Precedex(Registered) Intravenous Solution Special Investigation (in Pediatric Patients)
Conditions: Sedation
Sponsor: Pfizer

Precedex
C0801023 NON-INTERVENTIONAL STUDY PROTOCOL
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PFIZER CONFIDENTIAL
Page 1 of 32
(Appendix)
PrecedexIntravenous Solution Special Investigation (in pediatric patients)
FULL PROTOCOL
Pfizer Japan Inc.
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes. 
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.

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PFIZER CONFIDENTIAL
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STUDY INFORMATION
Title
Precedex! Intravenous Solution Special 
Investigation (in pediatric patients)
Protocol number
C0801023
Protocol version identifier
Version 5
Date
10 February 2022
Active substance
Dexmedetomidine Hydrochloride
Medicinal product
Precedex! Intravenous Solution 200 μg 
“PFIZER”
Precedex! Intravenous Solution 200 μg/
50 mL syringe “PFIZER”
Research question and objectives
To assess the data, including safety profile, 
of Precedex! Intravenous Solution 
administered for “sedation during and after 
mechanical ventilation in the intensive care 
setting” in pediatric patients under actual 
medical practice.
Author
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................3
2. LIST OF ABBREVIATIONS................................................................................................6
3. RESPONSIBLE PARTIES....................................................................................................7
4. AMENDMENTS AND UPDATES.......................................................................................7
5. MILESTONES.......................................................................................................................8
6. RATIONALE AND BACKGROUND..................................................................................8
7. RESEARCH QUESTION AND OBJECTIVES .................................................................10
7.1. Safety specifications................................................................................................10
7.2. Concerns for efficacy ..............................................................................................10
8. RESEARCH METHODS ....................................................................................................10
8.1. Study design ............................................................................................................10
8.2. Setting......................................................................................................................10
8.2.1. Registration criteria ....................................................................................10
8.2.2. Study sites...................................................................................................11
8.2.3. Planned study period...................................................................................11
8.2.4. Study procedures ........................................................................................11
8.2.4.1. Study method.............................................................................11
8.2.5. Observation period......................................................................................11
8.3. Variables..................................................................................................................11
8.3.1. Patient characteristics .................................................................................12
8.3.2. Administration record of targeted drug ......................................................14
8.3.3. Concomitant therapy...................................................................................14
8.3.3.1. Drug therapy..............................................................................14
8.3.4. Investigation completion (discontinuation) record (including the reason 
for discontinuation)..........................................................................................15
8.3.5. Effectiveness evaluation .............................................................................15
8.3.6. Adverse events............................................................................................15
8.4. Data sources ............................................................................................................16
8.5. Study size ................................................................................................................16
8.5.1. Planned sample size....................................................................................16

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8.5.2. Rationale for sample size............................................................................16
8.6. Data management....................................................................................................16
8.6.1. CRFs/Electronic data record.......................................................................16
8.6.2. Record retention..........................................................................................17
8.6.3. Data collection method...............................................................................17
8.6.4. Patient registration......................................................................................17
8.6.5. Points to consider for completion, revision, and submission of CRF ........17
8.6.5.1. Data entry ..................................................................................17
8.6.5.2. Data revision .............................................................................17
8.6.5.3. Submission ................................................................................17
8.7. Data analysis ...........................................................................................................17
8.8. Quality control.........................................................................................................18
8.9. Limitations of the research methods .......................................................................18
8.10. Other aspects .........................................................................................................18
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................19
9.1. Patient information..................................................................................................19
9.2. Patient consent.........................................................................................................19
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............20
9.4. Ethical conduct of the study....................................................................................20
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................21
10.1. Requirements.........................................................................................................21
10.2. Reporting period....................................................................................................22
10.3. Causality assessment.............................................................................................22
10.4. Definitions of safety events...................................................................................23
10.4.1. Adverse events..........................................................................................23
10.4.2. Serious adverse events..............................................................................24
10.4.3. Scenarios necessitating reporting to Pfizer Safety Unit within 24 hours .25
10.5. MEDICAL DEVICE COMPLAINT REPORTING REQUIREMENTS .............29
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........29
12. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION...........................29

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13. NAME, AND ADDRESS OF CONTRACTOR AS WELL AS SCOPE OF WORK
CONTRACTED..................................................................................................................30
14. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE 
STUDY RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION30
15. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR 
EVALUATION OF STUDY IMPLEMENTATION STATUS AND RESULTS AND 
REPORTING TO THE PMDA...........................................................................................30
16. OTHER NECESSARY MATTERS ..................................................................................30
17. CONTACT INFORMATION............................................................................................31
17.1. Contact information for inquiries about the study ................................................31
17.2. Contact information for inquiries about the EDC system.....................................31
18. REFERENCES ..................................................................................................................31
19. LIST OF TABLES.............................................................................................................31
20. LIST OF FIGURES ...........................................................................................................31
ANNEX 1. LIST OF STAND ALONE DOCUMENTS .........................................................31
ANNEX 2. ADDITIONAL INFORMATION.........................................................................31

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ADR
Adverse Drug Reaction
AE
Adverse Event
ASA
American Society of Anesthesiologists
CRF
Case Report Form
EDC
Electronic Data Capture
EDP
Exposure During Pregnancy
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MHLW
Ministry of Health, Labour and Welfare
NIS
Non-Interventional Study
PMDA
Pharmaceuticals and Medical Devices Agency
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Safety Analysis Set

