A Phase I, Open-label, Randomized, Four-period, Crossover, Fully Replicated, Reference-scaled, Single Center Study to Assess the Bioequivalence of a Single Oral Dose of 1200 mg of the Coated Cesol Tablet Formulation Versus Comparator Biltricide® in Healthy Male Volunteers
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Praziquantel
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004

Appendix 16.1.1
List of Protocols and Protocol Amendments
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MS200585_0004
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
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Study Number:
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Amendment Number
1RWDSSOLFDEOH
Merck Compound Number:
06&
Study Phase:
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Short Title:
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Principal Investigator:
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Replaces Version:
1RWDSSOLFDEOH
Approval Date:
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Sponsor Medical Responsible and 
Contact Information:
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This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2020 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
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1
Protocol Summary
1.1
Synopsis
Protocol Title: $ 3KDVH , RSHQODEHO UDQGRPL]HG IRXUSHULRG FURVVRYHU IXOO\ UHSOLFDWHG
UHIHUHQFHVFDOHGVLQJOHFHQWHUVWXG\ WRDVVHVVWKHELRHTXLYDOHQFHRIDVLQJOHRUDOGRVHRI PJ
RIWKH FRDWHG &HVROWDEOHWIRUPXODWLRQYHUVXVFRPSDUDWRU%LOWULFLGHLQKHDOWK\PDOHYROXQWHHUV
Short Title: %LRHTXLYDOHQFHVWXG\ RIFRDWHG&HVROWDEOHWIRUPXODWLRQYV%LOWULFLGH
Rationale: $VDUHTXLUHPHQWIRUWKHSUD]LTXDQWHOGRQDWLRQSURJUDPE\0HUFN.*D$WKH:+2
UHTXHVWHGWKHGHYHORSPHQWRIDQLPSURYHGIRUPXODWLRQRISUD]LTXDQWHOPJ WDEOHWV7KLVVWXG\
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E\WKH:+23UHTXDOLILFDWLRQ7HDP0HGLFLQHV
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Primary
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FRDWHG&HVROWDEOHWYHUVXVWKH
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Secondary
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MS200585_0004
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Overall Design: 7KLVLVD3KDVH,FURVVRYHURSHQODEHOVLQJOHGRVHIXOO\UHSOLFDWHGUHIHUHQFH
VFDOHGUDQGRPL]HGSHULRGFOLQLFDOSKDUPDFRORJ\VWXG\ WRDVVHVVWKHUHODWLYHELRDYDLODELOLW\RI
FRDWHG&HVROWDEOHWVYHUVXVYV%LOWULFLGHLQKHDOWK\PDOHYROXQWHHUV
Number of Participants:  SDUWLFLSDQWV DUH SODQQHG WR EH UDQGRPL]HG  SDUWLFLSDQWV SHU
VHTXHQFH,IRUPRUHSDUWLFLSDQWVGURSRXWRIWKHVWXG\EHIRUHFRPSOHWLQJSHULRGDGGLWLRQDO
SDUWLFLSDQWVPD\EHUDQGRPL]HGWRPHHWWKHUHTXLUHGPLQLPDOQXPEHURIHYDOXDEOHSDUWLFLSDQWV
1  
Study Intervention Groups and Duration: 3DUWLFLSDQWV ZLOO EH UDQGRPL]HG WR RQH RI WZR
VHTXHQFHV7575 RU 5757ZKHUH7LV7HVWSURGXFWDQG5LV5HIHUHQFHSURGXFW
ZLWKDZDVKRXWSHULRGRIDWOHDVWZHHNLQEHWZHHQ ,QDFFRUGDQFHZLWKWKHIXOO\UHSOLFDWHGVWXG\
GHVLJQWKHQXPEHUDIWHU7DQG5 UHIHUVWRWKHILUVWRU VHFRQGDGPLQLVWUDWLRQRIWKHWHVWRU UHIHUHQFH
SURGXFWUHVSHFWLYHO\ ZLWKLQWKHDVVLJQHGVHTXHQFH
Involvement of Special Committee(s): 1R
1.2
Schema
Period 1
Period 2
Period 3
Period 4
Sequence 1
(18 participants)
Test 1
Washout 
at least 7 
days
Reference
1
Washout 
at least 7 
days
Test 2
Washout 
at least 7 
days
Reference
2
Sequence 2
(18 participants)
Reference
1
Test 1
Reference
2
Test 2
Test = coated Cesol tablet, 2 tablets of praziquantel 600 mg; 
Reference = Biltricide, 2 tablets of praziquantel 600 mg.
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
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1.3
Schedule of Activities
Activity/Assessment
Screening 
(Baseline)
Treatment Period 1, 2, 3 and 4
End of 
Treatment 
/ Safety 
Follow-up
Comments
Study Day
Day -28 
to -1
Day 
-1/7/14/21
Day 1/8/15/22a
Day 
2/9/16/23
Day 27 
(+ 3 days)
a Assuming 7 days for washout between 
the 4 treatment periods.
Period Day
-1
1
2
Study Day timepoints
-1 h
-0.5 h
0 h
24 h
ICF signature available
X
Demographics (incl.
BW and BMI), medical 
history and history of 
medication
X
Smoking history, 
alcohol intake, use of 
caffeine or xanthine-
containing beverages
X
Serology test
X
Physical examinationb
X
X
X
b According to the CRO procedure.
Vital signsc (BP, HR, 
body temperature)
X
X
X
X
X
c At visits where assessment time points 
coincide with each other, the following 
procedure should be followed: perform 
vital signs and ECG assessments within 
15 min before the specific time point and 
PK blood sampling on time.
12-Lead-ECGc
X
X
X
X
c At visits where assessment time points 
coincide with each other, the following 
procedure should be followed: perform 
vital signs and ECG assessments within 
15 min before the specific time point and 
PK blood sampling on time.
Safety lab tests 
X
X
X
X
Drug screening urine
X
X
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Activity/Assessment
Screening 
(Baseline)
Treatment Period 1, 2, 3 and 4
End of 
Treatment 
/ Safety 
Follow-up
Comments
Study Day
Day -28 
to -1
Day 
-1/7/14/21
Day 1/8/15/22a
Day 
2/9/16/23
Day 27 
(+ 3 days)
a Assuming 7 days for washout between 
the 4 treatment periods.
Period Day
-1
1
2
Study Day timepoints
-1 h
-0.5 h
0 h
24 h
Alcohol breath test
X
X
Confinementd
[----------------------------------X---------------------------------------]
d Confinement from the morning of 
Day -1/7/14/21 (about 20-24 hours prior 
to each IMP administration) until the 
morning of Day 2/9/16/23.
Standardized breakfast
X
In/exclusion criteria 
check/recheck
X
X
X
Randomization
Xf
f Randomization will be performed in 
eligible participants on Day 1 only.
Administration of IMP
X
PK samplingc,e
          [-------X----]
c At visits where assessment time points 
coincide with each other, the following 
procedure should be followed: perform 
vital signs and ECG assessments within 
15 min before the specific time point and 
PK blood sampling on time.
e PK sampling at predose, 0.25, 0.5, 
0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 
5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 
12 hours.
AE and concomitant 
medication
X
[------------------------------------------------X-----------------------------------------------]
AE=adverse events; BP=blood pressure; CRO=Contract Research Organization; ECG=electrocardiogram; HR=heartrate; ICF=informed consent form; 
IMP=investigational medicinal product; PK=pharmacokinetics.
