Summary Review for Regulatory Action
`
`Date
`
`electronic stam
`
`Sharon Hertz, MD
`From
`
`Subject
`Division Director Summary Review
`NBA #
`208411/S-001
`
`Ada t Pharma, Inc.
`A . .licant Name
`
`Date of Submission
`March 25, 2016
`
`PDUFA Goal Date
`
`Jan .
`
`25, 2017
`
`Narcan nasal spray /
`Proprietary Name /
`
`Established (USAN) Name
`Naloxone hydrochloride
`Dosa_e Forms / Stren_ h
`Intranasal s ra / 20 m ml
`
`Proposed Indication(s)
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`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
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`be present
`3. Not a substitute for emer ,enc medical care
`A roval
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`emergency therapy in settings where opioids may
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`
`
`Material Reviewed/Consulted
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`0ND Action Package, including:
`CDTL Review
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`N/A
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`Pharmacology Toxicology Review
`
`Carlic Huynh, PhD, Newton Woo, PhD, R. Daniel
`Mellon, PhD
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`0P9 Review
`Venkat Pavuluri, PhD, Julia Pinto, PhD
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`CDRH/GHDB/DAGRID Review
`John McMichael, Alan Stevens, LCDR, USPHS
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`Clinical Pharmacology Review
`Suresh Narahaiisetti, PhD, Yun Xu, PhD
`
`081
`N/A
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`OSE/DMEPA
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`Millie Shah, PharmD, BCPS; Vicky Borders-Hemphill,
`PharmD; Quynh Nhu Nguyen; MS, Irene Chan,
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`PhaImD, BCPS
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`OPDP/DCDP
`OMP/DMPP
`
`Koung Lee, Olga Salis, L. Shenee Toombs
`Morgan Walker, PhalmD, MBA, CPH; Barbara Fuller,
`RN, MSN, CWOCN; LaShawn Griffiths, MSHS-PH,
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`BSN, RN
`
`Pediatric Maternal Health Staff
`
`Mona Khurana, MD; Leyla Sahin, MD; Hari Cheryl
`Sachs, MD; Miriam Dinatale, D0, LCDR, USPHS,
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`John Alexander, MD, MPH
`CDTIFCross-Discipline Tal- Leader
`0ND=0flice ofNew Drugs
`CDRH=Center for Device and Radiological Health
`OPQ= Office of Pharmaceutical Quality
`08E: Ofiice of Surveillance and Epidemiology
`OCP = Oflice ofCombination Products
`OSI=0flice of Scientific Investigations
`DMEPA=Division ofMedication Errors Prevention
`0PDP=Omce of Prescription Drug Promotion, DCDP=Division of Consumer Drug Promotion
`OMP=0flice of Medical Policy Initiatives, DMPP=Division of Medical Policy Programs
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`Reference ID: 4045894
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`Signatory Authority Review Template
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`1. Introduction
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` The current application is a supplemental NDA for Narcan (naloxone hydrochloride) Nasal
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`Spray 2 mg. Narcan Nasal Spray 4 mg was approved on November 18, 2015, as a 505(b)(2)
`application, which cross referenced the efficacy and safety information from Narcan, (NDA
`016636). The formulations for the approved 4 mg product and proposed 2 mg product
`
`
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`The application relies on a relative bioavailability study in healthy volunteers. As the
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`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
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`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.
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`2. Background
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`Naloxone HCl was first approved in 1971(Narcan, NDA 016636), for intravenous,
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`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
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`hydrochloride by the intranasal route of administration using a nasal atomizer has been
`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 U.S. relies heavily on the use
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`of chronic opioid treatment, there is risk of 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 (NDA 205787) is an autoinjector
`with audible and written instructions for use, and delivers 0.4 mg of naloxone in 0.4 mL to the
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`subcutaneous or intramuscular space. A higher dose version, Evzio 2 mg (NDA 209862) was
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`approved on October 19, 2016.
