CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`207865Orig1s000
`
`SUMMARY REVIEW
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`Division Director Review
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`Date
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`electronic stam-
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`Division Director Review
`
`Donna J. Griebel, MD
`From
`
`Subject
`Division Director Summary Review
`NBA
`207865
`
`Merck Sh u and Dohme Co oration
`A licant Name
`
`Date of Submission
`March 26, 2015
`
`PDUFA Goal Date
`
`December 26, 2015
`
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication(s)
`
`Emend
`aprepitant
`Powder for oral suspension/125 mg (to be reconstituted
`with (but) mL water to a concentration of 25 m -,
`Prevention of nausea and vomiting associated with
`initial and repeat courses of emetogenic chemotherapy
`in ediatric atients
`
`
`
`Material Reviewed/Consulted
`
`0ND Action Package, including:
`Medical Officer Review
`
`Names of discipline reviewers
`Karyn Berry, NED/Aisha Johnson, MD, MPH,
`MBA/Anil Rajpal, MD
`Statistical Review
`Wen-Jen Chen, PhD/Yeh-Fong Chen, PhD
`
`Pharmacology Toxicology Review
`Sushanta Chakder, PhD
`CMC Review
`Hamid Shafiei, PhD/Moojhong Rhee, PhD (see
`supplemental table below for OPS} reviewer list}
`Elizabeth Shang, PhD/Sue Chih Lee, PhD/ Jian Wang,
`PhD/Nitin Mehrotra, PhD
`
`Clinical Pharmacology Review
`
`OPDP
`
`081
`
`OSE/DMEPA
`
`DMPP
`
`Meeta Patel, PharmD
`
`Susan Leibenhaut, MD/Susan D. Thompson, MD/Kassa
`Ayalew, MD, MPH
`Sherly Abraham, RPh/Kendra Worthy, PharmD/Lubna
`Merchant, MS, PharmD
`
`Karen Dowdy, RN, BSN/ /Marcia Williams, PhD/Meeta
`Patel, PharmD/LaShawn Griffiths, MSHS-PH, BSN,RN
`
`
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`
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`DPMH
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`Amy M. Taylor, MD, MHS/Hari Cheryl Sachs,
`NIB/Christos Mastroyannis, NID/
`
`framara Johnson, MD, MS/Lynne P. Yao, MD
`
`0ND=0fice ofNew Drugs
`DPMH=Division of Pediatric and Maternal Health
`0PDP=0flice of Prescription Drug Promotion
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DMPP=Division ofMedical Policy Pregams
`OSI=Ofice of Scientific Investigations
`
`Reference ID: 3862225
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`

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`Division Director Review
`
`Office of Process and
`Facilities
`
`Biopharm
`
`Environmental
`Assessment
`Microbiology
`
`REVIEWER
`Vipul Dholakia
`
`Tien Mien Chen
`
`James Laurenson
`
`Bryan S. Riley
`
`2
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`Reference ID: 3862225
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`

`

`Division Director Review
`
`Division Director Review
`
`1. Introduction
`
`The trials submitted in this NDA for aprepitant powder for suspension were conducted to fulfill the
`PREA requirements associated with its approvals for prevention of acute and delayed nausea and
`vomiting associated with initial and repeat courses of highly emetogenic chemotherapy (HEC),
`including high-dose cisplatin, and moderately emetogenic chemotherapy (MEC). The Emend capsule
`product is currently marketed in a 40 mg, 80 mg and 125 mg dose presentation. The 125mg and 80
`mg capsules are used for the chemotherapy induced nausea and vomiting (CINV) indication. The 40
`mg capsule is used for the prevention of post-operative nausea and vomiting indication, which was
`approved on June 30, 2006.
`
`In order to address the full age range covered by the PMRs (ages 6 months to 17 years), the applicant
`developed an age appropriate oral suspension, which is subject to this new NDA, i.e., NDA 207865.
`The Emend capsule pediatric supplemental NDA (sNDA) for CINV was approved on August 28,
`2015; however, the review clock for the oral suspension NDA was extended to receive additional
`information to support appropriate labeling instructions for reconstitution and measurement of oral
`suspension doses.
