36-month Special Drug Use Surveillance on Frequency of Bone Fractures With Benet 75 mg Tablets
Conditions: Osteoporosis
Sponsor: Takeda

 
 
Title: Special Drug Use Surveillance on Fracture Incidence during 36-Month Treatment 
 
NCT Number: NCT02106442 
Protocol Approve Date: 02-Jun-2017 
 
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 
Benet 75 mg Tablets 
Special Drug Use Surveillance on Fracture Incidence 
during 36-Month Treatment 
 
 
 
 
 
 
 
 
Version number 
4th version 
Date of preparation 
2 June 2017 
Sponsor 
Takeda Pharmaceutical Co., Ltd. 
 

 
Table of Contents 
1.0 
Background of the Surveillance ..................................................................................................... 1 
2.0 
Objectives of the Surveillance ........................................................................................................ 1 
3.0 
Planned Sample Size and Rationale ............................................................................................. 1 
3.1 
Planned Sample Size .................................................................................................................. 1 
3.2 
Rationale ...................................................................................................................................... 1 
4.0 
Surveillance Population ................................................................................................................. 1 
5.0 
Dosage and Administration in Surveillance Patients .................................................................. 2 
6.0 
Planned Number of Medical Institutions by Department ........................................................... 2 
7.0 
Surveillance Method ....................................................................................................................... 2 
7.1 
Observation Period ...................................................................................................................... 2 
7.2 
Request to and Contract with the Study Site ........................................................................... 2 
7.3 
Method of Patient Registration .................................................................................................. 2 
7.4 
Completion and Submission of Case Report Form ................................................................... 3 
7.5 
Actions to be Taken in Case of Serious Adverse Events........................................................... 3 
8.0 
Planned Surveillance Period .......................................................................................................... 3 
9.0 
Surveillance Items .......................................................................................................................... 3 
9.1 
Entries into the Patient Registration Form .............................................................................. 4 
9.2 
Entries into the Case Report Form ............................................................................................ 4 
9.2.1 
Cover of the Case Report Form ........................................................................................... 4 
9.2.2 
Patient Baseline Characteristics ........................................................................................ 4 
9.2.3 
Treatment Given .................................................................................................................. 4 
9.2.4 
Tests/Observations ............................................................................................................... 5 
9.2.4.1 
Laboratory Tests ............................................................................................................... 5 
9.2.4.2 
Bone Mineral Density ...................................................................................................... 5 
9.2.4.3 
Bone Turnover Markers ................................................................................................... 5 
9.2.5 
Assessment of Vertebral Fracture ...................................................................................... 6 
9.2.6 
Assessment of Non-vertebral Fracture .............................................................................. 6 
9.2.7 
Clinical Findings .................................................................................................................. 6 
9.3 
Adverse Events (AEs) ................................................................................................................. 6 
10.0 Analysis Items and Methods .......................................................................................................... 8 
10.1 Matters on Patient Composition ................................................................................................ 8 
10.2 Patient Baseline Characteristics ............................................................................................... 8 
10.3 Treatment Compliance Status ................................................................................................... 9 
10.4 Matters on Safety ........................................................................................................................ 9 
10.5 Matters on Efficacy ..................................................................................................................... 9 
10.5.1 
Primary Endpoint ................................................................................................................ 9 
10.5.2 
Secondary Endpoints ........................................................................................................... 9 
10.6 Analysis Methods ........................................................................................................................ 9 
11.0 
Surveillance Organization.............................................................................................................. 9 

 
11.1 
Surveillance Administrative Manager....................................................................................... 9 
11.2 
Medical Expert ............................................................................................................................ 9 
11.3 
Central Registration Center ....................................................................................................... 9 
12.0 Name, Address, and Scope of Operations of Contract Research Organizations (CROs) ......... 10 
13.0 Other Necessary Matters ............................................................................................................. 10 
13.1 Revision of the Protocol ............................................................................................................ 10 
13.2 Actions to be Taken for Problems and Questions ................................................................... 10 
 
Appendix  Surveillance schedule...............................................................................................................11 

 
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1) A patient with evidence of 1 to 4 fractures from the fourth thoracic vertebra to the fourth 
lumbar vertebra (T4 to L4) provided by thoracic and lumbar spinal radiography 
performed before the start of the surveillance (within 3 months before the start of 
prescription of Benet) 
2) A patient aged 50 years or older (menopausal if female) 
3) An outpatient who can walk 
 
5.0 
Dosage and Administration in Surveillance Patients 
Patients will orally receive 75 mg of sodium risedronate with sufficient water (approximately 
180 mL) upon awakening once a month. They should not lie, consume food or beverages 
except water, or orally receive any other drugs for at least 30 minutes after dosing. In addition, 
the precautions concerning dosage and administration in the package insert should be referred 
to. 
 
6.0 
Planned Number of Medical Institutions by Department 
Orthopedics, internal medicine, and other departments Approximately 50 to 85 medical 
institutions 
 
7.0 
Surveillance Method 
7.1 Observation Period 
36 months 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a paper case report form (CRF). A representative of 
Takeda Pharmaceutical Co., Ltd. (hereinafter referred to as Takeda’s representative) will 
explain the objectives, contents, and methods of the surveillance to the investigator based on 
“Request for cooperation for special drug use surveillance,” “Implementation outline,” 
“Patient registration form (sample),” and “Case report form (sample)” 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 fax. After the start of the 
contract with the study site, the investigator shall register each surveillance patient for whom 
Benet is prescribed by faxing a patient registration form containing patient registration 
information (refer to Section 9.1) to the central registration center (refer to Section 11.3) 
within 15 days after the first prescription of Benet (day of the first prescription designated as 
day 1 and day following the day of the first prescription designated as 2 days after 
prescription). No patient can be registered before Benet is actually prescribed. Patients 
determined by the central registration center to be ineligible for any reason cannot be 

 
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4 
9.1 Entries into the Patient Registration Form 
1) Surveillance items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of the first prescription of Benet, date of the scheduled first dosing of Benet, 
patient identification number, patient initials, sex, date of birth, assessment based on the 
selection criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Entries into the Case Report Form 
9.2.1 Cover of the Case Report Form 
Date of final entry into the CRF, name of a physician who completes the CRF 
 