`
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`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
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` 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
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`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
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`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
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`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
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`occur in household contacts of a patient prescribed opioids by accidental exposure or through
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`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. Highly potent opioids have been found mixed
`into heroin, in particular fentanyl and carfentanil, and this has led to a number of overdose
`deaths among those abusing heroin. Also, it is important to realize that the duration of
`antagonists such as naloxone is generally shorter than the duration of action of most opioids.
`
`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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`Therefore, even when an antagonist is available, it is no substitute for seeking emergency
`medical help.
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`3.
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`OPQ/Device
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`NarcanNasalS ta 2
`
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`
` P
`ter pac
`e contamer c osure-spray
`vice is a single-entity
`combination (drug/device) product. The device contains 100 microliters of a 20 mg/mL
`solution of naloxone hydrochloride, and is intended to deliver a dose of 2 mg wiflr one spray.
`The device is displayed in the following figures:
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`This Imit-dose device is then
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`
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`The drug substance, DMF -, remains acceptable to support the product. As noted in the
`OPQ review, page 3:
`
`The proposed drug product, intended for intranasal delivery ofnaloxone hydrochloride, 2
`
`contains naloxone hydrochloride dihydrate as active ingredient
`
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`aqueous sohrtion alongwithdisodiumedetateas stabilizerand'T'lr.” I
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`tive. Thecompositionofproposeddrugproduct,
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`flissimflartotheapprovedNARC
`spray,4mg sprayandthus
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`corregulatoryeoncansonthecomponentsandcomposition.
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`erearenoscr
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`From the OPQ review, page 22:
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`Based on the data presented above for clinical and registration batches of naloxone formulations at
`concentration of 20 mg/mL, the worst case scenario for the forrmrlation at the concentration of 10
`mg/mLoutto24months,andthe lZmonflrstabflitydatafi'omtheMmg/mLclinicalandregisn'ation
`batches, sponsor proposed an expiration date of twenty four (24) months for the to be marketed 20
`mg/mL Naloxone Nasal Spray concentration.
`
`3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
`
`Sponsorcommitstoplacethefirstthreeproduction(validation)batchesandatleastoneproduction
`bakheachyearmueafiumsmbifitymmefinflcmmchmresystmmcmdingmmesmbflfiy
`protocol described in section 3.2.P.8.l.
`Sponsor also commits to perform the microbiological
`contaminationtests (TAMC, TYMC, E. coli, S. aureus, P. aeruginosa andB. cepaeia) on an annual basis
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`for the first
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`three (3) production batches
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`(b)(4)_
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`m“)
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`From Mr. McMichael’s CDRH review, p.42
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`The sprayer system is manufactured by a third part sponsor named M“) This third party sponsor has
`provided a number ofnon-clinical resources to support approval ofNDA 208411. The specific M“)
`sprayer devices used within the subject NDA is stated as also used
`mm)In) (4)
`spray products in the US.
`
`And from page 9 of the CDRH review:
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`The Design Controls of the NARCAN Nasal Spray was reviewed and established to be adequate under
`the original approved NDA submission NDA 208411. This supplement includes no changes to the
`design controls of the device constituent parts of the combination product. however due to the newly
`proposed dosage of 2 mg Naloxone. performance testing and stability data was required to re-verify the
`essential performance requirements of the device with the lower dosage form. It should be noted that the
`deliverable volume of the nasal spray remains the same for both dosage forms.
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`The Sponsor submitted updated stability testing for the 2 mg combination product that is adequate to the
`consultant reviewer.
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`A post-market requirement for reliability of the NARCAN nasal spray was established for the original
`NDA submission
`M“)
`
`After discussion with the CDER review team the same rationale applies for this supplemental dose that
`applied for the original NDA dosage in that the safety and efficacy of the drug product dosage is not in
`question and the concerns regarding the reliability of the device constituent do not outweigh the potential
`benefit of the device reaching market.
`M“)
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`The postmarket requirement in place from the original application is as follows:
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`1. Establish reliability requirements for the combination product and complete testing which verifies
`combination product reliability
`MM):
`
`0
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`0
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`0
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`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.