`
`A single key pediatric trial established the efficacy and safety of both formulations (capsule and
`suspension) for CINV. Patients 12 years of age and older in the trial received a flat/fixed dose of
`aprepitant capsules (same as the adult CINV dose) and patients ages <12 years received aprepitant
`suspension. The dose in patients <12 years of age was calculated based on patient weight. There was
`no prespecified analysis to evaluate efficacy by age group or formulation (capsule/suspension). My
`efficacy and safety review for the capsule formulation, which was signed on August 28, 2015,
`included all of the information from the full age range enrolled in this trial, including the patients who
`received the suspension.
`
`The inability to concurrently approve both formulations studied in the key efficacy and safety trial
`created review issues related to labeling the pediatric indication for the capsule sNDA. The review
`team evaluated whether capsule dosing could be appropriately extended to patients <12 years of age
`and who weigh ≥30 kg. In the trial, the aprepitant weight based suspension dose (3 mg/kg Day 1; 2
`mg/kg Days 2 and 3) for patients <12 years who weighed 40 kg would have been essentially the same
`as the flat dose of capsules studied in the subjects ≥12 years of age (trial suspension dose: 120 mg Day
`1 and 80 mg Days 2 and 3 vs. capsule dose: 125 mg Day 1 and 80 mg Days 2 and 3). For subjects <12
`years who weighed at least 30 kg, the weight based suspension dose was 30% lower than the flat dose
`of the capsules administered to the subjects ≥12 years of age (trial suspension dose: 90 mg Day 1 and
`60 mg Days 2 and 3 vs capsule dose: 120 mg day 1 and 80 mg Days 2 and 3). Ultimately, the review
`team for the capsule sNDA concluded that the capsule could be used in patients younger than 12 years
`who weighed at least 30 kg (assuming that the patient is able to swallow capsules). This
`recommendation was based on the pharmacometric reviewers’ conclusion that the applicant’s
`
`3
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`Reference ID: 3862225
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`Division Director Review
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`proposed nomogram dosing for the suspension NDA (volume per weight band) was reasonable, given
`that no safety concerns could be identified associated with the 30% higher exposures that would occur
`in some children dosed using the nomogram. At the time of the approval of the Emend capsule
`pediatric sNDA, there were significant concerns regarding whether the applicant would be able to
`successfully address issues about the ability of healthcare providers and caregivers to accurately
`reconstitute and measure the suspension doses. For this reason, it seemed important to assure that
`dosing instructions of the capsule be extended to the broadest age range possible. The approved
`pediatric indication for the capsule formulation was:
`
`EMEND“, in combination with other antiemetic agents. is indicated in patients 12 years of age and
`older and patients less than 12 years who weigh at least 30 kg for the prevention of:
`
`acute and delayed nausea and vomiting associated with initial and repeat courses of highly
`emetogenic cancer chemotherapy (HEC) including high-dose cisplatin [see Dosage and
`Administration (2. 1)].
`nausea and vomiting associated with initial and repeat courses of moderately emetogenic
`cancer chemotherapy (MEC) [see Dosage and Administration (2. 1)].
`
`There were also substantive discussions during the capsule review regarding whether the information
`on the full clinical trial could be presented in Section 14 of the label if only a subset of the studied
`population would be included in the Indication and the Dosage and Administration sections. The
`reviewers concluded that the full clinical trial data could be appropriately presented in Section 14 of
`the Emend capsule label. (The suspension product will share the same label.)
`
`This review of the NDA for the powder for suspension Emend product serves as both the CDTL
`review and the Division Director Summary review. I will reiterate the clinical efficacy and safety
`information presented in my review of the Emend capsule NDA for the pediatric ClNV indication, and
`will provide additional information specific to the suspension formulation, where applicable (e.g.,
`Sections 3 Chemistry/Manufactming, 5 Clinical Pharmacology, 12 Labeling). The following two
`major review issues in this NDA were related to the applicant’s proposed dosing instructions for
`product labeling:
`
`1)
`
`(um)
`
`(I!) (4)
`
`2) the proposed instructions for reconstitution and measurement of the suspension doses.
`
`The actual use studies submitted to support the adequacy of the proposed label’s instructions
`for reconstitution and measurement of the suspension raised significant concerns about the
`ability of parents and healthcare providers to correctly reconstitute the suspension and measure
`the dose. The review team discussed these concerns with the applicant during the review, and
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`Reference ID: 3862225
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`Division Director Review
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`the applicant conducted additional actual use studies during the course of the review to
`evaluate instruction modifications intended to improve user performance of these actions
`(reconstitution and measurement). To address the feasibility of a potential mitigation strategy
`of having the health care provider reconstitute the dose and preload the dose into an oral
`dosing dispenser to be sent home with the patient for subsequent dosing, the applicant also
`conducted additional stability studies to evaluate the stability of the suspension within an oral
`dosing syringe. These studies were conducted during the review clock.