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3. RESPONSIBLE PARTIES
The Japan Good Post-marketing Study Practice officer
4. AMENDMENTS AND UPDATES
Protocol 
version 
identifier
Date
Revised sections
Summary of 
revisions
Reason
Version 5
10 February 2022
Information 
about this 
study
5
8.2.3
13
17.1
Change in study
organization
Prolongation of 
both 
investigation
and registration 
periods
Enlargement of 
the scope of 
work contracted
Change in study
organization
Because it has been 
determined that the 
investigation period is 
to be prolonged for 1 
month and the 
registration period for 2 
months, considering the 
possibility that the 
study cannot accrue the 
target number of 
patients in the SAS by 
the end of the planned 
study period.
Also, because of a 
change in study
organization and 
enlargement of the 
scope of work 
contracted.
Version 4
1 October 2021
5
8.2.3
17.2
Prolongation of 
both 
investigation
and registration 
periods
Change in the 
Contact 
information for 
inquiries about 
the EDC system
Other editorial 
revisions
Because it has been 
determined that both 
investigation and 
registration periods are 
to be prolonged for 2 
months, considering the 
possibility that the 
study cannot accrue the 
target number of 
patients in the SAS by 
the end of the planned 
study period.
Version 3
25 February 2021
5
8.2.3
Prolongation of 
both 
investigation
Because it has been 
determined that both 
investigation and 
registration periods are 

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Protocol 
version 
identifier
Date
Revised sections
Summary of 
revisions
Reason
and registration 
periods
to be prolonged for 5 
months, considering the 
possibility that the 
study cannot accrue the 
target number of 
patients in the SAS by 
the end of the planned 
study period.
Version 2
24 July 2019
10
Addition of the
section
Because contents that 
had been described in 
another document were 
incorporated in this 
protocol.
Version 1
14 February 2019
NA
NA
NA
5. MILESTONES
Milestone
Planned date
Start of data collection
April 2019
End of data collection
May 2022
Final study report
Around 2022
6. RATIONALE AND BACKGROUND
PrecedexIntravenous Solution (nonproprietary name: dexmedetomidine hydrochloride) 
(hereinafter referred to as “this drug”) is an active dextrorotatory form (D-form) of 
medetomidine with an imidazole skeleton and is a potent and highly selective central 
α2-adrenoceptor agonist. In Japan, its marketing approval was granted for the indication of 
“sedation during mechanical ventilation and after extubation in patients managed in the intensive 
care setting and able to be extubated early” in January 2004, for the indication of “sedation 
during and after mechanical ventilation in the intensive care setting” in August 2010, and for the 
indication of “sedation during surgery and procedures without intubation under local anesthesia”
in June 2013. Regarding “sedation during and after mechanical ventilation in the intensive care 
setting,” an application for approval of partial changes in approved items for marketing was filed 
in December 2017 and an indication for pediatric dosage and administration was approved in 
November 2018.

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Among adverse events (AEs) for which a causal relationship with this drug could not be ruled 
out that were observed in a phase 3 multicenter, single-arm, open-label study to investigate the 
efficacy, safety, and pharmacokinetics of this drug in pediatric intensive care (C0801017), 
bradycardia, hypotension, and respiratory depression were observed in 12.7% (8/63 patients), 
7.9% (5/63 patients), and 3.2% (2/63 patients), respectively, as events related to the safety 
specification. All of these events have already been reported in patients treated with this drug, 
and no noteworthy AEs were observed in this study. For these reasons, it was considered that if 
this drug was used for the purpose of “sedation during and after mechanical ventilation in the 
intensive care setting” in pediatric patients, the risks of these events were unlikely to increase 
markedly. In addition, risks associated with this drug have been identified based on the overseas 
use experience, and therefore it is considered that there is no major concern about the use in 
Japan.
However, since inclusion/exclusion criteria and restricted concomitant medications were 
specified for study patients in the Japanese study C0801017, it was considered useful to 
accumulate data under actual medical practice in Japan and examine the safety of this drug. In 
the Japanese study C0801017, the patients undergoing elective surgery were only those 
undergoing cardiovascular surgery, and the number of patients in internal medicine was limited. 
For these reasons, it was considered significant to make efforts for collecting information from 
multiple clinical departments, including departments other than cardiovascular surgery and to 
assess the safety, etc. of this drug in pediatric patients under actual medical practice.
Based on the above, the special investigation of PrecedexIntravenous Solution (in pediatric 
patients) (hereinafter referred to as “this study”) will be conducted to assess the data, including 
safety profile, of this drug administered for “sedation during and after mechanical ventilation in 
the intensive care setting” in pediatric patients under actual medical practice.
This study shall be conducted in strict compliance with the “MHLW Ordinance on the Standard 
for Post-Marketing Studies and Clinical Trials of Medical Products” (MHLW Ordinance No. 
171, dated December 20, 2004), the “Enforcement of the MHLW Ordinance on the Standard for 
Post-Marketing Studies and Clinical Trials of Medical Products” (PFSB Notification No. 
1220008, dated December 20, 2004), “MHLW Ordinance to Partially Amend the MHLW 
Ordinance on the Standard for Post-Marketing Safety Control of Medical Products, 
Quasi-medical Products, Cosmetics, and Medical Devices and to Partially Amend the MHLW 
Ordinance on the Standard for Post-Marketing Studies and Clinical Trials of Medical Products”
(MHLW Ordinance No. 26, dated March 11, 2013), the “Enforcement of the MHLW Ordinance 
to Partially Amend the MHLW Ordinance on the Standard for Post-Marketing Safety Control of 
Medical Products, Quasi-medical Products, Cosmetics, and Medical Devices, and to Partially 
Amend the MHLW Ordinance on the Standard for Post-Marketing Studies and Clinical Trials of 
Medical Products” (PFSB Notification No. 0311-7, dated March 11, 2013), “MHLW Ordinance 
to Partially Amend the MHLW Ordinance on the Standard for Post-Marketing Studies and 
Clinical Trials of Medical Products” (MHLW Ordinance No. 116, dated October 26, 2017), and 
“Announcement of the MHLW Ordinance to Partially Amend the MHLW Ordinance on the 
Standard for Post-Marketing Studies and Clinical Trials of Medical Products (Regarding the 

