CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`209862Orig1s000
`
`SUMMARY REVIEW
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`Signatory Authority Review Template
`
`Sections 1 through 11 of this review have been reproduced, verbatim, from the CDTL memo
`written by Dr. Josh Lloyd.
`1. Introduction
`
`Evzio (naloxone hydrochloride) is an autoinjector intended for subcutaneous or intramuscular
`injection that was approved in a 0.4 mg strength on April 3, 2014, under NDA 205787, for the
`emergency treatment of known or suspected opioid overdose, as manifested by respiratory
`and/or central nervous system depression. Evzio 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 victims experiencing the life-threatening effects of an accidental or
`intentional opioid overdose while awaiting emergency medical attention. Evzio was the first
`naloxone product approved in this setting.
`
`Kaleo, Inc. (“Applicant”), submitted a supplemental new drug application (sNDA) to NDA
`205787 for Evzio to add a 2 mg strength for their product for the same indication. The
`applications for the 0.4 mg product and the 2 mg product were subsequently split into two
`separate NDAs for the reasons stated in Section 12 of this review. The primary reviews were
`entered under NDA 205787.
`
`The only difference between the proposed 2 mg formulation and the already-approved 0.4 mg
`formulation for Evzio is the concentration of naloxone hydrochloride (i.e., 5 mg/ml versus 1
`mg/ml, respectively). All other excipients, volume of medication delivered (0.4 ml), and
`product components, including the container-closure system, are unchanged. The Applicant
`conducted the clinical development program under IND 112,292.
`
`The original approval of Evzio was based on the submission of bioavailability data to reference
`the Agency’s previous finding of safety and effectiveness for Narcan (naloxone hydrochloride;
`NDA 16636), an injectable formulation of naloxone. Narcan was approved April 13, 1971, and
`is available for subcutaneous, intramuscular, and intravenous use 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 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).
`
`The Applicant requested priority review status for this application. The request was based on
`the assertion that the higher dose of naloxone would represent a significant improvement in the
`safety or effectiveness of the treatment of opioid overdose, particularly in opioid overdoses
`involving mixed agonist/antagonists (citing literature that higher doses are required for
`buprenorphine-induced respiratory depression) as well as overdoses in infants and children
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`(citing the higher doses recommended by the American Academy of Pediatrics, as described in
`Section 2 of this review). Narcan nasal spray (4 mg intranasal spray) is a recently approved
`naloxone product for community use that results in naloxone exposures of approximately five
`times greater than that achieved with a 0.4 mg intramuscular injection (e.g., approximates the
`exposures achieved with a 2 mg injection). However, approval of a 2 mg strength of Evzio
`would offer an alternative route of administration to the nasal route while potentially still
`delivering similar higher exposures to naloxone as compared to a 0.4 mg intramuscular
`injection. Therefore, priority review status was granted for this application.
`
`This review will explore in greater detail the data collected from the submitted bioavailability
`study to evaluate the naloxone exposures achieved with the 2 mg strength of Evzio and how
`those exposures intersect with naloxone dosing recommendations, including those for the
`pediatric population.
`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 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.
`
`Expanded access to naloxone in the community is one component of the Commissioner’s
`Opioids Action Plan which outlines FDA’s plan for addressing the epidemic of opioid abuse,
`addiction, and overdose.1 Evzio is currently approved as an injectable naloxone product that
`delivers 0.4 mg of naloxone hydrochloride intramuscularly or subcutaneously and is intended
`for use in the community. Narcan (naloxone hydrochloride) nasal spray is another drug-device
`combination product intended for use in the community and was approved on November 18,
`2015. It delivers 4 mg (40 mg/ml) of naloxone intranasally and was the first intranasal product
`approved in this setting.
`
`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
`
`1 http://www.fda.gov/NewsEvents/Newsroom/FactSheets/ucm484714.htm
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`with repeat doses of 0.1 mg/kg are recommended. In neonates, the recommended initial dose is
`the same as what is recommended in other pediatric age groups (i.e., 0.01 mg/kg); however, the
`recommended repeat dose remains at 0.01 mg/kg. In contrast, the American Academy of
`Pediatrics (AAP) currently recommends an initial dose of 0.1 mg/kg for children ≤20 kg or ≤5
`years of age. A fixed dose of 2 mg is recommended in children >20 kg or >5 years of age. The
`initial dose may be repeated at two to three minute intervals, as needed. The AAP
`recommendations often result in a higher initial dose than the lower end of the initial
`recommended dose range for adults. The AAP’s recommendations have been incorporated into
`a variety of published pediatric drug references (e.g., Harriet Lane Handbook and others).