`
`2. Background
`As stated above, aprepitant capsules have been approved for prevention of acute and delayed phase
`CINV in adults and in pediatric patients ≥12 years of age and pediatric patients <12 years of age who
`weigh at least 30 kg and can swallow capsules. Acute phase refers to the first 24 hours after initiation
`of chemotherapy, and the delayed phase refers to the subsequent period, between 24 and 120 hours
`after initiation of chemotherapy. Children receive chemotherapy drugs and regimens that qualify as
`MEC and HEC, and they experience acute and delayed CINV. The underlying pathophysiology of
`CINV is not known to differ between children and adults. Categorization of whether an agent (or
`combination of agents) is moderately or highly emetogenic in published treatment guidelines is based
`on the proportion of patients that would be expected to vomit if they received the drug without
`antiemetic prophylaxis. According to publications on the ASCO Guidelines for antiemetics in
`oncology1, highly emetogenic agents are associated with vomiting in ≥90% of patients. These
`categories are based on experience with adult patients. In its aprepitant pediatric program, the
`applicant categorized emetogenicity based on the Children’s Oncology Group (COG) Emetogenicity
`of Commonly Used Chemotherapeutic Agents, which uses different terminology, e.g., Very High Risk
`of Emetogenicity, High Risk of Emetogenicity, Moderate risk of emetogenicity. The COG
`categorization references Altman AJ, ed Supportive Care of Children with Cancer (3rd edition: The
`Johns Hopkins University Press; 2004), Perry MC et al, ed. Companion Handbook to Chemotherapy
`Source Book (2nd ed. Lippincott, Williams and Wilkins; 2004) and Antiemetics: National
`Comprehensive Cancer Network Practice Guidelines in Oncology (V3. 2008). The Very High Risk
`category (VHRC) list from COG is the same as the HEC list in the ASCO guidelines, with the
`following exceptions:
`1. High dose cyclophosphamide appears in both lists; however, the cyclophosphamide dose
`for HEC is ≥1500 mg/m2, whereas the dose in VHRC is >1500 mg/m2.
`2. Dacarbazine appears in both lists; however, there is no dose specified for HEC, whereas
`VHRC is specifically cites doses ≥500 mg/m2.
`3. Dactinomycin is considered HEC in adults; whereas it is not in the VHRC list (it is
`considered the next emetogenicity level lower, i.e., “High Risk” (60-90% frequency).
`Ifosfamide is considered MEC in the ASCO guidelines, whereas ifosfamide doses of
`≥1500 mg/m2 are categorized VHRC in COG guidelines.
`5. Lomustine appears in the VHRC list and does not appear in the HEC list.
`
`4.
`
`Aprepitant was the first NK-1 inhibitor approved in the US for CINV. There have been two other
`NK-1 inhibitors approved since (netupitant as part of the fixed combination with palonosetron, i.e.,
`Akynzeo, in September 2014 and rolapitant in September 2015). In adults, aprepitant is administered
`
`1 Basch E, et al. JCO.Vol 29, No 31. Nov 1 2011. pp.4189-4198.
`5
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`Reference ID: 3862225
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`Division Director Review
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`as part of a combination antiemetic regimen that includes a 5HT-3 antagonist and dexamethasone. In
`the HEC combination regimen, aprepitant is administered on Days 1-3, dexamethasone is
`administered on Days 1-4, and the 5HT-3 antagonist is administered on Day 1. The aprepitant dose on
`Day 1 is 125 mg, and the dose is reduced to 80 mg on Days 2 and 3. The MEC regimen is the same;
`with the exception that dexamethasone is only administered on Day 1. Until the recent approval of the
`pediatric indication for aprepitant capsules for patients 12 years and older (or <12 year and weight ≥
`30kg), there were no NK-1 inhibitors approved for use in the pediatric population in the U.S. There
`are no NK-1 inhibitors approved in a dosage form, e.g., oral suspension, chewable or IV, appropriate
`for use in children <12 years of age (and weight <30 kg). There are no data available to support that
`full extrapolation of efficacy from adults to the pediatric age group is appropriate for this drug class
`and indication. The applicant conducted a randomized, controlled pediatric CINV trial that was
`powered to establish aprepitant’s efficacy in pediatric patients.