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MHLW Ordinance on the Standard for Post-Marketing Studies and Clinical Trials of Medical 
Products)” (PSEHB Notification No. 1026-1, dated October 26, 2017).
7. RESEARCH QUESTION AND OBJECTIVES
To assess the data, including safety profile, of this drug administered for “sedation during and 
after mechanical ventilation in the intensive care setting” in pediatric patients under actual 
medical practice.
7.1. Safety specifications
Important Identified Risks: bradycardia, hypotension, hypertension, hyperglycaemia, withdrawal 
syndrome, and respiratory depression
Important Potential Risks: atrioventricular block, cardiac arrest, convulsions, cortisol 
suppression, hypothermia, ischaemic heart disease, and tachypnoeic potential
Important Missing Information: safety of concomitant use of other sedatives and analgesics in 
pediatric patients, safety of use for over 24 hours in pediatric patients, and safety by type of 
surgical procedure and type of clinical department in pediatric patients
7.2. Concerns for efficacy
Effectiveness by type of surgical procedure and type of clinical department in pediatric patients
8. RESEARCH METHODS
8.1. Study design
This is a multicenter cohort study to be conducted in patients treated with this drug. The case report form 
(CRF) will be filled out based on medical records in which data obtained in actual medical practice are 
described.
8.2. Setting
Patients who meet the registration criteria will be included in this study.
8.2.1. Registration criteria
Pediatric patients (45 weeks corrected gestational age to <18 years old) administered this drug 
for “sedation during and after mechanical ventilation in the intensive care setting”
Refer to the latest package insert of this drug for “INDICATIONS,” “DOSAGE AND 
ADMINISTRATION,” and “PRECAUTIONS” when this drug is administered.

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8.2.2. Study sites
The study is scheduled to be conducted at approximately 20 sites including intensive care 
departments and anesthesiology departments, etc. for both Maruishi Pharmaceutical Co., Ltd. 
and Pfizer Japan Inc.
8.2.3. Planned study period
The planned period covered by this study is as follows.
Investigation period: April 2019 to May 2022 (from the start of registration to the completion of 
the observation period of the last patient)
Registration period: April 2019 to April 2022
The registration is terminated if the target number of the patients has been collected, even before 
the end of the registration period.
8.2.4. Study procedures
8.2.4.1. Study method
Continuous registration system: This study will be conducted with continuous registration 
system that patients who meet the conditions of this study will be registered sequentially until 
data are collected on a target number of patients.
8.2.5. Observation period
From the start of administration of this drug to the discharge from the intensive care unit (ICU). 
However, if the patient leaves the ICU before 24 hours after the end of administration of this 
drug, AEs observed up to 24 hours after the end of administration should be entered in the CRF 
as much as possible, and the AEs should be monitored until the outcomes become known as far 
as possible.
8.3. Variables
This study will be conducted according to the following schedule of observation.

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Table 1.
Variables and schedule of observation
Variable
Registration 
form
CRF
At the start of 
administration 
of this drug
CRF
From the start of 
administration of 
this drug to ICU 
discharge
CRF
Until 24 hours 
after the end of 
administration 
of this drug
ID number
●
*
Sex
●
*
Birth year and month
●
*
Corrected gestational age a
●
*
Date of start of administration of this drug
●
Neonatal status b
●
Height
●
Body weight
●
Pregnancy status c
●
Primary disease
●
Medical history
●
Complication
●
Surgery status
●
Surgery name d
●
Presence or absence of heart-lung machine d
●
ASA classification d
●
Date/time of entering the operating room d
●
Date/time of leaving the operating room d
●
Start date/time of surgery d
●
End date/time of surgery d
●
Date/time of ICU admission
●
Date/time of ICU discharge
●
Start date/time of mechanical ventilation
●
Method of mechanical ventilation
●
End date/time of mechanical ventilation
●
Targeted drug use record
●
Concomitant therapy (Drug therapy)
●
Effectiveness e
●
Adverse events f
●
●
* Some elements in the Registration Form are automatically reflected in the CRF. The investigators should check and update the CRF as needed.
a. Enter the information only if the age at the start of administration of this drug is less than 1 year old.
b. Enter the information only if the age at the start of administration of this drug is 0 months of age.
c. Enter the information only if the sex is “Female.”
d. Enter the information only if the surgery status is “Yes.”
e. At the end of administration of this drug, overall effectiveness evaluation of this drug will be performed, and the results will be entered.
f. If the patient leaves ICU before 24 hours after the end of administration of this drug, AEs observed up to 24 hours after the end of 
administration should be entered in the CRF as much as possible, and the AEs should be monitored until the outcomes become known as far as 
possible.
ASA: American Society of Anesthesiologists, ICU: intensive care unit
8.3.1. Patient characteristics
1. The information at the start of administration of this drug will be recorded in registration 
form.
a.
ID number