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2
Introduction
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Table 1
Praziquantel enantiomers
Generic Name
Abbreviations
Alternate names
MSC# (Refers 
only to drug 
substance 
synthesized by 
the Sponsor)
Praziquantel
rac-PZQ
Generic: racemic Praziquantel
Trade: Biltricide, Cisticid, Cysticide, Cesol, Cestox
MSC1028703A
Enantiomers
Levo-
Praziquantel
L-PZQ, R-(−)-
praziquantel
R-(-)-Praziquantel, R-Praziquantel, L-Praziquantel, 
R Enantiomer, L Enantiomer
MSC2499550A
Dextro-
Praziquantel
D-PZQ, S-PZQ
D Praziquantel, S-(+)-Praziquantel, D Enantiomer, 
S Enantiomer
MSC2499551A
D-PZQ = Dextro-praziquantel, S-PZQ, MSC2499551A; PZQ = praziquantel; rac-PZQ = racemic praziquantel 
(mixture of L-PZQ and D-PZQ in a 1 to 1 ratio); L-PZQ = levo-praziquantel, R-(−)-praziquantel, MSC2499550A; S-
PZQ = S-(+)-praziquantel, dextro-praziquantel, D-PZQ, MSC2499551A.
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2.2
Background
6HH6HFWLRQ
2.3
Benefit/Risk Assessment
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Table 2
Side effects reported after use of Biltricide
Frequencies
System Organ Class
Very Common
≥1/10
Frequently
≥ 1/100 to < 1/10
Very Rare
<1/10,000
Immune system disorders
Allergic reactions 
Eosinophilia
Nervous system disorders
Headache 
Lightheadedness
Dizziness 
Somnolence
Convulsions
Cardiac disorders
Unspecific arrhythmias
Gastrointestinal disorders
Gastrointestinal and 
abdominal pain 
Nausea
Vomiting
Anorexia
Diarrhea (bloody diarrhea 
is very rare)
Skin and subcutaneous 
tissue disorders
Urticaria
Skin rash
Pruritus
Musculoskeletal and 
connective tissue and 
bone disorders
Myalgia
General disorders and 
administration site 
conditions
Fatigue
General discomfort 
Fever
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3
Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
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4
Study Design
4.1
Overall Design
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Scientific Rationale for Study Design
4.2.1
General
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4.2.2
Justification for using the reference scaled approach
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Washout Period
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4.3
Justification for Dose
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4.4
End of Study Definition
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5
Study Population
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5.1
Inclusion Criteria
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Age
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Type of Participant and Disease Characteristics
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5.2
Exclusion Criteria
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Medical Conditions
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Prior/Concomitant Therapy
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Diagnostic Assessments
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Other Exclusions
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
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5.3.2
Caffeine, Alcohol, Tobacco, and Cannabinoids
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5.3.3
Activity
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Screen Failures
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6
Study Intervention(s)
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6.1
Study Intervention(s) Administration
Study Intervention 
Name
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Drug Name on IMP 
Label 
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Strength(s) /Dosage 
Level(s)
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Route of 
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Supplier/
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Study Assessments and Procedures
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8.1
Efficacy Assessments and Procedures
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8.2
Safety Assessments and Procedures
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Physical Examinations
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Electrocardiograms
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Clinical Safety Laboratory Assessments
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Suicidal Risk Monitoring
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Adverse Events and Serious Adverse Events
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Follow-up of Adverse Events and Serious Adverse Events
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8.3.5
Pregnancy
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8.4
Treatment of Overdose
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MS200585_0004
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8.5
Pharmacokinetics
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Table 3
Pharmacokinetic Parameters Derived from rac-PZQ Concentrations
Cmax
Maximum observed drug concentration. 
tmax
Time of the maximum drug concentration. 
tlag
Time prior to the first measurable (non-zero) concentration; calculated as last time point at which 
the concentration is <LLOQ before the occurrence of the first quantifiable concentration
∀z
Terminal rate constant.
t1/2
Terminal elimination half-life. 
AUC0-t
Area under the drug concentration-time curve from time zero to the time of last measurable 
concentration using the linear-log trapezoidal method (linear up log down).
AUC0-∞
Area under the drug concentration-time curve from time zero extrapolated to infinity. 
%AUCextra
Percentage of AUC0-∞ obtained by extrapolation
CL/f
Apparent clearance
VZ/f
Apparent volume of distribution during terminal phase
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MS200585_0004
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8.6
Pharmacodynamics
1RWDSSOLFDEOH
8.7
Pharmacogenetics
1RWDSSOLFDEOH
8.8
Biomarkers
1RWDSSOLFDEOH
8.9
Immunogenicity Assessments
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MS200585_0004
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9.3
Populations for Analyses
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Analysis Set
Description
Screening (SCR)
All participants, who provided informed consent, regardless of the participant’s randomization 
and study intervention status in the study.
Safety (SAF)
All participants, who were administered any dose of any study intervention. Analyses will 
consider participants as treated.
PK
All participants, who receive at least one dose of study intervention, have no clinically 
important protocol deviations or important events affecting PK, and provide at least one 
measurable postdose concentration. Participants will be analyzed per the actual study 
intervention they received.
The PK population will include all participants:
!
Who have completed at least one study period without any relevant protocol deviations 
and factors likely to affect the comparability of PK results
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With adequate study intervention compliance
!
With evaluable PK data, i.e., nonmissing values for primary endpoints in each study 
period.
If participants received prohibited concomitant therapy or medicines, as specified in Section 
6.5, they will be excluded from the PK population. Relevant decisions will be made before 
database lock. All PK analyses will be based on this analysis set.
9.4
Statistical Analyses
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.4.1
Efficacy Analyses
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9.4.2
Safety Analyses
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.4.3
Other Analyses
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.4.4
Sequence of Analyses
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References 
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Appendix 1
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Source Documents
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential (WOCBP)
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$:2&%3LV not:
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MS200585_0004
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
!
Intrauterine device
!
Intrauterine hormone-releasing system (IUS)
!
Bilateral tubal occlusion
!
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation
o
Oral
o
Intravaginal
o
Transdermal
o
Injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulation
o
Oral
o
Injectable
!
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction).
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
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Severe:
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Related:
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Abnormal Laboratory Findings and Other Abnormal Investigational Findings
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MS200585_0004
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Serious Adverse Events
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Events that Do Not Meet the Definition of an SAE
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Reporting Serious Adverse Events
Serious Adverse Events
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Appendix 5
Clinical Laboratory Tests
Table 4:
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Mean Corpuscular Volume
WBC Count with Differentials 
and Absolute Counts a:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Hemoglobin
MCH
Hematocrit
Red Blood Cell Counts
Biochemistry
Blood Urea 
Nitrogen
Creatinine
Glucose;
CK b
Potassium
Sodium
Calcium
Uric acid
Aspartate Aminotransferase
Alanine Aminotransferase
Alkaline phosphatase
γ-Glutamyltransferase
Bilirubin c
Total Protein
Triglycerides
Cholesterol
Routine 
Urinalysis
!
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase] by 
dipstick
!
Microscopic examination d.