`
`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, typically from an injectable solution containing 2 mg of
`naloxone HCl in 2 ml of solution (off-label route of administration for this product). 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 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 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, as that achieved with
`an approved injectable naloxone product (i.e., Narcan 0.4 mg given intramuscularly). 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. This is the standard upon
`which the 0.4 mg strength of Evzio was approved.
`
`A pre-sNDA meeting was held in December 2014, where broad agreement was reached on the
`pharmacokinetic (PK) data that will be required to support this application and that additional
`nonclinical data will not be required provided that local tolerability is assessed in the context of
`the PK study.
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`As the Agency’s approach to naloxone products intended for use in the community and the
`market continue to evolve, we now require Applicants of these products to provide certain types
`of data to establish the reliability of the drug-device combination product under a variety of
`conditions, given the life-threatening nature of the condition and the grave consequences
`associated with device failure. CDRH determined that this application does not contain
`adequate information regarding the reliability of the product. Although this information was not
`requested with the original application for Evzio, CDRH recommends requesting this
`information as a post-marketing requirement (PMR) at this time due to the importance of the
`information and its impact on the overall safety considerations for the product. This approach is
`consistent with that taken for naloxone products intended for use in the community.
`
`The CDRH review team recommends approval for this application with PMRs for device
`reliability testing. The CDRH Office of Compliance recommendation for the device
`manufacturing facilities is pending at this time.
`
`I concur with the conclusions reached by the product quality and device reviewers. There are
`no outstanding product quality or device issues that preclude approval.
`
`Mónica Calderón, PharmD, BCPS, conducted the Division of Medication Error Prevention and
`Analysis (DMEPA) review, with secondary concurrence from Vicky Borders-Hemphill,
`PharmD, and Quynh Nhu Nguyen, MS. The Applicant submitted results from a labeling
`differentiation study to evaluate if participants can successfully differentiate between the 0.4 mg
`and the proposed 2 mg Evzio autoinjectors and cartons. The study consisted of 33 participants
`representing laypeople, pharmacists, and pharmacy technicians. DMEPA noted issues with the
`study to indicate that it was not a true label differentiation study. However, DMEPA focused
`their review on the information that the participants provided in terms of subjective feedback on
`what helped them in identifying the correct product, and DMEPA found the study results
`acceptable.
`4. Nonclinical Pharmacology/Toxicology
`
`Carlic K. Huynh, PhD, conducted the nonclinical pharmacology/toxicology review, with
`secondary concurrence from Elizabeth A. Bolan, PhD, and R. Daniel Mellon, PhD. No
`nonclinical studies were submitted with this application. Dr. Huynh noted that “[t]he drug
`substance and drug product specifications are identical to the approved 0.4 mg dosage strength
`product. The container closure is identical to the approved 0.4 mg dosage strength product, the
`extractable assessment was done appropriately with harsh solvents, and the leachable profile is
`not different than the currently approved drug product formulation.
` is present as a
`leachable; however, the levels do not represent a nonclinical safety concern.” The nonclinical
`pharmacology/toxicology team recommends approval from their perspective.
`
`I concur with the conclusions reached by the nonclinical pharmacology/toxicology reviewer.
`There are no outstanding nonclinical pharmacology/toxicology issues that preclude approval.
`5. Clinical Pharmacology/Biopharmaceutics
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`Source: Dr. Qiu’s review, pg. 3
`
`A mean Cmax of 7.90 ng/mL was reached at a median Tmax of 15 min, with a mean half-life of
`1.5 hours. The median Tmax and mean half-life values were similar for the 2 mg and 0.4 mg
`doses of Evzio.
`
`Dr. Qiu noted that “[d]ose proportionality for naloxone AUCt and AUCinf was demonstrated
`between 0.4 mg…and 2.0 mg…[However, n]aloxone Cmax values were slightly greater than
`dose proportional for the same treatment comparison…[T]he naloxone concentrations at each
`time point after administration are much higher for the 2.0 mg [Evzio] than the 0.4 mg [Evzio].”