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b. Sex
c.
Birth year and month
d. Corrected gestational age (only if <1 year old)
e.
Date of start of administration of this drug
2. The following information will be recorded in CRF.
<Basic Patient Information (at the start of administration of this drug)>
a.
ID number
b. Sex
c.
Birth year and month
d. Corrected gestational age (only if <1 year old)
e.
Neonatal status (only if 0 months of age)
f.
Height
g. Body weight
h. Pregnancy status (only if the sex is “Female”)
i.
Primary disease
j.
Medical history
k. Complication
<Surgery Information>
l.
Surgery status
(Enter information from “m. Surgery name” to “s. End date/time of surgery” only if the 
surgery status is “Yes”)
m. Surgery name
n. Presence or absence of heart-lung machine
o. American Society of Anesthesiologists (ASA) classification
p. Date/time of entering the operating room

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q. Date/time of leaving the operating room
r.
Start date/time of surgery
s.
End date/time of surgery
< ICU Information>
t.
Date/time of ICU admission
u. Date/time of ICU discharge
v. Start date/time of mechanical ventilation
w. Method of mechanical ventilation
x. End date/time of mechanical ventilation
8.3.2. Administration record of targeted drug
Regarding the use status of this drug during the observation period, the following information 
will be recorded:
1. Name of the clinical department of the physician administering this drug
2. Dosage form
3. Dilute concentration
4. Start date/time of administration; Infusion rate
5. Date/time of infusion rate change; Infusion rate; Reason
6. End date/time of administration; Reason
8.3.3. Concomitant therapy
8.3.3.1. Drug therapy
Regarding drugs used for sedation, analgesia, and anesthesia for surgery during the period of 
administration of this drug, the following information will be recorded:
1. Drug name (product name)
2. Dose or infusion rate
3. Start date/time of administration
4. End date/time of administration

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8.3.4. Investigation completion (discontinuation) record (including the reason for 
discontinuation)
The end date/time of the observation period or the date/time of discontinuation will be entered, 
and only one of the following will be selected and entered as completion or the primary reason 
for discontinuation. If AE or death is selected, the information will also be entered in the AE 
section.
1.
Completion
2.
AE
3.
Death
4.
Lost to follow-up
5.
Others
8.3.5. Effectiveness evaluation
At the end of administration of this drug, overall effectiveness evaluation of this drug will be 
performed, and the results will be recorded.
1. Effectiveness evaluation

Effective

Not effective

Indeterminate (In this case, the reason should be recorded.)
8.3.6. Adverse events
Occurrence of AEs from the start date of administration of this drug to the end date of 
observation period should be confirmed and the following information should be recorded. Also, 
further investigation should be separately conducted, if deemed necessary by Sponsor for 
patients who experienced a serious adverse reaction, an unexpected adverse reaction or other 
adverse reactions not listed in the package insert.

Presence/absence of AE

Name of AE

Date of occurrence

Intervention

Seriousness

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
Outcome up to the present

Causal relationship to this drug
8.4. Data sources
In this study, the investigators transcribe the necessary information from the medical record 
under daily medical practice in accordance with the protocol.
8.5. Study size
8.5.1. Planned sample size
Target sample size: 100 patients as the safety analysis set (SAS) (Maruishi Pharmaceutical Co., 
Ltd. and Pfizer Japan Inc. will collect 50 patients each.)
8.5.2. Rationale for sample size
When 100 patients are collected, AEs with a true incidence of 3% or higher would be observed 
in 1 or more subjects with a probability of 95% or higher. Based on the incidence proportions of 
bradycardia, hypotension, and respiratory depression observed in the Japanese study C0801017 
for which a causal relationship with this drug could not be ruled out (12.7%, 7.9% and 3.2%, 
respectively), these events were considered to be observable. Events related to the safety 
specification but with unknown incidence in Japanese pediatric patients would be collected as 
much as possible in this study. For rare events, routine pharmacovigilance activities such as 
spontaneous reports would also be utilized for evaluation.
8.6. Data management
8.6.1. CRFs/Electronic data record
A CRF in this protocol refers to the record of electronic data corresponding to the method of data 
collection during this study.
A CRF is required and should be completed for each included patient. The completed original 
CRFs are the sole property of Pfizer and should not be made available in any form to third 
parties, except for authorized representatives of Pfizer or appropriate regulatory authorities, 
without written permission from Pfizer.
The investigator shall ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and will be password protected or secured in a locked room to prevent access by 
unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety, 
and laboratory data entered on the CRFs and any other data collection forms (source documents) 
and ensuring that they are accurate, authentic/original, attributable, complete, consistent, legible, 
timely (contemporaneous), enduring, and available when required. The CRFs must be signed by 
the investigator or by an authorized staff member to attest that the data contained on the CRFs 

