal naloxone that are not the to-be-marketed formulation were
`also evaluated in this study. Subjects were assigned to one of five sequences, with six
`subjects planned in each sequence. A four-day washout period separated the
`treatments. Narcan nasal spray was administered using an
` single-dose device
` with the subject in a fully supine position. The left
`nostril was used for the 4-mg dose, and one spray was administered into each nostril
`for the 8-mg dose. Subjects were instructed not to breathe through the nose during
`administration of Narcan nasal spray and remained fully supine for approximately one
`hour post-dose. Intramuscular (IM) naloxone was administered as a 1-ml (i.e., 0.4
`mg/ml) single injection into the gluteus maximus muscle using a 23-gauge needle.
`
`The following figure and two tables from Dr. Naraharisetti’s review demonstrate the naloxone
`levels for one spray of Narcan Nasal Spray into one nostril, two sprays of Narcan Nasal Spray
`as one spray into each nostril, and an intramuscular injection of 0.4 mg of naloxone. The
`critical findings supporting the expected efficacy of Narcan Nasal Spray are best captured by
`the exposure in the first five minutes following dosing. The naloxone levels from one nasal
`spray rise as early as from the intramuscular injection and peak higher.
`
`Figure Mean plasma concentration time profiles of naloxone from 0 to 4 hours following
`
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`(b) (4)
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`(b) (4)
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`intranasal and intramuscular naloxone administration to healthy subjects (N = 29)
`
`Table Geometric mean ratios and 90% CIs for plasma naloxone pharmacokinetic
`parameters following intranasal and intramuscular administration.
`
`
`Table 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.
`
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`
`
`This pharmacokinetic profile from Narcan Nasal Spray demonstrates that a nasal spray can be
`formulated to result in efficacy comparable to the use of naloxone by intramuscular injection.
`In this case, the 4 mg dose of Narcan Nasal Spray provides naloxone concentrations ranging
`from 3.5-fold to 6-fold higher than a 0.4 mg intramuscular injection.
`
`I concur with the conclusions reached by the clinical pharmacology/biopharmaceutics reviewer
`that there are no outstanding clinical pharmacology issues that preclude approval.
`6. Clinical Microbiology
`
`Not Applicable.
`
`7. Clinical/Statistical-Efficacy
`
`No new clinical efficacy studies were submitted in support of this application. The Applicant
`is relying on cross reference to the efficacy and safety information from Narcan (naloxone
`hydrochloride), NDA 016636.
`8. Safety
`
`There were no new safety studies submitted in support of this application. Two relative
`bioavailability studies were conducted in normal volunteers, but as only Study 002 used the
`final to-be-marketed formulation, the safety data from this study will be used for product
`labeling along with information from the referenced drug.
`
`As described by Dr. Lloyd:
`
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`In study 002, there were a total of 87 single exposures of Narcan nasal spray to a
`nostril (Table 3). Thirty unique subjects received Narcan nasal spray, including 28
`subjects who received both 4 mg in one nostril and 4 mg in each nostril (8 mg total
`dose), 1 subject who received 4 mg in one nostril only (subject was discontinued due to
`an adverse event), and 1 subject who received 4 mg in each nostril (8 mg total dose)
`but not 4 mg in one nostril (discontinued at the subject’s request), as summarized in
`Table 4. The extent of exposure and nasal irritation monitoring are adequate to
`evaluate the potential for local toxicity.
`
`There were no deaths or serious adverse events during the clinical pharmacology studies. One
`subject was discontinued for because of elevated blood pressure measurements on the day
`prior to dosing of the second treatment period.
`
`From Dr. Lloyd’s review:
`
`There were 27 adverse events (AEs) reported by 17 subjects. All AEs were considered
`mild in severity except for the one subject who experienced a moderate increase in
`blood pressure that lead to discontinuation. Table 6Error! Reference source not
`found. lists all AEs that occurred in study 002. The list of AEs for a particular
`treatment includes all AEs recorded beginning with the administration of that treatment
`until the next treatment administration in the sequence. The Narcan nasal spray groups
`(40 mg/ml formulation) are highlighted in yellow in the table. AEs reported for
`subjects in the Narcan nasal spray groups included increased blood pressure,
`musculoskeletal pain, headache, and xeroderma, in addition to AEs indicative of local
`nasal irritation, including nasal dryness, nasal edema, nasal congestion, and nasal
`inflammation. The IM naloxone comparator arm reported nausea, dizziness, and
`headache.