`
`See the Clinical Review for a comprehensive and detailed summary of the regulatory history of the
`pediatric development program. Emend capsules were approved on March 26, 2003, for prevention of
`acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic
`chemotherapy (HEC), including high-dose cisplatin. At that time the FDA’s Pediatric Rule had been
`challenged in court and the court ruled (October 17, 2002) that the FDA did not have the authority to
`issue the Pediatric Rule. It barred FDA from enforcing it. The approval letter encouraged the
`applicant to submit a pediatric plan; it did not list any PMCs or PMRs related to pediatric studies.
`Passage of PREA later in the same year (2003) retroactively impacted the Emend NDA, as PREA
`contained a provision that for applications submitted between April 1, 1999 and the date of enactment,
`applications with no pediatric study waiver or deferral would be “deferred for at least 1 year unless
`FDA defers for longer period or waives the requirement.” On September 15, 2004, the applicant
`submitted a proposed pediatric study request (PPSR) for Emend capsules, which stated, “The
`proposed studies are also intended to fulfill the Pediatric Research Equity Act of 2003 obligations for
`NDA 21-549.” In that same letter, they proposed a partial waiver for the age group of <2 years
`“because necessary studies are impossible or highly impractical.” The Division responded in a letter
`dated January 21, 2005, denying a waiver of pediatric studies in patients < 2 years of age, and
`instructing the applicant to submit their pediatric drug development plan for this age group. That
`letter also granted a deferral for pediatric studies in patients ages 2 years to 17 years for the HEC
`CINV indication. Subsequently, on April 26, 2005, a letter was issued denying the PPSR. Comments
`in that letter included that pediatric studies of CINV should include pediatric patients ≥ 6 months of
`age, and that an age appropriate formulation should be developed for pediatric patients who cannot
`swallow capsules. Ultimately, the age range required in the PMR associated with the HEC approval
`was 2 years and greater; however, in the Written Request,
` (Written
`Request Amendment #1, dated April 8, 2011). The HEC approval PMR states:
`
`1395-7: Deferred pediatric studies in patients 2 years to 17 years of age for the prevention of
`acute and delayed nausea and vomiting associated with initial and repeat courses of highly
`emetogenic cancer chemotherapy, including high-dose cisplatin.
`
`Note that the lower limit of the age required for study in the HEC PMR also differs from that of PMR
`associated with the MEC PMR, presented next below.
`
`6
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`Reference ID: 3862225
`
`(b) (4)
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`Division Director Review
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`Emend capsules were subsequently approved on October 28, 2005, for prevention of nausea and
`vomiting associated with initial and repeat courses of MEC chemotherapy. The approval letter stated
`FDA waived the pediatric study requirement for ages 0 to less than 6 months and deferred pediatric
`studies for ages 6 months to less than 17 years. The deferred PREA studies listed in the letter were:
`
`1. Deferred pediatric study under PREA for the use of Emend ™ (aprepitant) in the prevention
`of nausea and vomiting associated with initial and repeat courses of moderately emetogenic
`cancer chemotherapy in pediatric patients 6 months to less than 17 years of age.
`
`Final Report Submission: December 31, 2007
`
`2. Conduct an appropriately powered randomized controlled clinical trial, in patients receiving
`moderately emetogenic chemotherapy (MEC), designed to document generalizability among
`various chemotherapies and an evaluation of efficacy in male patients.
`Protocol Submission: by March 31, 2006
`Study Start: by December 31, 2006
`Final Report Submission: by December 31, 2008
`
`The applicant submitted a proposed pediatric study request (PPSR) on September 15, 2004. A Written
`Request (WR) was issued on February 2, 2009. In the interim between the PPSR and the issuance of
`the WR, there were many communications between the applicant and FDA regarding the studies that
`should be included in the WR, the age range the studies should cover, and timeline extensions for
`submission of pediatric PMR studies. In the FDA’s response to the initial PPSR, on April 26, 2005,
`the applicant was told that the relative bioavailability of the age appropriate formulation should be
`assessed in adults. Subsequent to issuance of the Written Request there were a number of WR
`amendments and further requests for deferral extensions. On November 6, 2013, the Applicant was
`issued PREA non-compliance letters for NDA 21549 (original HEC approval) and NDA 21549/S-008
`(MEC approval), as the pediatric assessments had not been submitted by the required PREA date of
`October 31, 2013 (the most recent deferral extension that had been granted). The applicant then
`requested, and FDA granted, another deferral extension (July 31, 2014).