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are true. Any corrections to entries made in the CRFs or source documents must be dated, 
initialed, and explained (if necessary) and should not obscure the original entry.
The source documents are the hospital or the physician's chart. In these cases, data collected on 
the CRFs must match those charts.
8.6.2. Record retention
The records related to this study should be retained at the study site until the End of Study Letter 
by Pfizer is received or during the period defined by the study site, whichever is longer.
8.6.3. Data collection method
The data for this study will be entered and confirmed by using the electronic system on the 
internet designed for collecting post-marketing survey data (Electronic Data Capture, EDC, 
hereinafter referred to as “this system”).
8.6.4. Patient registration
The investigator will enter information on the patient registration screen of this system (the 
registration form) and save the data. Patient registration will be performed immediately after the 
first administration with this drug.
If information in the registration form require confirmation, the investigator may be requested to 
perform follow-up survey and respond to the query. Registration will be fixed after the query is 
resolved.
8.6.5. Points to consider for completion, revision, and submission of CRF
8.6.5.1. Data entry
The investigator should confirm the survey items and enter the data into this system based on 
information in the medical charts.
8.6.5.2. Data revision
Upon receiving query from Sponsor on the contents of the CRF (follow-up survey), the 
investigator will again confirm the information in the medical charts, and as required, correct 
relevant sections and save the data.
8.6.5.3. Submission
After data entry and revision are completed, CRFs should be signed electrically by the 
investigator following confirmation of entry and follow-up survey.
8.7. Data analysis
1. Definition of analysis set

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The SAS consists of a full analysis set (FAS) that is as closer as possible to all patients who 
received this drug. The effectiveness analysis set consists of patients included in the SAS 
considered evaluable for effectiveness according to the separately prescribed Statistical 
Analysis Plan (SAP) of this study.
2. Analysis method

Analysis for safety evaluation
Events for which a causal relationship with this drug could not be ruled out are considered as 
adverse drug reactions (ADRs). The number of patients with ADRs and the proportion 
([%]: number of patients with ADRs/number of patients included in the SAS) will be 
calculated.

Analysis for effectiveness evaluation
The effectiveness proportion ([%]: number of responders/[number of responders + number of 
non-responders]) will be calculated.
Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP may 
modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment.
8.8. Quality control
Prior to conducting the study, the site staff will explain to the investigator about the contents of 
the protocol, etc. and ask the investigator for completion of a CRF based on medical charts.
8.9. Limitations of the research methods
There may be potential limitations in this study:
1. Since no control group is included in this study, there is a limitation in determining whether 
or not a risk of developing AEs and adverse reactions increases with administration of the 
study drug.
2. Due consideration may not be given to confounding factors due to insufficient background 
information collected.
3. Since this study collects the information described in medical charts, specified data may not 
be collected or may be missing.
8.10. Other aspects
Not applicable

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9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient information
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of patient personal data. Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws. The personal data 
will be stored at the study site in encrypted electronic and/or paper form and will be password 
protected or secured in a locked room to ensure that only authorized study staff have access. The 
study site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster. In the event of a potential personal data 
breach, the study site shall be responsible for determining whether a personal data breach has in 
fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of personal 
data, when study data are compiled for transfer to Pfizer and other authorized parties, patient 
names will be removed and will be replaced by a single, specific, numerical code, based on a 
numbering system defined by Pfizer. All other identifiable data transferred to Pfizer or other 
authorized parties will be identified by this single, patient-specific code. The investigator site 
will maintain a confidential list of patients who participated in the study, linking each patient's 
numerical code to his or her actual identity. In case of data transfer, Pfizer will maintain high 
standards of confidentiality and protection of patients' personal data consistent with the clinical 
study agreement and applicable privacy laws.
9.2. Patient consent
As this study does not involve data subject to privacy laws according to applicable legal 
requirements, or it is an information provision based on the law (even though that involve data 
subject to privacy laws according to applicable legal requirements), obtaining informed consent 
from patients by Pfizer is not required with regard to the personal information provision from the 
study site to Pfizer. Also, because the report of information or results collected in this study to 
the local regulatory authority or healthcare providers by Pfizer as needed is an information 
provision based on the law, obtaining informed consent from patients by Pfizer is not required.
In this study, Pfizer will collect information that cannot identify specific patients from the study 
sites. The results of this study, which are prepared not to identify specific patients, may be 
reported to Pfizer Inc., which is the corporate parent of the sponsor of this study, or Group 
companies, or regulatory authorities in other countries, as needed, or published it as a 
presentation at academic conferences or manuscript for the purpose of providing proper use 
information for this drug. If these information falls under personal information of the Personal 
Information Protection Act, these actions may not be based on the laws or regulations, and 
therefore, may correspond to provision to the third party and using the information for purposes 
other than business that require consent from the patient. Therefore, the study sites will obtain 
written or verbal consent from the patients to be included in this study so that Pfizer can use the 
results of this study to report to Pfizer Inc., group companies or regulatory authorities in other 