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`Provide rationale and justification supporting the clinical acceptability of the established reliability
`requirements.
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`Perform a test to verify the reliability requirements specified in above.
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`0 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
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`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.
`0
`Shipping
`0 Aging
`0
`Storage orientation and conditions
`0 Vibration handling
`0
`Shock handling (e.g.. resistance to random impacts. such as being dropped)
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`0 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.
`0 Activation orientation
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`0
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`Environmental temperature
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`2
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`(um;
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`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
`device.
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`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.
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`3. Nonclinical Pharmacology/Toxicology
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`From Dr. Huynh’s review, page 4 review:
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`There were no nonclinical studies submitted in this NDA. The current proposed 2 mg naloxone
`hydrochloride formulation has a lowered amount of naloxone hydrochloride from the approved 4 mg
`dosage strength formulation with all excipients within safe limits.
`tb)(4)
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`The container closure is
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`identical to the approved 4 mg dosage strength product and as such, the extractable/leachable profile is
`not expected to be worse. Therefore. there are no additional nonclinical concerns with the 2 mg dosage
`strength for NARCAN Nasal Spray.
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`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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`4. Clinical Pharmacology
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`The basis for eflicacy for Narcan Nasal Spray 2 mg is the same relative bioavailability study
`submitted in support of the 4 mg product. The Applicant conducted study Naloxone-Phla-OOZ
`(also referred to as Study 002, in this review). Study 002 was an open-label, randomized, 5-
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` period, 5-treatment, 5-sequence, crossover study conducted in 30 adult male and female
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` healthy volunteers in an inpatient setting. The treatment arms were:
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`  Treatment A- 2 mg IN (one 0.1 mL spray of 20 mg/mL solution in one nostril)
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`  Treatment B- 4 mg IN (one 0.1 mL spray of 20 mg/mL solution in each nostril)
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`  Treatment C- 4 mg IN (one 0.1 mL spray of 40 mg/mL solution in one nostril)
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`  Treatment D- 8 mg IN (one 0.1 mL spray of 40 mg/mL solution in each nostril) and
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`  Treatment E- 0.4 mg IM (1 mL of 0.4 mg/mL commercial formulation)
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` The following two figures and table from Dr. Naraharisetti’ s review (pages 5,6) demonstrate
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` the naloxone levels for one spray of Narcan Nasal Spray 2 mg, one spray of Narcan Nasal
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` Spray 4 mg, and a 0.4 mg intramuscular injection into one nostril.
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` Figure 1.3 Mean plasma concentration time profiles of naloxone from 0 to 1 h following
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` intranasal (2 mg and 4 mg dose, 20 mg/mL) and intramuscular (0.4 mg) naloxone
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`administration to healthy subjects (N = 29)
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`The findings show that there is dose proportionality with the 2 mg and 4 mg Narcan Nasal
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`Spray doses, and that the 2 mg Narcan Nasal Spray dose exceeds the exposure of the 0.4 mg
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`IM injection, including during the first five minutes following dosing.
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`I concur with the conclusions reached by the clinical pharmacology reviewer that there are no
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`outstanding clinical pharmacology issues that preclude approval.
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` 5. Clinical Microbiology
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` Not Applicable.
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`6. Clinical/Statistical-Efficacy
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` No new clinical efficacy studies were submitted in support of this application. The Applicant
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` is relying on cross reference to the efficacy and safety information from Narcan (naloxone
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` hydrochloride), NDA 016636.
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`7. Safety
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`There were no new safety studies submitted in support of this application. Two relative
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`bioavailability studies were conducted in normal volunteers, but as only Study 002 used the
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`final to-be-marketed formulation, the safety data from this study will be used for product
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`labeling along with information from the referenced drug.
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`The following has been excerpted from my prior memo from the original application:
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`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).
