Special Drug Use Surveillance of Leuplin PRO for Injection Kit 22.5 mg in "Premenopausal Breast Cancer"
Conditions: Premenopausal Breast Cancer
Sponsor: Takeda

 
 
Title: Special drug use surveillance for “premenopausal breast cancer” 
 
NCT Number: NCT03209518 
Protocol Approve Date: 05-APR-2019 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Special Drug Use Surveillance of Leuplin PRO for 
Injection Kit 22.5 mg  
for “Premenopausal Breast Cancer” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Leuprorelin-5003 
Version number 
5th version 
Date of 
preparation 
5 April 2019  
 

 
Table of Contents 
1.0 Background of the Surveillance ...................................................................................................... 0 
2.0 Objectives ....................................................................................................................................... 0 
3.0 Planned Sample Size and Rationale ................................................................................................ 0 
3.1 Planned Sample Size ............................................................................................................... 0 
3.2 Rationale.................................................................................................................................. 0 
4.0 Surveillance Population .................................................................................................................. 0 
5.0 Dosage and Administration ............................................................................................................. 1 
6.0 Planned Number of Medical Institutions by Department................................................................ 1 
7.0 Methodology ................................................................................................................................... 1 
7.1 Observation Period .................................................................................................................. 1 
7.2 Request to and Contract with the Study Site ........................................................................... 1 
7.3 Method of Patient Registration ................................................................................................ 1 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature................................. 1 
8.0 Planned Surveillance Period ........................................................................................................... 2 
9.0 Surveillance Items ........................................................................................................................... 2 
9.1 Patient Registration ................................................................................................................. 2 
9.2 Patient Baseline Characteristics .............................................................................................. 2 
9.3 Treatment Given ...................................................................................................................... 3 
9.4 Assessments ............................................................................................................................ 3 
9.5 Adverse Events (AEs) ............................................................................................................. 3 
10.0 
Analysis Items and Methods ................................................................................................. 7 
10.1 Statistical Analysis Plan .......................................................................................................... 7 
10.2 Analysis Sets ........................................................................................................................... 7 
10.3 Matters on Patient Composition .............................................................................................. 7 
10.4 Patient Baseline Characteristics .............................................................................................. 7 
10.5 Treatment Given ...................................................................................................................... 7 
10.6 Matters on Safety..................................................................................................................... 7 
 Occurrence of Adverse Events ......................................................................................... 8 
 Factors that May Affect the Safety................................................................................... 8 
11.0 
Posting of Surveillance Information ...................................................................................... 8 
12.0 
Surveillance Organization ..................................................................................................... 8 
12.1 Administrative Manager .......................................................................................................... 8 
13.0 
Contract Research Organizations (CROs) ............................................................................. 8 
14.0 
Other Necessary Matters ....................................................................................................... 9 
14.1 Revision of the Protocol .......................................................................................................... 9 
14.2 Actions to be Taken for Problems and Questions .................................................................... 9 
 
Appendix Observation schedule........................................................................................................ 9 

 
0 
1.0 
Background of the Surveillance 
Since the amount of leuprorelin acetate administered in a single dose of Leuplin PRO 
for Injection Kit 22.5 mg (hereinafter referred to as Leuplin PRO) is as high as twice 
that of Leuplin SR for Injection Kit 11.25 mg (hereinafter referred to as Leuplin SR), 
and the time profile of serum leuprorelin concentration after administration differs 
between the two formulations, a special drug use surveillance (hereinafter referred to 
as the surveillance) is planned to evaluate potential effects of the differences on the 
safety.  
This surveillance will be conducted in compliance with the ministerial ordinance on 
Good Post-Marketing Study Practice (GPSP) and related regulatory requirements. 
 
2.0 
Objectives 
To investigate the safety of Leuplin PRO in patients with premenopausal breast 
cancer in routine clinical settings in order to evaluate potential effects of differences 
between Leuplin PRO and Leuplin SR, including the higher amount administered in 
a single dose and differences in time profile of serum drug concentration after 
administration, on the safety 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
300 patients 
 
3.2 Rationale 
To evaluate potential effects of differences between Leuplin PRO and Leuplin SR, 
that is, difference amounts of leuprorelin acetate administered in a single dose and 
different time profiles of serum drug concentration after administration, on the safety, 
it was decided to investigate the occurrence of injection site reaction and other 
adverse drug reactions (ADRs) with an incidence of 1% or higher, including the time 
of onset, incidence, and seriousness. 
The sample size of 300 patients was determined to detect ADRs with an incidence of 
1% or higher at a probability of 95% or higher. 
 
4.0 
Surveillance Population 
Patients with premenopausal breast cancer will be included in the surveillance. 
Patients should not meet the exclusion criterion listed below. Refer to the Precautions 
section of the package insert. 
<Exclusion criteria> 
Patients who meet the following criterion will not be included: 

 
1 
 
A history of hypersensitivity to any of the ingredients of Leuplin PRO or 
synthetic luteinizing hormone-releasing hormone (LH-RH) or LH-RH 
derivatives 
 
Pregnant or potentially pregnant patients and breastfeeding patients. 
 
5.0 
Dosage and Administration 
The usual adult dosage is 22.5 mg of leuprorelin acetate administered subcutaneously 
once every 24 weeks. Refer to the Precautions section of the package insert. 
 
6.0 
Planned Number of Medical Institutions by Department 
Breast surgery and other departments Approximately 60 medical institutions 
 
7.0 
Methodology 
7.1 Observation Period 
24 weeks 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a Web-based electronic data capture 
system (
). A representative of Takeda Pharmaceutical Company 
Limited (hereinafter referred to as Takeda’s representative) will explain the 
objectives and contents of the surveillance, operation method of 
, and 
handling of electronic signature, user ID, and password to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation 
outline,” “Entry screen image,” and “Operation manual of 
 (brief 
version)” to enter into a written contract with the study site and request the study 
site to conduct a surveillance within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration method via
. After 
the start of the contract with the study site, the investigator shall register each patient 
treated with Leuplin PRO by entering patient registration information (refer to 
Section 9.1) with his/her electronic signature within 14 days after administration of 
Leuplin PRO (day of administration designated as day 0 and day following the day 
of administration designated as 1 day post-dose). 
 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature 
The investigator or designee* shall enter patient baseline characteristics and 
treatment given into 
 with the investigator’s electronic signature within 
approximately 1 month after the end of required observation at 24 weeks after the 
CCI
CCI
CCI
CCI
CCI

 
2 
start of Leuplin PRO treatment. 
For any patient with an adverse event, the investigator or designee shall enter 
observation results into 
 with the investigator’s electronic signature after 
monitoring the patient as long after discontinuation of treatment as possible until the 
adverse event is confirmed to have resolved or be resolving. 
* The investigator’s designee should belong to the relevant medical institution (including 
those under contract with the medical institution such as temporary clinical research 
coordinators). Before the investigator’s designee begins to enter data into
, a 
physician responsible for the surveillance (one physician per medical institution or department 
appointed at the time of contract) shall document the designation with the date of designation 
(no specific style), affix his/her signature or name and seal to the document, and submit it to 
Takeda’s representative. 
 
8.0 
Planned Surveillance Period 
Surveillance period: From March 2016 to 31 August 2017 
Patient registration period: From April 2016 to 28 February 2017Note) 
 
Note) Patient registration (entry into
) will not be accepted on 1 March 
2018 onwards even if Leuplin PRO is administered by 28 February 2018. 
If the number of patients enrolled in the surveillance reaches the planned sample 
size before 28 February 2018, acceptance of registration will be terminated before 
the end of the patient registration period. If the patient registration period is 
shortened, the surveillance period will be changed accordingly. 
 
9.0 
Surveillance Items 
The investigator or designee shall enter the items listed below into
. The 
surveillance schedule is presented in Appendix. 
9.1 Patient Registration 
1) Surveillance items 
Date of administration of Leuplin PRO, patient identification number, patient 
initials, date of birth, assessment based on the exclusion criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Patient Baseline Characteristics 
1) Surveillance items 
Time of diagnosis of premenopausal breast cancer, ECOG Performance 
Status*, disease status, site of lesions before the start of Leuplin PRO 
treatment, presence or absence of hormone receptor expression, diagnostic category 
CCI
CCI
CCI
CCI

 
3 
(at the start of Leuplin PRO treatment), predisposition to hypersensitivity 
(presence or absence and details), concurrent illness (presence or absence and 
details), history of thromboembolism (presence or absence and details), height, 
body weight, treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment (presence or absence 
and name of the drug) 
2) Time points of surveillance 
At the start of Leuplin PRO treatment 
 
* ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
(Common Toxicity Criteria, Version 2.0 Published on April 30, 1999. Webpage of the JCOG at http://www.j
cog.jp/) 
 
9.3 Treatment Given 
1) Surveillance items 
Treatment status of Leuplin PRO (injection site* and full-treatment status of 
Leuplin PRO*), treatment status of premenopausal breast cancer drug other 
than Leuplin PRO (presence or absence and name of the drug), presence or 
absence of and reason for discontinuation of observation 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
* At the start of Leuplin PRO treatment 
 
9.4 Assessments 
1) Assessments 
Pregnancy during the observation period (females only) 
2) Outcome measure data collection timing 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 
9.5 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of injection site reaction, details of injection site reaction 
(specific symptom, date of onset, seriousness and reason for seriousness [refer 
to Table 2], cause of discontinuation of Leuplin PRO treatment, intervention 
(presence or absence and contents), date of outcome assessment, outcome, 
causal relationship to Leuplin PRO [refer to Table 3]). 
Presence or absence of AE other than injection site reaction (refer to Table 1), 
AE term, date of onset, seriousness and reason for seriousness (refer to Table 

