CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208411Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`
`Cross-Discipline Team Leader Review
`
`
`
`Joshua M. L10 (1, MD
`From
`m_——
`
`——
`
`Established
`
`S .
`
`names
`
`Naloxone h drochloride
`
`
`
`Proposed Indication(s)
`
`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 emergency medical care
`Approval
`
`1. Introduction
`
`Adapt Pharma, Inc. (“Applicant”), submitted this new drug application (NDA) for Narcan
`(naloxone hydrochloride) nasal spray for the emergency treatment of known or suspected
`opioid overdose, as manifested by respiratory and/or central nervous system depression.
`Narcan nasal spray is a single-use, drug-device combination product intended for use in the
`community.
`It is designed for use in non-healthcare settings by laypersons to rescue patients
`experiencing the life-threatening effects of an accidental or intentional opioid overdose while
`awaiting emergency medical attention. The Applicant conducted the clinical development
`program under IND 114,704 in collaboration with the National Institutes for Drug Abuse
`(NIDA) and proposes to market Narcan nasal spray in one strength (i.e., 40 mg/ml) that
`delivers 0.1 ml (4 mg) in a single intranasal spray and is for use in patients of all ages, both
`adult and pediatric. The investigational new drug (IND) application was submitted by
`Lightlake Therapeutics, Inc. (also referred to as the “Applicant” throughout this review), on
`July 18, 2014, and the ownership of the 1ND was transferred to Adapt Pharma, Inc., on
`December 16, 2014. This IND was granted fast track designation on January 27, 2015, for the
`proposed indication.
`
`The Applicant submitted bioavailability data to cross-reference their NDA for Narcanl
`(naloxone hydrochloride; NDA 16636), an injectable formulation of naloxone. Narcan was
`approved April 13, 1971, and is available for subcutaneous, intramuscular, and intravenous use
`
`1 The Narcan NDA was transferred from Endo Pharmaceuticals. Inc.. to the Applicant effective May 26. 2015
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`Cross Discipline Team Leader Review
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`for the complete or partial reversal of opioid depression, including respiratory depression,
`induced by natural and synthetic opioids, including propoxyphene, methadone and certain
`mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine.
`Narcan is also indicated for diagnosis of suspected or known acute opioid overdosage. The
`indication and usage section of the labeling further states that Narcan may be useful as an
`adjunctive agent to increase blood pressure in the management of septic shock. Narcan has
`been discontinued from marketing; however, the Agency determined that it was not withdrawn
`from sale for reasons of safety or effectiveness (74 FR 22751). Therefore, the Applicant used
`a generic naloxone product manufactured by
` in the pivotal
`relative bioavailability study to create a scientific bridge to their NDA for Narcan to establish
`the safety and efficacy of Narcan nasal spray for the proposed indication. Although the
`Applicant owns the Narcan NDA, this NDA for Narcan nasal spray is relying on the published
`literature to support the safety and efficacy of the product in the pediatric population and,
`therefore, was submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic
`Act.
`
`This NDA was accepted for rolling review and was granted priority review status upon
`submission of the final sections of the application reflecting the importance of this product
`from the public health perspective, as, currently, there are no approved intranasal naloxone
`products intended for use in the community.
`
`Both Narcan nasal spray and Narcan contain naloxone, and the proposed population for
`Narcan nasal spray (i.e., known or suspected opioid overdose) is encompassed by the indicated
`population for Narcan. However, several important differences exist between Narcan nasal
`spray and Narcan. Narcan nasal spray represents a change in the route of administration from
`intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection to intranasal (IN).
