CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`215859Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis 2 (DMEPA 2)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`December 7, 2021
`Requesting Office or Division:
`Division of Non-Malignant Hematology (DNH)
`Application Type and Number: NDA 215859
`Product Name and Strength:
`Xarelto (rivaroxaban) for oral suspension,
`1 mg/mL (after reconstitution)
`JANSSEN PHARMACEUTICALS INC
`2021-1248-1
`Ebony Whaley, PharmD, BCPPS
`Colleen Little, PharmD
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA 2 Safety Evaluator:
`DMEPA 2 Team Leader
`(Acting):
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised Instructions for Use (IFU), container label, and carton labeling
`received on November 24, 2021 for Xarelto. The Division of Non-Malignant Hematology (DNH)
`requested that we review the revised IFU, container label, and carton labeling for Xarelto
`(Appendix A) to determine if they are acceptable from a medication error perspective. The
`revisions are in response to recommendations that we made during a previous label and
`labeling review.a
`
` CONCLUSION
`2
`We determined that the revised IFU, container label, and carton labeling are acceptable from a
`medication error perspective, and we do not have additional recommendations at this time.
`
`Regarding the revised IFU, we note the Applicant did not increase the prominence of the
`caution statement in IFU Step 4 as previously recommended. The Applicant noted that they
`
`a Whaley, E. Human Factors Results and Label and Labeling Review for Xarelto (NDA 215859). Silver Spring (MD):
`FDA, CDER, OSE, DMEPA 2 (US); 2021 NOV 15. RCM No.: 2021-1248 2021-1257.
`
`1
`
`Reference ID: 4900071
`
`

`

`previously implemented post-validation revisions to make the caution statement more
`).
`noticeable (i.e., addition of the Caution symbol and removal
`We acknowledge the Applicant’s previously implemented revisions are intended to increase the
`prominence of the caution statement and to address performance in the HF validation study. As
`such, in this instance, we determined that additional IFU revisions to IFU Step 4 are not needed
`at this time.
`
`Regarding the revised container label and carton labeling, we note the Applicant did not
`implement our recommendation to include the total volume after reconstitution on the
`container label and carton labeling. The Applicant stated that inclusion of the total volume after
`reconstitution could cause confusion to the pharmacist (e.g., a pharmacist who sees the
`mL
`total volume on the label may be confused about how much water to use and could incorrectly
`reconstitute with
` mL of water). We note the carton labeling and Prescribing Information
`inform users of the volume needed for reconstitution (i.e., 150 mL) and the total contents of
`the bottle (i.e., 155 mg of rivaroxaban). In this instance, we determined that additional
`container label and carton labeling revisions are not needed at this time.
`
`Reference ID: 4900071
`
`2
`
`3 Pages of Draft Labeling have been Withheld in Full as b4
`(CCI/TS) immediately following this page
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`EBONY A WHALEY
`12/07/2021 08:58:28 AM
`
`COLLEEN L LITTLE
`12/07/2021 09:38:25 AM
`
`Reference ID: 4900071
`
`

`

`HUMAN FACTORS STUDY REPORT AND LABELS AND LABELING REVIEW
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`Requesting Office or Division:
`Application Type and Number:
`Product Type:
`Drug Constituent Name and
`Strength
`Device Constituent:
`Rx or OTC:
`Applicant/Sponsor Name:
`Submission Date:
`OSE RCM #:
`DMEPA 2 Safety Evaluator:
`DMEPA 2 Team Leader (Acting):
`DMEPA 2 Associate Director for
`Human Factors :
`DMEPA 2 Associate Director for
`Nomenclature and Labeling:
`
`November 15, 2021
`Division of Non-Malignant Hematology (DNH)
`NDA 215859
`Combination product
`Xarelto (rivaroxaban) for oral suspension,
`1 mg/mL (after reconstitution)
`Oral syringe
`Rx
`Janssen Pharmaceuticals, Inc.
`6/22/2021; 8/30/2021
`2021-1248; 2021-1257
`Ebony Whaley, PharmD, BCPPS
`Colleen Little, PharmD
`Lolita White, PharmD
`
`Chi-Ming (Alice) Tu, PharmD, BCPS
`
`Reference ID: 4888463
`
`1
`
`