9.2.2 Patient Baseline Characteristics 
1) Surveillance items 
Disease to be treated, time of diagnosis of osteoporosis, body weight, predisposition to 
hypersensitivity (presence or absence and details), concurrent illness (presence or absence 
and details), medical history (except previous fracture) (presence or absence and details), 
risk factors for fracture [medical history (previous fracture), previous steroid use, parental 
history of femur fracture], drinking history, smoking history 
2) Time points of surveillance 
At the start of Benet treatment 
 
9.2.3 Treatment Given 
1) Surveillance items 
Treatment status of Benet (date of dosing indicated by a prescribing physician, patient’s 
treatment status, reason for discontinuation of treatment, and date of discontinuation), 
treatment status of osteoporosis drug (including calcium and vitamin D) other than Benet 
given from 3 months before the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) (presence or absence, name of the drug, daily 
dose, and duration of treatment), treatment status of steroid (presence or absence, name of 
the drug, daily dose, duration of treatment, and purpose of treatment), treatment status of 
concomitant medication other than osteoporosis drugs and steroids* (presence or absence, 
name of the drug, and purpose of treatment), presence or absence of concomitant therapy 
for osteoporosis (physical therapy, other concomitant therapy) 
* The daily dose and duration of treatment will be confirmed in the following situations: 
 • An adverse event occurs; or 
 • The sponsor considers it necessary to collect this information. 
2) Time points of surveillance 
Period from the start of Benet treatment to 36 months after the start of treatment (or 

 
5 
discontinuation of treatment) 
 
9.2.4 Tests/Observations 
9.2.4.1 Laboratory Tests 
1) Surveillance items 
If laboratory testing such as hematology or blood chemistry is performed during Benet 
treatment, any abnormal change in laboratory parameter will be entered into the adverse 
event column in the CRF. In addition, only relevant laboratory values will be entered into 
the column for adverse event-related clinically significant change in laboratory parameter.  
2) Time points of surveillance 
Time points of test from the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) 
 
9.2.4.2 Bone Mineral Density 
1) Surveillance items 
 Lumbar dual-energy x-ray absorptiometry (DXA), proximal femur DXA, radius 
DXA/peripheral quantitative computed tomography (pQCT), calcaneal DXA/quantitative 
ultrasound (QUS), second metacarpal bone microdensitometry (MD)/computed x-ray 
densitometry (CXD)/digital image processing (DIP) 
2) Time points of surveillance 
 At the start of Benet treatment (within 3 months before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 
* Performed if necessary 
 
9.2.4.3 Bone Turnover Markers 
1) Surveillance items 
Bone resorption markers: 
Serum N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen 
(CTX), serum tartrate-resistant acid phosphatase (TRACP-5b), urinary NTX, urinary CTX, 
urinary deoxypyridinoline (DPD) 
Bone formation markers: 
Serum bone-specific alkaline phosphatase (BAP), serum N-propeptide of type I 
procollagen (P1NP) 
Bone matrix-related marker:  
Serum undercarboxylated osteocalcin (ucOC) 
2) Time points of surveillance 
At the start of Benet treatment (within 1 month before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 

 
6 
* Performed if necessary 
 
9.2.5 Assessment of Vertebral Fracture 
1) Surveillance items 
Vertebral fracture before the start of Benet treatment (baseline) will be confirmed, and the 
date of radiography, radiographic location, and location of vertebral fracture will be entered 
into the CRF. Then, the presence or absence and location of new vertebral fracture, 
presence or absence of worsening of prevalent vertebral fracture, and presence or absence 
of apparent trauma during treatment and at the end of the observation period (or 
discontinuation of treatment) relative to baseline will be entered into the CRF. 
2) Time points of surveillance 
At the start of Benet treatment, 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment), and when vertebral fracture is suspected during the 
observation period 
 
9.2.6 Assessment of Non-vertebral Fracture 
1) Surveillance items 
Non-vertebral fracture during Benet treatment involving the femur, wrist, forearm, upper 
arm, pelvis, lower limb, etc. will be entered into the CRF. Confirmed non-vertebral fracture 
will be handled as an adverse event, and the fracture site, date of fracture (date of onset), 
presence or absence and details of apparent trauma, seriousness, reason for seriousness, 
presence or absence of discontinuation of Benet treatment, date of outcome assessment, 
outcome, and causal relationship to Benet will be entered into the CRF. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when non-vertebral fracture is confirmed during the observation period 
 
9.2.7 Clinical Findings 
1) Surveillance items 
Height, low back pain 
2) Time points of surveillance 
Time points of medical examination at the start of treatment and 3, 6, 12, 18, 24, 30, and 
36 months after the start of treatment (or discontinuation of treatment) 
Only at the start of treatment and 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment) for height 
 
9.3 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and reason 
for seriousness (refer to Table 2), presence or absence of discontinuation of Benet treatment, 
date of outcome assessment, outcome, causal relationship to Benet* (refer to Table 3) 

 
7 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
Any new vertebral fracture or worsening of prevalent fracture during treatment will be 
entered into the adverse event column. 
The following events will also be entered into the adverse event column: upper 
gastrointestinal disorder, hepatic function disorder/jaundice, osteonecrosis of 
jaw/osteomyelitis of jaw, atypical fracture of subtrochanteric section of femur or shaft of 
proximal femur, musculoskeletal pain, atrial fibrillation, esophageal carcinoma, and 
gastrointestinal disorders including diarrhea. 
* For the causal relationship to Benet, the rationale for “not related” and the reason for “unevaluable” shall 
be collected. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when an AE is confirmed during the observation period 
 
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 
• Symptoms and so forth that occur in children treated with a drug 
• Symptoms and so forth that occur after administration or self-administration of a drug at higher doses 
than the approved dose 
 
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. Otherwise, is an important medical event (for instance, bronchospasm requiring short-term 
intensive care in an emergency room), including AEs in Takeda Medically Significant AE List 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
• Anaphylactic shock 

 
8 
• 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 
• 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 
 
Table 3  Criteria for assessing the relationship of each adverse event to Benet 
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 
Data from patients enrolled for Benet and Actonel 75 mg Tablets will be combined for 
analysis. 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients for whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Baseline Characteristics 
Patient baseline characteristics, including age, sex, duration of disease, height, body weight, 

 
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12 
○: Surveyed/examined/observed 
(○): Examined if necessary 
     ○      : Surveyed/examined/observed throughout the period 
* Height will be measured at the start of treatment and 12, 24, and 36 months after the start of treatment 
(or discontinuation of treatment). 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Benet 75 mg Tablets 
Special Drug Use Surveillance on Fracture Incidence 
during 36-Month Treatment 
 
 
 
 
 
 
 
 
Version number 
3rd version 
Date of preparation 
1 April 2015 
Sponsor 
Takeda Pharmaceutical Co., Ltd. 
 