`Therefore, the Applicant evaluated the potential for local toxicity in the relative bioavailability
`studies. Narcan nasal spray also represents a change in the intended setting. Narcan is
`generally used in healthcare settings by healthcare professionals, whereas Narcan nasal spray
`is intended to be used in a community setting by laypersons. The Applicant submitted a
`human factors evaluation to support use in this different setting. Lastly, the proposed dosing
`for Narcan nasal spray represents a change in dosing regimen for pediatric patients. Narcan
`labeling recommends weight-based dosing in pediatric patients, whereas Narcan nasal spray
`contains a fixed dose of naloxone. This review will explore these issues in greater detail, in
`addition to confirming that Narcan nasal spray achieves comparable or greater systemic
`exposures to naloxone as compared to Narcan, particularly in the period immediately after
`drug administration, as this represents a critical period in which the patient’s opioid overdose
`must be reversed to avoid irreversible injury or death.
`2. Background
`
`
`Accidental or intentional overdose and death associated with the use, misuse, and abuse of
`illicit and/or prescription opioids is a public health crisis in the United States. Opioid overdose
`can occur in a patient prescribed an opioid medication or in household contacts of the patient
`and in people who misuse or abuse opioids. Opioid overdose is characterized by life-
`threatening respiratory and central nervous system (CNS) depression that, if not immediately
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`Cross Discipline Team Leader Review
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`treated, may lead to significant morbidity and mortality due to irreversible hypoxic injury.
`Naloxone is a nonselective opioid receptor antagonist, with the greatest affinity for the mu-
`opioid receptor that, if immediately administered, can reverse these life-threatening effects in
`an opioid overdose and prevent hypoxia-associated injury and death. However, there are
`limitations to the use of naloxone 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 not a substitute for seeking emergency medical help.
`
`The US Department of Health and Human Services (HHS) has made addressing this public
`health crisis a top priority and has outlined a targeted initiative to do so that includes providing
`training and educational resources, increasing the use of naloxone, and expanding the use of
`medication-assisted treatment. The availability of an approved intranasal naloxone product
`intended for use in the community would contribute towards meeting these goals and is of
`great importance from a public health perspective.
`
`Generic versions of Narcan are currently available; the approved Narcan labeling recommends
`initial doses of 0.4 mg to 2 mg for known or suspected opioid overdose in adults with repeat
`doses every two to three minutes up to a total of 10 mg. In children, initial doses of 0.01
`mg/kg with repeat doses of 0.1 mg/kg are recommended. Additionally, Evzio, an injectable
`naloxone product that delivers 0.4 mg of naloxone HCl intramuscularly or subcutaneously
`intended for use in the community, was approved on April 3, 2014, and is available.
`
`Naloxone has also been increasingly available in the community through a variety of public
`health programs, which have generally supplied an injectable formulation of naloxone (i.e.,
`either a vial or syringe) along with a needle or mucosal atomizer device (MAD) to provide
`access to this life-saving medicine. The MAD allows for the injectable formulation to be
`delivered as an intranasal spray (currently, an off-label route of administration), typically from
`an injectable solution containing 2 mg of naloxone HCl in 2 ml of solution. The
`bioavailability of this off-label intranasal route of administration using an MAD may be less
`than the exposure following approved routes of administration for naloxone, based on reports
`in the literature, but there are also reports in the literature and from addiction treatment
`programs that naloxone administered this way has been successful in reversing opioid
`overdose. Therefore, the minimum effective dose of naloxone is unclear.
`
`Evaluating the efficacy of a new formulation or route of administration of naloxone to
`establish an effective dose range presents significant logistical and ethical challenges, as
`already-approved naloxone-containing products are available for treatment of this life-
`threatening condition, which, if not immediately treated, could result in substantial morbidity
`and mortality. The Division has determined that it would not be ethical to deliver an
`experimental naloxone (i.e., through a novel formulation or via a novel route of
`administration) to an actual patient suffering from opioid overdose and potentially delay life-
`saving treatment with an already-approved naloxone product in the context of a clinical
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`efficacy study. Furthermore, intentionally administering enough opioid to actually create a
`clinically meaningful opioid overdose is not ethical.