`
`Dr. Qiu also noted that:
`
`From clinical pharmacology perspective, [the] sponsor has adequately
`characterized the PK of the proposed new strength of [Evzio] (2 mg) and
`dose proportionality between 0.4 mg [Evzio] and 2 mg [Evzio]. According
`to the approved labeling for Narcan (naloxone HCl injection), the list[ed]
`drug product identified for [Evzio] in the original NDA submission, an
`initial dose of 0.4 to 2.0 mg is given IV (or via IM/SC administration if IV
`route is not available). In the original NDA, the 0.4 mg [Evzio] exhibited
`slightly (15%) greater Cmax and equivalent AUC values [for] naloxone in
`comparison to the 0.4 mg naloxone HCl delivered via a standard syringe.
`The 2.0 mg [Evzio] showed about 5-fold AUC and Cmax values compared
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`to the 0.4 mg [Evzio]; and the naloxone concentrations at each time point
`after administration are much higher for the 2.0 mg [Evzio] than the 0.4 mg
`[Evzio]. These PK results support the addition of the new strength for the
`indication of opioid overdosage.
`
`I concur with the conclusions reached by the clinical pharmacology and biopharmaceutics
`reviewers. There are no outstanding clinical pharmacology or biopharmaceutics 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
`referencing the finding of safety and effectiveness for the reference product, Narcan (naloxone
`hydrochloride, NDA 16636), which is approved for known or suspected opioid overdose, to
`establish efficacy of the proposed product.
`8. Safety
`
`Elizabeth Kilgore, MD, conducted the clinical safety review with secondary concurrence from
`me. There were no new safety studies submitted in support of this application. However, the
`Applicant submitted the results of a pharmacokinetic study (study 05A), in which safety
`assessments were performed throughout the study, including evaluation of the injection site.
`
`The Applicant is referencing the finding of safety and effectiveness for the reference product,
`Narcan (naloxone hydrochloride, NDA 16636), which is approved for known or suspected
`opioid overdose, to establish safety of the proposed product. The relative bioavailability study
`demonstrated that Evzio 2 mg achieves approximately 5-fold AUC and Cmax values, as
`compared to Evzio 0.4 mg, which falls within the initial doses recommended in the approved
`Narcan labeling. Narcan labeling recommends repeat doses every two to three minutes up to a
`total dose of 10 mg.
`
`Regarding the safety results from study 05A, Dr. Kilgore noted that:
`
`There were no deaths, non-fatal serious adverse events (SAEs), or
`treatment-emergent AEs (TEAEs) that led to discontinuation from the
`study. Overall, 10 subjects experienced 15 TEAEs. The most frequently
`reported TEAE was mild erythema observed in all treatment groups and
`noted as localized erythema thought by the Applicant to be due to pressure
`markings from the device (10 events reported in seven subjects). Events of
`catheter site swelling, injection site bruising, dizziness, headache, and
`contact dermatitis were reported in one subject each. All TEAEs were
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`considered mild by the Investigator except for the event of headache that
`was considered moderate in intensity. The events of erythema, injection
`site bruising, and headache were considered by the Investigator to be
`possibly related or related to study drug. All events had an outcome of
`resolved. With the exception of erythema, no TEAEs occurred in more
`than one subject and no treatment-specific trends in TEAEs were noted
`among the three treatments. The number of subjects experiencing erythema
`was similar between the treatments, when taking into account that
`Treatment B [(two injections of 0.4 mg Evzio, given 2 minutes apart)]
`involved two injections.
`
`There were no clinically significant safety laboratory values, vital signs,
`ECGs values, or physical examinations findings.
`
`Dr. Kilgore concluded that “there were no new safety findings identified in this submission
`which would alter the known risk-benefit profile of naloxone.” I concur with Dr. Kilgore’s
`assessment.
`9. Advisory Committee Meeting
`
`An Advisory Committee (AC) meeting was not held to discuss this specific product. However,
`a general matters joint meeting of the Anesthetic and Analgesic Drug Products Advisory
`Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee
`(DSaRM) was held to discuss naloxone products for community use.
`
`The committees were asked 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.
`
`The following questions were asked of the committees:
`
`1. DISCUSS: The current pharmacokinetic standard for approval of naloxone products for
`use in the community requires demonstration of naloxone levels comparable to or
`greater than the 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), intramuscular (IM), or subcutaneous injection (SQ)], with a minimum
`of two doses packaged together.
`
`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 products. Please take into consideration the
`variety of opioids that may be involved in an overdose in the community
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`b.
`
`c.
