Post Marketing Surveillance Study of Safety and Efficacy of Samsca® Tablets Under the "New Drug Re-Examination"
Conditions: Hypervolemic and Euvolemic Hyponatremia
Sponsor: Korea Otsuka Pharmaceutical Co., Ltd.

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Protocol Synopsis 
 
Name of Sponsor:  Korea Otsuka Pharmaceutical Co., Ltd. 
Name of Investigational Medicinal Product: Samsca® Tablets 
Protocol# 
156-KOA-1201n 
Protocol Title: 
Post Marketing Surveillance Study of Safety and Efficacy of 
Samsca® Tablets under the “New Drug Re-Examination” 
Clinical Phase: 
Post Marketing Surveillance 
Treatment Indication:  
The treatment of clinically significant hypervolemic and 
euvolemic hyponatremia [serum sodium < 125 mEq/L or 
hyponatremia that is symptomatic and has resisted correction 
with fluid restriction], including patients with heart failure, 
and Syndrome of Inappropriate Antidiuretic Hormone 
(SIADH) and etc. 
Objective(s): 
The objective of this study is to evaluate following items in 
relation with use of Samsca® in normal medical practice; 
1. Serious adverse event and adverse drug reaction 
profile 
2. Unexpected adverse event/adverse drug reaction 
profile 
3. Known adverse drug reaction profile 
4. Non-serious adverse drug reaction profile 
5. Other information related to the product safety and 
efficacy 
The hypothesis of this study is that Samsca® is safe and 
efficacious in the treatment. 

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Trial Design: 
This is a Post-Marketing Surveillance study of Samsca® 
tablets in accordance with Korean regulations on New Drug 
Re-examination (i.e. New Drug Re-examination Standards: 
MFDS Notification No. 2015-79 dated 30Oct2015). This 
study will be conducted in a prospective, single-arm, multi-
center format. As this study is observational in nature, the 
patient’s follow-up is not prescriptive in nature and must be 
left up to the judgment of the physician (investigator), within 
the period of observation set forth in the protocol.  
The protocol will be developed in accordance with the MFDS 
guideline. 
*MFDS : Ministry of Food and Drug Safety 
Trial Population: 
At least 3000 patients will be enrolled for surveillance to 
meet the local regulatory requirements. About 100~150 
investigators across the country will be participating in this 
surveillance and the number of patients to be enrolled by each 
investigator will vary. 

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Inclusion/Exclusion 
Criteria: 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to 
be eligible for enrollment into the study : 
1. Patients who have hyponatremia in euvolemic or 
hypervolemic states, defined as serum sodium level < 
125 mEq/L or hyponatremia that is symptomatic and 
has resisted correction with fluid restriction 
2. Patients who are prescribed Samsca® treatment as per 
investigator’s medical judgment 
3. Patients who gave written authorization to use their 
personal and health data 
4. Patients starting Samsca® treatment after agreement is 
in place 
Investigators will refer to the product market authorization 
(label) for inclusion criteria. 
Exclusion Criteria 
Subjects presenting with any of the following will not be 
included in the study: 
1. Patients who have been treated with Samsca® 
2. Patients with known or suspected hypersensitivity to 
tolvaptan or to any ingredient of the drug 
3. Patients requiring urgent intervention to raise serum 
sodium acutely. 
4. Inability of the patient to sense or appropriately 
respond to thirst. 
5. Hypovolemic hyponatremia 
6. Concomitant use of strong CYP3A inhibitors 
7. Anuric patients 
8. Volume depletion patients 

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9. Hypernatremia patients 
10.  Women who are pregnant or possibly pregnant and 
lactation 
11.  Patients with rare hereditary problems of galactose 
intolerance, the Lapp lactase deficiency or glucose-
galactose malabsorption 
Investigators will refer to the product market authorization 
(label) for exclusion criteria. 
Investigational 
Medicinal Product(s), 
Dose, Dosage 
regimen, Treatment 
period, Formulation, 
Mode of 
Administration: 
Dose:  Samsca® (Tolvaptan spray dry powder) Tablets, 15mg 
& 30mg 
Dosage regimen: Samsca® is being used 15mg/day to 
60mg/day as per approved marketing authorization (labeling). 
Do not administer Samsca® for more than 30 days to minimize 
the risk of liver injury . 
Mode of administration: P.O 
Treatment period: It should be based on the patient’s 
clinical response. Refer to the package insert for the detailed 
information on prescription. 
Safety Measure: 
1. Adverse Events (AEs)/Adverse Drug Reactions(ADRs), 
Serious Adverse Events(SAEs)/ Serious Adverse Drug 
Reactions(SADRs), Unexpected Adverse 
Events(UAEs)/Unexpected Adverse Drug Reactions(UADRs) 
2. Others: vital signs (blood pressure and pulse), height, 
weight ,BMI 
Efficacy Measures: 
1. The change of serum sodium level from baseline to end of 
treatment period or discharge for a given hyponatremia 
treatment: Efficacy measurement covers a maximum of 4 
days. 
2. Overall judgement 
Holistically judge it according to the judgement of serum 
sodium level and clinical symptoms: Effective, No effect, 
Worsen 