 
Table of Contents 
1.0 
Background of the Surveillance ..................................................................................................... 1 
2.0 
Objectives of the Surveillance ........................................................................................................ 1 
3.0 
Planned Sample Size and Rationale ............................................................................................. 1 
3.1 
Planned Sample Size .................................................................................................................. 1 
3.2 
Rationale ...................................................................................................................................... 1 
4.0 
Surveillance Population ................................................................................................................. 1 
5.0 
Dosage and Administration in Surveillance Patients .................................................................. 2 
6.0 
Planned Number of Medical Institutions by Department ........................................................... 2 
7.0 
Surveillance Method ....................................................................................................................... 2 
7.1 
Observation Period ...................................................................................................................... 2 
7.2 
Request to and Contract with the Study Site ........................................................................... 2 
7.3 
Method of Patient Registration .................................................................................................. 2 
7.4 
Completion and Submission of Case Report Form ................................................................... 3 
7.5 
Actions to be Taken in Case of Serious Adverse Events........................................................... 3 
8.0 
Planned Surveillance Period .......................................................................................................... 3 
9.0 
Surveillance Items .......................................................................................................................... 3 
9.1 
Entries into the Patient Registration Form .............................................................................. 4 
9.2 
Entries into the Case Report Form ............................................................................................ 4 
9.2.1 
Cover of the Case Report Form ........................................................................................... 4 
9.2.2 
Patient Baseline Characteristics ........................................................................................ 4 
9.2.3 
Treatment Given .................................................................................................................. 4 
9.2.4 
Tests/Observations ............................................................................................................... 5 
9.2.4.1 
Laboratory Tests ............................................................................................................... 5 
9.2.4.2 
Bone Mineral Density ...................................................................................................... 5 
9.2.4.3 
Bone Turnover Markers ................................................................................................... 5 
9.2.5 
Assessment of Vertebral Fracture ...................................................................................... 6 
9.2.6 
Assessment of Non-vertebral Fracture .............................................................................. 6 
9.2.7 
Clinical Findings .................................................................................................................. 6 
9.3 
Adverse Events (AEs) ................................................................................................................. 6 
10.0 Analysis Items and Methods .......................................................................................................... 8 
10.1 Matters on Patient Composition ................................................................................................ 8 
10.2 Patient Baseline Characteristics ............................................................................................... 8 
10.3 Treatment Compliance Status ................................................................................................... 9 
10.4 Matters on Safety ........................................................................................................................ 9 
10.5 Matters on Efficacy ..................................................................................................................... 9 
10.5.1 
Primary Endpoint ................................................................................................................ 9 
10.5.2 
Secondary Endpoints ........................................................................................................... 9 
10.6 Analysis Methods ........................................................................................................................ 9 
11.0 
Surveillance Organization.............................................................................................................. 9 

 
11.1 
Surveillance Administrative Manager....................................................................................... 9 
11.2 
Medical Expert ............................................................................................................................ 9 
11.3 
Central Registration Center ....................................................................................................... 9 
12.0 Name, Address, and Scope of Operations of Contract Research Organizations (CROs) ......... 10 
13.0 Other Necessary Matters ............................................................................................................. 10 
13.1 Revision of the Protocol ............................................................................................................ 10 
13.2 Actions to be Taken for Problems and Questions ................................................................... 10 
 
Appendix  Surveillance schedule...............................................................................................................11 

 
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2 
1) A patient with evidence of 1 to 4 fractures from the fourth thoracic vertebra to the fourth 
lumbar vertebra (T4 to L4) provided by thoracic and lumbar spinal radiography 
performed before the start of the surveillance (within 3 months before the start of 
prescription of Benet) 
2) A patient aged 50 years or older (menopausal if female) 
3) An outpatient who can walk 
 
5.0 
Dosage and Administration in Surveillance Patients 
Patients will orally receive 75 mg of sodium risedronate with sufficient water (approximately 
180 mL) upon awakening once a month. They should not lie, consume food or beverages 
except water, or orally receive any other drugs for at least 30 minutes after dosing. In addition, 
the precautions concerning dosage and administration in the package insert should be referred 
to. 
 
6.0 
Planned Number of Medical Institutions by Department 
Orthopedics, internal medicine, and other departments Approximately 50 to 85 medical 
institutions 
 
7.0 
Surveillance Method 
7.1 Observation Period 
36 months 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a paper case report form (CRF). A representative of 
Takeda Pharmaceutical Co., Ltd. (hereinafter referred to as Takeda’s representative) will 
explain the objectives, contents, and methods of the surveillance to the investigator based on 
“Request for cooperation for special drug use surveillance,” “Implementation outline,” 
“Patient registration form (sample),” and “Case report form (sample)” 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 fax. After the start of the 
contract with the study site, the investigator shall register each surveillance patient for whom 
Benet is prescribed by faxing a patient registration form containing patient registration 
information (refer to Section 9.1) to the central registration center (refer to Section 11.3) 
within 15 days after the first prescription of Benet (day of the first prescription designated as 
day 1 and day following the day of the first prescription designated as 2 days after 
prescription). No patient can be registered before Benet is actually prescribed. Patients 
determined by the central registration center to be ineligible for any reason cannot be 

 
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4 
9.1 Entries into the Patient Registration Form 
1) Surveillance items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of the first prescription of Benet, date of the scheduled first dosing of Benet, 
patient identification number, patient initials, sex, date of birth, assessment based on the 
selection criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Entries into the Case Report Form 
9.2.1 Cover of the Case Report Form 
Date of final entry into the CRF, name of a physician who completes the CRF 
 
9.2.2 Patient Baseline Characteristics 
1) Surveillance items 
Disease to be treated, time of diagnosis of osteoporosis, body weight, predisposition to 
hypersensitivity (presence or absence and details), concurrent illness (presence or absence 
and details), medical history (except previous fracture) (presence or absence and details), 
risk factors for fracture [medical history (previous fracture), previous steroid use, parental 
history of femur fracture], drinking history, smoking history 
2) Time points of surveillance 
At the start of Benet treatment 
 