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` Thirty unique subjects received Narcan nasal spray, including 28 subjects who received both 4 mg in one
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` nostril and 4 mg in each nostril (8 mg total dose), 1 subject who received 4 mg in one nostril only
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` (subject was discontinued due to an adverse event), and 1 subject who received 4 mg in each nostril (8
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` mg total dose) but not 4 mg in one nostril (discontinued at the subject’s request), as summarized in Table
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` 4. The extent of exposure and nasal irritation monitoring are adequate to evaluate the potential for local
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` There were no deaths or serious adverse events during the clinical pharmacology
` studies. One subject was discontinued for because of elevated blood pressure
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` measurements on the day prior to dosing of the second treatment period.
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` From Dr. Lloyd’s review:
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` There were 27 adverse events (AEs) reported by 17 subjects. All AEs were considered mild in severity
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` discontinuation. Table 6Error! Reference source not found. lists all AEs that occurred in study 002.
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` The list of AEs for a particular treatment includes all AEs recorded beginning with the administration of
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` that treatment until the next treatment administration in the sequence. The Narcan nasal spray groups
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` (40 mg/ml formulation) are highlighted in yellow in the table. AEs reported for subjects in the Narcan
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` nasal spray groups included increased blood pressure, musculoskeletal pain, headache, and xeroderma,
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` in addition to AEs indicative of local nasal irritation, including nasal dryness, nasal edema, nasal
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` congestion, and nasal inflammation. The IM naloxone comparator arm reported nausea, dizziness, and
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` These safety findings are acceptably balanced by the potential benefit of Narcan Nasal Spray.
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` Naloxone is generally not administered outside of the setting of a suspected opioid overdose. Based on
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` administration of naloxone can result in precipitation of an acute withdrawal syndrome characterized by
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` body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or
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` trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps,
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` increased blood pressure, and tachycardia. In the neonate, opioid withdrawal signs and symptoms also
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`included: convulsions, excessive crying, and hyperactive reflexes.
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`Also as noted in the labelling for Narcan, in the postoperative setting, there have been post-marketing reports of
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` 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.
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`While the adverse events described previously were observed in the 4 mg treatment group, the
`2 mg groups had some of these too but additionally had constipation, toothache, muscle
`spasms, and rhinalgia. These additional terms will be included in the label.
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` 8. Advisory Committee Meeting
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` This application was not taken to an advisory committee meeting. However, a joint meeting of
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`the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk
`Management Advisory Committee was convened on October 5, 2016, to discuss naloxone
`products intended for use in the community, specifically the most appropriate dose or doses of
`naloxone to reverse the effects of life-threatening opioid overdose in all ages, and the role of
`having multiple doses available in this setting. The committees were also asked to discuss the
`criteria prescribers will use to select the most appropriate dose in advance of an opioid
`overdose event and the labeling to inform this decision, if multiple doses are available.
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`The following are the meeting minutes from this joint meeting:3
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` 1. DISCUSS: The current pharmacokinetic standard for approval of naloxone products for use
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`in the community requires demonstration of naloxone levels comparable to or greater than the
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` levels achieved with the approved starting dose of 0.4 mg of naloxone injection administered
`by one of the approved, labeled routes of administration in adults [intravenous (IV),
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`intramuscular (IM), or subcutaneous injection (SQ)], with a minimum of two doses packaged
`together.
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`a. Discuss whether matching or exceeding the naloxone exposure from a 0.4 mg injection of
`naloxone represents a high enough naloxone exposure to remain the basis for approval of novel
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`products. Please take into consideration the variety of opioids that may be involved in an
`overdose in the community including: prescribed opioids vs. illicit opioids (heroin, heroin
`laced with fentanyl or carfentanil); partial agonists vs. full agonists.
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` 3 See
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`http://www fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndAnalge
`sicDrugProductsAdvisoryCommittee/UCM527701.pdf
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`outputfile-32839332.pdf
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`Reference ID: 4045894
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` b. If you think a higher minimum naloxone level is more appropriate as the basis for approval
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` of new products intended for use in the community, describe the target naloxone level and the
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` rationale for this approach.