 
4 
2), cause of discontinuation of Leuplin PRO treatment, intervention (presence 
or absence and name of the drug/intervention), date of outcome assessment, 
outcome, causal relationship to Leuplin PRO* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal 
relationship should be followed up wherever possible. 
* For the causal relationship to Leuplin PRO, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected 
natural course of the disease, will be handled as an AE.  
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 

 
5 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
· 
Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with 
a drug 
· Untoward symptoms and so forth that occur in children treated with a drug 
· Symptoms and so forth that occur as a result of occupational exposure to a drug 
· Symptoms and so forth that occur after administration of counterfeit medicines of our ethical 
drugs 
· Untoward symptoms that have become known to occur in drug users through lawsuits or 
other legal actions 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
· Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
· Anaphylactic shock 
· Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
· Acute renal failure 
· Malignant hypertension 
· Pulmonary hypertension 
· Convulsive seizures (including convulsions and epilepsy) 
· Pulmonary fibrosis (including interstitial pneumonia) 
· Agranulocytosis 
· Malignant syndrome / malignant hyperthermia 

 
6 
· Aplastic anemia 
· Spontaneous abortion / stillbirth and fetal death 
· Toxic epidermal necrolysis / mucocutaneous ocular syndrome (Stevens-Johnson syndrome) 
· Confirmed or suspected transmission of infectious agent by a medicinal product 
· Hepatic necrosis 
· Confirmed or suspected endotoxin shock 
· Acute liver failure 
 

 
7 
Table 3 Criteria for assessing the relationship of each adverse event to Leuplin PRO 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of 
the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying 
diseases, concurrent illnesses, concomitant drugs, and 
concomitant treatments, may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained 
by other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal 
sequence from administration of a drug (including the course after 
withdrawal of the drug), underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before finalization of data. The statistical 
analysis plan will include definitions of endpoints and detailed analysis methods. 
 
10.2 Analysis Sets 
The analysis set is patients included in safety evaluation. 
 
10.3 Matters on Patient Composition 
The number of enrolled patients, number of patients with the (electronic) CRF 
collected, number of patients included in safety evaluation, number of patients 
excluded from safety evaluation, and reason for exclusion will be tabulated. 
 
10.4 Patient Baseline Characteristics 
Patient baseline characteristics, including age, predisposition to hypersensitivity, and 
concurrent illness, will be tabulated. 
 
10.5 Treatment Given 
The treatment status of Leuplin PRO and treatment status of premenopausal breast 
cancer drug other than Leuplin PRO will be tabulated. 
 
10.6 Matters on Safety 
For patients included in safety evaluation, data will be tabulated as described below. 
AEs will be coded according to the MedDRA/J and summarized using preferred term 
(PT) and system organ class (SOC). 

 
8 
 Occurrence of Adverse Events 
For AEs reported during the observation period, the incidence will be tabulated 
by type, time of onset, seriousness, and causal relationship to Leuplin PRO. In 
addition, events listed as the safety specifications for the surveillance in “2. 
Summary of Pharmacovigilance Plan” in the risk management plan will be 
tabulated separately. 
 
 
Factors that May Affect the Safety 
For ADRs reported during the observation period, the incidence will be tabulated 
by patient background factors (e.g., disease status, presence or absence of 
concurrent renal impairment, presence or absence of concurrent hepatic 
impairment) and treatment status of Leuplin PRO. 
 
11.0 
Posting of Surveillance Information 
Surveillance information will be posted on the following open website before 
starting the surveillance:  
· 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Surveillance Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations (CROs) 
PPD
PPD

 
9 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of 
progression of the surveillance, presence or absence of ADRs that are unexpected 
based on the precautions/serious ADRs, presence or absence of increased incidence 
of certain ADRs, and appropriateness of surveillance items, and this protocol will be 
reviewed and revised if necessary. If partial change to dosage and administration or 
indications is approved during the surveillance, the necessity of revising the protocol 
will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety problem is detected, data will be carefully examined to discuss measures. 
 
PPD

 
10 
Appendix Observation schedule 
 
                 Time point of surveillance 
 
 
 
 
 
 
 
   Surveillance item 
Observation period 
At patient 
registration 
At the start of 
treatment 
After 24 weeks 
or at 
discontinuation 
of observation 
Patient 
registration 
Date of administration of Leuplin PRO 
○ 
 
 
Patient identification number 
○ 
 
 
Patient initials 
○ 
 
 
Date of birth 
○ 
 
 
Assessment based on the exclusion criteria 
○ 
 
 
Patient 
baseline 
characterist
ics 
Time of diagnosis of premenopausal breast cancer 
 
○ 
 
ECOG Performance Status 
 
○ 
 
Disease status 
 
○ 
 
Diagnostic category 
 
○ 
 
Site of lesions before the start of Leuplin PRO 
treatment 
 
○ 
 
Presence or absence of hormone receptor expression 
 
○ 
 
Predisposition to hypersensitivity 
 
○ 
 
Concurrent illness 
 
○ 
 
History of thromboembolism 
 
○ 
 
Height, body weight 
 
○ 
 
Treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment 
 
○ 
 
Treatment 
given 
Treatment status of Leuplin PRO 
 
○ 
Treatment status of premenopausal breast cancer drug 
other than Leuplin PRO 
 
○ 
Assess 
-ments 
Pregnancy during the observation period (females 
only) 
 
○ 
Adverse 
event 
Injection site reaction 
 
○ 
Adverse event other than injection site reaction 
 
○ 
○  : Performed 
○  : Performed throughout the period 
 
 
 
 
 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Special Drug Use Surveillance of Leuplin PRO for 
Injection Kit 22.5 mg  
for “Premenopausal Breast Cancer” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Leuprorelin-5003 
Version number 
4th version 
Date of 
preparation 
2 June 2017 
 

 
Table of Contents 
1.0 Background of the Surveillance ...................................................................................................... 0 
2.0 Objectives ....................................................................................................................................... 0 
3.0 Planned Sample Size and Rationale ................................................................................................ 0 
3.1 Planned Sample Size ............................................................................................................... 0 
3.2 Rationale.................................................................................................................................. 0 
4.0 Surveillance Population .................................................................................................................. 0 
5.0 Dosage and Administration ............................................................................................................. 1 
6.0 Planned Number of Medical Institutions by Department................................................................ 1 
7.0 Methodology ................................................................................................................................... 1 
7.1 Observation Period .................................................................................................................. 1 
7.2 Request to and Contract with the Study Site ........................................................................... 1 
7.3 Method of Patient Registration ................................................................................................ 1 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature................................. 1 
8.0 Planned Surveillance Period ........................................................................................................... 2 
9.0 Surveillance Items ........................................................................................................................... 2 
9.1 Patient Registration ................................................................................................................. 2 
9.2 Patient Baseline Characteristics .............................................................................................. 2 
9.3 Treatment Given ...................................................................................................................... 3 
9.4 Assessments ............................................................................................................................ 3 
9.5 Adverse Events (AEs) ............................................................................................................. 3 
10.0 
Analysis Items and Methods ................................................................................................. 7 
10.1 Statistical Analysis Plan .......................................................................................................... 7 
10.2 Analysis Sets ........................................................................................................................... 7 
10.3 Matters on Patient Composition .............................................................................................. 7 
10.4 Patient Baseline Characteristics .............................................................................................. 7 
10.5 Treatment Given ...................................................................................................................... 7 
10.6 Matters on Safety..................................................................................................................... 7 
 Occurrence of Adverse Events ......................................................................................... 8 
 Factors that May Affect the Safety................................................................................... 8 
11.0 
Posting of Surveillance Information ...................................................................................... 8 
12.0 
Surveillance Organization ..................................................................................................... 8 
12.1 Administrative Manager .......................................................................................................... 8 
13.0 
Contract Research Organizations (CROs) ............................................................................. 8 
14.0 
Other Necessary Matters ....................................................................................................... 9 
14.1 Revision of the Protocol .......................................................................................................... 9 
14.2 Actions to be Taken for Problems and Questions .................................................................... 9 
 
Appendix Observation schedule........................................................................................................ 9 

 
0 
1.0 
Background of the Surveillance 
Since the amount of leuprorelin acetate administered in a single dose of Leuplin PRO 
for Injection Kit 22.5 mg (hereinafter referred to as Leuplin PRO) is as high as twice 
that of Leuplin SR for Injection Kit 11.25 mg (hereinafter referred to as Leuplin SR), 
and the time profile of serum leuprorelin concentration after administration differs 
between the two formulations, a special drug use surveillance (hereinafter referred to 
as the surveillance) is planned to evaluate potential effects of the differences on the 
safety.  
This surveillance will be conducted in compliance with the ministerial ordinance on 
Good Post-Marketing Study Practice (GPSP) and related regulatory requirements. 
 
2.0 
Objectives 
To investigate the safety of Leuplin PRO in patients with premenopausal breast 
cancer in routine clinical settings in order to evaluate potential effects of differences 
between Leuplin PRO and Leuplin SR, including the higher amount administered in 
a single dose and differences in time profile of serum drug concentration after 
administration, on the safety 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
300 patients 
 
3.2 Rationale 
To evaluate potential effects of differences between Leuplin PRO and Leuplin SR, 
that is, difference amounts of leuprorelin acetate administered in a single dose and 
different time profiles of serum drug concentration after administration, on the safety, 
it was decided to investigate the occurrence of injection site reaction and other 
adverse drug reactions (ADRs) with an incidence of 1% or higher, including the time 
of onset, incidence, and seriousness. 
The sample size of 300 patients was determined to detect ADRs with an incidence of 
1% or higher at a probability of 95% or higher. 
 