Other Tests
Urine drug screen:
amphetamines, methamphetamines, barbiturates, cocaine, opiates, cannabinoids, 
benzodiazepines, methadone, tricyclic antidepressants, 3,4-methylenedioxymethamphetamine, 
and cotinine 
Serology: 
Hepatitis B surface antigen
Hepatitis C antibody
HIV1/HIV2 antibodies
Alcohol breath test
Thyroid-stimulating hormone (TSH)
CK = creatine phosphokinase; CK-MB = CK- myocardium/brain type; HIV = human immunodeficiency virus,
MCH = Mean Cell Hemoglobin; WBC = white blood cell.
a
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
b
In case of an increased CK, CK-MB will be determined; if the ratio of CK-MB/CK is above 6%, troponin will be 
determined as well.
c
In case of an increased bilirubin (total) the direct bilirubin will be determined
d
Only if blood, protein, nitrite, or leukocytes are positive on the dipstick.
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Appendix 6
Protocol Amendment History
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Appendix 7
Periodic Benefit-Risk Evaluation Report for Praziquantel 
(01 May 2015 to 30 April 2018; Sections 15-18)
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Overview of Signals: New, Ongoing, or Closed
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Increase in Liver Enzymes
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16
Signal and Risk Evaluation
16.1
Summary of Safety Concerns
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Important Identified Risks
16.1.1.1
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16.1.1.2
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QHXURF\VWLFHUFRVLV6XFKFDVHVZKLFKPD\RFFXUHVSHFLDOO\LQHQGHPLFUHJLRQVRITaenia solium
Cysticercus cellulosaeVKRXOGEHFODULILHGDVTXLFNO\DVSRVVLEOH
3DJHRI

16.1.2
Important Potential Risks
16.1.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
&DXWLRQLVZDUUDQWHG LQGHFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\RULQSDWLHQWVZLWKKHSDWRVSOHQLF
VFKLVWRVRPLDVLVVLQFHGXHWRUHGXFHGGUXJPHWDEROLVDWLRQLQWKHOLYHUDQGRUFROODWHUDOFLUFXODWLRQV
DSSUHFLDEO\KLJKHUVHUXPFRQFHQWUDWLRQVDUHUHDFKHGDQGWKHKDOIOLIHPD\EHSURORQJHG,QVXFK
FDVHVWUHDWPHQWVKRXOGEHFDUULHGRXWRQDQLQSDWLHQWEDVLV
6LQFH WKHVH LQFUHDVHV RI WKH OLYHU WUDQVDPLQDVHV LQ SDWLHQWV ZLWK GHFRPSHQVDWHG KHSDWLF
LQVXIILFLHQF\RULQSDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLVFDQEHOLQNHGWRWKHXQGHUO\LQJ
VFKLVWRVRPLDVLVUDWKHUWKDQWKHWUHDWPHQWQRVLJQLILFDQWLPSDFWRQSXEOLFKHDOWKLVIRUHVHHQZLWK
WKLVSRWHQWLDOULVN
16.2
Signal Evaluation
1R VDIHW\VLJQDOV ZHUH QHZO\ LGHQWLILHGRU FORVHGIRU3=4 GXULQJWKH SHULRGFRYHUHGE\ WKLV
3%5(5
16.3
Evaluation of Risks and New Information
16.3.1
Important Identified Risks
16.3.1.1
Cardiac Arrhythmias
$ VHDUFKSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQIRUWKH
604³&DUGLDFDUUK\WKPLDV´ EURDGVFRSHUHYHDOHGDWRWDORI ,&65VFXPXODWLYHO\ ZLWKD WRWDO
RI QRQVHULRXV QRWPHGLFDOO\FRQILUPHG HYHQWVSHUWDLQLQJWRFDUGLDFDUUK\WKPLDV %RWK,&65V
DUHSUHVHQWHGLQ7DEOH DQGHYHQWVSHUWDLQLQJWRFDUGLDFDUUK\WKPLDV DUHLQbold
3DJHRI
PPD

$VDQRYHUDOODVVHVVPHQWIRUFDUGLDFDUUK\WKPLDV,&65VZLWKWDFK\FDUGLD KDYHEHHQUHSRUWHGWR
WKH&RPSDQ\7KHUHLQ DOWHUQDWLYHH[SODQDWLRQVVXFKDVXQGHUO\LQJLQWHVWLQDOSDUDVLWRVLVDQGRU
FRQFRPLWDQWPHGLFDWLRQH[LVWH[SODLQLQJWKHUHSRUWHGHYHQW,QDGGLWLRQDQHYLGHQFHEDVHGFDXVDO
UHODWLRQVKLSEHWZHHQWKHLQWDNHRISUD]LTXDQWHODQGWKHGHYHORSPHQWRIFDUGLDFDUUK\WKPLDVFRXOG
QRWEHSURYLGHGE\DOLWHUDWXUHVHDUFK
16.3.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
$ VHDUFKZDVSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQ IRU
WKH604³&RQYXOVLRQV´EURDGVFRSHDQG37³1HXURF\VWLFHUFRVLV´ 7KHVHDUFKGLGQRWUHYHDO
DQ\FDVHV
16.3.2
Important Potential Risks
16.3.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
$ VHDUFKSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQIRUWKH
37V ³$ODQLQH DPLQRWUDQVIHUDVH DEQRUPDO´ ³$ODQLQH DPLQRWUDQVIHUDVH LQFUHDVHG´ ³$VSDUWDWH