`
`These safety findings are acceptably balanced by the potential benefit of Narcan Nasal Spray.
`
`Naloxone is generally not administered outside of the setting of a suspected opioid overdose.
`Based on the adverse events reported in the labeling for Narcan, in the setting of an opioid-
`tolerant patient, administration of naloxone can result in precipitation of an acute withdrawal
`syndrome characterized by body aches, fever, sweating, runny nose, sneezing, piloerection,
`yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea,
`nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia. In the
`neonate, opioid withdrawal signs and symptoms also included: convulsions, excessive crying,
`and hyperactive reflexes.
`
`Also as noted in the labelling for Narcan, in the postoperative setting, there have been post-
`marketing reports of hypotension, hypertension, ventricular tachycardia and fibrillation,
`dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been
`reported as sequelae of these events. Excessive doses of naloxone hydrochloride in post-
`operative patients have resulted in significant reversal of analgesia and have caused agitation.
`
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`There is minimal to no risk from administration of a dose of 4 mg of intranasal naloxone to a person
`who has not had an opioid overdose if the person is not opioid-tolerant. In the setting of a patient
`who is obtunded with respiratory depression, if the cause is not opioid overdose, no ill effect is
`expected, the instructions to seek emergency medical care are appropriate, and use of Narcan nasal
`spray should not result in substantial delay in seeking that emergency care.
`
`9. Advisory Committee Meeting
`
`This application was not taken to an advisory committee meeting. There were no issues that
`arose during the review period requiring external advice.
`
`10.
`
`Pediatrics
`
`Pediatric patients and children may be at risk for an opioid overdose in the community as a
`result of several scenarios. Similar to adults, pediatric patients may receive an inadvertent
`overdose based on an error in dosing (too soon, too much), initiation of a concomitant drug
`that inhibits metabolism of the opioid, or cessation of a concomitant drug that had induced the
`metabolism of the opioid. In addition, children in a home where opioids are in use may come
`in contact with an opioid through improper storage or disposal with the risk of resultant
`overdose. Older children may experiment with opioid analgesics in an attempt to get high and
`inadvertently overdose. Therefore, pediatricians caring for pediatric patients prescribed
`opioids or caring for children who are otherwise well, but may be at risk for coming in contact
`with an opioid, may find it appropriate to prescribe naloxone to be kept in the home as a safety
`precaution.
`
`The package insert for Narcan includes pediatric labeling as follows:
`
`USAGE IN CHILDREN
`o Narcotic Overdose—Known or Suspected: The usual initial dose in children is 0.01
`mg/kg body weight given I.V. If this dose does not result in the desired degree of
`clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be
`administered. If an I.V. route of administration is not available, naloxone may be
`administered I.M. or S.C. in divided doses. If necessary, naloxone hydrochloride
`injection can be diluted with sterile water for injection.
`
`This is in contrast to the following dosing regimen in adults:
`
`USAGE IN ADULTS
`o Narcotic Overdose—Known or Suspected: An initial dose of 0.4 mg to 2 mg of
`naloxone hydrochloride may be administered intravenously. If the desired degree of
`counteraction and improvement in respiratory functions is not obtained, it may be
`repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of naloxone
`hydrochloride have been administered, the diagnosis of narcotic-induced or partial
`
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`Reference ID: 3848916
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`narcotic induced toxicity should be questioned. Intramuscular or subcutaneous
`administration may be necessary if the intravenous route is not available.
`
`The efficacy of Narcan Nasal Spray in pediatric patients is based on cross reference to the
`efficacy findings for naloxone as described in the labeling for Narcan for injection. Narcan
`Nasal Spray can be expected to be effective, settings where a child has signs of an opioid
`overdose requiring emergency treatment.
`
`There is, however, a narrow set of situations in which a naloxone product that can be titrated to
`effect and/or is administered by a route other than the nasal route may be better suited.
`Neonates born to born to mothers using prescription opioids to manage pain or to treat opioid
`dependence or using illicit opioids may require an opioid antagonist to reverse respiratory
`depression immediately after birth. Rather than risking an a