4.0 
Surveillance Population 
Patients with premenopausal breast cancer will be included in the surveillance. 
Patients should not meet the exclusion criterion listed below. Refer to the Precautions 
section of the package insert. 
<Exclusion criteria> 
Patients who meet the following criterion will not be included: 

 
1 
 
A history of hypersensitivity to any of the ingredients of Leuplin PRO or 
synthetic luteinizing hormone-releasing hormone (LH-RH) or LH-RH 
derivatives 
 
Pregnant or potentially pregnant patients and breastfeeding patients. 
 
5.0 
Dosage and Administration 
The usual adult dosage is 22.5 mg of leuprorelin acetate administered subcutaneously 
once every 24 weeks. Refer to the Precautions section of the package insert. 
 
6.0 
Planned Number of Medical Institutions by Department 
Breast surgery and other departments Approximately 60 medical institutions 
 
7.0 
Methodology 
7.1 Observation Period 
24 weeks 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a Web-based electronic data capture 
system (
). A representative of Takeda Pharmaceutical Company 
Limited (hereinafter referred to as Takeda’s representative) will explain the 
objectives and contents of the surveillance, operation method of
, and 
handling of electronic signature, user ID, and password to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation 
outline,” “Entry screen image,” and “Operation manual of 
 (brief 
version)” to enter into a written contract with the study site and request the study 
site to conduct a surveillance within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration method via
. After 
the start of the contract with the study site, the investigator shall register each patient 
treated with Leuplin PRO by entering patient registration information (refer to 
Section 9.1) with his/her electronic signature within 14 days after administration of 
Leuplin PRO (day of administration designated as day 0 and day following the day 
of administration designated as 1 day post-dose). 
 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature 
The investigator or designee* shall enter patient baseline characteristics and 
treatment given into 
 with the investigator’s electronic signature within 
approximately 1 month after the end of required observation at 24 weeks after the 
CCI
CCI
CCI
CCI
CCI

 
2 
start of Leuplin PRO treatment. 
For any patient with an adverse event, the investigator or designee shall enter 
observation results into 
 with the investigator’s electronic signature after 
monitoring the patient as long after discontinuation of treatment as possible until the 
adverse event is confirmed to have resolved or be resolving. 
* The investigator’s designee should belong to the relevant medical institution (including 
those under contract with the medical institution such as temporary clinical research 
coordinators). Before the investigator’s designee begins to enter data into
, a 
physician responsible for the surveillance (one physician per medical institution or department 
appointed at the time of contract) shall document the designation with the date of designation 
(no specific style), affix his/her signature or name and seal to the document, and submit it to 
Takeda’s representative. 
 
8.0 
Planned Surveillance Period 
Surveillance period: From March 2016 to 31 August 2017 
Patient registration period: From April 2016 to 28 February 2017Note) 
 
Note) Patient registration (entry into 
) will not be accepted on 1 March 
2018 onwards even if Leuplin PRO is administered by 28 February 2018. 
If the number of patients enrolled in the surveillance reaches the planned sample 
size before 28 February 2018, acceptance of registration will be terminated before 
the end of the patient registration period. If the patient registration period is 
shortened, the surveillance period will be changed accordingly. 
 
9.0 
Surveillance Items 
The investigator or designee shall enter the items listed below into
. The 
surveillance schedule is presented in Appendix. 
9.1 Patient Registration 
1) Surveillance items 
Date of administration of Leuplin PRO, patient identification number, patient 
initials, date of birth, assessment based on the exclusion criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Patient Baseline Characteristics 
1) Surveillance items 
Time of diagnosis of premenopausal breast cancer, ECOG Performance 
Status*, disease status, site of lesions before the start of Leuplin PRO 
treatment, presence or absence of hormone receptor expression, diagnostic category 
CCI
CCI
CCI
CCI

 
3 
(at the start of Leuplin PRO treatment), predisposition to hypersensitivity 
(presence or absence and details), concurrent illness (presence or absence and 
details), history of thromboembolism (presence or absence and details), height, 
body weight, treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment (presence or absence 
and name of the drug) 
2) Time points of surveillance 
At the start of Leuplin PRO treatment 
 
* ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
(Common Toxicity Criteria, Version 2.0 Published on April 30, 1999. Webpage of the JCOG at http://www.j
cog.jp/) 
 
9.3 Treatment Given 
1) Surveillance items 
Treatment status of Leuplin PRO (injection site* and full-treatment status of 
Leuplin PRO*), treatment status of premenopausal breast cancer drug other 
than Leuplin PRO (presence or absence and name of the drug), presence or 
absence of and reason for discontinuation of observation 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
* At the start of Leuplin PRO treatment 
 
9.4 Assessments 
1) Assessments 
Pregnancy during the observation period (females only) 
2) Outcome measure data collection timing 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 
9.5 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of injection site reaction, details of injection site reaction 
(specific symptom, date of onset, seriousness and reason for seriousness [refer 
to Table 2], cause of discontinuation of Leuplin PRO treatment, intervention 
(presence or absence and contents), date of outcome assessment, outcome, 
causal relationship to Leuplin PRO [refer to Table 3]). 
Presence or absence of AE other than injection site reaction (refer to Table 1), 
AE term, date of onset, seriousness and reason for seriousness (refer to Table 

 
4 
2), cause of discontinuation of Leuplin PRO treatment, intervention (presence 
or absence and name of the drug/intervention), date of outcome assessment, 
outcome, causal relationship to Leuplin PRO* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal 
relationship should be followed up wherever possible. 
* For the causal relationship to Leuplin PRO, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected 
natural course of the disease, will be handled as an AE.  
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 

 
5 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
· 
Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with 
a drug 
· Untoward symptoms and so forth that occur in children treated with a drug 
· Symptoms and so forth that occur as a result of occupational exposure to a drug 
· Symptoms and so forth that occur after administration of counterfeit medicines of our ethical 
drugs 
· Untoward symptoms that have become known to occur in drug users through lawsuits or 
other legal actions 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
· Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
· Anaphylactic shock 
· Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
· Acute renal failure 
· Malignant hypertension 
· Pulmonary hypertension 
· Convulsive seizures (including convulsions and epilepsy) 
· Pulmonary fibrosis (including interstitial pneumonia) 
· Agranulocytosis 
· Malignant syndrome / malignant hyperthermia 

 
6 
· Aplastic anemia 
· Spontaneous abortion / stillbirth and fetal death 
· Toxic epidermal necrolysis / mucocutaneous ocular syndrome (Stevens-Johnson syndrome) 
· Confirmed or suspected transmission of infectious agent by a medicinal product 
· Hepatic necrosis 
· Confirmed or suspected endotoxin shock 
· Acute liver failure 
 

 
7 
Table 3 Criteria for assessing the relationship of each adverse event to Leuplin PRO 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of 
the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying 
diseases, concurrent illnesses, concomitant drugs, and 
concomitant treatments, may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained 
by other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal 
sequence from administration of a drug (including the course after 
withdrawal of the drug), underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before finalization of data. The statistical 
analysis plan will include definitions of endpoints and detailed analysis methods. 
 
10.2 Analysis Sets 
The analysis set is patients included in safety evaluation. 
 
10.3 Matters on Patient Composition 
The number of enrolled patients, number of patients with the (electronic) CRF 
collected, number of patients included in safety evaluation, number of patients 
excluded from safety evaluation, and reason for exclusion will be tabulated. 
 
10.4 Patient Baseline Characteristics 
Patient baseline characteristics, including age, predisposition to hypersensitivity, and 
concurrent illness, will be tabulated. 
 
10.5 Treatment Given 
The treatment status of Leuplin PRO and treatment status of premenopausal breast 
cancer drug other than Leuplin PRO will be tabulated. 
 
10.6 Matters on Safety 
For patients included in safety evaluation, data will be tabulated as described below. 
AEs will be coded according to the MedDRA/J and summarized using preferred term 
(PT) and system organ class (SOC). 

 
8 
 Occurrence of Adverse Events 
For AEs reported during the observation period, the incidence will be tabulated 
by type, time of onset, seriousness, and causal relationship to Leuplin PRO. In 
addition, events listed as the safety specifications for the surveillance in “2. 
Summary of Pharmacovigilance Plan” in the risk management plan will be 
tabulated separately. 
 
 
Factors that May Affect the Safety 
For ADRs reported during the observation period, the incidence will be tabulated 
by patient background factors (e.g., disease status, presence or absence of 
concurrent renal impairment, presence or absence of concurrent hepatic 
impairment) and treatment status of Leuplin PRO. 
 
11.0 
Posting of Surveillance Information 
Surveillance information will be posted on the following open website before 
starting the surveillance:  
· 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Surveillance Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations (CROs) 
PPD
PPD

 
9 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of 
progression of the surveillance, presence or absence of ADRs that are unexpected 
based on the precautions/serious ADRs, presence or absence of increased incidence 
of certain ADRs, and appropriateness of surveillance items, and this protocol will be 
reviewed and revised if necessary. If partial change to dosage and administration or 
indications is approved during the surveillance, the necessity of revising the protocol 
will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety problem is detected, data will be carefully examined to discuss measures. 
 