`

`1 REASON FOR REVIEW
`
`This review evaluates the humanfactors (HF) validation study report and labels and labeling
`submitted under NDA 215859forXarelto (rivaroxaban)for oral suspension.
`
`1.1 PRODUCT DESCRIPTION
`
`This is a combination product with a proposedoral syringe device constituent part thatis
`intended to support the proposedindicationsof (a) treatment of venous thromboembolism
`(VTE) and the reductionin the risk of recurrent VTE in pediatric patients from birth to less
`than 18 years after at least 5 days ofinitial parenteral anticoagulant treatment and (b)
`thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart
`disease who have undergonethe Fontan procedure. The proposed product will be supplied
`in a 200 mLglass bottle containing rivaroxaban granules along with two 5 mLoral dosing
`syringes and a press in bottle adapter (PIBA). After reconstitution with 150 mL water, the
`concentration of the suspension is 1 mg/mL. The oral syringe includes both graduation marks
`in milliliter units and color bandsto facilitate dosing. Pediatric doses range from 0.8 mg to 20
`mg administered up to three times a day. Users must perform the measurement and
`administration process multiple times to achieve the 7.5 mg, 10 mg, 15 mg, and 20 mgdoses.
`See Figure 1 below and Appendix A.
`
`Figure 1. Proposed oral syringe graduations, cap, bottle and
`
`PIBA
`
`Reference ID: 4888463
`
`

`

`
`
`1.2 REGULATORY HISTORY RELATED TO THE PROPOSED PRODUCT’S HUMANFACTORS
`
`DEVELOPMENT PROGRAM
`
`Xarelto (rivaroxaban) tablets was approved on 7/1/2011 under NDA 022406,andis available as
`2.5 mg, 10 mg, 15 mg, and 20 mgtablets. Xarelto is currently approved for the treatment of the
`following indications in adults:
`
`to reduce risk of stroke and systemic embolism in nonvalvularatrial fibrillation
`for treatment of deep vein thrombosis (DVT)
`for treatment of pulmonary embolism (PE)
`
`for reductionin the risk of recurrence of DVT or PE
`
`for the prophylaxis of DVT, which may lead to PE in patients undergoing kneeor hip
`replacementsurgery
`for prophylaxis of venous thromboembolism (VTE)in acutelyill medical patients
`to reducethe risk of major cardiovascular events in patients with chronic coronary
`artery disease (CAD)or peripheral artery disease (PAD)
`
`On August 6, 2019, we provided comments for the Type B Pre-NDA meeting under IND 064892
`requesting the Applicant determine whetherthe results of a HF validation study need to be
`submitted to support safe and effective use of their proposed granules for oral suspension
`
`
`
`Reference ID: 4888463
`
`