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countries, or to present it at academic conferences or publish manuscript, etc. Whether consent is 
obtained from patients or not is described in the CRF. The original of the written informed 
consent form should be retained by the study investigator.
In general, the investigator must obtain consent from a patient personally. However, if the 
investigator determines that a patient's decisional capacity is so limited that he or she cannot 
reasonably be consulted or he or she is a minor, consent is obtained from legally acceptable 
representative or parent(s). In this case, every effort should be made to obtain the patient's assent 
as far as possible after obtaining consent from legally acceptable representative or parent(s) if the 
patient is a minor. If the study patient does not provide his or her own consent, the source 
documents must record the relationship of the person signing the consent and the patient (e.g., 
parent(s), spouse). If a minor registered in the study reaches adulthood during the study, the 
consent will be reacquired as far as possible from the patient at the time of adulthood according 
to Japanese law.
At the time of obtaining informed consent, the investigator must use informed consent form and 
other materials and ensure that each study patient, or his or her legally acceptable representative, 
or parent(s) if a minor, is fully informed about the information provided to Pfizer and the 
objectives of use and possible risks associated with consent.
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
In this study, review by the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) is not required.
9.4. Ethical conduct of the study
This study will be conducted in compliance with the “MHLW Ordinance on the Standard for 
Post-Marketing Studies and Clinical Trials of Medical Products” (MHLW Ordinance No. 171, 
dated December 20, 2004). Also, the study will be conducted in accordance with legal and 
regulatory requirements, as well as with scientific purpose, value and rigor.

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10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS
10.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events to Pfizer Safety Unit using the Non-Interventional Study Adverse Event 
Report Form (NIS AE Report Form). These requirements are specified for three types of events: 
(1) serious adverse events (SAEs); (2) non-serious AEs (as applicable); and (3) scenarios 
involving drug exposure, including exposure during pregnancy, exposure during breast feeding, 
medication error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure. 
These events are defined in the section “Definitions of safety events.”
Safety event
Recorded on the case report form 
Reported on the NIS AE 
Report Form to Pfizer 
Safety Unit within 24 hours 
of awareness
SAE
All
All
Non-serious AE
All
None
Scenarios involving exposure to a 
drug under study, including exposure 
during pregnancy, exposure during 
breast feeding, medication error, 
overdose, misuse, extravasation, lack 
of efficacy, and occupational 
exposure
All (regardless of whether 
associated with an AE), except 
occupational exposure
All (regardless of whether 
associated with an AE)
Note: Any associated AE is 
reported together with the 
exposure scenario.
For each AE, the investigator must pursue and obtain information adequate both to determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a SAE (refer to 
the section “Serious adverse events” below).
Safety events listed in the table above must be reported to Pfizer Safety Unit within 24 hours of 
awareness of the event by the investigator regardless of whether the event is determined by 
the investigator to be related to this drug. In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available event 
information. This timeframe also applies to additional new (follow-up) information on 
previously forwarded safety event reports. In the rare situation that the investigator does not 
become immediately aware of the occurrence of a safety event, the investigator must report the 
event within 24 hours after learning of it and document the date and time of his/her first 
awareness of the events.

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For safety events that are considered serious or that are identified in the far right column of the 
table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with this 
24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain specific 
follow-up information in an expedited fashion. This information is more detailed than that 
recorded on the CRF. In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of possible 
causality. Any information relevant to the event, such as concomitant medications and 
complications, must be provided. In the case of a patient death, a summary of available autopsy 
findings must be submitted as soon as possible to Pfizer or its designated representative.
10.2. Reporting period
For each patient, the safety event reporting period begins at the time of the patient’s first dose of 
this drug, and lasts through the end of the observation period of the study, which must include at 
least 28 calendar days following the last administration of a drug under study; a report must be 
submitted to Pfizer Safety Unit (or its designated representative) for any of the types of safety 
events listed in the table above occurring during this period. If a patient was administered a drug 
under study on the last day of the observation period, then the reporting period should be 
extended for 28 calendar days following the end of observation.
If the investigator becomes aware of a SAE occurring at any time after completion of the study 
and he or she considers the SAE to be related to this drug, the SAE also must be reported to 
Pfizer Safety Unit.
10.3. Causality assessment
The investigator is required to assess and record the causal relationship. For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of each AE. For 
AEs with a causal relationship to this drug, follow-up by the investigator is required until the 
event and/or its sequelae resolve or stabilize at a level acceptable to the investigator, and Pfizer 
concurs with that assessment.
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that this drug caused or contributed to an AE. If the investigator’s final determination 
of causality is “unknown” and he or she cannot determine whether this drug caused the event, the 
safety event must be reported within 24 hours.
If the investigator cannot determine the etiology of the event but he or she determines that this 
drug did not cause the event, this should be clearly documented on the CRF and the NIS AE 
Report Form.