`
`including: prescribed opioids vs. illicit opioids (heroin, heroin laced with
`fentanyl or carfentanil); partial agonists vs. full agonists.
`If you think a higher minimum naloxone level is more appropriate as the
`basis for approval of new products intended for use in the community,
`describe the target naloxone level and the rationale for this approach.
`In controlled settings with trained health care providers and adequate
`ventilatory support, naloxone can be titrated to reverse an opioid overdose
`and minimize the risk for precipitating an acute withdrawal syndrome in an
`opioid-tolerant individual. In the community, trained health care providers
`and adequate ventilatory support may not be available, and naloxone may be
`administered by a layperson relying solely on the instructions for use that
`accompanies the naloxone product. In this latter setting, there is a 5-to 10-
`minute window before hypoxic injury becomes irreversible. Discuss how to
`balance the need for rapid reversal of an opioid overdose with the risk for
`precipitating an acute opioid withdrawal syndrome when selecting the
`minimum naloxone exposure that forms the basis for approval of novel
`products.
`
`2. DISCUSS: The approved dosing for known or suspected opioid overdose in adults is as
`follows: 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 opioid induced or partial opioid induced toxicity should be questioned.
`Intramuscular or subcutaneous administration may be necessary if the intravenous route
`is not available. The approved dosing for known or suspected overdose in the pediatric
`population is as follows: The usual initial dose in pediatric patients 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. The
`past AAP recommendations for naloxone dosing in infants and children are as follows:
`0.1 mg/kg for infants and children from birth to 5 years of age or 20 kg of body weight.
`Children older than 5 years of age or weighing more than 20 kg may be given 2.0 mg.
`These doses may be repeated as needed to maintain opiate reversal.
`
`a. Discuss whether the minimum exposure criterion (naloxone levels comparable to
`or greater than the levels achieved with 0.4 mg of naloxone injection) is
`appropriate for managing opioid overdose in children. If you do not think the
`standard is appropriate for children, discuss the criteria that should be used for
`naloxone products intended for use in children. Discuss whether the
`recommended criteria are suitable for use in adults.
`If different standards and resultant naloxone products are recommended for
`adults and children, one concern is that the presence of more than one naloxone
`product in a home may result in confusion about which product to administer in
`an emergency setting. Discuss how the risk of medication errors can be reduced
`in this setting.
`
`b.
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`c. Discuss the need (if any) for PK and safety information in pediatric patients,
`depending on the route of administration and inactive ingredients, and any
`recommendations for how these data can be obtained.
`
`3. VOTE: Is the pharmacokinetic standard based on 0.4 mg of naloxone given by an
`approved route (IV, IM, SQ) appropriate for approval of naloxone products for use in
`the community or are higher doses and/or exposures required?
`a. Continue with the current minimum standard of comparable or greater exposure
`compared to 0.4 mg of naloxone injection
`Increase the minimum acceptable naloxone exposure to that comparable to or
`greater than a higher dose of naloxone injection
`
`b.
`
`4. VOTE: Should there be different minimum standards used to support the approval of
`products intended for use in adults and in children?
`
`5. DISCUSS: Some Sponsors have proposed marketing more than one dose strength for
`their naloxone products intended for use in the community. When these strengths all
`meet or exceed the minimum naloxone exposure level set forth by the Agency, it is
`unclear what factors to describe in labeling to assist health care providers in making a
`decision to prescribe one dose strength over another.
`
`Discuss what, if any, data Sponsors should provide to support the approval of more than
`one dose strength for any one naloxone product, and that can provide guidance to assist
`clinicians in dose selection.
`
`6. DISCUSS: As part of the standard for approval, naloxone products intended for use in
`the community have Instructions for Use (IFU) suitable for use by laypersons as
`supported by human factors studies and addition al training is not required.
`a. Discuss whether there is a role for new naloxone products intended for use in the
`community that requires training beyond the IFU.
`b. Discuss the characteristics that should be considered for the study population
`enrolled in human factor studies of novel naloxone products. In particular,
`discuss the appropriate age range of study participants and whether the studies
`should specifically enroll adolescents, and if so, down to what minimum age.
`Also discuss whether these studies should specifically enroll caregivers of infants
`and children.
`
`In a community setting, where there is often lack of adequate supportive measures, including
`respiratory support, the risk of giving too low of a dose of naloxone is that overdose patients
`may die or develop irreversible hypoxic injury. In contrast, the risk of providing too much
`naloxone is precipitating opioid withdrawal symptoms.