`
`The pediatric CINV NDAs for the aprepitant capsule and powder for oral suspension were both
`submitted in July 2014. The capsule sNDA was submitted on July 28, 2014. The NDA for the
`powder for oral suspension (NDA 207865) was initially submitted on July 25, 2014; however, it was
`not fileable because the manufacturing facilities were not ready for inspection. The applicant
`submitted a request for fast track designation, which was granted. A request for rolling review (of
`NDA 207865) followed, and it was granted (on October 29, 2014). The necessary CMC information
`was submitted on March 26, 2015, which started the review clock for this NDA.
`
`. The applicant indicated they
`The Written Request included pediatric studies for
`would not meet the deadline for the WR to qualify for pediatric exclusivity.
`
`7
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`Reference ID: 3862225
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`(b) (4)
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`Division Director Review
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`3. CMC
`
`This NDA proposes a powder for oral suspension for prevention of CINV in pediatric patients less
`than 12 years of age. The drug substance used to produce the oral suspension
`(we) used
`in the approved capsule formulation. In contrast to the capsule product, API (active pharmaceutical
`ingredient) is formulated with soluble excipients in the suspension drug product to allow formation of
`a suspension when the drug product (powder for suspension) is mixed with water. The powder for
`suspension drug substance is
`(we)
`
`. The reviewers determined that the excipients unique to this formulation (as
`compared to the oral capsule formulation) are suitable, as they are compendial components.
`
`(I!) (4)
`
`(b) (4)
`
`(b) (4)
`
`The powder for suspension drug product is filled into
`containing 125 mg of the active ingredient
`Studies of potential extractables from the container detected “microgram levels of
`”, which the reviewers found acceptable. The stability data submitted in
`the application supported the applicant’s proposed 30 months expiration dating period, with storage
`conditions of 20-25 degrees C (68—77 degrees F) and excursions between 15-30 degrees C (59-86
`degrees F). The 6 months accelerated stability data for 3 registration batches from conditions of 40
`degrees C and 75% relative humidity showed “no significant loss in potency”. Acceptance criteria
`for degradation products for the proposed product are the same as those that have been approved for
`the oral capsule product. The data from in-use stability testing of the reconstituted suspension kept at
`ambient conditions for 5 hours (from the formal stability batches of the drug product) are consistent
`with and support a recommendation that the reconstituted dose be administered
`M4) of
`reconstitution if kept in ambient conditions after reconstitution. (However, see discussion of additional
`data submitted during the review clock regarding stability testing of product stored in oral dispensing
`syringes, presented below.)
`
`(m4) and oral
`The drug product will be co-packaged with a mixing cup
`dosing dispensers (oral syringes, Class I medical device), which the reviewers found comply with food
`contact materials regulations. All are intended for single use. The provider will fill the mixing cup
`with
`GM) of water, and the powder suspension will be emptied from the
`a”) into the mixing cup.
`The lid will be closed and the provider will shake the cup, resulting in a suspension of aprepitant 25
`mg/ml. The appropriate dose will be drawn 11p into the oral dosing dispensers from the cup. The cup
`has been used with other CDER approved products. The oral dosing dispensers consist of (61(4)
`components:
`which complies with the USP National Formulary (NF) requirements.
`
`(5) (4)
`
`The CMC reviewers stated: “The compatibility of the mixing cup and the dosing dispenser with
`aprepitant suspension for the expected duration of use by the patient has been appropriately addressed
`by the in—use stability studies .......Both the dispenser and the mixing cup come in contact with
`reconstituted suspension for a short period of time (less than 15 minutes) during preparation and oral
`administration”. However, based on concerns about the ability of caregivers/patients to reconstitute
`the suspension and measure doses, the review team asked the applicant to conduct an in—use stability
`study of the reconstituted product in the planned oral dispensing device to ensure the product remains
`8
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`Reference ID: 3862225
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`Division Director Review
`
`stable for at least 3 days when stored in the oral dispenser as a suspension under refrigerated
`conditions. These data would support that it is appropriate for healthcare providers to reconstitute and
`measure all three days’ doses at one time and send the Days 2 and 3 doses home with the
`caregiver/patient for subsequent administration.