PPD

 
10 
Appendix Observation schedule 
 
                 Time point of surveillance 
 
 
 
 
 
 
 
   Surveillance item 
Observation period 
At patient 
registration 
At the start of 
treatment 
After 24 weeks 
or at 
discontinuation 
of observation 
Patient 
registration 
Date of administration of Leuplin PRO 
○ 
 
 
Patient identification number 
○ 
 
 
Patient initials 
○ 
 
 
Date of birth 
○ 
 
 
Assessment based on the exclusion criteria 
○ 
 
 
Patient 
baseline 
characterist
ics 
Time of diagnosis of premenopausal breast cancer 
 
○ 
 
ECOG Performance Status 
 
○ 
 
Disease status 
 
○ 
 
Diagnostic category 
 
○ 
 
Site of lesions before the start of Leuplin PRO 
treatment 
 
○ 
 
Presence or absence of hormone receptor expression 
 
○ 
 
Predisposition to hypersensitivity 
 
○ 
 
Concurrent illness 
 
○ 
 
History of thromboembolism 
 
○ 
 
Height, body weight 
 
○ 
 
Treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment 
 
○ 
 
Treatment 
given 
Treatment status of Leuplin PRO 
 
○ 
Treatment status of premenopausal breast cancer drug 
other than Leuplin PRO 
 
○ 
Assess 
-ments 
Pregnancy during the observation period (females 
only) 
 
○ 
Adverse 
event 
Injection site reaction 
 
○ 
Adverse event other than injection site reaction 
 
○ 
○  : Performed 
○  : Performed throughout the period 
 
 
 
 
 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Special Drug Use Surveillance of Leuplin PRO for 
Injection Kit 22.5 mg  
for “Premenopausal Breast Cancer” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Leuprorelin-5003 
Version number 
3rd version 
Date of 
preparation 
5 September 2016 
 

 
Table of Contents 
1.0 Background of the Surveillance ...................................................................................................... 0 
2.0 Objectives ....................................................................................................................................... 0 
3.0 Planned Sample Size and Rationale ................................................................................................ 0 
3.1 Planned Sample Size ............................................................................................................... 0 
3.2 Rationale.................................................................................................................................. 0 
4.0 Surveillance Population .................................................................................................................. 0 
5.0 Dosage and Administration ............................................................................................................. 1 
6.0 Planned Number of Medical Institutions by Department................................................................ 1 
7.0 Methodology ................................................................................................................................... 1 
7.1 Observation Period .................................................................................................................. 1 
7.2 Request to and Contract with the Study Site ........................................................................... 1 
7.3 Method of Patient Registration ................................................................................................ 1 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature................................. 2 
8.0 Planned Surveillance Period ........................................................................................................... 2 
9.0 Surveillance Items ........................................................................................................................... 2 
9.1 Patient Registration ................................................................................................................. 2 
9.2 Patient Baseline Characteristics .............................................................................................. 3 
9.3 Treatment Given ...................................................................................................................... 3 
9.4 Assessments ............................................................................................................................ 3 
9.5 Adverse Events (AEs) ............................................................................................................. 4 
10.0 
Analysis Items and Methods ................................................................................................. 7 
10.1 Statistical Analysis Plan .......................................................................................................... 7 
10.2 Analysis Sets ........................................................................................................................... 7 
10.3 Matters on Patient Composition .............................................................................................. 7 
10.4 Patient Baseline Characteristics .............................................................................................. 7 
10.5 Treatment Given ...................................................................................................................... 7 
10.6 Matters on Safety..................................................................................................................... 7 
 Occurrence of Adverse Events ......................................................................................... 8 
 Factors that May Affect the Safety................................................................................... 8 
11.0 
Posting of Surveillance Information ...................................................................................... 8 
12.0 
Surveillance Organization ..................................................................................................... 8 
12.1 Administrative Manager .......................................................................................................... 8 
13.0 
Contract Research Organizations (CROs) ............................................................................. 8 
14.0 
Other Necessary Matters ....................................................................................................... 9 
14.1 Revision of the Protocol .......................................................................................................... 9 
14.2 Actions to be Taken for Problems and Questions .................................................................... 9 
 
Appendix Observation schedule........................................................................................................ 9 

 
0 
1.0 
Background of the Surveillance 
Since the amount of leuprorelin acetate administered in a single dose of Leuplin PRO 
for Injection Kit 22.5 mg (hereinafter referred to as Leuplin PRO) is as high as twice 
that of Leuplin SR for Injection Kit 11.25 mg (hereinafter referred to as Leuplin SR), 
and the time profile of serum leuprorelin concentration after administration differs 
between the two formulations, a special drug use surveillance (hereinafter referred to 
as the surveillance) is planned to evaluate potential effects of the differences on the 
safety.  
This surveillance will be conducted in compliance with the ministerial ordinance on 
Good Post-Marketing Study Practice (GPSP) and related regulatory requirements. 
 
2.0 
Objectives 
To investigate the safety of Leuplin PRO in patients with premenopausal breast 
cancer in routine clinical settings in order to evaluate potential effects of differences 
between Leuplin PRO and Leuplin SR, including the higher amount administered in 
a single dose and differences in time profile of serum drug concentration after 
administration, on the safety 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
300 patients 
 
3.2 Rationale 
To evaluate potential effects of differences between Leuplin PRO and Leuplin SR, 
that is, difference amounts of leuprorelin acetate administered in a single dose and 
different time profiles of serum drug concentration after administration, on the safety, 
it was decided to investigate the occurrence of injection site reaction and other 
adverse drug reactions (ADRs) with an incidence of 1% or higher, including the time 
of onset, incidence, and seriousness. 
The sample size of 300 patients was determined to detect ADRs with an incidence of 
1% or higher at a probability of 95% or higher. 
 
4.0 
Surveillance Population 
Patients with premenopausal breast cancer will be included in the surveillance. 
Patients should not meet the exclusion criterion listed below. Refer to the Precautions 
section of the package insert. 
<Exclusion criteria> 
Patients who meet the following criterion will not be included: 

 
1 
 
A history of hypersensitivity to any of the ingredients of Leuplin PRO or 
synthetic luteinizing hormone-releasing hormone (LH-RH) or LH-RH 
derivatives 
 
Pregnant or potentially pregnant patients and breastfeeding patients. 
 
5.0 
Dosage and Administration 
The usual adult dosage is 22.5 mg of leuprorelin acetate administered subcutaneously 
once every 24 weeks. Refer to the Precautions section of the package insert. 
 
6.0 
Planned Number of Medical Institutions by Department 
Breast surgery and other departments Approximately 60 medical institutions 
 
7.0 
Methodology 
7.1 Observation Period 
24 weeks 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a Web-based electronic data capture 
system (
). A representative of Takeda Pharmaceutical Company 
Limited (hereinafter referred to as Takeda’s representative) will explain the 
objectives and contents of the surveillance, operation method of 
, and 
handling of electronic signature, user ID, and password to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation 
outline,” “Entry screen image,” and “Operation manual of 
 (brief 
version)” to enter into a written contract with the study site and request the study 
site to conduct a surveillance within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration method via
. After 
the start of the contract with the study site, the investigator shall register each patient 
treated with Leuplin PRO by entering patient registration information (refer to 
Section 9.1) with his/her electronic signature within 14 days after administration of 
Leuplin PRO (day of administration designated as day 0 and day following the day 
of administration designated as 1 day post-dose). 
* The investigator’s designee should belong to the relevant medical institution (including 
those under contract with the medical institution such as temporary clinical research 
coordinators). Before the investigator’s designee begins to enter data into
, a 
physician responsible for the surveillance (one physician per medical institution or department 
CCI
CCI
CCI
CCI
CCI

 
2 
appointed at the time of contract) shall document the designation with the date of designation 
(no specific style), affix his/her signature or name and seal to the document, and submit it to 
Takeda’s representative. 
 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature 
The investigator or designee* shall enter patient baseline characteristics and 
treatment given into 
 with the investigator’s electronic signature within 
approximately 1 month after the end of required observation at 24 weeks after the 
start of Leuplin PRO treatment. 
For any patient with an adverse event, the investigator or designee shall enter 
observation results into 
 with the investigator’s electronic signature after 
monitoring the patient as long after discontinuation of treatment as possible until the 
adverse event is confirmed to have resolved or be resolving. 
* The investigator’s designee should belong to the relevant medical institution (including 
those under contract with the medical institution such as temporary clinical research 
coordinators). Before the investigator’s designee begins to enter data into
, a 
physician responsible for the surveillance (one physician per medical institution or department 
appointed at the time of contract) shall document the designation with the date of designation 
(no specific style), affix his/her signature or name and seal to the document, and submit it to 
Takeda’s representative. 
 
8.0 
Planned Surveillance Period 
Surveillance period: From March 2016 to 31 August 2017 
Patient registration period: From April 2016 to 28 February 2017Note) 
 
Note) Patient registration (entry into 
) will not be accepted on 1 March 
2018 onwards even if Leuplin PRO is administered by 28 February 2018. 
If the number of patients enrolled in the surveillance reaches the planned sample 
size before 28 February 2018, acceptance of registration will be terminated before 
the end of the patient registration period. If the patient registration period is 
shortened, the surveillance period will be changed accordingly. 
 