`

`product.b We also provided risks and potential errors for the Applicant’s consideration including
`the following:
`
`
`
`
`Evaluate the color of the plunger with respect to the readability of the dose markings.
`If the proposed oral syringe will support accurate measurement of all potential doses
`(i.e., will some patients require more than 5 mL).
` Consider any issues that may arise from not incorporating any unit graduation marks on
`the oral syringe and forcing your intended users to rely on a purely color-based
`perception model.
` Consider confusion by your intended users who are color vision deficient (color blind)
`and not color vision deficient and how that user characteristic may influence user
`interaction with the proposed product.
`
`On August 24, 2020, the Applicant submitted a HF validation study protocol under IND 064892
`for the proposed granules for oral suspension. We completed our review of the HF validation
`study protocol on October 21, 2020c and provided recommendations for the Applicant. On
`December 11, 2020, the Applicant submitted a response to our October 22, 2020 HF Validation
`Study Protocol Advice Letter, which included the Applicant’s justification to enroll adolescent
`participants 14 to 17 years old instead of 10 to 17 years. Subsequently, we completed an HF
`protocol memo on May 10, 2021d and provided additional recommendations to the Applicant
`regarding the pediatric user group, the product design, and the Instructions for Use (IFU).
`
`On June 22, 2021, the Applicant submitted the results of the HF validation study under NDA
`215859, which is the subject of this review.
`
`1.3 MATERIALS REVIEWED
`We considered the materials listed in Table 1 for this review. The Appendices provide our
`findings and evaluation of each material reviewed.
`Table 1. Materials Considered for this Review
`Material Reviewed
`
`Appendix Section (for
`Methods and Results)
`
`b Chon, W. Meeting- Preliminary Comments for rivaroxaban (IND 064892). Silver Spring (MD): FDA, CDER, OHOP,
`DHP (US); 2019 JUL 31. Available from:
`https://darrts.fda.gov/darrts/faces/ViewDocument?documentId=090140af80509c0a
`c Oguntimein, O. HF Validation Study Protocol Review for rivaroxaban granules for oral suspension (IND 064892).
`Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2020 OCT 21. RCM No.: 2020-1767.
`d Yokum, A. HF Protocol Memo for rivaroxaban granules for oral suspension (IND 064892). Silver Spring (MD): FDA,
`CDER, OSE, DMEPA (US); 2021 MAY 13. RCM No.: 2020-2641.
`
`Reference ID: 4888463
`
`4
`
`

`

`Table 1. Materials Considered for this Review
`Material Reviewed
`
`Product Information/Prescribing Information
`Background Information
` Previous HF Reviews (DMEPA and CDRH)
`Background Information on Human Factors
`Engineering (HFE) Process
`Human Factors Validation Study Report
`Information Requests Issued During the Review
`Labels and Labeling
`
`Appendix Section (for
`Methods and Results)
`A
`B
`
`C
`
`D
`E
`F
`
`2 OVERALL ASSESSMENT OF MATERIALS REVIEWED
`The sections below provide a summary of the study design, errors/close calls/use difficulties
`observed , and our analysis to determine if the results support the safe and effective use of
`the proposed product.
`2.1 SUMMARY OF STUDY DESIGN
`We previously reviewed the HF validation study protocol, and we note that the Applicant did
`not implement our recommendation to include HF validation study data for pediatric users.
`Specifically, the Applicant noted that they conducted additional HF studies with children
`aged 10-17 years to assess the usability of the product by that age group. However, the
`results from the HF studies did not support self-administration by children aged 10-17 years.
`As such, the Applicant proposes to include labeling statements to indicate the product
`should be administered by adults only.
`Additionally, we note the Applicant did not implement our recommendations for
`improvement to the oral syringe labeled graduations or for revisions to add units of measure
`to the IFU labeling. The Applicant determined that the HF validation testing demonstrated
`that the revisions are not needed.
`
`Overall, we determined the aforementioned deviations from Agency recommendations do
`not preclude our review of the results.
`
`We also note that following our HF protocol review, the Applicant revised the protocol to
`add a IFU mandatory testing scenario (Trial 2) in which caregiver participants simulated
`administration of a second dose and were required to refer to the IFU during testing.
`Additionally, the Applicant revised the protocol to include a caregiver user group that
`received pharmacist consultation prior to testing. See Table 2 below for additional details.
`Because Trial 1 is simulated before Trial 2 and participants were not directed to use the IFU,
`we find the addition of Trial 2 acceptable. However, we find the methodology for
`
`Reference ID: 4888463
`
`5
`
`

`

`pharmacist to consult the caregiver user group unacceptable because with real-world use,
`training or pharmacist counseling may not consistently or routinely occur. As such, this
`review does not consider the data for the 15 participants in the pharmacist consultation
`caregiver user group.
`
`Table 2 presents a summary of the HF validation study design. See Appendix D for more
`details on the study design.
`
`Table 2. Study Methodology for Human Factors (HF) Validation Study
`Study Design Elements Details
`Pharmacists/pharmacy technicians, n = 16
`Participants
`-
`15 participants completed simulated use and 1 pharmacist participant
`provided the consultation to caregivers
`Lay Caregivers, n = 30
`- Group 1, n = 15 - received no consultation from a pharmacist prior to
`testing
`- Group 2, n = 15 - received a consultation from a pharmacist prior to testing
`No formal training was provided. However, caregiver group 2 received a
`consultation from a pharmacist prior to testing.
`The test environment included a well-lit room with flat working surface,
`background noise (typical of an office setting).
`-
`Simulated pharmacy environment
`
`Test Environment
`
`Training
`
`-
`
`Simulated home environment
`
`Sequence of Study
`
`Pharmacists/pharmacy technicians
`-
`Simulated use (reconstitution for either 0.9 mL or 15 mL doses)
`
`6
`
`Reference ID: 4888463
`
`