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` c. In controlled settings with trained health care providers and adequate ventilatory support,
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` naloxone can be titrated to reverse an opioid overdose and minimize the risk for precipitating
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` an acute withdrawal syndrome in an opioid-tolerant individual. In the community, trained
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` health care providers and adequate ventilatory support may not be available, and naloxone may
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` be administered by a layperson relying solely on the instructions for use that accompanies the
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` naloxone product. In this latter setting, there is a 5- to 10-minute window before hypoxic injury
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` becomes irreversible. Discuss how to balance the need for rapid reversal of an opioid overdose
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` with the risk for precipitating an acute opioid withdrawal syndrome when selecting the
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` minimum naloxone exposure that forms the basis for approval of novel products.
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` Committee Discussion: The committee members did not come to a consensus on the
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` appropriateness of a higher starting dose of naloxone versus the current dose. The committee
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` members discussed that it is unclear what should be the basis to choose an absolute correct
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` dose; however, the committee noted that the risk of not having a high enough dose is much
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` greater than not having enough. Some committee members stated that there is concern that
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` lower doses of naloxone might require rescuers to titrate, taking time, and risking further
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` hypoxic injury to the patient. Many committee members stated that the risk of acute withdrawal
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` is acceptable for the benefit of saving a patient. Please see the transcript for details of the
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` committee discussion.
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` 2. DISCUSS: The approved dosing for known or suspected opioid overdose in adults is as
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` follows: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered
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` intravenously. If the desired degree of counteraction and improvement in respiratory functions
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` is not obtained, it may be repeated at 2 to 3 minute intervals. If no response is observed after 10
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` mg of naloxone hydrochloride have been administered, the diagnosis of opioid induced or
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` partial opioid induced toxicity should be questioned. Intramuscular or subcutaneous
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` administration may be necessary if the intravenous route is not available.
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` The approved dosing for known or suspected overdose in the pediatric population is as follows:
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` The usual initial dose in pediatric patients is 0.01 mg/kg body weight given I.V. If this dose
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` does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg
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` body weight may be administered.
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` The past AAP recommendations for naloxone dosing in infants and children are as follows: 0.1
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` older than 5 years of age or weighing more than 20 kg may be given 2.0 mg. These doses may
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` be repeated as needed to maintain opiate reversal.
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` a. Discuss whether the minimum exposure criterion (naloxone levels comparable to or greater
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` than the levels achieved with 0.4 mg of naloxone injection) is appropriate for managing opioid
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` overdose in children. If you do not think the standard is appropriate for children, discuss the
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` criteria that should be used for naloxone products intended for use in children. Discuss whether
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` the recommended criteria are suitable for use in adults.
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` b. If different standards and resultant naloxone products are recommended for adults and
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` children, one concern is that the presence of more than one naloxone product in a home may
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`outputfile-32839332.pdf
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`Reference ID: 4045894
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` Page 11 of 19
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` result in confusion about which product to administer in an emergency setting. Discuss how the
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` risk of medication errors can be reduced in this setting.
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` c. Discuss the need (if any) for PK and safety information in pediatric patients, depending on
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` the route of administration and inactive ingredients, and any recommendations for how these
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` Committee Discussion: There was much discussion amongst the committee members
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` concerning the need for trials to determine PK and PD data in children. The committee
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` members stated that single products and simpler administration is important as is dosing
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` information that can be used by those at reduced cognitive levels. The committee members
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` stated that different standards do not seem to be necessary based on the limited data presented,
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` and that the safety profile of naloxone is excellent based on forty years of history of safe use in
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` even the tiniest infants. Some committee members discussed that PK and safety information in
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` pediatric patients is not necessarily needed at this time. The committee members stated that if
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` studies were done, they would most likely need to be done on postoperative patients receiving
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` intravenous opioids and naloxone on an inpatient basis. The committee members also
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` discussed some models of waiver of conse