`
`The committees’ discussion was largely split on the issue of whether the 0.4 mg standard is too
`low. Some members expressed the need to have a higher standard to ensure adequate reversal
`in this setting, due to the grave consequences associated with under treatment, while others felt
`that there were insufficient data to suggest that the 0.4 mg standard is not adequate. Many
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`members also expressed concern that withdrawal could be associated with a variety of
`behavioral manifestations, including violence, but noted that we do not have adequate data to
`suggest that a 2 mg standard would be too high.
`
`When the question was taken to vote (Question 3), 13 members voted to keep the current
`minimum pharmacokinetic standard (i.e., 0.4 mg) and 15 members voted to increase the
`standard. Those in favor of increasing the standard felt that the availability of more potent
`opioids, including those that are illicit (e.g., street fentanyl and carfentanil), and extended-
`release/long-acting opioids is concerning and would require higher exposures to naloxone for
`adequate reversal. Those members felt that the benefit of utilizing higher exposures to save
`lives outweighed the risk of precipitating opioid withdrawal.
`
`The committees also voted 21 to 7 to have the same standard in adults and pediatrics (Question
`4). Some committee members also expressed concern that the 0.4 mg minimum standard is too
`low for the pediatric population and opined that weight-based dosing, as is recommended in the
`labeling for Narcan, is not appropriate for the community setting.
`
`Although there was limited time available to discuss how to differentiate multiple doses in
`labeling, when available, some committee members noted a high potential for confusion among
`laypersons and favored not having multiple strengths available. Others noted that if the right
`dose is established that will work in the vast majority of adults and children, multiple doses are
`not necessary and it is an unnecessary exercise to try and describe different doses in labeling.
`
`The committees did not have an opportunity to opine on Question 6.
`
`10.
`
`Pediatrics
`
`The Applicant received agreement on their pediatric study plan (PSP) for Evzio 2 mg on
`October 16, 2015.
`
`Because Evzio 2 mg represents a change in dosing regimen (a fixed 2 mg dose) for naloxone,
`the Applicant is required to conduct a pediatric assessment under the Pediatric Research Equity
`Act (PREA). Efficacy studies are not feasible in pediatric patients in the same way they are not
`feasible in adults. However, unlike in adults, pediatric pharmacokinetic studies in healthy
`children are not feasible because of limits on the ability to conduct studies in normal, healthy
`children where the study involves more than minimal risk. Therefore, the Applicant was
`required to support the safety and efficacy of Evzio 2 mg in pediatrics, based on a review of
`available information, including the published literature, clinical practice guidelines, and the
`approved labeling for Narcan.
`
`The Applicant submitted a pediatric assessment to support the efficacy and safety of the 2 mg
`dose in the entire pediatric age range, consistent with that described in the PSP, for which the
`Division of Pediatric and Maternal Health (DPMH) was consulted to review the adequacy of
`that assessment.
`
`outputfile-1175697911.pdf
`
`Reference ID: 4001454
`
`Page 13 of 18
`
`Opiant Exhibit 2137
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685
`Page 14
`
`

`

`The DPMH review was conducted by Mona Khurana, MD, with secondary concurrence from
`John J. Alexander, MD, MPH.
`
`Dr. Khurana concluded that:
`
`The pediatric assessment supports the utility of the higher fixed naloxone
`dose provided by [Evzio 2 mg] to achieve and sustain opioid reversal,
`particularly in cases of pediatric exposure to long-acting opioids, large
`opioid ingestions, or both. The pediatric assessment also suggests that
`pediatric patients with acute opioid exposure may safely receive naloxone
`at cumulative doses of up to nearly 0.8 mg/kg. The assessment provides
`further evidence that precipitation of acute opioid withdrawal is unlikely to
`occur with use of [Evzio 2 mg] in the majority of the intended pediatric
`population since the most likely cause of opioid exposure in younger
`pediatric patients, particularly those less than 6 years of age, is acute
`accidental opioid ingestion. However, administration of the 2 mg fixed
`dose [of Evzio] in the subset of opioid-dependent pediatric patients,
`including neonates, may result in an abrupt and complete reversal of opioid
`effects, precipitating an acute opioid withdrawal syndrome which can be
`life-threatening in neonates.
`
`DPMH recommends approval of this application in the proposed indication in
`pediatric patients of all ages and provided pediatric labeling recommendations,
`including those to address the pote