`

`-
`-
`-
`
`Knowledge tasks
`Root cause analysis (RCA)
`Subjective feedback
`
`-
`
`Lay Caregivers
`-
`Pharmacist consultation (pharmacist consultation caregiver group only)
`-
`Simulated use Trial 1 (IFU optional): The IFU was available, but participants
`were not directed to use it unless they indicated they would in actual use
`Simulated use Trial 2 (IFU Mandatory): Participants were asked to use the
`IFU step-by-step to administer the second dose.
`o Note: All caregiver participants simulated the administration of two
`doses (i.e., first dose in Trial 1 followed by a second dose in Trial 2)
`Knowledge tasks
`RCA
`Subjective feedback
`
`-
`-
`-
`
`Reference ID: 4888463
`
`7
`
`

`

`3 RESULTS AND ANALYSES
`Section 3.1 describes the analyses of use errors, close calls, and use difficulties identified
`with critical tasks in the HF validation study. Section 3.2 describes use errors, close calls and
`use difficulties with non-critical tasks in the HF validation study. As previously noted, this
`review does not consider the data for the 15 participants in the pharmacist consultation
`caregiver user group to be representative of real use; thus, the data was excluded.
`
`3.1 ANALYSIS OF CRITICAL TASK ERRORS
`Table 3 describes the study results, the Applicant’s analyses of the results, and DMEPA’s
`analyses and findings for use errors, close calls and use difficulties with critical tasks.
`
`Reference ID: 4888463
`
`8
`
`

`

`Table 3. Identified Issues and DMEPA’s Findings
`* indicates pharmacist/pharmacist technician only task
`- Note: In Trial 1, caregiver participants simulated administration of a first-time dose and use of the IFU was optional. In Trial 2, caregiver participants
`simulated administration of a second dose and use of the IFU was mandatory.
`Identified Issue and Rationale for Concern
`Pharmacists/pharmacy technicians
`For the task “Check expiration date of granules”*, there were 5 use
`1.
`errors (5 failures) in which pharmacy participants did not check the
`expiration date.
`
`DMEPA’s Analysis and Findings
`
`Regarding subjective feedback, participants noted that they either
`check expiration date separate from preparation steps, the product is
`new, or that dry powders have a long shelf life. The Applicant’s RCA
`attributed the use errors to the nature of the study environment.
`
`The Applicant did not propose mitigations in response to the use
`errors and noted that pharmacists have internal workplace procedure
`to check expiration dates of medications.
`
`2.
`
`For the task “Tap bottle until all granules flow freely”*, there was 1
`use error (1 failure) in which the pharmacy participant did not tap the
`bottle.
`
`Regarding subjective feedback, the participant noted that tapping the
`bottle is not a typical reconstitution step and that the information
`about flavoring is unusual and draws more attention. The Applicant’s
`RCA attributed the use error to the information being difficult to
`locate due to the presence of other information.
`
`9
`
`Reference ID: 4888463
`
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (e.g., if pharmacist uses expired granules to
`prepare medicine and the suspension does not have the specified
`potency resulting in repetitive underdoses).
`
`Our review of the study results identified subjective feedback that
`indicated that users would check the expiration date in a separate step
`or expected that the product would have a long shelf life.
`
`Our review of the labels and labeling finds that the carton labeling and
`container label include expiration dates. Additionally, we find that it is
`standard practice to check the expiration in the pharmacy setting prior
`to dispensing.
`
`Thus, based on our review of the user interface, subjective feedback,
`and RCA, we agree with the Applicant that the residual risk is acceptable
`for this task. We did not identify areas of improvement and have no
`recommendations at this time.
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (i.e., if the granules do not fully suspend due
`to clumping resulting in underdose).
`
`Our review of the study results identified subjective feedback that
`indicated the participant noted the prominence of the information could
`be improved.
`
`