DPLQRWUDQVIHUDVH DEQRUPDO´ ³$VSDUWDWH DPLQRWUDQVIHUDVH LQFUHDVHG´ ³*DPPDJOXWDP\O
WUDQVIHUDVH DEQRUPDO´ ³*DPPDJOXWDP\OWUDQVIHUDVH LQFUHDVHG´ ³+HSDWLF HQ]\PH DEQRUPDO´
³+HSDWLF HQ]\PH LQFUHDVHG´ ³+HSDWLF IXQFWLRQ DEQRUPDO´ ³+\SHUWUDQVDPLQDVDHPLD´ ³/LYHU
IXQFWLRQ WHVW DEQRUPDO´ ³/LYHU IXQFWLRQ WHVW GHFUHDVHG´ ³/LYHU IXQFWLRQ WHVW LQFUHDVHG´
³7UDQVDPLQDVHV DEQRUPDO´ ³7UDQVDPLQDVHV LQFUHDVHG´ 604 ³+HSDWLF IDLOXUH ILEURVLV DQG
FLUUKRVLVDQGRWKHUOLYHUGDPDJHUHODWHGFRQGLWLRQV´EURDGVFRSHDQG37³6FKLVWRVRPLDVLVOLYHU´
GLGQRWUHYHDODQ\FDVHV
3DJHRI
PPD

16.4
Characterization of Risks
16.4.1
Important Identified Risks
16.4.1.1
Cardiac Arrhythmias
Frequency: 
,QFOLQLFDOWULDOVZLWK3=4QRVHULRXVQRQVHULRXVHYHQWVFRQVLGHUHGDVUHODWHGWR3=4KDYHEHHQ
UHSRUWHG
$ VHDUFKSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQIRUWKH
604³&DUGLDFDUUK\WKPLDV´ EURDGVFRSHUHYHDOHGDWRWDORI ,&65VFXPXODWLYHO\ZLWKD WRWDO
RI QRQVHULRXV QRWPHGLFDOO\FRQILUPHG HYHQWVSHUWDLQLQJWRFDUGLDFDUUK\WKPLDV
Seriousness:
6RPH DUUK\WKPLDV WUXO\ DUH DV\PSWRPDWLF DQG WKHVH DUH XVXDOO\ GLVFRYHUHG GXULQJ D URXWLQH
SK\VLFDO H[DPLQDWLRQ 7KHVH DUUK\WKPLDV FDQ EH FRQVLGHUHG QRQVHULRXV 6RPH V\PSWRPDWLF
DUUK\WKPLDVPD\EHVHULRXVRU OLIHWKUHDWHQLQJ%RWK ,&65VUHSRUWHGFXPXODWLYHO\ QRQVHULRXV
Severity and nature of risk:
,QJHQHUDOVXSUDYHQWULFXODUDUUK\WKPLDVDUHQRWVHULRXVRUOLIHWKUHDWHQLQJ,QFRQWUDVWYHQWULFXODU
DUUK\WKPLDVPD\EHOLIHWKUHDWHQLQJ1RQOLIHWKUHDWHQLQJ DUUK\WKPLDVPD\KRZHYHUKDYHVHULRXV
ORQJWHUPFRQVHTXHQFHV)RUH[DPSOHDWULDODUUK\WKPLDVWKDWDUHSUHVHQWIRUDWOHDVWRIWKH
GD\DQGUHVXOWLQJLQDQDYHUDJHGDLO\KHDUWUDWHRIDWOHDVWEHDWVSHUPLQXWHPD\OHDGWROHIW
YHQWULFXODUFDUGLRP\RSDWK\DQGFRQJHVWLYHKHDUWIDLOXUH
Background incidence/prevalence:
7KH PRVW FRPPRQ W\SHV RI FDUGLDF DUUK\WKPLDV DPRQJ WKH JHQHUDO SRSXODWLRQ LQFOXGH DWULDO
ILEULOODWLRQ $)LEDWULDOIOXWWHUVXSUDYHQWULFXODUWDFK\FDUGLD DQGYHQWULFXODUWDFK\FDUGLD$)LE LV
WKHPRVW FRPPRQ VXVWDLQHGDUUK\WKPLDZLWK DQHVWLPDWHGSUHYDOHQFHRI PLOOLRQDPRQJDOO
(XURSHDQV ZKLFK SODFHV D KXJH SXEOLF KHDOWK EXUGHQ LQ WHUPV RI PRUELGLW\ DQG PRUWDOLW\
>3LOODULVHWWL-/DNNLUHGG\'@,QWKHHVWLPDWHGQXPEHUVRIPHQDQGZRPHQZLWK
$)LE ZRUOGZLGH ZHUH  PLOOLRQ DQG  PLOOLRQ UHVSHFWLYHO\ ZLWK KLJKHU LQFLGHQFH DQG
SUHYDOHQFHUDWHVLQGHYHORSHGFRXQWULHV>.LUFKKRI3HWDO@$WULDOIOXWWHU LVOHVVFRPPRQ
WKDQ $)LE DQG PRUH SUHYDOHQW LQ SDWLHQWV ZLWK RUJDQLF KHDUW GLVHDVH $FFRUGLQJ WR DQ
HSLGHPLRORJLFDOVWXG\LQWKH8QLWHG6WDWHVWKHHVWLPDWHGSUHYDOHQFHRIDWULDOIOXWWHU LQFOXGLQJ
SDWLHQWVFRPSOLFDWHGZLWK$)LEZDVDQGWKDWRIDWULDOIOXWWHU DORQHZLWKRXW$)LEZDV
7KHSUHYDOHQFHRISDUR[\VPDOVXSUDYHQWULFXODUWDFK\FDUGLDLVDSSUR[LPDWHO\ WRSHU
 SHUVRQV DQG WKH LQFLGHQFH LV  SHU  SHUVRQ\HDUV LQ WKH JHQHUDO SRSXODWLRQ
>0XUDNRVKL1$RQXPD.@
3DJHRI

Risk groups or risk factors:
$UUK\WKPLDVDUH YHU\FRPPRQLQROGHUDGXOWV 0RVWVHULRXVDUUK\WKPLDVDIIHFWSHRSOHROGHUWKDQ
 \HDUV RI DJH EHFDXVH ROGHU DGXOWV DUH PRUH OLNHO\ WR KDYH KHDUW GLVHDVH DQG RWKHU KHDOWK
SUREOHPVWKDWFDQOHDGWRDUUK\WKPLDV2OGHUDGXOWVDOVRWHQGWREHPRUHVHQVLWLYHWRWKHVLGHHIIHFWV
RIPHGLFLQHVVRPHRIZKLFKFDQFDXVHDUUK\WKPLDV6RPHPHGLFLQHVXVHGWRWUHDWDUUK\WKPLDVFDQ
HYHQFDXVHDUUK\WKPLDVDVDVLGHHIIHFW6RPHW\SHVRIDUUK\WKPLDKDSSHQPRUHRIWHQLQFKLOGUHQ
DQG \RXQJ DGXOWV 3DUR[\VPDO VXSUDYHQWULFXODU WDFK\FDUGLD LQFOXGLQJ :ROII3DUNLQVRQ:KLWH
V\QGURPHLVPRUHFRPPRQLQ\RXQJSHRSOH$UUK\WKPLDVDUHPRUHFRPPRQLQSHRSOHZKRKDYH
GLVHDVHVRUFRQGLWLRQVWKDWZHDNHQWKHKHDUWVXFKDVKHDUWDWWDFNKHDUWIDLOXUH RU FDUGLRP\RSDWK\
KHDUWWLVVXHWKDW
VWRRWKLFNRUVWLIIRUWKDWKDVQ
WIRUPHGQRUPDOO\OHDNLQJRUQDUURZHGKHDUWYDOYHV
ZKLFKPDNHWKHKHDUWZRUNWRRKDUGDQGFDQOHDGWRKHDUWIDLOXUHFRQJHQLWDOKHDUWGHIHFWV WKDW
DIIHFWWKHKHDUW
VVWUXFWXUHRUIXQFWLRQDQGRWKHUFRQGLWLRQVDOVRFDQUDLVHWKHULVNIRUDUUK\WKPLDV
VXFKDVKLJKEORRGSUHVVXUHLQIHFWLRQVWKDWGDPDJHWKHKHDUWPXVFOHRUWKHVDFDURXQGWKHKHDUW
GLDEHWHVVOHHSDSQHDDQRYHUDFWLYHRUXQGHUDFWLYHWK\URLGJODQGKHDUWVXUJHU\FHUWDLQGUXJVVXFK