9.2.3 Treatment Given 
1) Surveillance items 
Treatment status of Benet (date of dosing indicated by a prescribing physician, patient’s 
treatment status, reason for discontinuation of treatment, and date of discontinuation), 
treatment status of osteoporosis drug (including calcium and vitamin D) other than Benet 
given from 3 months before the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) (presence or absence, name of the drug, daily 
dose, and duration of treatment), treatment status of steroid (presence or absence, name of 
the drug, daily dose, duration of treatment, and purpose of treatment), treatment status of 
concomitant medication other than osteoporosis drugs and steroids* (presence or absence, 
name of the drug, and purpose of treatment), presence or absence of concomitant therapy 
for osteoporosis (physical therapy, other concomitant therapy) 
* The daily dose and duration of treatment will be confirmed in the following situations: 
 • An adverse event occurs; or 
 • The sponsor considers it necessary to collect this information. 
2) Time points of surveillance 
Period from the start of Benet treatment to 36 months after the start of treatment (or 

 
5 
discontinuation of treatment) 
 
9.2.4 Tests/Observations 
9.2.4.1 Laboratory Tests 
1) Surveillance items 
If laboratory testing such as hematology or blood chemistry is performed during Benet 
treatment, any abnormal change in laboratory parameter will be entered into the adverse 
event column in the CRF. In addition, only relevant laboratory values will be entered into 
the column for adverse event-related clinically significant change in laboratory parameter.  
2) Time points of surveillance 
Time points of test from the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) 
 
9.2.4.2 Bone Mineral Density 
1) Surveillance items 
 Lumbar dual-energy x-ray absorptiometry (DXA), proximal femur DXA, radius 
DXA/peripheral quantitative computed tomography (pQCT), calcaneal DXA/quantitative 
ultrasound (QUS), second metacarpal bone microdensitometry (MD)/computed x-ray 
densitometry (CXD)/digital image processing (DIP) 
2) Time points of surveillance 
 At the start of Benet treatment (within 3 months before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 
* Performed if necessary 
 
9.2.4.3 Bone Turnover Markers 
1) Surveillance items 
Bone resorption markers: 
Serum N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen 
(CTX), serum tartrate-resistant acid phosphatase (TRACP-5b), urinary NTX, urinary CTX, 
urinary deoxypyridinoline (DPD) 
Bone formation markers: 
Serum bone-specific alkaline phosphatase (BAP), serum N-propeptide of type I 
procollagen (P1NP) 
Bone matrix-related marker:  
Serum undercarboxylated osteocalcin (ucOC) 
2) Time points of surveillance 
At the start of Benet treatment (within 1 month before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 

 
6 
* Performed if necessary 
 
9.2.5 Assessment of Vertebral Fracture 
1) Surveillance items 
Vertebral fracture before the start of Benet treatment (baseline) will be confirmed, and the 
date of radiography, radiographic location, and location of vertebral fracture will be entered 
into the CRF. Then, the presence or absence and location of new vertebral fracture, 
presence or absence of worsening of prevalent vertebral fracture, and presence or absence 
of apparent trauma during treatment and at the end of the observation period (or 
discontinuation of treatment) relative to baseline will be entered into the CRF. 
2) Time points of surveillance 
At the start of Benet treatment, 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment), and when vertebral fracture is suspected during the 
observation period 
 
9.2.6 Assessment of Non-vertebral Fracture 
1) Surveillance items 
Non-vertebral fracture during Benet treatment involving the femur, wrist, forearm, upper 
arm, pelvis, lower limb, etc. will be entered into the CRF. Confirmed non-vertebral fracture 
will be handled as an adverse event, and the fracture site, date of fracture (date of onset), 
presence or absence and details of apparent trauma, seriousness, reason for seriousness, 
presence or absence of discontinuation of Benet treatment, date of outcome assessment, 
outcome, and causal relationship to Benet will be entered into the CRF. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when non-vertebral fracture is confirmed during the observation period 
 
9.2.7 Clinical Findings 
1) Surveillance items 
Height, low back pain 
2) Time points of surveillance 
Time points of medical examination at the start of treatment and 3, 6, 12, 18, 24, 30, and 
36 months after the start of treatment (or discontinuation of treatment) 
Only at the start of treatment and 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment) for height 
 
9.3 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and reason 
for seriousness (refer to Table 2), presence or absence of discontinuation of Benet treatment, 
date of outcome assessment, outcome, causal relationship to Benet* (refer to Table 3) 

 
7 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
Any new vertebral fracture or worsening of prevalent fracture during treatment will be 
entered into the adverse event column. 
The following events will also be entered into the adverse event column: upper 
gastrointestinal disorder, hepatic function disorder/jaundice, osteonecrosis of 
jaw/osteomyelitis of jaw, atypical fracture of subtrochanteric section of femur or shaft of 
proximal femur, musculoskeletal pain, atrial fibrillation, esophageal carcinoma, and 
gastrointestinal disorders including diarrhea. 
* For the causal relationship to Benet, the rationale for “not related” and the reason for “unevaluable” shall 
be collected. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when an AE is confirmed during the observation period 
 
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 
• Symptoms and so forth that occur in children treated with a drug 
• Symptoms and so forth that occur after administration or self-administration of a drug at higher doses 
than the approved dose 
 
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. Otherwise, is an important medical event (for instance, bronchospasm requiring short-term 
intensive care in an emergency room), including AEs in Takeda Medically Significant AE List 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
• Anaphylactic shock 

 
8 
• 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 
• 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 
 
Table 3  Criteria for assessing the relationship of each adverse event to Benet 
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 
Data from patients enrolled for Benet and Actonel 75 mg Tablets will be combined for 
analysis. 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients for whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Baseline Characteristics 
Patient baseline characteristics, including age, sex, duration of disease, height, body weight, 

 
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12 
○: Surveyed/examined/observed 
(○): Examined if necessary 
     ○      : Surveyed/examined/observed throughout the period 
* Height will be measured at the start of treatment and 12, 24, and 36 months after the start of treatment 
(or discontinuation of treatment). 
 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Benet 75 mg Tablets 
Special Drug Use Surveillance on Fracture Incidence 
during 36-Month Treatment 
 
 
 
 
 
 
 
 
Version number 
2nd version 
Date of preparation 
16 April 2013 
Sponsor 
Takeda Pharmaceutical Co., Ltd. 
 