`
`Therefore, the Division has outlined a path for the clinical development of novel naloxone
`products,
`including those intended to be used in the community, which consists of
`demonstrating comparable or greater systemic exposure to naloxone with the new naloxone
`product, particularly in the early critical period after drug administration. This relative
`bioavailability study would be conducted in healthy volunteers, thus obviating the need to
`conduct a study in patients suffering from an opioid overdose. The necessary clinical
`development program was discussed with the Applicant at a Pre-IND meeting held May 24,
`2012.
`It was further discussed that, although the proposed product represents a new route of
`administration, nonclinical studies to evaluate local toxicity 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, provided that the Applicant includes
`adequate clinical monitoring of local tissues in the relative bioavailability studies. A Pre-NDA
`meeting was held March 27, 2015.
`
`3. CMCIDevice
`
`The Quality Assessment review consisted of the following disciplines: Drug Substance and
`Drug Product (Venkat Pavuluri, PhD), Process (Christina Capacci-Daniel, PhD and Edwin Jao,
`PhD), Microbiology (Christina Capacci-Daniel, PhD, and Erika Pfeiler, PhD), Facility
`(Christina Capacci-Daniel PhD and Grace McNally, PhD), Regulatory Business Process
`Manager (Steve Kinsley), Application Technical Lead (Julia Pinto, PhD), and CDRH 0C
`Combination Products (Juandria Williams). CDRH was also consulted (Ryan McGowan and
`Rick Chapman). The information for the naloxone drug substance is referenced in DMF (m4)
`for which
`(m4)
`is the holder, and the information for the nasal spray device is
`referenced in DIVIF
`(W for which
`(m4)
`is the holder. Both DMFs were found to be
`
`adequate. The quality review team recommended approval for this NDA. The following is a
`summary of the quality review.
`
`The quality review team noted that:
`
`is
`M0. The drug product
`is supplied by
`The naloxone API
`)(4) comprising the following excipients: sodilnn
`formulated in
`(5) (4)
`and benzalkonium chloride, in a concentration of
`chloride,
`40 mg/ml. The container closure system is a glass vial with a
`mo
`stopper, which is then encased within a nasal actuator and container holder.
`The nasal spray device is by
`(m4), 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
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`Cross Discipline Tea- Leada' Review
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`temperature. Further, the Oflice of Process and Facilities, has made an overall
`recommendation of adequate for all facilities related to this application.
`
`Dr. Pavuluri noted that “the drug substance specifications include both USP and EP
`monograph specified tests and acceptance criteria (wherever the methods and acceptance
`criteria in the two compendia are different),” and formd this to be adequate. He further noted
`that “[t]he drug substance complies with the USP monograph and USP <467> Residual
`Solvents” and found this to be acceptable. The drug product solution is presented in a 125 uL
`
`0.125 mL
`glass vial (fulfills the requirements of USP) closed with a
`plunger (container closure system), which in turn is mounted into a unit-
`
`dose non- ressurized nasal
`device and container holder assembl . When the device is
`actuated
`
`100 [IL (0.] ml) spray of the naloxone intIanasal solution. There is no priming required before
`use and that the device can be used in any orientation.
`
`and deliver a
`
`Figure l. Selle—tie Representations of the Namn Nasal Spray Drug Product
`
`After Use
`
`
`
`
`Before Use
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`Dr. Pavuluri found the drug product specifications to be adequate. Dr. Pavuluri noted that
`“[a]vailable stability data support [the] proposed expiration dating of 24 months from the date
`of manufacture of the drug product.
`[The Applicant] also commits to conduct stability studies
`on [an] additional three validation/commercial batches of the drug product, 40 mg / mL (4 mg
`/ spray) post approval, stored at accelerated and long-term storage conditions and on one batch
`annually at 25°C/60 % RH as long as the drug product is manufactured ,” as is required.
`
`Over the course of labeling negotiations, the Applicant proposed to allow excursions from the
`storage conditions to 4°C to 40°C. The CMC team held a teleconference with the Applicant
`on November, 16, 2015, and found the Applicant’s proposal acceptable, based on existing
`preliminary data, provided that the Applicant agree to a postmarketing commitment to test
`drug product batches on stability through the course of expiry at the excursion conditions of
`4°C to 40°C .