`
`The applicant submitted the results of the in-use stability testing on October 29, 2015. The CMC
`reviewers found the data adequate to support the drug product is stable for more than 3 hours at room
`temperature (25 degrees C/60% RH) and for more than 3 days under refrigeration (2 degrees C – 8
`degrees C). Based on these data, the reviewers concluded the product is adequately stable to allow
`healthcare providers to prepare the suspension, and provide caregivers the prefilled oral dispensing
`syringes, to be used within 3 days and stored under appropriate conditions (refrigeration). However,
`the CMC reviewers pointed out that the oral dispensing syringe utilized in the stability study was the 5
`cc syringe, and raised concerns that dosing errors could be expected for dose volumes of <1 ml, if a 5
`cc syringe is only provided for doses (given the small dose volume vs. the overall syringe size). They
`noted that the markings on the 5 cc syringe were increments of 0.2 cc. They recommended including a
`1 cc oral dispensing syringe to measure total dose volumes of less than 1 cc. The applicant agreed to
`conduct a similar 3-day in–use stability study using the 1-mL oral dispenser syringe. These data were
`submitted on December 2, 2015, and the CMC reviewers found that the results supported dispensing
`total dose volumes of ≤ 1cc in the 1 cc oral dispensing syringe. The CMC reviewer also stated that
`“The assay results illustrated a more accurate dose volume delivery for dosage volumes of ≤ 1cc using
`the 1-mL oral dispenser.” This conclusion was based on the observation of reduced variability in
`assay results and assay values that were closer to the 100% target when the 1 cc oral dosing syringe
`was used to measure small volume as compared to the 5 cc oral dosing syringe.
`
`Biopharmaceutics review. The Biopharmaceutics reviewers issued a number of information requests
`during the course of the review, and met with the sponsor to facilitate resolution of their review issues.
`Ultimately, the reviewers recommended approval of the NDA, with two PMCs listed below.
`
`Summary. The CMC reviewers have determined that the “NDA has provided sufficient information
`to assure the identity, strength, purity and quality of the drug product.” The Office of Process and
`Facilities has made an overall “Acceptable” recommendation for the facilities involved in this NDA.
`All identified labeling issues have been satisfactorily resolved, from a CMC standpoint. I concur with
`the CMC reviewers’ recommendation to approve this NDA. The following PMCs requested by the
`Biopharmaceutics reviewers will be included in the approval letter:
`
`3013-1 Monitor the particle size distribution (PSD) of commercial drug product in the primary
`package (at release and on stability testing) and submit the data to support a proposed
`D specification for the particle size.
`
`Final Report Submission: 04/18
`
`3013-2 Generate dissolution data using the following dissolution method: USP Apparatus II
`(Paddle) with 50 rpm in water (with 1.2% Tween 80), 900 mL at 37°C. Submit the new
`dissolution data for at least three commercial/stability batches to support the dissolution
`acceptance criterion of Q= % at 10 minutes.
`
`9
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`Reference ID: 3862225
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`(b) (4)
`
`(b)
`(4)
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`Division Director Review
`
`Final Report Submission: 12/16
`
`4. Nonclinical Pharmacology/Toxicology
`
`I concur with the conclusions reached by the Pharmacology/Toxicology reviewer that there are no
`outstanding pharm/tox issues that preclude approval. The applicant conducted an oral toxicity study
`of aprepitant in juvenile rats to support the pediatric development program. In addition, the applicant
`conducted an IV toxicity study in juvenile dogs, primarily to evaluate the effects of the EDTA present
`in the IV formulation.
`
`The juvenile rat toxicity study was designed to evaluate the potential effects of aprepitant on
`development, growth, behavior and reproductive performance from postnatal day 10 through postnatal
`week 17. The study supported the youngest pediatric age of 6 months. The highest dose studied was
`2000 mg/kg/day (administered 1000 mg/kg BID). In female rats, the systemic exposures, as measured
`by AUC0-24h at the highest tested dose, were similar to the exposure observed in pediatric patients.
`However, the exposures in male rats were less than that of pediatric patients (11.5 microgram.hr/ml in
`male juvenile rats vs. 20.9 microgram.hr/ml in humans 6 months to <12 years and 17 microgram.hr/ml
`in humans 12 -17 years).