`

`In response to the use error, the Applicant revised the carton labeling
`to relocate the information about flavoring to a separate area above
`the reconstitution steps so the information about tapping the bottle
`is more noticeable. The Applicant determined that this labeling
`revision did not require validation.
`
`3.
`
`For the task “Shake for 60 seconds until all granules wetted and
`suspension is uniform”*, there were 10 use errors (10 failures).
`Specifically, 5 pharmacy participants shook the bottle ~40-50
`seconds, 4 pharmacy participants shook the bottle ~30 seconds or
`less, and 1 pharmacy participant rolled the bottle upside down for
`~20 seconds and then shook the bottle for ~40 seconds.
`
`Regarding subjective feedback, participants indicated that shaking
`the bottle for the time designated doesn’t seem important as long as
`the medication is fully resuspended and that they counted too quicky
`or estimated the time. The Applicant’s RCA attributed the use errors
`to participants incorrectly estimated the 60 second shaking time.
`
`The Applicant did not propose mitigations in response to the use
`errors and noted that the 60 seconds instruction is a guideline, but
`the key endpoint is that reconstitution is complete, which all
`participants successfully completed. The Applicant also noted that if
`the granules are not resuspended, additional shaking and a visual
`check later in the process assures proper mixing and homogeneity of
`the suspension.
`
`Our review of the labels and labeling finds that the Applicant revised the
`carton labeling to relocate the information about flavoring to a separate
`area above the reconstitution steps in order to make the information
`about tapping the bottle more noticeable. We also note this information
`appears in the Prescribing Information (PI). However, we find the
`Applicant’s post-validation carton labeling revision can be improved to
`increase the prominence of this step and decrease the prominence of
`the information regarding flavoring the product. We provide a
`recommendation in Table 5 to address this concern We have
`determined that this change can be implemented without additional HF
`validation testing data to be submitted for review.
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (e.g., due to low drug concentration resulting
`in an underdose).
`
`Our review of the study results identified subjective feedback that
`indicated that participants who experienced use errors were aware they
`needed to shake the bottle; however, they did not shake for the full 60
`seconds. We also note that all participants successfully suspended the
`product.
`
`Our review of the labels and labeling finds that the carton labeling, and
`Section 2.7 of the PI include instructions to shake the product for 60
`seconds until the granules are wetted and the suspension is uniform.
`Additionally, the IFU and container label instruct users to shake the
`bottle for 10 seconds prior to each use; as such, ideally, patients and
`caregivers will also shake the bottle which helps to mitigate the risk of
`administered granules that are not wetted/uniform suspension. Based
`on our review of the user interface, subjective feedback, and RCA, we
`agree with the Applicant that the residual risk is acceptable for this task.
`We did not identify areas of improvement and have no
`recommendations at this time.
`
`Reference ID: 4888463
`
`10
`
`