`
`Dr. Capacci-Daniel noted that the manufacturing process controls are adequate and that “there
`are no significant, outstanding manufacturing process risks that prevent approval of this
`application” and that “there are no significant, outstanding microbiological risks that prevent
`approval of this application.”
`
`Dr. Capacci—Daniel found all of the facilities to be acceptable; however, she recommended
`post-approval inspections of several of the facilities (drug product and device).
`
`The CDRH design review was conducted by Ryan McGowan, biomedical engineer. This
`review was conducted to evaluate the information submitted in this NDA that is intended to
`
`support the safety and flmctionality of the of the device constituent parts of the propose drug-
`device combination product. 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. Mr.
`McGowan recommends approval,
`from the device constituent design perspective, with
`postmarket requirements / commitments to verify combination product reliability.
`I concur
`with Mr. McGowan. Because this product should only be made available in a two-pack
`configuration,
`W" (refer to Section 12
`below for additional discussion), of the impressive pharmacokinetic profile of this product,
`and of the importance of having an approved intranasal product available for use in the
`community, it is acceptable to approve this product with a postmarketing requirement to
`evaluate reliability of the product in a variety of conditions.
`
`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
`(on)
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`(5) (4)
`
`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 up 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 IND, the lower limit of these specifications
`are also acceptable. Additionally, Narcan nasal spray should only be made available in a two-
`pack configuration,
`(m4) (refer to Section
`12 below for additional discussion), ensuring that a second dose is available in the event of an
`inadequate response.
`
`Vicky Borders—Hemphill, PharmD, conducted the Division of Medication Error Prevention
`and Analysis (DNIEPA) surnmative human factors study review. The human factors study was
`conducted in 53 participants who were representative of the intended user group, which
`consists of the general population of individuals 12 years and older and low literacy layusers
`who were untrained on the use of the device. Dr. Borders-Hemphill notes that “[o]f the 53
`participants, 5 participants did not successfully complete one of the two critical tasks of
`inserting the nozzle into the nostril and pressing the plunger to release the dose in the nose:
`
`0 Two of the five participants administered the dose into the mouth of the overdose
`victim (mannequin). The Applicant’s root cause analysis indicated that one of the
`participants used common sense rather than reading the IFU, and the other participant
`thought that they only saw one opening on the mannequin, which was the mouth.
`None of the root causes were attributed to the product design or labeling.
`
`0 Two of the five participants did not press the plunger completely to release the dose.
`The Applicant’s root cause analysis showed that these participants were confused by
`the setting of simulation, and attributed these failures to study artifacts.
`0 One of the five participants expelled the product into the air prior to inserting it into the
`nasal opening. The participant indicated that he was trying to test how hard to push the
`plunger prior to administering to the mannequin.
`
`Dr. Borders-Hemphill concluded that “the human factors validation study report provides
`sufficient data to conclude that the product can be used safely and effectively by intended
`users for intended uses and environments” and recommended revised labeling based on this
`study.
`
`4. Nonclinical Pharmacology/Toxicology
`
`The nonclinical pharmacology/toxicology review was conducted by Newton Woo, PhD, with
`secondary concurrence by R. Daniel Mellon, PhD. The following is a summary of the
`nonclinical pharmacology/toxicology review.
`
`The Applicant did not submit any new nonclinical studies to support this NDA and none were
`required. Dr. Woo concluded that “[t]he Applicant has provided adequate data to support the
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`safety of the drug substance, drug product, and drug product formulation.” There are no novel
`excipients in Narcan nasal spray. All of the excipients are listed in the FDA Inactive
`Ingredients Database (IID) and are present at lower levels than contained in several FDA-
`approved nasal drug products. The Applicant’s specifications for the drug substance comply
`with the requirements of the United States Pharmacopeia (USP) and European Pharmacopoeia
`(EP) monographs, based on a maximum daily dose of two sprays (8 mg of naloxone
`hydrochloride). Dr. Woo found the impurity specifications acceptable, including the
`specification for
` (not detected). Dr. Woo noted that the drug product specifications
`for the degradants were acceptable, including for
`(not detected).