DVFRFDLQHRUDPSKHWDPLQHVRUDQLPEDODQFHRIFKHPLFDOVRURWKHUVXEVWDQFHVVXFKDVSRWDVVLXP
LQWKHEORRGVWUHDPKWWSVZZZQKOELQLKJRYQRGH6FDUULQJRUDEQRUPDOWLVVXHGHSRVLWV
FDQFDXVHEUDG\FDUGLDE\LQWHUIHULQJZLWKWKHZRUNRIWKHVLQXVQRGHRURYHUDOODWULRYHQWULFXODU
FRQGXFWLRQ/LNHZLVHWKH\FDQFDXVHWDFK\FDUGLDRULJLQDWLQJLQHLWKHUWKHDWULDRUYHQWULFOHVE\
FDXVLQJ FHOOV WR ILUH DEQRUPDOO\ RU E\ FUHDWLQJ LVODQGV RI HOHFWULFDOO\ LQHUW WLVVXH
KWWSZZZKHDUWRUJ+($5725*&RQGLWLRQV$UUK\WKPLD8QGHUVWDQG<RXU5LVNIRU$UUK\WKPLD
8QGHUVWDQG<RXU5LVNIRU$UUK\WKPLDB8&0BB$UWLFOHMVS:]60:8]D
Potential mechanisms:
3UD]LTXDQWHOLVDUDFHPLFPL[WXUHRI/3=4 DQG'3=47KH/3=4HQDQWLRPHU KDVDEHWWHU
WR[LFRORJLFDOSURILOHWKDQ'3=4RUUDF3=4)RUH[DPSOHLQUDEELWVWKDWZHUHDGPLQLVWHUHGD
VLQJOH  PJNJ LQWUDYHQRXV GRVH RI '3=4 UDF3=4 RU /3=4 WKH IUHTXHQFLHV RI HFWRSLF
UK\WKPVZHUHDQGUHVSHFWLYHO\:KHQUDEELWVZHUHLQMHFWHGZLWKDVLQJOH
PJNJLQWUDYHQRXVGRVHRISUD]LTXDQWHODUUK\WKPLDDQGEUDG\FDUGLDDSSHDUHGLQPRVWRIWKHP
7KHVHYHULW\RIDUUK\WKPLDDQGEUDG\FDUGLDLQGXFHGE\'3=4 ZDVKLJKHUWKDQWKDWLQGXFHGE\/
3=4$UUK\WKPRJHQLF HIIHFWVRI SUD]LTXDQWHOPD\ SDUWO\EH PHGLDWHGYLDWKHFHQWUDOQHUYRXV
V\VWHPDQGWKHDUUK\WKPRJHQLFHIIHFWVRISUD]LTXDQWHOPD\EHFDXVHGPDLQO\E\'3=4>;LDRHW
DO@
$GGLWLRQDOO\WKHUHDUHUDUHUHSRUWVRIFRQYXOVLRQV DQGFDUGLDFDUUK\WKPLDVIROORZLQJWUHDWPHQWRI
VFKLVWRVRPLDVLV>%DUWOH\3@ SchistosomaLQGXFHGSXOPRQDU\K\SHUWHQVLRQFDUULHVDJUDYH
SURJQRVLV VLQFH LW XVXDOO\ GHQRWHV DQ DGYDQFHG VWDJH RI KHSDWRVSOHQLF VFKLVWRVRPLDVLV
7KURPERVLVLQVLWXSDUWLFXODUO\RIWKHULJKWSXOPRQDU\DUWHU\DVZHOODVFDUGLDFDUUK\WKPLDVDQG
VXGGHQFDUGLDFGHDWKV\QGURPHV PD\RFFXU>+LGURQ$HWDO@
Preventability:
3DWLHQWV ZLWK FDUGLDF DUUK\WKPLDV VKRXOG EH PRQLWRUHG UHJXODUO\ GXULQJ WKHUDS\ 5RXWLQH
HOHFWURFDUGLRJUDPPRQLWRULQJFRXOGEHFRQVLGHUHGIRUHDUO\GHWHFWLRQ
3DJHRI

Impact on individual patient:
'HSHQGLQJRQWKHVHULRXVQHVVSDWLHQWVPD\EHVOLJKWO\RUVHYHUHO\DIIHFWHG 6RPHSDWLHQWVWUXO\
DUH DV\PSWRPDWLF DQG WKH DUUK\WKPLD FDQ EH GLVFRYHUHG RQO\ GXULQJ D URXWLQH SK\VLFDO
H[DPLQDWLRQ+RZHYHUPRVWSDWLHQWVDUHV\PSWRPDWLFLQVRPHZD\ZKHQDQDUUK\WKPLDRFFXUV
3DWLHQWVKDYLQJSDUR[\VPVRIDUUK\WKPLDPD\KDYHV\PSWRPVRISDOSLWDWLRQVRURXWULJKWKHDUW
UDFLQJ2WKHUV\PSWRPVPD\LQFOXGHFKHVWSDLQSXOVDWLRQVLQWKHQHFNG\VSQHDOLJKWKHDGHGQHVV
IDWLJXHVZHDWLQJ HWF$IWHUDVSHOORIDUUK\WKPLDWKHSDWLHQWPD\KDYHIUHTXHQWXULQDWLRQGXHWR
UHOHDVHRIDWULDOQDWULXUHWLFIDFWRUDSRO\SHSWLGHUHOHDVHGIURPWKHDWULDWKDWVWLPXODWHVGLXUHVLVRU
IHHOIDWLJXHGIRUKRXUVWRGD\V2WKHUDUUK\WKPLDVPD\FDXVHV\QFRSH ZLWKWKHDWWHQGDQWULVNRI
LQMXU\0RUHVHULRXVDUUK\WKPLDVPD\UHVXOWLQFDUGLDFDUUHVWRUGHDWK
Potential public health impact of safety concern:
&DUGLDFDUUK\WKPLDVVKRXOGUHVROYHZLWKDSSURSULDWHWUHDWPHQW,QDGGLWLRQJLYHQWKHXQFRPPRQ
IUHTXHQF\ EDVHGRQWKHFXPXODWLYHUHSRUWLQJUDWH WKHUHLVQRUHOHYDQWLPSDFWRQSXEOLFKHDOWK
Evidence source:
3RVWPDUNHWLQJH[SHULHQFHFXPXODWLYHUHYLHZRIFDVHVDQGOLWHUDWXUHUHYLHZ
16.4.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
3UD]LTXDQWHO VKRXOG EH XVHG ZLWK FDXWLRQ EHFDXVH WKHUH LV D ULVN DOWKRXJK UDUH WKDW WKH
DGPLQLVWUDWLRQ RI DQWLSDUDVLWLF GUXJV WR DQ LQGLYLGXDO ZKR KDV VLOHQW QHXURF\VWLFHUFRVLV FRXOG
WULJJHUVHL]XUHV>'HO%UXWWR2+DQG*DUFLD++@ DQG>)RJDQJ<)HWDO@
Frequency:
,QFOLQLFDOWULDOVZLWK3=4QRHYHQWRIFRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLV
FRQVLGHUHGDVUHODWHGWR3=4KDYHEHHQUHSRUWHG
$ VHDUFKSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQIRUWKH
604³&RQYXOVLRQV´EURDGVFRSHDQG37³1HXURF\VWLFHUFRVLV´GLGQRWUHYHDODQ\FDVHV
Seriousness:
&RQYXOVLRQVLQDSDWLHQWZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLVLVVHULRXVEXWLVXVXDOO\UHYHUVLEOH
ZLWKDGHTXDWHWUHDWPHQW
Severity and nature of risk:
7KHFRQYXOVLRQVFDQEHVHULRXVRU OLIHWKUHDWHQLQJDQGLQWKHDEVHQFHRISRWHQWFRUWLFRVWHURLG
WUHDWPHQWPD\EHIDWDO
3DJHRI

Background incidence/prevalence:
1HXURF\VWLFHUFRVLVLVWKHPRVWFRPPRQKHOPLQWKLFLQIHFWLRQRIWKHFHQWUDOQHUYRXVV\VWHP DQGD
PDMRUFDXVHRIDFTXLUHGHSLOHSV\ZRUOGZLGH &\VWLFHUFRVLVLVFRQVLGHUHGE\WKH:+2WREHWKH
