PREemptive Pharmacogenomic Testing for Preventing Adverse Drug REactions
Phase: NA
Conditions: Adverse Drug Reaction
Sponsor: J.J.Swen

CONFIDENTIAL 
 
 
CLINICAL STUDY PROTOCOL: 
PREemptive Pharmacogenomic testing for Preventing 
Adverse drug REactions 
(PREPARE) 
 
March 4th 2022, Protocol Framework  
Version 8.0 
 
 
On behalf of The Ubiquitous Pharmacogenomics Consortium 
 
 
 

 
 
 
 
 
 
PREPARE  
 
 
CONFIDENTIAL 
GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
Change History: 
 
Version 
Date 
Change 
Original 
Revised 
Page in 
relevant 
version 
1.0 
October 
2016 
(never 
submitted 
in NL) 
- 
- 
- 
 
2.0 
November 
2016 
(initial 
submission 
in NL) 
Removal of buccal 
swab to be 
collected    
Patients who endure an ADR 
which is categorized as an 
“extreme phenotype” will be 
asked to provide an 
additional blood spot sample 
and (buccal) saliva sample at 
the time of the ADR. 
Patients who endure an ADR which is 
categorized as an “extreme phenotype” 
will be asked to provide an additional 
blood spot sample within 24 hours of the 
ADR. 
43 
 
 
Addition of 
information on 
logistics if a 
patient 
discontinues with 
the index drug 
- 
If a patient discontinues the index drug 
during the 12 week follow-up period, 
follow-up will also discontinue. However, 
the cross-sectional end-of study survey will 
be performed. 
15 
 
 
Addition of 
information on 
LIM registration 
- 
Research nurses will register patients for 
the LIM tool at baseline. Their study-ID 
number, e-mail address, drug of inclusion 
and initiation date will be reported in the 
LIM registration portal. An automated e-
mail will be sent to the patient at week 
two and eight after drug initiation. This e-
mail will include a link to the LIM portal. 
Patients will be asked to log-in to the LIM 
portal using their e-mail address and a 
standard password. Patients will be asked 
to change this password once they log in. 
This will give patients access to the LIM 
surveys. 
15 
 
 
Addition of 
information on 
local storage of 
patient contact 
information 
- 
Research nurses will collect and store 
patient contact information (e-mail 
address, telephone number, name and 
study-ID number) in a separate, local file 
(national subject identification code list).  
16 
 
 
Removal of 
sample and PGx 
result logistics 
Inpatients must provide a 
blood sample at least 24 
hours after signing informed 
consent, but preferably 
directly after providing 
informed consent. 
Outpatients will provide a 
saliva sample at least 24 
hours after inclusion, but 
preferably directly after 
providing informed consent.  
Samples will be sent to the 
local genetic laboratory for 
analysis. Once the genetic 
laboratory has received the 
blood or saliva sample PGx 
results must be provided to 
the prescribing physician or 
dispensing pharmacist within 
3 working days.  
- 
19 
 
 
Additional 
information on 
DNA sample 
collection and 
storage 
- 
Blood samples will be stored at 2-8OC 
before DNA isolation. 
Saliva samples will be collected using the 
ORAGENE DNA 500 collection kit and 
stored at room temperature. 
26 

 
 
 
 
 
 
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CONFIDENTIAL 
GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
 
 
Addition and 
removal of  
information 
regarding patient 
recruitment 
logistics 
Patients who have previously 
started with this prescription 
for a maximum of 48 hours 
are still be eligible for 
inclusion. In this case the time 
of first dose will be noted in 
the eCRF. 
Patients who are planned to receive a first 
prescription for a drug listed in Table 5 are 
also eligible for inclusion and may be 
recruited in the study. The time of the first 
dose of the index drug (t=0) will be noted 
in the eCRF. 
31 
 
 
Addition of 
information on 
blood plasma 
sub-study 
- 
See Chapter 6.3.3. on page 49. 
49 
3.0 
February 
2017 
Exemption of 
patient insurance 
 
Removal of patient insurance information 
59 
4.0 
March 
2017 
Revised wording 
of secondary 
outcomes  
2) reduces the total number 
of ‘serious’ ADRs (causally 
related to both the index drug 
and subsequent drug) 
2) reduces the total number of ‘serious’ 
ADRs (causally related to the index drug) 
17 
 