`
`Regarding the container-closure system, the Applicant provided data on extractables; however,
`the Applicant did not conduct a leachables assessment. The Applicant noted that leachables
`will be evaluated in long-term stability samples. The nonclinical review team concluded that
`“the absence of leachables data does not preclude marketing approval for the following
`reasons: 1) the
` plunger 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.” Dr. Woo recommends approval with a
`postmarketing commitment (PMC) to complete the leachables assessment in addition to
`providing comments to the Applicant on the leachables assessment (see Section 13 below). I
`concur with the conclusions reached by the nonclinical reviewer, including that there are no
`nonclinical issues that would preclude approval.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`The clinical pharmacology review was conducted by Suresh Naraharisetti, PhD, with
`secondary concurrence by Yun Xu, PhD. According to the clinical pharmacology team, this
`NDA is acceptable. The following is a summary of the findings from the clinical
`pharmacology review.
`
`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.
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`Cross Discipline Team Leader Review
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`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.
`
`Both one Narcan nasal spray in one nostril (i.e., 4-mg dose) and one Narcan nasal spray in
`each nostril (i.e., 8-mg dose) demonstrated much higher systemic exposure to naloxone, in
`terms of both AUC and Cmax values, in comparison to the reference product. The naloxone
`plasma concentration-time profiles are shown in Figure 2. Narcan nasal spray exhibited a 5.5 -
`fold higher Cmax and 4.7 –fold higher AUCt from one spray in one nostril (4 mg total dose)
`and 11 -fold higher Cmax and 8.9 -fold higher AUCt from one spray in each nostril (8 mg total
`dose) compared to the reference, a single dose of naloxone 0.4 mg given via IM injection.
`
`Figure 2. Mean Plasma Concentration-Time Profiles of Naloxone from 0 to 4 hours Following
`Intranasal and Intramuscular Naloxone Administration to Healthy Subjects (N = 30; n=29 for each
`treatment)
`
`Source: Dr. Naraharisetti’s review, pg. 3
`
`Both Narcan nasal spray doses demonstrated higher naloxone concentrations than the
`reference product at all time points, as described in Table 1.
`
`
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`Table 1. Comparison of Mean Naloxone Concentrations between Intramuscular Naloxone and Two Doses
`of Narcan Nasal Spray from 2.5 to 60 Minutes Post Dose.
`
`Source: Dr. Naraharisetti’s review, pg. 4
`
`
`Dr. Naraharisetti noted that “[t]he median naloxone Tmax after IN administration was not
`significantly different compared to the IM administration.” However, the Tmax for the IM
`route exhibited relatively high variability (i.e., range of 0.08 to 2.05 hours) compared to the IN
`route. Further, the IN route had slightly longer half-life of 2.1 hours compared to 1.2 hours for
`IM route.
`
`
`
` I
`
` concur with the conclusions reached by the clinical pharmacology reviewer. 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 cross-referencing their NDA for Narcan (naloxone hydrochloride, NDA 16636), which is
`approved for known or suspected opioid overdose, to establish the safety and efficacy of the
`proposed product.
`8. Safety
`
`
`There were no new safety studies submitted in support of this application. The Applicant is
`cross-referencing their NDA for Narcan (naloxone hydrochloride; NDA 16636) to establish
`the safety and efficacy of the proposed product. The relative bioavailability study
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`demonstrated that the naloxone levels achieved with Narcan nasal spray are approximately five
`times that of 0.4 mg naloxone given IM. This exposure is likely to fall well within the doses
`recommended in the approved Narcan labeling, which recommends up to a 2 mg initial dose
`and repeating the dose every two to three minutes up to a total dose of 10 mg.