PRVWFRPPRQSUHYHQWDEOHFDXVHRIHSLOHSV\LQWKHGHYHORSLQJZRUOGZLWKDQHVWLPDWHGPLOOLRQ
SHRSOHKDYLQJHSLOHSV\FDXVHGE\Taenia solium LQIHFWLRQ>)RJDQJ<)HWDO@ 6\PSWRPDWLF
QHXURF\VWLFHUFRVLV DFFRXQWV IRU DSSUR[LPDWHO\ RQHWKLUG RI VHL]XUH GLVRUGHUV LQ GHYHORSLQJ
FRXQWULHVLQVXE6DKDUDQ$IULFD$VLDDQG/DWLQ$PHULFD
$ PHWDDQDO\VLV WKDW RQO\ LQFOXGHG $IULFDQ VWXGLHV VKRZHG D VLJQLILFDQW DVVRFLDWLRQ EHWZHHQ
HSLOHSV\DQGF\VWLFHUFRVLVZLWKDQ25 RI3UHYDOHQFHUDWHVRIIRUQHXURF\VWLFHUFRVLV
ZHUH UHSRUWHG LQ UXUDO VHWWLQJV LQ (FXDGRU 7KH WRWDO QXPEHU RI DOO SHRSOH VXIIHULQJ IURP
QHXURF\VWLFHUFRVLV LQFOXGLQJ V\PSWRPDWLF DQG DV\PSWRPDWLF FDVHV LV HVWLPDWHG VRPHZKHUH
EHWZHHQDQGPLOOLRQEDVHGRQWKHUDQJHRIHSLOHSV\SUHYDOHQFHGDWDDYDLODEOHZKLFKLV
EHWZHHQ  DQG  IRU VXE6DKDUDQ $IULFD ,Q QRQHQGHPLF DUHDV WKH SUHYDOHQFH RI
QHXURF\VWLFHUFRVLV LV WRSHULQKDELWDQWVLQVRPHZHVWHUQVWDWHVRIWKH8QLWHG6WDWHV
DQGLWLVGLDJQRVHGLQPRUHWKDQRISDWLHQWVDWWHQGLQJHPHUJHQF\URRPVEHFDXVHRIVHL]XUHV
>)RJDQJ<)HWDO@
Risk groups or risk factors:
1HXURF\VWLFHUFRVLVLVDPDMRUFDXVHRIDFTXLUHGHSLOHSV\LQPRVWRIWKHGHYHORSLQJZRUOGDQGKDV
EHHQFRQVLGHUHGDVWKHVLQJOHFDXVHH[SODLQLQJWKHLQFUHDVHGLQFLGHQFHDQGSUHYDOHQFHRIHSLOHSV\
LQWKHVHUHJLRQV%ORFKHUHWDO&DUDELQHWDO'HO%UXWWRHWDOO0HGLQDHWDO
 3UHX[ DQG 'UXHW&DEDQDF  9LOODUDQ HW DO  >'HO %UXWWR 2+ DQG *DUFLD ++
@6HL]XUHVPD\RFFXUDWDQ\VWDJHRI&\VWLFHUFL LQYROXWLRQZLWKLQWKHEUDLQSDUHQFK\PD
IURPYLDEOHF\VWVWRFDOFLILFDWLRQV8QK\JLHQLFSUDFWLFHVUHVXOWLQJLQLQJHVWLRQRITaenia solium
HJJVGLUHFWO\IURPDTaenia FDUULHU RUOHVVRIWHQE\FRQWDPLQDWHGIRRG DUHFDXVDOIDFWRUVIRU
F\VWLFHUFRVLV1HXURF\VWLFHUFRVLVLVFRPPRQZKHUHWKHUHLVFOXVWHULQJRIFRQGLWLRQVIDYRULQJWKH
WUDQVPLVVLRQRITaenia soliumLQFOXGLQJORZOHYHORIHGXFDWLRQSRYHUW\GHILFLHQWGLVSRVDORI
KXPDQIHFHVVODXJKWHULQJRISLJVZLWKRXWYHWHULQDU\FRQWURODQGSUHVHQFHRIIUHHURDPLQJSLJV
DURXQGKRXVHKROGV
7KHUDS\ZLWKWKHF\VWLFLGDOGUXJDOEHQGD]ROH GLVUXSWLQJWKHVWDEOHQHXURF\VWLFHUFRVLV GLVHDVHGXH
WRVHFRQGDU\LQIODPPDWLRQ LVDQDGGLWLRQDOULVNIDFWRU>1DVK7(HWDO@
Potential mechanisms:
7KH DQWKHOPLQWKLF WUHDWPHQW PD\ GLVUXSW WKH XVXDO VWDEOH QRQLQIODPPDWRU\ KRVW±SDUDVLWH
UHODWLRQVKLS LQLWLDWLQJ DQ DFXWH LPPXQH UHVSRQVH ZKLFK KDV EHHQ DWWULEXWHG WR LQÀDPPDWLRQ
VHFRQGDU\ WR NLOOLQJ RI WKH F\VWLFHUFL $V DOO SDUDVLWHV DUH DIIHFWHG DW WKH VDPH WLPH FOLQLFDO
GHWHULRUDWLRQLVIUHTXHQW
3DJHRI

Preventability:
$Q\ HDUO\ V\PSWRPV VXJJHVWLYH RI FRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLV
VKRXOG EH LQYHVWLJDWHG DQG LI FRQFOXVLYH FRUWLFRVWHURLG WKHUDS\ PD\ EH LQLWLDWHG DORQJ ZLWK
PHGLFDWLRQVWRSUHYHQWRUDOOHYLDWHFRQYXOVLRQV WKDWKDYHFRPPHQFHG
Impact on individual patient:
%HWZHHQWKHQG DQGWK GD\RIWUHDWPHQWZLWK DQDQWLSDUDVLWLFDJHQW WKHUHPD\EHDQH[DFHUEDWLRQ
RIQHXURORJLFV\PSWRPV VXFKDVFRQYXOVLRQVKHDGDFKHQDXVHDDQGYRPLWLQJDQGVHL]XUHVZLWK
JHQHUDOL]DWLRQ PD\ DOVR EH QRWHG $V DOO SDUDVLWHV DUH DIIHFWHG DW WKH VDPH WLPH FOLQLFDO
GHWHULRUDWLRQLVIUHTXHQWDQGLQWKHDEVHQFHRISRWHQWDQWLLQIODPPDWRU\WKHUDS\DQGV\PSWRPDWLF
WUHDWPHQWPD\EHOHWKDO
Potential public health impact of safety concern:
,IWUHDWHGDSSURSULDWHO\ WKHFRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLVVKRXOG
UHVROYH ,I XQWUHDWHG WKH FRQYXOVLRQV PD\ SURJUHVV WR D OLIHWKUHDWHQLQJ FRQGLWLRQ DQG WKH
XQGHUO\LQJ QHXURF\VWLFHUFRVLV PD\ IXUWKHU GHWHULRUDWH 7KH SURJQRVLV RI HSLOHSV\ GHSHQGV RQ
PXOWLSOHIDFWRUVUHODWHGWRGHJUHHRILQIHFWLRQDQGKRVWUHVSRQVHWRSDUDVLWH1HDUO\RISDWLHQWV
ZLWKDVROLWDU\FHUHEUDO F\VWLFHUFXV JUDQXORPD KDYHDJRRGVHL]XUHRXWFRPHIROORZLQJUHVROXWLRQ
RIWKHOHVLRQ EXWWKHSURJQRVLVRIHSLOHSV\ LQ SDWLHQWVZLWKPXOWLSOHF\VWVDQGUHVLGXDO FDOFLILFDWLRQV
LV QRW DV EHQLJQ+RZHYHUJLYHQWKHYHU\UDUHIUHTXHQF\WKHUHLVQRUHOHYDQWLPSDFWRQSXEOLF
KHDOWK
Evidence source:
/LWHUDWXUHUHYLHZ
16.4.2
Important Potential Risks
16.4.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
Frequency: 
1R,&65VZHUHUHWULHYHGIROORZLQJDFXPXODWLYHUHYLHZRIWKH&RPSDQ\ VDIHW\GDWDEDVHXSWR