`
`The reviewer noted there were minimal treatment related effects across the full panel of evaluations,
`and he commented that the highest dose was well-tolerated. There were no treatment related effects
`on tests of passive avoidance, auditory startle habituation or open field motor activity. There were
`transient decreases in mean body weight gain in all drug treated groups and slight changes in clinical
`pathology parameters in all groups. These effects were similar to those that had been observed in prior
`adult animal studies. There were slight decreases in hemoglobin, hematocrit, MCV, MCH and MCHC
`and increased platelet counts in both sexes at the 250 mg/kg BID and the 1000 mg/kg BID doses. At
`Week 7, a dose related increase in cholesterol levels was noted in female rats only, which was
`statistically significant; however, it had diminished by Study Week 13. There was significantly early
`vaginal opening in mid- and high dose group females and significantly delayed preputial separation in
`all male groups; however, the reviewer did not find these to be clinically significant. Increased organ
`weight and hepatocellular hypertrophy and increased thyroid weight with follicular cell hypertrophy
`were also observed, but these findings had also been observed in prior adult rat studies and were
`determined to be secondary to hepatic enzyme induction.
`
`These changes in adult rats occurred at similar exposures (by AUC) as in the juvenile rats. In 5 week
`and 14 week adult rat oral dosing studies, the hepatic changes were observed at the 250 mg/kg BID
`dosing level, which was associated with a 7.19 microgram.hr/ml AUC in males and 33.2
`microgram.hr/ml AUC in females in the 5 week dosing study, and 6.37 and 25.7 microgram.hr/ml
`AUCs for each sex respectively in the 14 week study; the next lowest dose studied in the 5 week
`study, 250 mg/kg/d, resulted in AUCs of 3.21 and 13.9 microgram.hr/ml AUCs, by sex, respectively.
`In the 14 week study, the next lowest dose studied - 125 mg/kg BID – resulted in respective AUCs by
`sex of 6.04 and 27.3 microgram.hr/ml. The thyroid changes were observed at all dose levels. There
`were no significant treatment related effects on mating performance and fertility parameters observed
`in any group, and no treatment related effects on embryonic/fetal survival.
`10
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`Reference ID: 3862225
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`Division Director Review
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`The juvenile rat study was preceded by a dose-ranging study in juvenile rats (to identify appropriate
`doses for the definitive study). The reviewer stated that aprepitant was tolerated to doses up to 1000
`mg/kg BID (the upper level studied in the definitive study). Dose and treatment related decreases in
`mean weight gain were noted relative to control, starting at 125 mg/kg BID. Of note, there were 11
`deaths during the study (“found dead”), of which only one occurred in the control group. However,
`the reviewer didn’t consider the deaths treatment related because the “incidences were not dose-
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`related.” There were 3 deaths in the 5 mg/kg BID group, 2 in the 125 mg/kg BID group, 3 in the 500
`mg/kg BID group and 2 in the 1000 mg/kg BID group. Furthermore, there were no deaths in the
`definitive juvenile rat study discussed above.
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`The 4 week juvenile beagle dog study evaluated daily IV dosing, up to a maximum dose of 6
`mg/kg/day. The reviewer concluded that there were no findings in this study that were attributable to
`EDTA in the intravenous product. The dog age in this study corresponded to a hmnan age of <1
`month, based on overall CNS and reproductive development. Systemic exposure at the highest dose
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`was approximately 6X the exposure associated with the pediatric oral dose. The 4 mg/kg dose was
`determined to be the NOAEL; however, the reviewer stated that the higher 6 mg/kg dose studied was
`well tolerated. An approximate 23% decrease in relative heart weight was noted at the 6 mg/kg/day
`dose level; however, there were no histopathological changes associated with this observation.
`Endometrial and myometrial hypertrophy of the uterine horns and body, hypertrophy of the cervical
`muscularis and edema of the vaginal lamina propria and submucosa were observed in females at the 4
`mg/kg/day and 6 mg/kg/day dose levels. In males, reduced size of Leydig cells of the testes was
`observed, associated with “more compact connective tissue surrounding the seminiferous tubules
`when compared with controls” at the 6 mg/kg/day dose level. Reduced testicular weight was also
`observed at this dose level. The applicant stated these changes were “considered to be reversible, to
`have no impact on further development, and to be of minimal toxicological significance,” and the
`reviewer did not disagree with this conclusion. No treatment related effects on ECG, heart rate or
`arterial blood pressure were observed. On Day 35 of dosing, a statistically significant decrease (9.8%)
`in prothrombin time was observed in the female dogs administered 6 mg/kg day; however, on Day 42
`the values were c