 
Table of Contents 
1.0 
Background of the Surveillance ..................................................................................................... 1 
2.0 
Objectives of the Surveillance ........................................................................................................ 1 
3.0 
Planned Sample Size and Rationale ............................................................................................. 1 
3.1 
Planned Sample Size .................................................................................................................. 1 
3.2 
Rationale ...................................................................................................................................... 1 
4.0 
Surveillance Population ................................................................................................................. 1 
5.0 
Dosage and Administration in Surveillance Patients .................................................................. 2 
6.0 
Planned Number of Medical Institutions by Department ........................................................... 2 
7.0 
Surveillance Method ....................................................................................................................... 2 
7.1 
Observation Period ...................................................................................................................... 2 
7.2 
Request to and Contract with the Study Site ........................................................................... 2 
7.3 
Method of Patient Registration .................................................................................................. 2 
7.4 
Completion and Submission of Case Report Form ................................................................... 3 
7.5 
Actions to be Taken in Case of Serious Adverse Events........................................................... 3 
8.0 
Planned Surveillance Period .......................................................................................................... 3 
9.0 
Surveillance Items .......................................................................................................................... 3 
9.1 
Entries into the Patient Registration Form .............................................................................. 4 
9.2 
Entries into the Case Report Form ............................................................................................ 4 
9.2.1 
Cover of the Case Report Form ........................................................................................... 4 
9.2.2 
Patient Baseline Characteristics ........................................................................................ 4 
9.2.3 
Treatment Given .................................................................................................................. 4 
9.2.4 
Tests/Observations ............................................................................................................... 5 
9.2.4.1 
Laboratory Tests ............................................................................................................... 5 
9.2.4.2 
Bone Mineral Density ...................................................................................................... 5 
9.2.4.3 
Bone Turnover Markers ................................................................................................... 5 
9.2.5 
Assessment of Vertebral Fracture ...................................................................................... 6 
9.2.6 
Assessment of Non-vertebral Fracture .............................................................................. 6 
9.2.7 
Clinical Findings .................................................................................................................. 6 
9.3 
Adverse Events (AEs) ................................................................................................................. 6 
10.0 Analysis Items and Methods .......................................................................................................... 8 
10.1 Matters on Patient Composition ................................................................................................ 8 
10.2 Patient Baseline Characteristics ............................................................................................... 8 
10.3 Treatment Compliance Status ................................................................................................... 9 
10.4 Matters on Safety ........................................................................................................................ 9 
10.5 Matters on Efficacy ..................................................................................................................... 9 
10.5.1 
Primary Endpoint ................................................................................................................ 9 
10.5.2 
Secondary Endpoints ........................................................................................................... 9 
10.6 Analysis Methods ........................................................................................................................ 9 
11.0 
Surveillance Organization.............................................................................................................. 9 

 
11.1 
Surveillance Administrative Manager....................................................................................... 9 
11.2 
Medical Expert ............................................................................................................................ 9 
11.3 
Central Registration Center ....................................................................................................... 9 
12.0 Name, Address, and Scope of Operations of Contract Research Organizations (CROs) ......... 10 
13.0 Other Necessary Matters ............................................................................................................. 10 
13.1 Revision of the Protocol ............................................................................................................ 10 
13.2 Actions to be Taken for Problems and Questions ................................................................... 10 
 
Appendix  Surveillance schedule...............................................................................................................11 

 
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2 
1) A patient with evidence of 1 to 4 fractures from the fourth thoracic vertebra to the fourth 
lumbar vertebra (T4 to L4) provided by thoracic and lumbar spinal radiography 
performed before the start of the surveillance (within 3 months before the start of 
prescription of Benet) 
2) A patient aged 50 years or older (menopausal if female) 
3) An outpatient who can walk 
 
5.0 
Dosage and Administration in Surveillance Patients 
Patients will orally receive 75 mg of sodium risedronate with sufficient water (approximately 
180 mL) upon awakening once a month. They should not lie, consume food or beverages 
except water, or orally receive any other drugs for at least 30 minutes after dosing. In addition, 
the precautions concerning dosage and administration in the package insert should be referred 
to. 
 
6.0 
Planned Number of Medical Institutions by Department 
Orthopedics, internal medicine, and other departments Approximately 50 to 85 medical 
institutions 
 
7.0 
Surveillance Method 
7.1 Observation Period 
36 months 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a paper case report form (CRF). A medical 
representative of Takeda Pharmaceutical Co., Ltd. (hereinafter referred to as Takeda’s MR) 
will explain the objectives, contents, and methods of the surveillance to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation outline,” 
“Patient registration form (sample),” and “Case report form (sample)” 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 fax. After the start of the 
contract with the study site, the investigator shall register each surveillance patient for whom 
Benet is prescribed by faxing a patient registration form containing patient registration 
information (refer to Section 9.1) to the central registration center (refer to Section 11.3) 
within 15 days after the first prescription of Benet (day of the first prescription designated as 
day 1 and day following the day of the first prescription designated as 2 days after 
prescription). No patient can be registered before Benet is actually prescribed. Patients 
determined by the central registration center to be ineligible for any reason cannot be 

 
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4 
9.1 Entries into the Patient Registration Form 
1) Surveillance items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of the first prescription of Benet, date of the scheduled first dosing of Benet, 
patient identification number, patient initials, sex, date of birth, assessment based on the 
selection criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Entries into the Case Report Form 
9.2.1 Cover of the Case Report Form 
Date of final entry into the CRF, name of a physician who completes the CRF 
 
9.2.2 Patient Baseline Characteristics 
1) Surveillance items 
Disease to be treated, time of diagnosis of osteoporosis, body weight, predisposition to 
hypersensitivity (presence or absence and details), concurrent illness (presence or absence 
and details), medical history (except previous fracture) (presence or absence and details), 
risk factors for fracture [medical history (previous fracture), previous steroid use, parental 
history of femur fracture], drinking history, smoking history 
2) Time points of surveillance 
At the start of Benet treatment 
 
9.2.3 Treatment Given 
1) Surveillance items 
Treatment status of Benet (date of dosing indicated by a prescribing physician, patient’s 
treatment status, reason for discontinuation of treatment, and date of discontinuation), 
treatment status of osteoporosis drug (including calcium and vitamin D) other than Benet 
given from 3 months before the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) (presence or absence, name of the drug, daily 
dose, and duration of treatment), treatment status of steroid (presence or absence, name of 
the drug, daily dose, duration of treatment, and purpose of treatment), treatment status of 
concomitant medication other than osteoporosis drugs and steroids* (presence or absence, 
name of the drug, and purpose of treatment), presence or absence of concomitant therapy 
for osteoporosis (physical therapy, other concomitant therapy) 
* The daily dose and duration of treatment will be confirmed in the following situations: 
 • An adverse event occurs; or 
 • The sponsor considers it necessary to collect this information. 
2) Time points of surveillance 
Period from the start of Benet treatment to 36 months after the start of treatment (or 