`
`Naloxone is generally administered in the setting of opioids, and many of the adverse events
`described in approved Narcan labeling may be attributable to the reversal of the effects of the
`opioid. Narcan labeling describes the potential for precipitation of opioid withdrawal in
`opioid-tolerant patients characterized by body aches, diarrhea, tachycardia, fever, runny nose,
`sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or
`irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure.
`In the neonate, opioid withdrawal may also include convulsions, excessive crying, and
`hyperactive reflexes.
`
`Narcan labeling also notes that, in the postoperative setting, there have been postmarketing
`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. These have occurred in patients most of whom had pre-existing
`cardiovascular disorders or received other drugs, which may have similar adverse
`cardiovascular effects. Excessive doses of naloxone hydrochloride in postoperative patients
`have resulted in significant reversal of analgesia and have caused agitation.
`
`Because of the higher fixed dose of this product (i.e., 4 mg, which provide roughly 5 times the
`systemic exposure of a 0.4 mg IM dose), as compared to other naloxone-containing products
`intended for use in the community (e.g., Evzio), and the concern for precipitating adverse
`events related to the reversal of the opioid (i.e., in an inpatient postoperative population and in
`opioid-tolerant neonates), additional warning language is warranted to inform prescribers that:
`
`
`In monitored settings, in situations where it is preferable to avoid the abrupt
`precipitation of opioid withdrawal symptoms, consider use of an alternate
`naloxone-containing product that can be titrated to effect and, where
`applicable, dosed according to weight. These situations include the
`emergency treatment of opioid overdose, as manifested by respiratory and/or
`central nervous system depression in the immediate, inpatient postoperative
`period, particularly in patients with pre-existing cardiac disease, and in the
`postpartum period in neonates with known or suspected exposure to maternal
`opioid use.
`
`
`Refer to the discussion under “Section 10 Pediatrics” regarding additionally addressing the
`potential for inducing neonatal opioid withdrawal.
`
`Narcan labeling recommends dosing with naloxone for suspected opioid overdose with repeat
`dosing in adults up to 10 mg before questioning the diagnosis of opioid overdose. The risk of
`administering Narcan nasal spray to a patient who is not opioid-tolerant and whose symptoms
`are caused by an emergency other than opioid overdose is minimal given this wide safety
`margin. Because Narcan nasal spray can be administered in a very timely fashion and the
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`Reference ID: 3848571
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`Cross Discipline Team Leader Review
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`labeling recommends immediately seeking emergency medical attention after the first dose, it
`is unlikely that administering Narcan nasal spray to a patient suffering another emergency
`would significantly delay their definitive treatment.
`
`The Applicant conducted two Phase 1 relative bioavailability studies in healthy volunteers,
`Naloxone-Ph1a-001 (also referred to as study 001, in this review) and Naloxone-Ph1a-002
`(also referred to as study 002, in this review), comparing various intranasal (IN) formulations
`of naloxone to an approved injectable formulation of naloxone given via the intramuscular
`(IM) route. Because this NDA represents a change in the route of administration from the
`original Narcan NDA, the development program was required to evaluate the potential for
`local toxicity with this new route of administration. The Division determined that nonclinical
`studies to evaluate local toxicity would not be required, provided that the clinical studies
`included an assessment of nasal irritation (see discussion under Section 2). Both of the
`relative bioavailability studies collected safety data and included a formal assessment of nasal
`irritation. Only study 002 evaluated the to-be-marketed drug product.
`
`Study 001
`Study 001 was an open-label, randomized, 3-period, 3-treatment, 6-sequence, crossover,
`inpatient study conducted in 14 healthy adult volunteers to compare the pharmacokinetics of 2
`doses of IN naloxone to IM naloxone and to evaluate safety. Subjects received a single 2 mg
`IN dose (one spray of 0.1 mL of a 10 mg/mL solution in each nostril), a single 4 mg IN dose (2
`sprays of 0.1 mL of a 10mg/mL solution in each nostril), and a single 0.4 mg IM dose. The to-
`be-marketed formulation was not used in these studies, th