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Statistical Methods: 
Safety analysis set includes all subjects who received 
Samsca® tablets at least once and followed up for the safety 
evaluation. Efficacy analysis set includes all subjects who 
received Samsca® tablets and efficacy evaluation data is 
available. 
In interim reports, the descriptive statistics for continuous 
variables and frequency (n) and percentage (%) for 
categorical variables will be presented in overall patients.  
In final report (Re-examination report), safety and efficacy 
measures will be summarized and analyzed in overall patients 
and by background factors.  
For continuous variables, the descriptive statistics will be 
presented, and the analysis will be performed using the 
analysis of covariance (ANCOVA) model with background 
as a factor and baseline serum sodium level as a covariate. 
For categorical variables, frequency (n) and percentage (%) 
will be presented, and the analysis will be performed using 
Chi-square test or Fisher’s exact test between categories of 
background factors. Also, 95% confidence interval of 
incidence rate of adverse event will be described. 
Data for special population (i.e. pregnant women, elderly 
patients, patients with liver or renal disease) will be presented 
as well. 
Estimated Duration of 
study 
Planned study schedule as per local regulation is as below; 
1. Regulatory approval on Samsca®: September 2011 
2. Product launch date: December 2012 
3. Study period: September 2011 – August 2017 
4. Interim reports to MFDS: every 6 months for first 2 
years, then annually thereafter. 
5. Final report to MFDS: within 3 months of study 
completion 
 
 
 

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[Appendix]  
 
Management and reporting of safety information  
Collection period of safety information is after first use of Otsuka product until 2 days after 
discontinuation RESEARCHER shall submit to OTSUKA any SAFETY EVENT within the 
following timeline: 
(a) Twenty-four (24) hours from RESEARCHER’s receipt of SAFETY EVENT classified as 
serious adverse event and non-serious adverse event (defined below) or Product Quality 
Complaint (PQC) or Pregnancy;  
(b) For all other safety information as defined above and not specified in (a), RESEARCHER 
shall send the line-listing to OTSUKA at the end of each study, or during the study upon 
OTSUKA’s request. 
Procedures for the collection, management and reporting of individual cases of  safety 
information while the study is being conducted, and for the periodic and end of study 
reconciliation of serious/non-serious adverse events between PV database and study 
database, aligned with the current version of G-SOP-ALL-007. Safety data reconciliation 
will be conducted comparing the safety database and the clinical database when study 
report (annual report& re-examination report) is submitted. The detail of reconciliation 
including frequency will be described in the Data Management Plan (DMP). 
Below is the definition of Safety information including Adverse Event(AE), Serious Adverse 
Event(SAE), Non-Serious Adverse Event(NSAE). 
Safety 
information 
Safety Information as below will be reported in accordance with the current 
Otsuka Global GxP/Pharmacovigilance Glossary. “Any information from any 
source containing information including 
- 
Adverse event or suspension thereof 
- 
Lack of efficacy 
- 
Overdose/incorrect dosage (accidental or intentional) 
- 
Abuse/misuse (e.g., patients sharing medication) – even without resulting 
adverse reaction 
- 
Accidental exposure (e.g., child takes parent’s medication) 
- 
Medication error 

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- 
Withdrawal reactions 
- 
Disease progression/exacerbation of existing disease 
- 
Drug-drug/Drug-food interactions 
- 
Exposure to drug during pregnancy, where the embryo or fetus may have 
been exposed to medicinal products (either through maternal exposure or 
transmission of a medicinal product via semen following paternal 
exposure) 
- 
Exposure to drug during lactation (including uneventful) 
- 
Suspected counterfeit product 
- 
Suspected transfer of infectious disease/agent by the medicinal product 
concerned 
- 
Product Quality Complaint (PQC) with safety related/medically 
important information 
- 
Pediatric use (if not an approved use) 
- 
Occupational exposure 
-       Off-label use 
Adverse 
Event (AE) 
Any untoward medicinal occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment (Directive 2001/83/EC amended by Directive 
2010/84/ EU).  
An adverse event can therefore be any unfavorable and unintended sign (e.g. 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not it is considered causally related to the 
medicinal product. 
Serious 
Adverse 
Event (SAE) 
Any adverse drug experience/event occurring at any dose which 
- 
results in death, 
- 
is life-threatening,  
- 
requires inpatient hospitalization or prolonged of existing hospitalization, 
- 
results in persistent or significant disability or incapacity, 
- 
is a congenital anomaly/birth defect, 

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- 
is medically significant 
Life-threatening refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe. 
A medically significant event is an important medical event (defined as a medical 
event(s) that may not be immediately life-threatening or result in death or 
hospitalization but, based on appropriate medical and scientific judgment, may 
jeopardize the patient/subject or may require intervention (e.g. medical, surgical) 
to prevent one of the other outcomes listed in the definition above) might be 
considered serious as well, examples of such include, but not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias; or convulsions that do not result in hospitalization; or development of 
drug dependency of drug abuse. 
Non-serious 
Adverse 
Event 
All Adverse Events that do not meet the definition of a Serious Adverse Event are 
considered Non-serious Adverse Events.