 
5 
discontinuation of treatment) 
 
9.2.4 Tests/Observations 
9.2.4.1 Laboratory Tests 
1) Surveillance items 
If laboratory testing such as hematology or blood chemistry is performed during Benet 
treatment, any abnormal change in laboratory parameter will be entered into the adverse 
event column in the CRF. In addition, only relevant laboratory values will be entered into 
the column for adverse event-related clinically significant change in laboratory parameter.  
2) Time points of surveillance 
Time points of test from the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) 
 
9.2.4.2 Bone Mineral Density 
1) Surveillance items 
 Lumbar dual-energy x-ray absorptiometry (DXA), proximal femur DXA, radius 
DXA/peripheral quantitative computed tomography (pQCT), calcaneal DXA/quantitative 
ultrasound (QUS), second metacarpal bone microdensitometry (MD)/computed x-ray 
densitometry (CXD)/digital image processing (DIP) 
2) Time points of surveillance 
 At the start of Benet treatment (within 3 months before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 
* Performed if necessary 
 
9.2.4.3 Bone Turnover Markers 
1) Surveillance items 
Bone resorption markers: 
Serum N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen 
(CTX), serum tartrate-resistant acid phosphatase (TRACP-5b), urinary NTX, urinary CTX, 
urinary deoxypyridinoline (DPD) 
Bone formation markers: 
Serum bone-specific alkaline phosphatase (BAP), serum N-propeptide of type I 
procollagen (P1NP) 
Bone matrix-related marker:  
Serum undercarboxylated osteocalcin (ucOC) 
2) Time points of surveillance 
At the start of Benet treatment (within 1 month before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 

 
6 
* Performed if necessary 
 
9.2.5 Assessment of Vertebral Fracture 
1) Surveillance items 
Vertebral fracture before the start of Benet treatment (baseline) will be confirmed, and the 
date of radiography, radiographic location, and location of vertebral fracture will be entered 
into the CRF. Then, the presence or absence and location of new vertebral fracture, 
presence or absence of worsening of prevalent vertebral fracture, and presence or absence 
of apparent trauma during treatment and at the end of the observation period (or 
discontinuation of treatment) relative to baseline will be entered into the CRF. 
2) Time points of surveillance 
At the start of Benet treatment, 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment), and when vertebral fracture is suspected during the 
observation period 
 
9.2.6 Assessment of Non-vertebral Fracture 
1) Surveillance items 
Non-vertebral fracture during Benet treatment involving the femur, wrist, forearm, upper 
arm, pelvis, lower limb, etc. will be entered into the CRF. Confirmed non-vertebral fracture 
will be handled as an adverse event, and the fracture site, date of fracture (date of onset), 
presence or absence and details of apparent trauma, seriousness, reason for seriousness, 
presence or absence of discontinuation of Benet treatment, date of outcome assessment, 
outcome, and causal relationship to Benet will be entered into the CRF. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when non-vertebral fracture is confirmed during the observation period 
 
9.2.7 Clinical Findings 
1) Surveillance items 
Height, low back pain 
2) Time points of surveillance 
Time points of medical examination at the start of treatment and 3, 6, 12, 18, 24, 30, and 
36 months after the start of treatment (or discontinuation of treatment) 
Only at the start of treatment and 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment) for height 
 
9.3 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and reason 
for seriousness (refer to Table 2), presence or absence of discontinuation of Benet treatment, 
date of outcome assessment, outcome, causal relationship to Benet* (refer to Table 3) 

 
7 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 
Any new vertebral fracture or worsening of prevalent fracture during treatment will be 
entered into the adverse event column. 
The following events will also be entered into the adverse event column: upper 
gastrointestinal disorder, hepatic function disorder/jaundice, osteonecrosis of 
jaw/osteomyelitis of jaw, atypical fracture of subtrochanteric section of femur or shaft of 
proximal femur, musculoskeletal pain, atrial fibrillation, esophageal carcinoma, and 
gastrointestinal disorders including diarrhea. 
* For the causal relationship to Benet, the rationale for “not related” and the reason for “unevaluable” shall 
be collected. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when an AE is confirmed during the observation period 
 
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 
• Symptoms and so forth that occur in children treated with a drug 
• Symptoms and so forth that occur after administration or self-administration of a drug at higher doses 
than the approved dose 
 
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. Otherwise, is an important medical event (for instance, bronchospasm requiring short-term 
intensive care in an emergency room), including AEs in Takeda Medically Significant AE List 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
• Anaphylactic shock 

 
8 
• 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 
• 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 
 
Table 3  Criteria for assessing the relationship of each adverse event to Benet 
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 
Data from patients enrolled for Benet and Actonel 75 mg Tablets will be combined for 
analysis. 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients for whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Baseline Characteristics 
Patient baseline characteristics, including age, sex, duration of disease, height, body weight, 

 
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12 
○: Surveyed/examined/observed 
(○): Examined if necessary 
     ○      : Surveyed/examined/observed throughout the period 
* Height will be measured at the start of treatment and 12, 24, and 36 months after the start of treatment 
(or discontinuation of treatment). 

 
 
 
 
 
Special Drug Use Surveillance Protocol 
Benet 75 mg Tablets 
Special Drug Use Surveillance on Fracture Incidence 
during 36-Month Treatment 
 
 
 
 
 
 
 
 
Version number 
1st version 
Date of preparation 
27 February 2013 
Sponsor 
Takeda Pharmaceutical Co., Ltd. 
 