9.0 
Surveillance Items 
The investigator or designee shall enter the items listed below into
. The 
surveillance schedule is presented in Appendix. 
9.1 Patient Registration 
1) Surveillance items 
Date of administration of Leuplin PRO, patient identification number, patient 
CCI
CCI
CCI
CCI
CCI

 
3 
initials, date of birth, assessment based on the exclusion criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Patient Baseline Characteristics 
1) Surveillance items 
Time of diagnosis of premenopausal breast cancer, ECOG Performance 
Status*, disease status, site of lesions before the start of Leuplin PRO 
treatment, presence or absence of hormone receptor expression, diagnostic category 
(at the start of Leuplin PRO treatment), predisposition to hypersensitivity 
(presence or absence and details), concurrent illness (presence or absence and 
details), history of thromboembolism (presence or absence and details), height, 
body weight, treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment (presence or absence 
and name of the drug) 
2) Time points of surveillance 
At the start of Leuplin PRO treatment 
 
* ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
(Common Toxicity Criteria, Version 2.0 Published on April 30, 1999. Webpage of the JCOG at http://www.j
cog.jp/) 
 
9.3 Treatment Given 
1) Surveillance items 
Treatment status of Leuplin PRO (injection site* and full-treatment status of 
Leuplin PRO*), treatment status of premenopausal breast cancer drug other 
than Leuplin PRO (presence or absence and name of the drug), presence or 
absence of and reason for discontinuation of observation 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
* At the start of Leuplin PRO treatment 
 
9.4 Assessments 
1) Assessments 
Pregnancy during the observation period (females only) 
2) Outcome measure data collection timing 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 

 
4 
 
9.5 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of injection site reaction, details of injection site reaction 
(specific symptom, date of onset, seriousness and reason for seriousness [refer 
to Table 2], cause of discontinuation of Leuplin PRO treatment, intervention 
(presence or absence and contents), date of outcome assessment, outcome, 
causal relationship to Leuplin PRO [refer to Table 3]). 
Presence or absence of AE other than injection site reaction (refer to Table 1), 
AE term, date of onset, seriousness and reason for seriousness (refer to Table 
2), cause of discontinuation of Leuplin PRO treatment, intervention (presence 
or absence and name of the drug/intervention), date of outcome assessment, 
outcome, causal relationship to Leuplin PRO* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal 
relationship should be followed up wherever possible. 
* For the causal relationship to Leuplin PRO, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected 
natural course of the disease, will be handled as an AE.  
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 

 
5 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
· 
Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with 
a drug 
· Untoward symptoms and so forth that occur in children treated with a drug 
· Symptoms and so forth that occur as a result of occupational exposure to a drug 
· Symptoms and so forth that occur after administration of counterfeit medicines of our ethical 
drugs 
· Untoward symptoms that have become known to occur in drug users through lawsuits or 
other legal actions 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
· Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
· Anaphylactic shock 
· Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
· Acute renal failure 
· Malignant hypertension 
· Pulmonary hypertension 
· Convulsive seizures (including convulsions and epilepsy) 
· Pulmonary fibrosis (including interstitial pneumonia) 
· Agranulocytosis 
· Malignant syndrome / malignant hyperthermia 

 
6 
· Aplastic anemia 
· Spontaneous abortion / stillbirth and fetal death 
· Toxic epidermal necrolysis / mucocutaneous ocular syndrome (Stevens-Johnson syndrome) 
· Confirmed or suspected transmission of infectious agent by a medicinal product 
· Hepatic necrosis 
· Confirmed or suspected endotoxin shock 
· Acute liver failure 
 

 
7 
Table 3 Criteria for assessing the relationship of each adverse event to Leuplin PRO 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of 
the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying 
diseases, concurrent illnesses, concomitant drugs, and 
concomitant treatments, may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained 
by other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal 
sequence from administration of a drug (including the course after 
withdrawal of the drug), underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before finalization of data. The statistical 
analysis plan will include definitions of endpoints and detailed analysis methods. 
 
10.2 Analysis Sets 
The analysis set is patients included in safety evaluation. 
 
10.3 Matters on Patient Composition 
The number of enrolled patients, number of patients with the (electronic) CRF 
collected, number of patients included in safety evaluation, number of patients 
excluded from safety evaluation, and reason for exclusion will be tabulated. 
 
10.4 Patient Baseline Characteristics 
Patient baseline characteristics, including age, predisposition to hypersensitivity, and 
concurrent illness, will be tabulated. 
 
10.5 Treatment Given 
The treatment status of Leuplin PRO and treatment status of premenopausal breast 
cancer drug other than Leuplin PRO will be tabulated. 
 
10.6 Matters on Safety 
For patients included in safety evaluation, data will be tabulated as described below. 
AEs will be coded according to the MedDRA/J and summarized using preferred term 
(PT) and system organ class (SOC). 

 
8 
 Occurrence of Adverse Events 
For AEs reported during the observation period, the incidence will be tabulated 
by type, time of onset, seriousness, and causal relationship to Leuplin PRO. In 
addition, events listed as the safety specifications for the surveillance in “2. 
Summary of Pharmacovigilance Plan” in the risk management plan will be 
tabulated separately. 
 
 
Factors that May Affect the Safety 
For ADRs reported during the observation period, the incidence will be tabulated 
by patient background factors (e.g., disease status, presence or absence of 
concurrent renal impairment, presence or absence of concurrent hepatic 
impairment) and treatment status of Leuplin PRO. 
 
11.0 
Posting of Surveillance Information 
Surveillance information will be posted on the following open website before 
starting the surveillance:  
· 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Surveillance Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations (CROs) 
 
 
PPD
PPD

 
9 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of 
progression of the surveillance, presence or absence of ADRs that are unexpected 
based on the precautions/serious ADRs, presence or absence of increased incidence 
of certain ADRs, and appropriateness of surveillance items, and this protocol will be 
reviewed and revised if necessary. If partial change to dosage and administration or 
indications is approved during the surveillance, the necessity of revising the protocol 
will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety problem is detected, data will be carefully examined to discuss measures. 
 
PPD

 
10 
Appendix Observation schedule 
 
                 Time point of surveillance 
 
 
 
 
 
 
 
   Surveillance item 
Observation period 
At patient 
registration 
At the start of 
treatment 
After 24 weeks 
or at 
discontinuation 
of observation 
Patient 
registration 
Date of administration of Leuplin PRO 
○ 
 
 
Patient identification number 
○ 
 
 
Patient initials 
○ 
 
 
Date of birth 
○ 
 
 
Assessment based on the exclusion criteria 
○ 
 
 
Patient 
baseline 
characterist
ics 
Time of diagnosis of premenopausal breast cancer 
 
○ 
 
ECOG Performance Status 
 
○ 
 
Disease status 
 
○ 
 
Diagnostic category 
 
○ 
 
Site of lesions before the start of Leuplin PRO 
treatment 
 
○ 
 
Presence or absence of hormone receptor expression 
 
○ 
 
Predisposition to hypersensitivity 
 
○ 
 
Concurrent illness 
 
○ 
 
History of thromboembolism 
 
○ 
 
Height, body weight 
 
○ 
 
Treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment 
 
○ 
 
Treatment 
given 
Treatment status of Leuplin PRO 
 
○ 
Treatment status of premenopausal breast cancer drug 
other than Leuplin PRO 
 
○ 
Assess 
-ments 
Pregnancy during the observation period (females 
only) 
 
○ 
Adverse 
event 
Injection site reaction 
 
○ 
Adverse event other than injection site reaction 
 
○ 
○  : Performed 
○  : Performed throughout the period 
 
 
 
 
 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Special Drug Use Surveillance of Leuplin PRO for 
Injection Kit 22.5 mg  
for “Premenopausal Breast Cancer” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Leuprorelin-5003 
Version number 
2nd version 
Date of 
preparation 
25 February 2016 
 

 
Table of Contents 
1.0 Background of the Surveillance ...................................................................................................... 0 
2.0 Objectives ....................................................................................................................................... 0 
3.0 Planned Sample Size and Rationale ................................................................................................ 0 
3.1 Planned Sample Size ............................................................................................................... 0 
3.2 Rationale.................................................................................................................................. 0 
4.0 Surveillance Population .................................................................................................................. 0 
5.0 Dosage and Administration ............................................................................................................. 1 
6.0 Planned Number of Medical Institutions by Department................................................................ 1 
7.0 Methodology ................................................................................................................................... 1 
7.1 Observation Period .................................................................................................................. 1 
7.2 Request to and Contract with the Study Site ........................................................................... 1 
7.3 Method of Patient Registration ................................................................................................ 1 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature................................. 2 
8.0 Planned Surveillance Period ........................................................................................................... 2 
9.0 Surveillance Items ........................................................................................................................... 2 
9.1 Patient Registration ................................................................................................................. 2 
9.2 Patient Baseline Characteristics .............................................................................................. 2 
9.3 Treatment Given ...................................................................................................................... 3 
9.4 Assessments ............................................................................................................................ 3 
9.5 Adverse Events (AEs) ............................................................................................................. 3 
10.0 
Analysis Items and Methods ................................................................................................. 7 
10.1 Statistical Analysis Plan .......................................................................................................... 7 
10.2 Analysis Sets ........................................................................................................................... 7 
10.3 Matters on Patient Composition .............................................................................................. 7 
10.4 Patient Baseline Characteristics .............................................................................................. 7 
10.5 Treatment Given ...................................................................................................................... 7 
10.6 Matters on Safety..................................................................................................................... 7 
 Occurrence of Adverse Events ......................................................................................... 8 
 Factors that May Affect the Safety................................................................................... 8 
11.0 
Posting of Surveillance Information ...................................................................................... 8 
12.0 
Surveillance Organization ..................................................................................................... 8 
12.1 Administrative Manager .......................................................................................................... 8 
13.0 
Contract Research Organizations (CROs) ............................................................................. 8 
14.0 
Other Necessary Matters ....................................................................................................... 9 
14.1 Revision of the Protocol .......................................................................................................... 9 
14.2 Actions to be Taken for Problems and Questions .................................................................... 9 
 
Appendix Observation schedule........................................................................................................ 9 

 
0 
1.0 
Background of the Surveillance 
Since the amount of leuprorelin acetate administered in a single dose of Leuplin PRO 
for Injection Kit 22.5 mg (hereinafter referred to as Leuplin PRO) is as high as twice 
that of Leuplin SR for Injection Kit 11.25 mg (hereinafter referred to as Leuplin SR), 
and the time profile of serum leuprorelin concentration after administration differs 
between the two formulations, a special drug use surveillance (hereinafter referred to 
as the surveillance) is planned to evaluate potential effects of the differences on the 
safety.  
This surveillance will be conducted in compliance with the ministerial ordinance on 
Good Post-Marketing Study Practice (GPSP) and related regulatory requirements. 
 