$SU  SHUWDLQLQJ WR WKH ULVN RI LQFUHDVH RI WKH OLYHU WUDQVDPLQDVHV LQ SDWLHQWV ZLWK
GHFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\RULQSDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV
Seriousness:
,QFUHDVH RIWKHOLYHUWUDQVDPLQDVHV LVIUHTXHQWO\QRQVHULRXVEXWPD\EHVHULRXV GHSHQGLQJRQ WKH
OLYHUHQ]\PHYDOXHV
3DJHRI

Severity and nature of risk:
7KHLQFUHDVH RIWKHOLYHUWUDQVDPLQDVHVLQSDWLHQWVZLWKGHFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\RULQ
SDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV VKRXOGEHPRQLWRUHGZLWKFDXWLRQVLQFHGXHWR WKH
UHGXFHG GUXJ PHWDEROLVP LQ WKH OLYHU DQGRU FROODWHUDO FLUFXODWLRQV DSSUHFLDEO\ KLJKHU VHUXP
FRQFHQWUDWLRQVRI SUD]LTXDQWHODUH UHDFKHG DQGWKHKDOIOLIHPD\ EHSURORQJHG ,Q VXFK FDVHV
WUHDWPHQWVKRXOGEHFDUULHGRXWRQDQLQSDWLHQWEDVLV
Background incidence/prevalence:
3UD]LTXDQWHOWKHUDS\KDVEHHQDVVRFLDWHGZLWKHOHYDWLRQVLQVHUXPDPLQRWUDQVIHUDVHOHYHOVLQXSWR
RISDWLHQWVEXWWKHVHDEQRUPDOLWLHVZHUHVHOIOLPLWLQJ3UD]LTXDQWHOKDVQRWEHHQDVVRFLDWHG
ZLWKFOLQLFDOO\DSSDUHQWOLYHULQMXU\ ,QDODUJHUHWURVSHFWLYHVXUYH\IURP&KLQDRIWUHDWHG
SDWLHQWVZHUHUHSRUWHGWRKDYHGHYHORSHGMDXQGLFHEXWQRVSHFLILFLQIRUPDWLRQDERXWWKHWZRFDVHV
ZDVSURYLGHG7KHUHKDYHEHHQIHZVWXGLHVRIORQJWHUPWKHUDS\ZLWKSUD]LTXDQWHODQGPRVW
FRQWUROOHG WULDOV RI WKLV DJHQW KDYH XVHG RQHGD\ FRXUVHV ZLWKRXW VHUXP DPLQRWUDQVIHUDVH
PRQLWRULQJ+RZHYHUPLOOLRQVRISHRSOHKDYHEHHQWUHDWHGZLWKSUD]LTXDQWHODVDSDUWRIODUJH
VFDOH FRQWURO VWUDWHJLHV LQ &KLQD ZKHUH S. japonicum ZDV HQGHPLF 7KH FRPELQDWLRQ RI
SUD]LTXDQWHO SUHYHQWLYH WKHUDS\ DQG VQDLO FRQWURO KDV UHVXOWHG LQ PDUNHG GHFUHDVHV LQ WKH
SUHYDOHQFH RI LQIHFWLRQ LQ WKH SRSXODWLRQ
ZLWK QR HYLGHQFH RI VLJQLILFDQW WR[LFLW\
KWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Risk groups or risk factors:
3DUDVLWLFLQIHFWLRQFDQLWVHOIUHVXOWLQKHSDWLFLPSDLUPHQW3UD]LTXDQWHOLVVLJQLILFDQWO\PHWDEROL]HG
E\WKHOLYHUDQGWKXVFRQFRPLWDQWDGPLQLVWUDWLRQRISUD]LTXDQWHOZLWKDVWURQJLQGXFHURIKHSDWLF
&<3HQ]\PHV VXFKDVULIDPSLQ LVDQDGGLWLRQDOULVNIDFWRU
Potential mechanisms:
3UD]LTXDQWHOLVH[WHQVLYHO\PHWDEROL]HGE\WKHOLYHUYLDWKHF\WRFKURPH3V\VWHPDQGPLJKW
FDXVH KHSDWLF LQMXU\ DV D UHVXOW RI D WR[LF LQWHUPHGLDWH RI LWV PHWDEROLVP 3ODVPD OHYHOV RI
SUD]LTXDQWHO DUH DIIHFWHG E\ LQGXFHUV ULIDPSLQ GHFUHDVHV GUXJ OHYHOV DQG LQKLELWRUV RI 3
DFWLYLW\
FLPHWLGLQH
NHWRFRQD]ROH
DQG
HU\WKURP\FLQ
FDQ
UHGXFH
GUXJ
OHYHOV
KWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Preventability:
3UD]LTXDQWHOVKRXOGEHXVHGZLWKFDXWLRQLQSDWLHQWVZLWKKHSDWLFGLVHDVH&HVVDWLRQRIWUHDWPHQW
VKRXOGEHXQGHUWDNHQDWRQVHWRIV\PSWRPV RUIROORZLQJGHWHFWLRQRILQFUHDVHLQWUDQVDPLQDVH
OHYHOV $GGLWLRQDOO\WUHDWPHQWLQVXFKFRQGLWLRQVVKRXOGEHFDUULHGRXWRQDQLQSDWLHQWEDVLV
Impact on individual patient:
,QXQFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\DQGLQSDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV WKHUH
LVUHGXFHGKHSDWLFPHWDEROLVPRISUD]LTXDQWHO ZKLFKFDQUHVXOWLQVLJQLILFDQWO\KLJKHUDQGORQJHU
ODVWLQJ SODVPD FRQFHQWUDWLRQV RI XQPHWDEROL]HG SUD]LTXDQWHO 0LQLPDO LQFUHDVHV LQ KHSDWLF
HQ]\PHVKDYHEHHQUHSRUWHGLQVRPHSDWLHQWV
3DJHRI

Potential public health impact of safety concern:
3UD]LTXDQWHOLVXVXDOO\ZHOOWROHUDWHGDQGFOLQLFDOO\DSSDUHQWOLYHULQMXU\GXHWRLWVXVHZRXOGEH
YHU\UDUH LILWRFFXUVDWDOOKWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Evidence source:
/LWHUDWXUHUHYLHZ
16.5
Effectiveness of Risk Minimization
16.5.1
Important Identified Risks
16.5.1.1
Cardiac Arrhythmias
Safety concern
Cardiac arrhythmias
Objective(s) of the risk 
minimization measures
To inform of risk of cardiac arrhythmias
Routine risk minimization 
measures
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
Patients with cardiac arrhythmias should be monitored during therapy. The same 
applies to patients with heart failure requiring digitalis therapy, since a digitalis-
antagonistic effect has been demonstrated in animal studies. 