 
Table of Contents 
1.0 
Background of the Surveillance ..................................................................................................... 1 
2.0 
Objectives of the Surveillance ........................................................................................................ 1 
3.0 
Planned Sample Size and Rationale ............................................................................................. 1 
3.1 
Planned Sample Size .................................................................................................................. 1 
3.2 
Rationale ...................................................................................................................................... 1 
4.0 
Surveillance Population ................................................................................................................. 1 
5.0 
Dosage and Administration in Surveillance Patients .................................................................. 2 
6.0 
Planned Number of Medical Institutions by Department ........................................................... 2 
7.0 
Surveillance Method ....................................................................................................................... 2 
7.1 
Observation Period ...................................................................................................................... 2 
7.2 
Request to and Contract with the Study Site ........................................................................... 2 
7.3 
Method of Patient Registration .................................................................................................. 2 
7.4 
Completion and Submission of Case Report Form ................................................................... 3 
7.5 
Actions to be Taken in Case of Serious Adverse Events........................................................... 3 
8.0 
Planned Surveillance Period .......................................................................................................... 3 
9.0 
Surveillance Items .......................................................................................................................... 3 
9.1 
Entries into the Patient Registration Form .............................................................................. 4 
9.2 
Entries into the Case Report Form ............................................................................................ 4 
9.2.1 
Cover of the Case Report Form ........................................................................................... 4 
9.2.2 
Patient Baseline Characteristics ........................................................................................ 4 
9.2.3 
Treatment Given .................................................................................................................. 4 
9.2.4 
Tests/Observations ............................................................................................................... 5 
9.2.4.1 
Laboratory Tests ............................................................................................................... 5 
9.2.4.2 
Bone Mineral Density ...................................................................................................... 5 
9.2.4.3 
Bone Turnover Markers ................................................................................................... 5 
9.2.5 
Assessment of Vertebral Fracture ...................................................................................... 6 
9.2.6 
Assessment of Non-vertebral Fracture .............................................................................. 6 
9.2.7 
Clinical Findings .................................................................................................................. 6 
9.3 
Adverse Events (AEs) ................................................................................................................. 6 
10.0 Analysis Items and Methods .......................................................................................................... 8 
10.1 Matters on Patient Composition ................................................................................................ 8 
10.2 Patient Baseline Characteristics ............................................................................................... 8 
10.3 Treatment Compliance Status ................................................................................................... 9 
10.4 Matters on Safety ........................................................................................................................ 9 
10.5 Matters on Efficacy ..................................................................................................................... 9 
10.5.1 
Primary Endpoint ................................................................................................................ 9 
10.5.2 
Secondary Endpoints ........................................................................................................... 9 
10.6 Analysis Methods ........................................................................................................................ 9 
11.0 
Surveillance Organization.............................................................................................................. 9 

 
11.1 
Surveillance Administrative Manager....................................................................................... 9 
11.2 
Medical Expert ............................................................................................................................ 9 
11.3 
Central Registration Center ....................................................................................................... 9 
12.0 Name, Address, and Scope of Operations of Contract Research Organizations (CROs) ......... 10 
13.0 Other Necessary Matters ............................................................................................................. 10 
13.1 Revision of the Protocol ............................................................................................................ 10 
13.2 Actions to be Taken for Problems and Questions ................................................................... 10 
 
Appendix  Surveillance schedule...............................................................................................................11 

 
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2 
1) A patient with evidence of 1 to 4 fractures from the fourth thoracic vertebra to the fourth 
lumbar vertebra (T4 to L4) provided by thoracic and lumbar spinal radiography 
performed before the start of the surveillance (within 3 months before the start of 
prescription of Benet) 
2) A patient aged 50 years or older (menopausal if female) 
3) An outpatient who can walk 
 
5.0 
Dosage and Administration in Surveillance Patients 
Patients will orally receive 75 mg of sodium risedronate with sufficient water (approximately 
180 mL) upon awakening once a month. They should not lie, consume food or beverages 
except water, or orally receive any other drugs for at least 30 minutes after dosing. In addition, 
the precautions concerning dosage and administration in the package insert should be referred 
to. 
 
6.0 
Planned Number of Medical Institutions by Department 
Orthopedics, internal medicine, and other departments Approximately 50 to 85 medical 
institutions 
 
7.0 
Surveillance Method 
7.1 Observation Period 
36 months 
 
7.2 Request to and Contract with the Study Site 
This surveillance will be conducted using a paper case report form (CRF). A medical 
representative of Takeda Pharmaceutical Co., Ltd. (hereinafter referred to as Takeda’s MR) 
will explain the objectives, contents, and methods of the surveillance to the investigator based 
on “Request for cooperation for special drug use surveillance,” “Implementation outline,” 
“Patient registration form (sample),” and “Case report form (sample)” 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 fax. After the start of the 
contract with the study site, the investigator shall register each surveillance patient for whom 
Benet is prescribed by faxing a patient registration form containing patient registration 
information (refer to Section 9.1) to the central registration center (refer to Section 11.3) 
within 15 days after the first prescription of Benet (day of the first prescription designated as 
day 1 and day following the day of the first prescription designated as 2 days after 
prescription). No patient can be registered before Benet is actually prescribed. Patients 
determined by the central registration center to be ineligible for any reason cannot be 

 
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4 
9.1 Entries into the Patient Registration Form 
1) Surveillance items 
Name of the medical institution, name of a physician who completes the patient registration 
form, date of the first prescription of Benet, date of the scheduled first dosing of Benet, 
patient identification number, patient initials, sex, date of birth, assessment based on the 
selection criteria 
2) Time points of surveillance 
At patient registration 
 
9.2 Entries into the Case Report Form 
9.2.1 Cover of the Case Report Form 
Date of final entry into the CRF, name of a physician who completes the CRF 
 
9.2.2 Patient Baseline Characteristics 
1) Surveillance items 
Disease to be treated, time of diagnosis of osteoporosis, body weight, predisposition to 
hypersensitivity (presence or absence and details), concurrent illness (presence or absence 
and details), medical history (except previous fracture) (presence or absence and details), 
risk factors for fracture [medical history (previous fracture), previous steroid use, parental 
history of femur fracture], drinking history, smoking history 
2) Time points of surveillance 
At the start of Benet treatment 
 
9.2.3 Treatment Given 
1) Surveillance items 
Treatment status of Benet (date of dosing indicated by a prescribing physician, patient’s 
treatment status, reason for discontinuation of treatment, and date of discontinuation), 
treatment status of osteoporosis drug (including calcium and vitamin D) other than Benet 
given from 3 months before the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) (presence or absence, name of the drug, and date 
of completion of treatment), treatment status of concomitant medication other than 
osteoporosis drugs (presence or absence, name of the drug, and purpose of treatment), 
presence or absence of concomitant therapy for osteoporosis (physical therapy, other 
concomitant therapy) 
2) Time points of surveillance 
Period from the start of Benet treatment to 36 months after the start of treatment (or 
discontinuation of treatment) 
 