2.0 
Objectives 
To investigate the safety of Leuplin PRO in patients with premenopausal breast 
cancer in routine clinical settings in order to evaluate potential effects of differences 
between Leuplin PRO and Leuplin SR, including the higher amount administered in 
a single dose and differences in time profile of serum drug concentration after 
administration, on the safety 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
300 patients 
 
3.2 Rationale 
To evaluate potential effects of differences between Leuplin PRO and Leuplin SR, 
that is, difference amounts of leuprorelin acetate administered in a single dose and 
different time profiles of serum drug concentration after administration, on the safety, 
it was decided to investigate the occurrence of injection site reaction and other 
adverse drug reactions (ADRs) with an incidence of 1% or higher, including the time 
of onset, incidence, and seriousness. 
The sample size of 300 patients was determined to detect ADRs with an incidence of 
1% or higher at a probability of 95% or higher. 
 
4.0 
Surveillance Population 
Patients with premenopausal breast cancer will be included in the surveillance. 
Patients should not meet the exclusion criterion listed below. Refer to the Precautions 
section of the package insert. 
<Exclusion criteria> 
Patients who meet the following criterion will not be included: 

 
1 
 
A history of hypersensitivity to any of the ingredients of Leuplin PRO or 
synthetic luteinizing hormone-releasing hormone (LH-RH) or LH-RH 
derivatives 
 
Pregnant or potentially pregnant patients and breastfeeding patients. 
 
5.0 
Dosage and Administration 
The usual adult dosage is 22.5 mg of leuprorelin acetate administered subcutaneously 
once every 24 weeks. Refer to the Precautions section of the package insert. 
 
6.0 
Planned Number of Medical Institutions by Department 
Breast surgery and other departments Approximately 60 medical institutions 
 
7.0 
Methodology 
7.1 Observation Period 
24 weeks 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a Web-based electronic data capture 
system (
). A representative of Takeda Pharmaceutical Company 
Limited (hereinafter referred to as Takeda’s representative) will explain the 
objectives and contents of the surveillance, operation method of 
, and 
handling of electronic signature, user ID, and password to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation 
outline,” “Entry screen image,” and “Operation manual of 
 (brief 
version)” to enter into a written contract with the study site and request the study 
site to conduct a surveillance within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration method via
. After 
the start of the contract with the study site, the investigator shall register each patient 
treated with Leuplin PRO by entering patient registration information (refer to 
Section 9.1) with his/her electronic signature within 14 days after administration of 
Leuplin PRO (day of administration designated as day 0 and day following the day 
of administration designated as 1 day post-dose). 
* The investigator’s designee should belong to the relevant medical institution (including 
those under contract with the medical institution such as temporary clinical research 
coordinators). Before the investigator’s designee begins to enter data into
, a 
physician responsible for the surveillance (one physician per medical institution or department 
CCI
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2 
appointed at the time of contract) shall document the designation with the date of designation 
(no specific style), affix his/her signature or name and seal to the document, and submit it to 
Takeda’s representative. 
 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature 
The investigator or designee* shall enter patient baseline characteristics and 
treatment given into 
 with the investigator’s electronic signature within 
approximately 1 month after the end of required observation at 24 weeks after the 
start of Leuplin PRO treatment. 
For any patient with an adverse event, the investigator or designee shall enter 
observation results into 
 with the investigator’s electronic signature after 
monitoring the patient as long after discontinuation of treatment as possible until the 
adverse event is confirmed to have resolved or be resolving. 
 
8.0 
Planned Surveillance Period 
Surveillance period: From March 2016 to 31 August 2017 
Patient registration period: From April 2016 to 28 February 2017Note) 
 
Note) Patient registration (entry into 
) will not be accepted on 1 March 
2018 onwards even if Leuplin PRO is administered by 28 February 2018. 
If the number of patients enrolled in the surveillance reaches the planned sample 
size before 28 February 2018, acceptance of registration will be terminated before 
the end of the patient registration period. If the patient registration period is 
shortened, the surveillance period will be changed accordingly. 
 
9.0 
Surveillance Items 
The investigator or designee shall enter the items listed below into
. The 
surveillance schedule is presented in Appendix. 
9.1 Patient Registration 
1) Surveillance items 
Date of administration of Leuplin PRO, patient identification number, patient 
initials, date of birth, assessment based on the exclusion criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Patient Baseline Characteristics 
1) Surveillance items 
Time of diagnosis of premenopausal breast cancer, ECOG Performance 
Status*, disease status, site of lesions before the start of Leuplin PRO 
treatment, presence or absence of hormone receptor expression, diagnostic category 
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3 
(at the start of Leuplin PRO treatment), predisposition to hypersensitivity 
(presence or absence and details), concurrent illness (presence or absence and 
details), history of thromboembolism (presence or absence and details), height, 
body weight, treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment (presence or absence 
and name of the drug) 
2) Time points of surveillance 
At the start of Leuplin PRO treatment 
 
* ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
(Common Toxicity Criteria, Version 2.0 Published on April 30, 1999. Webpage of the JCOG at http://www.j
cog.jp/) 
 
9.3 Treatment Given 
1) Surveillance items 
Treatment status of Leuplin PRO (injection site* and full-treatment status of 
Leuplin PRO*), treatment status of premenopausal breast cancer drug other 
than Leuplin PRO (presence or absence and name of the drug), presence or 
absence of and reason for discontinuation of observation 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
* At the start of Leuplin PRO treatment 
 
9.4 Assessments 
1) Assessments 
Pregnancy during the observation period (females only) 
2) Outcome measure data collection timing 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 
9.5 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of injection site reaction, details of injection site reaction 
(specific symptom, date of onset, seriousness and reason for seriousness [refer 
to Table 2], cause of discontinuation of Leuplin PRO treatment, intervention 
(presence or absence and contents), date of outcome assessment, outcome, 
causal relationship to Leuplin PRO [refer to Table 3]). 
Presence or absence of AE other than injection site reaction (refer to Table 1), 
AE term, date of onset, seriousness and reason for seriousness (refer to Table 

 
4 
2), cause of discontinuation of Leuplin PRO treatment, intervention (presence 
or absence and name of the drug/intervention), date of outcome assessment, 
outcome, causal relationship to Leuplin PRO* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal 
relationship should be followed up wherever possible. 
* For the causal relationship to Leuplin PRO, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected 
natural course of the disease, will be handled as an AE.  
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 

 
5 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
· 
Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with 
a drug 
· Untoward symptoms and so forth that occur in children treated with a drug 
· Symptoms and so forth that occur as a result of occupational exposure to a drug 
· Symptoms and so forth that occur after administration of counterfeit medicines of our ethical 
drugs 
· Untoward symptoms that have become known to occur in drug users through lawsuits or 
other legal actions 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
· Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
· Anaphylactic shock 
· Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
· Acute renal failure 
· Malignant hypertension 
· Pulmonary hypertension 
· Convulsive seizures (including convulsions and epilepsy) 
· Pulmonary fibrosis (including interstitial pneumonia) 
· Agranulocytosis 
· Malignant syndrome / malignant hyperthermia 

 
6 
· Aplastic anemia 
· Spontaneous abortion / stillbirth and fetal death 
· Toxic epidermal necrolysis / mucocutaneous ocular syndrome (Stevens-Johnson syndrome) 
· Confirmed or suspected transmission of infectious agent by a medicinal product 
· Hepatic necrosis 
· Confirmed or suspected endotoxin shock 
· Acute liver failure 
 

 
7 
Table 3 Criteria for assessing the relationship of each adverse event to Leuplin PRO 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of 
the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying 
diseases, concurrent illnesses, concomitant drugs, and 
concomitant treatments, may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained 
by other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal 
sequence from administration of a drug (including the course after 
withdrawal of the drug), underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before finalization of data. The statistical 
analysis plan will include definitions of endpoints and detailed analysis methods. 
 
10.2 Analysis Sets 
The analysis set is patients included in safety evaluation. 
 
10.3 Matters on Patient Composition 
The number of enrolled patients, number of patients with the (electronic) CRF 
collected, number of patients included in safety evaluation, number of patients 
excluded from safety evaluation, and reason for exclusion will be tabulated. 
 
10.4 Patient Baseline Characteristics 
Patient baseline characteristics, including age, predisposition to hypersensitivity, and 
concurrent illness, will be tabulated. 
 
10.5 Treatment Given 
The treatment status of Leuplin PRO and treatment status of premenopausal breast 
cancer drug other than Leuplin PRO will be tabulated. 
 
10.6 Matters on Safety 
For patients included in safety evaluation, data will be tabulated as described below. 
AEs will be coded according to the MedDRA/J and summarized using preferred term 
(PT) and system organ class (SOC). 