Prescription-only medicine
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
cardiac arrhythmias was detected during the reporting period
MS200661-0005: no case reporting of cardiac arrhythmias was detected during the 
reporting period
Impact of risk minimization
no increase in the reporting rate of cardiac arrhythmias was observed
Comment
none
3DJHRI

16.5.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
Safety concern
Convulsions in patients with co-existing neurocysticercosis
Objective(s) of the risk 
minimization measures
To inform of risk of convulsions in patients with co-existing neurocysticercosis
Routine risk minimization 
measures
Section 4.2 of the Merck Master SmPC Posology and method of administration:
The usefulness of additional corticosteroid administration is to be decided from case 
to case; 4 to 16 mg dexamethasone daily, for example, can be considered. The 
same applies to the necessity of using drugs to prevent or alleviate convulsions.
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
After the administration of praziquantel for treating tapeworm infection, convulsions 
have occurred in rare individual cases, which have proved to be a reaction to co-
existing neurocysticercosis. Such cases, which may occur especially in endemic 
regions of Taenia solium (Cysticercus cellulosae), should be clarified as quickly as 
possible. 
Section 4.8 of the Merck Master SmPC Undesirable effects:
applies only to tablets containing 150 mg praziquantel: Not known: Convulsions
(see section 4.4)
additional corticosteroid administration
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
convulsions in patients with co-existing neurocysticercosis was detected during the 
reporting period
MS200661-0005: no case reporting of convulsions in patients with co-existing 
neurocysticercosis was detected during the reporting period
Impact of risk minimization
no increase in the reporting rate of convulsions in patients with co-existing 
neurocysticercosis was observed
Comment
none
3DJHRI

16.5.2
Important Potential Risks
16.5.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
Safety concern
Increases of the liver transaminases in patients with decompensated hepatic 
insufficiency or in patients with hepatosplenic schistosomiasis
Objective(s) of the risk 
minimization measures
To inform of risk of increases of liver transaminases in patients with 
decompensated hepatic insufficiency or in patients with hepatosplenic 
schistosomiasis
Routine risk minimization 
measures
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
Caution is warranted in decompensated hepatic insufficiency or in patients with 
hepatosplenic schistosomiasis since, due to reduced drug metabolisation in the 
liver and/or collateral circulations, appreciably higher serum concentrations are 
reached and the half-life may be prolonged. In such cases, treatment should be 
carried out on an inpatient basis.
Prescription-only medicine
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
increases of liver transaminases in patients with decompensated hepatic 
insufficiency or in patients with hepatosplenic schistosomiasis was detected during 
the reporting period
MS200661-0005: one case reporting increases of liver transaminases in a patient 
with decompensated hepatic insufficiency or in a patient with hepatosplenic 
schistosomiasis was detected during the reporting period - 8120255(5)
Impact of risk minimization
no increase in the reporting rate of increases of liver transaminases in patients with 
decompensated 
hepatic 
insufficiency 
or 
in 
patients 
with 
hepatosplenic 
schistosomiasis was observed
Comment
none
3DJHRI

17
Benefit Evaluation
17.1
Important Baseline Efficacy /Effectiveness Information
,Q  DPRQJ D ODUJH QXPEHU RI UHODWHG FRPSRXQGV SUD]LTXDQWHO F\FORKH[\OFDUERQ\O
EKH[DK\GUR+S\UD]LQRDLVRTXLQROLQ RQHZDVGHYHORSHGDVDQHZEURDG
VSHFWUXPDQWKHOPLQWKLFDJHQW &KDL7KH,%' LV0D\
$IWHUUDSLGDQGUHYHUVLEOHXSWDNH SUD]LTXDQWHOKDVWZRPDMRUDQWKHOPLQWKLFHIIHFWV$WWKHORZHVW
HIIHFWLYHFRQFHQWUDWLRQVSUD]LTXDQWHOFDXVHVLQFUHDVHGPXVFXODUDFWLYLW\IROORZHGE\FRQWUDFWLRQ
DQG VSDVWLF SDUDO\VLV $W KLJKHU FRQFHQWUDWLRQV SUD]LTXDQWHO FDXVHV WHJXPHQWDO GDPDJH DQG
H[SRVHVDQXPEHURIWHJXPHQWDODQWLJHQV0F&DUWK\HWDO
7KHPDMRUDVVHWRISUD]LTXDQWHOLV LWVEURDG DQWLKHOPLQWKLFVSHFWUXPRIDFWLYLW\
3UD]LTXDQWHOLVLQGLFDWHGIRU
PJ WDEOHWV 7UHDWPHQW RI LQIHFWLRQV FDXVHG E\ Taenia saginata EHHI WDSHZRUP Taenia
solium SRUN WDSHZRUP Hymenolepis nana GZDUI WDSHZRUP Diphyllobothrium pacificum
6RXWK$PHULFDQILVKWDSHZRUP
PJ WDEOHWV 7UHDWPHQW RI LQIHFWLRQV FDXVHG E\ WKH ODUYDH RI SRUN WDSHZRUP Cysticercus
cellulosaeLQWKHFHQWUDOQHUYRXVV\VWHPQHXURF\VWLFHUFRVLV
PJWDEOHWV
! 7UHDWPHQW RI Schistosoma LQIHFWLRQV GXH WR S. haematobium S. mansoni, S.intercalatum
S.japonicum, S. mekongi
! 7UHDWPHQWRILQIHFWLRQVZLWKOLYHUIOXNHVHJClonorchis sinensis, Opisthorchis viverriniDQG
OXQJIOXNHVHJParagonimus westermani DQGRWKHUVSHFLHV
! 7UHDWPHQWRIF\VWLFHUFRVLVQHXURF\VWLFHUFRVLV SDUHQFK\PDODQGVXEDUDFKQRLG DQGYLVFHUDO
DQG FXWDQHRXV F\VWLFHUFRVLV DQG LQIHFWLRQV ZLWK LQWHVWLQDO QHPDWRGHV OLYHU FORQRUFKLDVLV
RSLVWKRUFKLDVLVDQGIDVFLROLDVLVDQGSXOPRQDU\SDUDJRQLPLDVLV
17.1.1
Infections caused by Taenia saginata, Taenia solium, 
Hymenolepis nana, Diphyllobothrium pacificum and caused 
by the larvae of pork tapeworm in the Central Nervous System 
(praziquantel 150 and 500 mg)
$FFRUGLQJWRWKHUHYLHZHODERUDWHGE\&KDLVLQFHSUD]LTXDQWHOZDVILUVWLQWURGXFHGDVD
EURDGVSHFWUXPDQWKHOPLQWLF LQFOLQLFDOGHYHORSPHQW LQQXPHURXVFKHPRWKHUDSHXWLFWULDOV
KDYHEHHQSHUIRUPHGWRHYDOXDWHWKHFOLQLFDOXVHRISUD]LTXDQWHOLQWKHWUHDWPHQWRIKXPDQFHVWRGH
KXPDQ WDSHZRUP LQIHFWLRQV DQG PXOWLSOH SDSHUV UHSRUWLQJ VXFFHVVIXO UHVXOWV KDYH EHHQ
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Integrated Benefit-Risk Analysis for Authorized Indications
18.1
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
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Appendix 8
Reference ranges of laboratory parameters
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