 
5 
9.2.4 Tests/Observations 
9.2.4.1 Laboratory Tests 
1) Surveillance items 
If laboratory testing such as hematology or blood chemistry is performed during Benet 
treatment, any abnormal change in laboratory parameter will be entered into the adverse 
event column in the CRF. In addition, only relevant laboratory values will be entered into 
the column for adverse event-related clinically significant change in laboratory parameter.  
2) Time points of surveillance 
Time points of test from the start of Benet treatment to 36 months after the start of 
treatment (or discontinuation of treatment) 
 
9.2.4.2 Bone Mineral Density 
1) Surveillance items 
 Lumbar dual-energy x-ray absorptiometry (DXA), proximal femur DXA, radius 
DXA/peripheral quantitative computed tomography (pQCT), calcaneal DXA/quantitative 
ultrasound (QUS), second metacarpal bone microdensitometry (MD)/computed x-ray 
densitometry (CXD)/digital image processing (DIP) 
2) Time points of surveillance 
 At the start of Benet treatment (within 3 months before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 
* Performed if necessary 
 
9.2.4.3 Bone Turnover Markers 
1) Surveillance items 
Bone resorption markers: 
Serum N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen 
(CTX), serum tartrate-resistant acid phosphatase (TRACP-5b), urinary NTX, urinary CTX, 
urinary deoxypyridinoline (DPD) 
Bone formation markers: 
Serum bone-specific alkaline phosphatase (BAP), serum N-propeptide of type I 
procollagen (P1NP) 
Bone matrix-related marker:  
Serum undercarboxylated osteocalcin (ucOC) 
2) Time points of surveillance 
At the start of Benet treatment (within 1 month before the start of Benet treatment), 6*, 12, 
18*, 24, 30*, and 36 months after the start of treatment (or discontinuation of treatment), 
and time points of test during the observation period 
* Performed if necessary 
 

 
6 
9.2.5 Assessment of Vertebral Fracture 
1) Surveillance items 
Vertebral fracture before the start of Benet treatment (baseline) will be confirmed, and the 
date of radiography, radiographic location, and location of vertebral fracture will be entered 
into the CRF. Then, the presence or absence and location of new vertebral fracture, 
presence or absence of worsening of prevalent vertebral fracture, and presence or absence 
of apparent trauma during treatment and at the end of the observation period (or 
discontinuation of treatment) relative to baseline will be entered into the CRF. 
2) Time points of surveillance 
At the start of Benet treatment, 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment), and when vertebral fracture is suspected during the 
observation period 
 
9.2.6 Assessment of Non-vertebral Fracture 
1) Surveillance items 
Non-vertebral fracture during Benet treatment involving the femur, wrist, forearm, upper 
arm, pelvis, lower limb, etc. will be entered into the CRF. Confirmed non-vertebral fracture 
will be handled as an adverse event, and the fracture site, date of fracture (date of onset), 
presence or absence and details of apparent trauma, seriousness, reason for seriousness, 
presence or absence of discontinuation of Benet treatment, date of outcome assessment, 
outcome, and causal relationship to Benet will be entered into the CRF. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when non-vertebral fracture is confirmed during the observation period 
 
9.2.7 Clinical Findings 
1) Surveillance items 
Height, low back pain 
2) Time points of surveillance 
Time points of medical examination at the start of treatment and 3, 6, 12, 18, 24, 30, and 
36 months after the start of treatment (or discontinuation of treatment) 
Only at the start of treatment and 12, 24, and 36 months after the start of treatment (or 
discontinuation of treatment) for height 
 
9.3 Adverse Events (AEs) 
1) Surveillance items 
Presence or absence of AE (refer to Table 1), AE term, date of onset, seriousness and reason 
for seriousness (refer to Table 2), presence or absence of discontinuation of Benet treatment, 
date of outcome assessment, outcome, causal relationship to Benet* (refer to Table 3) 
Patients with “not resolved” or “unknown” outcome or “unevaluable” causal relationship 
should be followed up wherever possible. 

 
7 
Any new vertebral fracture or worsening of prevalent fracture during treatment will be 
entered into the adverse event column. 
The following events will also be entered into the adverse event column: upper 
gastrointestinal disorder, hepatic function disorder/jaundice, osteonecrosis of 
jaw/osteomyelitis of jaw, atypical fracture of subtrochanteric section of femur or shaft of 
proximal femur, musculoskeletal pain, atrial fibrillation, esophageal carcinoma, and 
gastrointestinal disorders including diarrhea. 
* For the causal relationship to Benet, the rationale for “not related” and the reason for “unevaluable” shall 
be collected. 
Clinical findings associated with progression of osteoporosis, such as decreased height and 
worsening of low back pain, should not be handled as AEs. 
2) Time points of surveillance 
12, 24, and 36 months after the start of Benet treatment (or discontinuation of treatment) 
and when an AE is confirmed during the observation period 
 
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 
• Symptoms and so forth that occur in children treated with a drug 
• Symptoms and so forth that occur after administration or self-administration of a drug at higher doses 
than the approved dose 
 
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. Otherwise, is an important medical event (for instance, bronchospasm requiring short-term 
intensive care in an emergency room), including AEs in Takeda Medically Significant AE List 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress syndrome (ARDS) 
• Anaphylactic shock 

 
8 
• 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 
• 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 
 
Table 3 Criteria for assessing the relationship of each adverse event to Benet 
Assessment 
Criteria for assessment 
Related 
(Involvement is suspected) 
An AE that follows an apparently 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 
(Involvement is unlikely) 
An AE that does not follow an apparently 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 
Data from patients enrolled for Benet and Actonel 75 mg Tablets will be combined for 
analysis. 
10.1 Matters on Patient Composition 
The number of enrolled patients, number of patients for whom the CRF is collected, number 
of patients included in safety/efficacy analysis, number of patients excluded from analysis, and 
reason for exclusion will be tabulated. 
 
10.2 Patient Baseline Characteristics 
Patient baseline characteristics, including age, sex, duration of disease, height, body weight, 

 
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10 
 
12.0 
Name, Address, and Scope of Operations of Contract Research Organizations (CROs) 
Not determined 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance, attention will be paid to comprehend the status of progression of the 
surveillance, presence or absence of adverse drug reactions (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. 
 
13.2 Actions to be Taken for Problems and Questions 
If any safety or efficacy problem is detected, data will be carefully examined to discuss 
measures. 
 

 
12 
○: Surveyed/examined/observed 
(○): Examined if necessary 
   ○      : Surveyed/examined/observed throughout the period 
* Height will be measured at the start of treatment and 12, 24, and 36 months after the start of treatment 
(or discontinuation of treatment).