 
8 
 Occurrence of Adverse Events 
For AEs reported during the observation period, the incidence will be tabulated 
by type, time of onset, seriousness, and causal relationship to Leuplin PRO. In 
addition, events listed as the safety specifications for the surveillance in “2. 
Summary of Pharmacovigilance Plan” in the risk management plan will be 
tabulated separately. 
 
 
Factors that May Affect the Safety 
For ADRs reported during the observation period, the incidence will be tabulated 
by patient background factors (e.g., disease status, presence or absence of 
concurrent renal impairment, presence or absence of concurrent hepatic 
impairment) and treatment status of Leuplin PRO. 
 
11.0 
Posting of Surveillance Information 
Surveillance information will be posted on the following open website before 
starting the surveillance:  
· 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Surveillance Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations (CROs) 
 
 
PPD
PPD

 
9 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of 
progression of the surveillance, presence or absence of ADRs that are unexpected 
based on the precautions/serious ADRs, presence or absence of increased incidence 
of certain ADRs, and appropriateness of surveillance items, and this protocol will be 
reviewed and revised if necessary. If partial change to dosage and administration or 
indications is approved during the surveillance, the necessity of revising the protocol 
will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety problem is detected, data will be carefully examined to discuss measures. 
 

 
10 
Appendix Observation schedule 
 
                 Time point of surveillance 
 
 
 
 
 
 
 
   Surveillance item 
Observation period 
At patient 
registration 
At the start of 
treatment 
After 24 weeks 
or at 
discontinuation 
of observation 
Patient 
registration 
Date of administration of Leuplin PRO 
○ 
 
 
Patient identification number 
○ 
 
 
Patient initials 
○ 
 
 
Date of birth 
○ 
 
 
Assessment based on the exclusion criteria 
○ 
 
 
Patient 
baseline 
characterist
ics 
Time of diagnosis of premenopausal breast cancer 
 
○ 
 
ECOG Performance Status 
 
○ 
 
Disease status 
 
○ 
 
Diagnostic category 
 
○ 
 
Site of lesions before the start of Leuplin PRO 
treatment 
 
○ 
 
Presence or absence of hormone receptor expression 
 
○ 
 
Predisposition to hypersensitivity 
 
○ 
 
Concurrent illness 
 
○ 
 
History of thromboembolism 
 
○ 
 
Height, body weight 
 
○ 
 
Treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment 
 
○ 
 
Treatment 
given 
Treatment status of Leuplin PRO 
 
○ 
Treatment status of premenopausal breast cancer drug 
other than Leuplin PRO 
 
○ 
Assess 
-ments 
Pregnancy during the observation period (females 
only) 
 
○ 
Adverse 
event 
Injection site reaction 
 
○ 
Adverse event other than injection site reaction 
 
○ 
○  : Performed 
○  : Performed throughout the period 
 
 
 
 
 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Special Drug Use Surveillance of Leuplin PRO for 
Injection Kit 22.5 mg  
for “Premenopausal Breast Cancer” 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol number 
Leuprorelin-5003 
Version number 
1st version 
Date of 
preparation 
22 January 2016 
 

 
Table of Contents 
1.0 Background of the Surveillance ...................................................................................................... 0 
2.0 Objectives ....................................................................................................................................... 0 
3.0 Planned Sample Size and Rationale ................................................................................................ 0 
3.1 Planned Sample Size ............................................................................................................... 0 
3.2 Rationale.................................................................................................................................. 0 
4.0 Surveillance Population .................................................................................................................. 0 
5.0 Dosage and Administration ............................................................................................................. 1 
6.0 Planned Number of Medical Institutions by Department................................................................ 1 
7.0 Methodology ................................................................................................................................... 1 
7.1 Observation Period .................................................................................................................. 1 
7.2 Request to and Contract with the Study Site ........................................................................... 1 
7.3 Method of Patient Registration ................................................................................................ 1 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature................................. 1 
8.0 Planned Surveillance Period ........................................................................................................... 2 
9.0 Surveillance Items ........................................................................................................................... 2 
9.1 Patient Registration ................................................................................................................. 2 
9.2 Patient Baseline Characteristics .............................................................................................. 2 
9.3 Treatment Given ...................................................................................................................... 3 
9.4 Assessments ............................................................................................................................ 3 
9.5 Adverse Events (AEs) ............................................................................................................. 3 
10.0 
Analysis Items and Methods ................................................................................................. 7 
10.1 Statistical Analysis Plan .......................................................................................................... 7 
10.2 Analysis Sets ........................................................................................................................... 7 
10.3 Matters on Patient Composition .............................................................................................. 7 
10.4 Patient Baseline Characteristics .............................................................................................. 7 
10.5 Treatment Given ...................................................................................................................... 7 
10.6 Matters on Safety..................................................................................................................... 7 
 Occurrence of Adverse Events ......................................................................................... 8 
 Factors that May Affect the Safety................................................................................... 8 
11.0 
Posting of Surveillance Information ...................................................................................... 8 
12.0 
Surveillance Organization ..................................................................................................... 8 
12.1 Administrative Manager .......................................................................................................... 8 
13.0 
Contract Research Organizations (CROs) ............................................................................. 8 
14.0 
Other Necessary Matters ....................................................................................................... 9 
14.1 Revision of the Protocol .......................................................................................................... 9 
14.2 Actions to be Taken for Problems and Questions .................................................................... 9 
 
Appendix Observation schedule........................................................................................................ 9 

 
0 
1.0 
Background of the Surveillance 
Since the amount of leuprorelin acetate administered in a single dose of Leuplin PRO 
for Injection Kit 22.5 mg (hereinafter referred to as Leuplin PRO) is as high as twice 
that of Leuplin SR for Injection Kit 11.25 mg (hereinafter referred to as Leuplin SR), 
and the time profile of serum leuprorelin concentration after administration differs 
between the two formulations, a special drug use surveillance (hereinafter referred to 
as the surveillance) is planned to evaluate potential effects of the differences on the 
safety.  
This surveillance will be conducted in compliance with the ministerial ordinance on 
Good Post-Marketing Study Practice (GPSP) and related regulatory requirements. 
 
2.0 
Objectives 
To investigate the safety of Leuplin PRO in patients with premenopausal breast 
cancer in routine clinical settings in order to evaluate potential effects of differences 
between Leuplin PRO and Leuplin SR, including the higher amount administered in 
a single dose and differences in time profile of serum drug concentration after 
administration, on the safety 
 
3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
300 patients 
 
3.2 Rationale 
To evaluate potential effects of differences between Leuplin PRO and Leuplin SR, 
that is, difference amounts of leuprorelin acetate administered in a single dose and 
different time profiles of serum drug concentration after administration, on the safety, 
it was decided to investigate the occurrence of injection site reaction and other 
adverse drug reactions (ADRs) with an incidence of 1% or higher, including the time 
of onset, incidence, and seriousness. 
The sample size of 300 patients was determined to detect ADRs with an incidence of 
1% or higher at a probability of 95% or higher. 
 
4.0 
Surveillance Population 
Patients with premenopausal breast cancer will be included in the surveillance. 
Patients should not meet the exclusion criterion listed below. Refer to the Precautions 
section of the package insert. 
<Exclusion criteria> 
Patients who meet the following criterion will not be included: 

 
1 
 
A history of hypersensitivity to any of the ingredients of Leuplin PRO or 
synthetic luteinizing hormone-releasing hormone (LH-RH) or LH-RH 
derivatives 
 
Pregnant or potentially pregnant patients and breastfeeding patients. 
 
5.0 
Dosage and Administration 
The usual adult dosage is 22.5 mg of leuprorelin acetate administered subcutaneously 
once every 24 weeks. Refer to the Precautions section of the package insert. 
 
6.0 
Planned Number of Medical Institutions by Department 
Breast surgery and other departments Approximately 60 medical institutions 
 
7.0 
Methodology 
7.1 Observation Period 
24 weeks 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a Web-based electronic data capture 
system (
). A representative of Takeda Pharmaceutical Company 
Limited (hereinafter referred to as Takeda’s representative) will explain the 
objectives and contents of the surveillance, operation method of 
, and 
handling of electronic signature, user ID, and password to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation 
outline,” “Entry screen image,” and “Operation manual of 
 (brief 
version)” to enter into a written contract with the study site and request the study 
site to conduct a surveillance within a specified period. 
 
7.3 Method of Patient Registration 
Patients will be registered using the central registration method via 
. After 
the start of the contract with the study site, the investigator shall register each patient 
treated with Leuplin PRO by entering patient registration information (refer to 
Section 9.1) with his/her electronic signature within 14 days after administration of 
Leuplin PRO (day of administration designated as day 0 and day following the day 
of administration designated as 1 day post-dose). 
 
7.4 Entry into the (Electronic) Case Report Form and Electronic Signature 
The investigator or designee* shall enter patient baseline characteristics and 
treatment given into 
 with the investigator’s electronic signature within 
approximately 1 month after the end of required observation at 24 weeks after the 
CCI
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2 
start of Leuplin PRO treatment. 
For any patient with an adverse event, the investigator or designee shall enter 
observation results into 
 with the investigator’s electronic signature after 
monitoring the patient as long after discontinuation of treatment as possible until the 
adverse event is confirmed to have resolved or be resolving. 
 
8.0 
Planned Surveillance Period 
Surveillance period: From March 2016 to 31 August 2017 
Patient registration period: From April 2016 to 28 February 2017Note) 
 
Note) Patient registration (entry into 
) will not be accepted on 1 March 
2018 onwards even if Leuplin PRO is administered by 28 February 2018. 
If the number of patients enrolled in the surveillance reaches the planned sample 
size before 28 February 2018, acceptance of registration will be terminated before 
the end of the patient registration period. If the patient registration period is 
shortened, the surveillance period will be changed accordingly. 
 