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10.4. Definitions of safety events
10.4.1. Adverse events
An AE is any untoward medical occurrence in a patient administered a medicinal product. The 
event need not necessarily have a causal relationship with the product treatment or usage. The 
same definition is applied for medical devices and nutritional products (including infant and 
toddler formulas [hereinafter “pediatric formulas”]). Examples of AEs include but are not limited 
to:

Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an AE);

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Lack of efficacy;

Drug abuse;

Drug dependence.
Additionally, for medicinal products, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse;

Off-label use;

Drug interactions;

Extravasation;

Exposure during pregnancy;

Exposure during breast feeding;

Medication error;

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
Occupational exposure.
Abnormal test findings
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE are as follows:

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, and/or

Test result leads to a change in study drug dosing or discontinuation from the study, 
additional concomitant drug treatment, or other therapy, and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test result, in the absence of any of the above conditions, does not 
constitute an AE. Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
10.4.2. Serious adverse events
An SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional 
product (including pediatric formulas) at any dose or using a medical device that:

Results in death;

Is life-threatening;

Requires hospitalization or prolongation of hospitalization (see below for circumstances that 
do not constitute AEs);

Results in persistent or significant disability/dysfunction (substantial disruption of the ability 
to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependence or drug abuse.

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Additionally, any suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, is considered serious. Such event may be suspected from clinical symptoms 
or laboratory findings indicating an infection in a patient exposed to a Pfizer product. The terms 
“suspected infectious transmission” and “infection transmission” are considered synonymous. 
These cases are considered unexpected and handled as serious expedited cases by the Safety 
Unit. Such cases are also considered for reporting as product defects, if appropriate.
Hospitalization
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to an internal medicine floor, internal medicine floor to an intensive care unit for coronary 
disease, or neurological floor to a tuberculosis unit). An emergency room visit does not 
necessarily constitute a hospitalization; however, an event leading to an emergency room visit 
should be assessed for medical importance.
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For 
example, the following reports of hospitalization without a medical AE are not to be reported.

Social admission (e.g., patient has no place to sleep)

Administrative admission (e.g., for yearly exam)

Optional admission not associated with a sudden change in clinical conditions (e.g., for 
elective cosmetic surgery)

Hospitalization for observation without a medical AE

Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-
treatment lab abnormality)

Protocol-specified admission during clinical study (e.g., for laboratory tests and/or
procedures required by the study protocol)
10.4.3. Scenarios necessitating reporting to Pfizer Safety Unit within 24 hours 
Scenarios involving exposure during pregnancy, exposure during breastfeeding, medication 
error, overdose, misuse, extravasation, lack of efficacy, and occupational exposure are described 
below.
Exposure during pregnancy
An exposure during pregnancy (EDP) occurs if:

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1. A female becomes, or is found to be, pregnant either while receiving or having been exposed 
to (e.g., environmental) this drug, or the female becomes, or is found to be, pregnant after 
discontinuing and/or being exposed to this drug (maternal exposure).
An example of environmental exposure would be a case involving direct contact with a Pfizer 
product in a pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed to 
chemotherapeutic products).
2. A male has been exposed, either due to treatment or environmental exposure to this drug
prior to or around the time of conception and/or is exposed during the partner pregnancy 
(paternal exposure).
As a general rule, prospective and retrospective exposure during pregnancy reports from any 
source are reportable irrespective of the presence/absense of an associated AE and the 
procedures for SAE reporting should be followed.
If a study participant or study participant’s partner becomes, or is found to be, pregnant during 
the study participant’s treatment with this drug, this information must be submitted to Pfizer, 
irrespective of whether an AE has occurred using the NIS AE Report Form and the EDP 
Supplemental Form.
In addition, the information regarding environmental exposure to this drug in a pregnant woman 
(e.g., a patient reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) must be submitted using the NIS AE Report Form and the EDP 
Supplemental Form. This must be done irrespective of whether an AE has occurred.
Information submitted should include the expected delivery date (see below for information 
related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up is 
conducted to obtain information on EDP outcome for all EDP reports with pregnancy outcome 
unknown. A pregnancy is followed until completion or until pregnancy termination (e.g., 
induced abortion) and Pfizer is notified of the outcome. This information is provided as a follow 
up to the initial EDP report. In the case of a live birth, the structural integrity of the neonate 
should be assessed at the time of birth. In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the aborted fetus should 
be assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a 
congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (e.g., extrauterine pregnancy, 
spontaneous abortion, intrauterine fetal death, neonatal death, or congenital anomaly [in a live 
born, an aborted fetus, an intrauterine fetal death, or a neonatal death]), the procedures for 
reporting SAEs should be followed.
Additional information about pregnancy outcomes that are reported as SAEs follows:

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
Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when 
the investigator assesses the infant death as related or possibly related to exposure to this 
drug.
Additional information regarding the exposure during pregnancy may be requested. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm 
infants to identify developmental delays).
In the case of paternal exposure, the study participant will be provided with the Pregnant Partner 
Release of Information Form to deliver to his partner. It must be documented that the study 
participant was given this letter to provide to his partner.
Exposure during breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the 
presence/absence of an associated AE. An exposure during breastfeeding report is not created 
when a Pfizer drug specifically approved for use in breastfeeding women (e.g., vitamins) is 
administered in accordance with authorized use. However, if the infant experiences an AE 
associated with such a drug’s administration, the AE is reported together with the exposure 
during breastfeeding.
Medication error
A medication error is any unintentional error, which could have been prevented from occurring, 
and may cause or lead to inappropriate medication use or patient harm while in the control of the 
health care professional, patient, or consumer. Such events may be related to professional 
practice, health care products, procedures, and systems including: prescribing; order 
communication; product labeling, packaging, and nomenclature; compounding; dispensing; 
distribution; administration; education; monitoring; and use.
Medication errors include:

Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription on 
the part of the healthcare provider or the patient/consumer);

Confusion with regard to drug name (e.g., trade name, brand name).
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence/absence of an associated AE/SAE:

Medication errors involving patient exposure to the product, whether or not the medication 
error is accompanied by an AE.