`

`4.
`
`For the task “Apply use-by date on bottle”*, there were 2 use errors
`(1 failure and 1 close call). One pharmacy participant said they would
`apply a use-by sticker to the carton but not on the bottle, and 1
`pharmacy participant expressed concern that caregivers would miss
`the use-by date (post-reconstitution expiration date) on the
`container label and would use a sticker instead.
`
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (e.g., due to use of expired granules which
`may result in reduced drug potency and a repetitive underdose).
`
`Our review of the study results identified subjective feedback that
`indicated the location of the use-by date labeling could be improved.
`
`Regarding subjective feedback, the participants indicated applying a
`sticker to outer packaging is more convenient and that the post-
`reconstitution expiration date is not noticeable on the container
`label. The Applicant’s RCA attributed the use errors to the
`participants thinking that the area to apply the post-reconstitution
`expiration date would not be noticeable.
`
`5.
`
`The Applicant did not propose mitigations in response to the use
`errors and noted that placement of the post-reconstitution expiration
`date is dependent on pharmacy practice and all pharmacists applied
`a post-reconstitution expiration date in the study.
`For the knowledge task “Do not add flavor as product is already
`flavored”* (Question: Is the product already flavored?), there was 1
`use error (1 use difficulty). One pharmacy participant did not locate
`relevant information on the carton but reported would not add any
`additional flavor without confirming compatibility.
`
`Regarding subjective feedback, the participant noted that the
`instruction is located between 2 steps that draw more attention
`because they begin with action words. The Applicant’s RCA attributed
`the use error to the information being difficult to locate due to
`presence of other information.
`
`In response to the use error, the Applicant revised the labeling to
`make the instruction more prominent. The Applicant determined that
`this labeling revision did not require HF validation.
`
`Our review of the labels and labeling finds that the proposed container
`label includes a space for the pharmacist to write in the post-
`reconstitution expiration date. However, the prominence and format
`can be improved. We also find the carton labeling can be improved to
`include a space for the post-reconstitution expiration date. Additionally,
`instructions for the post-reconstitution expiration date in the PI can be
`improved. We provide recommendations in Tables 4 and 5 to address
`these concerns. We have determined that these changes can be
`implemented without additional HF validation testing data to be
`submitted for review.
`
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis because added flavor dilutes the formulation
`and could impact the stability of the formulation.
`
`Our review of the study results identified subjective feedback that the
`participant considered the labeling information difficult to locate.
`
`Our review of the labels and labeling finds that the Section 2.7 of the PI
`and the carton labeling instruct users not to add flavor to the product.
`We also note the Applicant revised the carton labeling following the HF
`validation study; specifically, the Applicant moved the guidance to not
`add flavoring (previously Step 2) to a separate area above the
`reconstitution steps and used red font with bolding. However, as
`previously noted, we find the Applicant’s post-validation revision can be
`improved to decrease the prominence of the information regarding
`
`Reference ID: 4888463
`
`11
`
`

`

`6.
`
`7.
`
`For the knowledge task “Product must be dispensed in original
`bottle”* (Question: Can the product be dispensed in a bottle other
`than the original bottle?), there 1 use error (1 failure). One pharmacy
`participant reported they would transfer the medication to another
`amber bottle.
`
`Regarding subjective feedback, the participant stated that
`transferring to another bottle is common practice. The Applicant’s
`RCA attributed the use error to the information being difficult to
`locate due to presence of other information.
`
`In response to the use error, the Applicant moved the information
`about flavoring to a separate area of the labeling above the
`reconstitution steps so the information about dispensing in original
`bottle is more noticeable. The Applicant did not validate the revision.
`
`For the knowledge task “Store the granules and reconstituted
`suspension”* (Question: What are the storage conditions for the
`granules and reconstituted suspension?), there was 1 use error (1
`close call). The pharmacy participant reported the medication should
`be stored from 59 to 86 degrees, and then self-corrected.
`
`Regarding subjective feedback, the participant said the temperature
`range permitted for excursions is the first temperature range
`encountered when reading the carton label from the bottom up. The
`Applicant’s RCA attributed the use error to the pharmacist reading
`the label from the bottom up.
`
`The Applicant stated this was a “one-off event,” and did not propose
`mitigations in response to the use error.
`
`12
`
`flavoring the product and we provide a carton labeling recommendation
`in Table 5 to address this concern.
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (e.g., if stored in a bottle leading to
`underdosing due to stability, extractables or leachables issues) or
`bleeding (e.g., if stored in plastic bottle leading to water evaporation and
`higher concentration resulting in repetitive large overdoses).
`
`Our review of the study results identified subjective feedback that
`indicated the use error may have occurred in part due to negative
`transfer.
`
`Our review of the labels and labeling finds that Section 2.7 of the PI and
`the carton labeling state the product should be dispensed in the original
`bottle. We also note the Applicant revised the carton labeling;
`specifically, the Applicant revised the “dispensing the product” section
`(previously Step 7) and moved it to a new section with red colored font.
`We have determined that this change can be implemented without
`additional HF validation testing data to be submitted for review. We did
`not identify any other areas of improvement.
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis due to reduced potency.
`
`Our review of the study results identified subjective feedback that
`indicated the participant was reading the labeling in reverse order than
`typically expected. However, we note that the response provided is
`listed as a permissible storage temperature excursion on the carton
`labeling and the participant was able to self-correct and provide the
`correct answer.
`
`Our review of the labels and labeling finds that the carton labeling and
`container label include product storage information. Based on our
`review of the user interface, subjective feedback, and RCA, we agree
`
`Reference ID: 4888463
`
`