9.0 
Surveillance Items 
The investigator or designee shall enter the items listed below into
. The 
surveillance schedule is presented in Appendix. 
9.1 Patient Registration 
1) Surveillance items 
Date of administration of Leuplin PRO, patient identification number, patient 
initials, date of birth, assessment based on the exclusion criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Patient Baseline Characteristics 
1) Surveillance items 
Time of diagnosis of premenopausal breast cancer, ECOG Performance 
Status*, disease status, site of lesions before the start of Leuplin PRO 
treatment, presence or absence of hormone receptor expression, diagnostic category 
(at the start of Leuplin PRO treatment), predisposition to hypersensitivity 
(presence or absence and details), concurrent illness (presence or absence and 
details), history of thromboembolism (presence or absence and details), height, 
body weight, treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment (presence or absence 
and name of the drug) 
2) Time points of surveillance 
At the start of Leuplin PRO treatment 
 
CCI
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3 
* ECOG Performance Status 
Score 
Definition 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or chair 
(Common Toxicity Criteria, Version 2.0 Published on April 30, 1999. Webpage of the JCOG at http://www.j
cog.jp/) 
 
9.3 Treatment Given 
1) Surveillance items 
Treatment status of Leuplin PRO (injection site* and full-treatment status of 
Leuplin PRO*), treatment status of premenopausal breast cancer drug other 
than Leuplin PRO (presence or absence and name of the drug), presence or 
absence of and reason for discontinuation of observation 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
* At the start of Leuplin PRO treatment 
 
9.4 Assessments 
1) Assessments 
Pregnancy during the observation period (females only) 
2) Outcome measure data collection timing 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 
9.5 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of injection site reaction, details of injection site reaction 
(specific symptom, date of onset, seriousness and reason for seriousness [refer 
to Table 2], cause of discontinuation of Leuplin PRO treatment, intervention 
(presence or absence and contents), date of outcome assessment, outcome, 
causal relationship to Leuplin PRO [refer to Table 3]). 
Presence or absence of AE other than injection site reaction (refer to Table 1), 
AE term, date of onset, seriousness and reason for seriousness (refer to Table 
2), cause of discontinuation of Leuplin PRO treatment, intervention (presence 
or absence and name of the drug/intervention), date of outcome assessment, 
outcome, causal relationship to Leuplin PRO* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal 
relationship should be followed up wherever possible. 
* For the causal relationship to Leuplin PRO, the rationale for “not related” and the reason 
for “unevaluable” shall be collected. 
Note) Additional points to consider for AEs 
Abnormal worsening of target disease, for instance, worsening beyond the expected 
natural course of the disease, will be handled as an AE.  

 
4 
2) Time points of surveillance 
Period from the start of Leuplin PRO treatment to 24 weeks after the start of 
treatment (or discontinuation of observation) 
 

 
5 
Table 1 Definition of adverse events 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable or unintended sign (e.g., abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, whether or not it is considered 
related to the drug. 
The following are also handled as AEs:  
· 
Symptoms and so forth that occur in infants breast-fed by their mothers under treatment with 
a drug 
· Untoward symptoms and so forth that occur in children treated with a drug 
· Symptoms and so forth that occur as a result of occupational exposure to a drug 
· Symptoms and so forth that occur after administration of counterfeit medicines of our ethical 
drugs 
· Untoward symptoms that have become known to occur in drug users through lawsuits or 
other legal actions 
 
Table 2 Criteria for assessing seriousness 
An AE satisfying any of the following is assessed as serious:  
1. Results in death (death) 
2. Is life-threatening (risk of death) 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event according to 1 to 5 described above, including AEs in Takeda 
Medically Significant AE List 
 
Takeda Medically Significant AE List 
· Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
· Anaphylactic shock 
· Torsade de pointes / ventricular fibrillation / ventricular tachycardia 
· Acute renal failure 
· Malignant hypertension 
· Pulmonary hypertension 
· Convulsive seizures (including convulsions and epilepsy) 
· Pulmonary fibrosis (including interstitial pneumonia) 
· Agranulocytosis 
· Malignant syndrome / malignant hyperthermia 

 
6 
· Aplastic anemia 
· Spontaneous abortion / stillbirth and fetal death 
· Toxic epidermal necrolysis / mucocutaneous ocular syndrome (Stevens-Johnson syndrome) 
· Confirmed or suspected transmission of infectious agent by a medicinal product 
· Hepatic necrosis 
· Confirmed or suspected endotoxin shock 
· Acute liver failure 
 

 
7 
Table 3 Criteria for assessing the relationship of each adverse event to Leuplin PRO 
Assessment 
Criteria for assessment 
Related 
An AE that follows a reasonable temporal sequence from 
administration of a drug (including the course after withdrawal of 
the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying 
diseases, concurrent illnesses, concomitant drugs, and 
concomitant treatments, may also be responsible 
Not related 
An AE that does not follow a reasonable temporal sequence from 
administration of a drug and/or that can reasonably be explained 
by other factors, such as underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments 
Unevaluable 
Information necessary for evaluation, including temporal 
sequence from administration of a drug (including the course after 
withdrawal of the drug), underlying diseases, concurrent illnesses, 
concomitant drugs, and concomitant treatments, is not sufficient. 
 
10.0 
Analysis Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before finalization of data. The statistical 
analysis plan will include definitions of endpoints and detailed analysis methods. 
 
10.2 Analysis Sets 
The analysis set is patients included in safety evaluation. 
 
10.3 Matters on Patient Composition 
The number of enrolled patients, number of patients with the (electronic) CRF 
collected, number of patients included in safety evaluation, number of patients 
excluded from safety evaluation, and reason for exclusion will be tabulated. 
 
10.4 Patient Baseline Characteristics 
Patient baseline characteristics, including age, predisposition to hypersensitivity, and 
concurrent illness, will be tabulated. 
 
10.5 Treatment Given 
The treatment status of Leuplin PRO and treatment status of premenopausal breast 
cancer drug other than Leuplin PRO will be tabulated. 
 
10.6 Matters on Safety 
For patients included in safety evaluation, data will be tabulated as described below. 
AEs will be coded according to the MedDRA/J and summarized using preferred term 
(PT) and system organ class (SOC). 

 
8 
 Occurrence of Adverse Events 
For AEs reported during the observation period, the incidence will be tabulated 
by type, time of onset, seriousness, and causal relationship to Leuplin PRO. In 
addition, events listed as the safety specifications for the surveillance in “2. 
Summary of Pharmacovigilance Plan” in the risk management plan will be 
tabulated separately. 
 
 
Factors that May Affect the Safety 
For ADRs reported during the observation period, the incidence will be tabulated 
by patient background factors (e.g., disease status, presence or absence of 
concurrent renal impairment, presence or absence of concurrent hepatic 
impairment) and treatment status of Leuplin PRO. 
 
11.0 
Posting of Surveillance Information 
Surveillance information will be posted on the following open website before 
starting the surveillance:  
· 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Surveillance Organization 
12.1 Administrative Manager 
Takeda Pharmaceutical Company Limited 
 
13.0 
Contract Research Organizations (CROs) 
 
 
PPD
PPD

 
9 
 
14.0 
Other Necessary Matters 
14.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of 
progression of the surveillance, presence or absence of ADRs that are unexpected 
based on the precautions/serious ADRs, presence or absence of increased incidence 
of certain ADRs, and appropriateness of surveillance items, and this protocol will be 
reviewed and revised if necessary. If partial change to dosage and administration or 
indications is approved during the surveillance, the necessity of revising the protocol 
will be discussed if necessary, and the protocol will be revised as needed. 
 
14.2 Actions to be Taken for Problems and Questions 
If any safety problem is detected, data will be carefully examined to discuss measures. 
 

 
10 
Appendix Observation schedule 
 
                 Time point of surveillance 
 
 
 
 
 
 
 
   Surveillance item 
Observation period 
At patient 
registration 
At the start of 
treatment 
After 24 weeks 
or at 
discontinuation 
of observation 
Patient 
registration 
Date of administration of Leuplin PRO 
○ 
 
 
Patient identification number 
○ 
 
 
Patient initials 
○ 
 
 
Date of birth 
○ 
 
 
Assessment based on the exclusion criteria 
○ 
 
 
Patient 
baseline 
characterist
ics 
Time of diagnosis of premenopausal breast cancer 
 
○ 
 
ECOG Performance Status 
 
○ 
 
Disease status 
 
○ 
 
Diagnostic category 
 
○ 
 
Site of lesions before the start of Leuplin PRO 
treatment 
 
○ 
 
Presence or absence of hormone receptor expression 
 
○ 
 
Predisposition to hypersensitivity 
 
○ 
 
Concurrent illness 
 
○ 
 
History of thromboembolism 
 
○ 
 
Height, body weight 
 
○ 
 
Treatment status of premenopausal breast cancer drug 
immediately before the start of Leuplin PRO treatment 
 
○ 
 
Treatment 
given 
Treatment status of Leuplin PRO 
 
○ 
Treatment status of premenopausal breast cancer drug 
other than Leuplin PRO 
 
○ 
Assess 
-ments 
Pregnancy during the observation period (females 
only) 
 
○ 
Adverse 
event 
Injection site reaction 
 
○ 
Adverse event other than injection site reaction 
 
○ 
○  : Performed 
○  : Performed throughout the period