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
Medication errors that do not involve a patient directly (e.g., potential medication errors or 
near misses). When a medication error does not involve patient exposure to the product the 
following minimum criteria constitute a medication error report:

An identifiable reporter;

A suspect product;

The event medication error.
Overdose, misuse, and extravasation
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reportable to Pfizer by the investigator, irrespective of the presence/absence of an associated 
AE/SAE.
Lack of efficacy
Reports of lack of efficacy to a Pfizer product are reportable to Pfizer by the investigator, 
irrespective of the presence/absence of an associated AE/SAE or the indication for use of the 
Pfizer product.
Occupational exposure
Reports of occupational exposure to a Pfizer product are reportable to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE.

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10.5. MEDICAL DEVICE COMPLAINT REPORTING REQUIREMENTS
All complaints about medical devices, regardless of whether the medical device complaint is 
associated with an AE, will be collected on the applicable pages within the CRF. This includes 
potential incident or malfunctions associated with the use of a medical device product. An
incident or malfunction is an event that might have led to death or serious deterioration in health, 
or if it occurred again, might have led to death or serious deterioration in health.
Pfizer is to be notified of all medical device complaints within 24 hours of awareness of the 
event by the investigator.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Information collected in this study will be used for reporting purposes to report Ministry of 
Health, Labour and Welfare (MHLW), Pharmaceuticals and Medical Devices Agency (PMDA), 
Pfizer Inc., which is the corporate parent of the sponsor of this study, and the group companies, 
or regulatory agency in other countries. Also, it will be used for submitting application of 
re-examination (including Periodic Safety Update Report), re-evaluation, preparation of material 
for proper use information of this drug, publications and activities for information provision. In 
addition, Pfizer may disclose the study results to provide information for proper use, as needed, 
on www.clinicaltrials.gov (ClinicalTrials.gov), as presentations at academic conferences, or as 
manuscripts, etc.
Data obtained from the patients registered in this study will be reported to the MHLW pursuant 
to the Pharmaceutical and Medical Device Act. In this case, the data may be publicly posted in 
MHLW's “Pharmaceutical and Medical Device Safety Information” and “Pharmaceuticals and 
Medical Devices Information Website (https://www.pmda.go.jp) ” as a listing of patients, which 
will include the names of drugs, adverse reactions, sex, age (increment of 10 years), and other 
relevant information. Furthermore, data collected may also be disclosed if the MHLW is required 
to disclose such information in accordance with the “Act on Access to Information Held by 
Administrative Organs” (Law No. 42 dated May 14, 1999); provided that in no event will the 
names of physicians, medical institutions, and other personal information be subject to such 
disclosure, nor will it be posted or disclosed.
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.
12. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION
Refer to the appendix 1 of the risk management plan “Organizational structure for safety 
management and post-marketing surveillance, etc.”

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13. NAME, AND ADDRESS OF CONTRACTOR AS WELL AS SCOPE OF WORK 
CONTRACTED
Company name:
Address: 
Scope of work contracted: Works related to planning of study, drafting of plan, operating the 
study, monitoring, etc.
Company name:
Address: 
Scope of work contracted: Establishment, operation and maintenance of the EDC system, 
and research service other than management of the Post-Marketing Study, etc.
Company name:
Address:
Scope of work contracted: Registration, establishment of the EDC system, data management, 
statistical analysis, and research service other than management of the Post-Marketing Study, 
etc.
14. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE 
STUDY RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION
Review the risk management plan including the following contents at the scheduled timing of 
milestones.
1. Review the necessity for changing the contents of risk minimization activities for the current 
safety specifications.
2. Review the necessity for changing the contents of this study plan including the presence or 
absence of new safety specifications (continuation of the study, implementation of additional 
study, etc.).
3. Review the necessity for formulating risk minimization measures for new safety 
specifications.
15. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR 
EVALUATION OF STUDY IMPLEMENTATION STATUS AND RESULTS AND 
REPORTING TO THE PMDA
At the time of making periodic safety reports and at the end of the survey. To comprehensively 
examine safety information. The interim analysis results will be reported at the time of making 
the first periodic safety report after the CRFs for 50 subjects have been fixed.
16. OTHER NECESSARY MATTERS
Not applicable
PPD
PPD
PPD
PPD
PPD
PPD

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17. CONTACT INFORMATION
17.1. Contact information for inquiries about the study
Name
Address
FAX
E-mail address
17.2. Contact information for inquiries about the EDC system
Name
Business Hours
TEL
E-mail address
18. REFERENCES
Not applicable
19. LIST OF TABLES
Page 12. Table 1.
Variables and schedule of observation
20. LIST OF FIGURES
Not applicable
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
Not applicable
ANNEX 2. ADDITIONAL INFORMATION
A. Special Investigation registration form
B. Special Investigation case report form
PPD
PPD
PPD
PPD
PPD
PPD

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