`

`Lay Caregivers
`For the task “Check ‘use-by’ date on bottle”, there were 8 use errors
`8.
`(8 failures). Specifically, 7 caregiver participants in Trial 1 (IFU
`optional) did not check the post-reconstitution expiration date and 1
`caregiver participant in Trial 1 referred to the expiration date for the
`granules instead.
`
`Regarding subjective feedback, the participants indicated they did
`not read the instructions, focused on administration, assumed they
`had just come from the pharmacy and expired medication wasn’t
`provided, and first saw expiration date and did not look further. The
`Applicant’s RCA attributed the use errors to participants not reading
`the IFU and did not recognize the need to check the post-
`reconstitution expiration date.
`
`The Applicant did not propose mitigations in response to the use
`errors and noted that reading the IFU was effective in checking the
`post-reconstitution expiration date and that the reconstituted
`medication is good for 60 days which is longer than the expected
`duration of the longest prescription period (50 days).
`
`9.
`
`For the task “Shake bottle slowly for 10 seconds before each use”,
`there were 6 use errors (6 failures). Three caregiver participants in
`Trial 1 (IFU optional) did not shake the bottle prior to withdrawing
`the medication and 3 caregiver participants in Trial 1 shook the bottle
`aggressively.
`
`13
`
`with the Applicant that the residual risk is acceptable for this task. We
`did not identify areas of improvement and have no recommendations at
`this time.
`
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of biocontamination or thrombosis (i.e., expired suspension
`may result in reduced drug potency and a repetitive underdose).
`
`Our review of the study results identified subjective feedback that
`indicated some participants did not read the instructions and that study
`artifact might have also contributed to some use errors. Also, we
`disagree with the Applicant’s assertion that the longest prescription
`period is 50 days. Specifically, we note that if a patient is prescribed 2.2
`mL daily, their prescription would last approximately 70 days. However,
`we note there are other approved products in which users may need to
`discard product that remains after the post-reconstitution date; as such,
`this characteristic is not unique.
`
`Our review of the labels and labeling finds that the container label
`includes a space for the post-reconstitution expiration date. Additionally,
`IFU Step 1 instructs users to check the
` date. However, as
`previously noted, we recommend revisions to the post-reconstitution
`expiration date on the container label and inclusion of the post-
`reconstitution expiration date on the carton labeling to address this use
`error concern (see Row 4 in this table
`
`
`Based on the URRA, if this task is omitted or not performed correctly
`there is risk of thrombosis (i.e., due to low drug concentration resulting
`in underdose).
`
`Our review of the study results identified subjective feedback that
`indicated that the language in the IFU could be improved upon.
`
`Reference ID: 4888463
`
`(b) (4)
`
`(b) (4)
`
`

`

`Regarding subjective feedback, participants stated they did not read
`the instructions, focused on administration, shook aggressively out of
`habit or misinterpreted the meaning of “slow”. The Applicant’s RCA
`attributed the use errors to participants not reading the IFU and
`negative transfer from other medications.
`
`The Applicant did not propose mitigations in response to the use
`errors and indicated reading the IFU was effective.
`10. For the task “Check suspension. If lumps or granules are on the
`bottom of the bottle, shake slowly again for 10 seconds” there were
`6 use errors (6 failures). Specifically, 6 caregiver participants in Trial 1
`(IFU optional) did not check for lumps or granules.
`
`Regarding subjective feedback, the participants indicated th