 
Revised 
information on 
logistics if a 
patient 
discontinues the 
index drug 
If a patient discontinues the 
index drug during the 12 
week follow-up period, 
follow-up will also 
discontinue. However, the 
cross-sectional end-of study 
survey will be performed. 
When the index drug is discontinued 
within the twelve week follow-up period, 
the follow-up will continue as initially 
anticipated. 
20 
 
 
Revised LIM 
logistics 
 If patients are not able to do 
so, research nurses will assist 
the patients. 
If patients do not have an email address or 
are not able to fill in an online survey, then 
the LIM tool will not be used. 
20 
 
 
Addition of 
information in 
LIM portal  
- 
The patient’s date of birth is recorded in 
the LIM registration portal 
20 
 
 
Summary matrix 
for data collection 
is updated to fit 
eCRF database 
structure 
- 
See Chapter 3.1.2. on page 22. 
22 
 
 
Clozapine was 
removed from 
the list of drugs of 
inclusion due to 
removal of 
CYP1A2 from 
panel 
 
 
29 
 
 
Addition of 
information 
regarding PGx 
result logistics 
- 
PGx results related to  the drug of interest 
must be returned to the treating HCP 
within seven days of index drug initiation 
(the three working day turnaround time 
for genotyping after receiving the sample 
is included within these seven days) 
32 
 
 
Removal of 
patient exclusion 
in study arm if 
logistical 
requirements are 
not met 
PGx-results regarding the 
gene of interest must be 
reported to the 
physician/pharmacist within 
one week of index drug 
initiation. The “Safety-Code 
card” may be provided after 
this week. If this is not 
complied, the patient is 
excluded.  
 
Study arm: PGx-results regarding the gene 
of interest must be reported to the 
physician/pharmacist within one week of 
index drug initiation. The “Safety-Code 
card” may be provided after this week.  If 
this is not complied then the patient will 
be excluded from the data set in a 
sensitivity analysis (see statistical analysis 
plan for details). 
32 
 
 
Removal of 
patient exclusion 
in control arm if 
logistical 
requirements are 
not met 
Patients must provide 
informed consent and provide 
a DNA sample within one 
week of index drug initiation. 
The mock “Safety-Code card” 
may be provided after this 
week. If this is not complied, 
the patient is excluded.  
 
Control arm: patients must provide 
informed consent and provide a DNA 
sample within one week of index drug 
initiation. The mock “Safety-Code card” 
may be provided after this week.  If this is 
not complied then the patient will be 
excluded from the data set in a sensitivity 
analysis (see statistical analysis plan for 
more detail). 
32 

 
 
 
 
 
 
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Horizon 2020 Research and Innovation  
 
  
 
 
Addition of index 
drug in patient 
log- book  
The recruiting physicians and 
pharmacists shall note all 
patients (including their age, 
sex and indication) that are 
considered for participation in 
their study logbook. 
The recruiting physicians and pharmacists 
shall note all patients (including their age, 
sex, index drug and indication) that are 
considered for participation in their study 
logbook. 
32 
 
 
Handling missing 
data in more 
detail 
Data from patients who 
withdraw after 12 weeks 
follow-up will be included in 
the primary analyses. When 
patients withdraw before 12 
weeks follow-up, they will be 
included in secondary 
analyses. 
How missing data is handled in the 
analyses is described in detail in the 
statistical analysis plan. 
34 
 
 
Panel was edited 
due to expert 
discussion 
See 5.1.1. on page 36 
See 5.1.1. on page 37 
37 
 
 
Revised wording 
of primary 
endpoint 
The primary endpoint is the 
frequency of causal (definite, 
probable or possible), 
clinically relevant (classified 
as NCI-CTCAE grade 2, 3, 4, or 
5), drug-genotype specific 
ADRs, for the index drug, for 
each patient.   
The primary outcome is the occurrence of 
at least one causal (definite, probable or 
possible), clinically relevant (classified as 
NCI-CTCAE grade 2, 3, 4, or 5), drug-
genotype specific ADR, attributable to the 
index drug, within 12 weeks of follow-up. 
43 
 
 
Different version 
of NCI-CTCAE will 
be used to assess 
severity 
NCI-CTCAE version 5.0 will be 
used to assess severity 
NCI-CTCAE version 4.0 will be used to 
assess severity 
45 
 
 
Addition of 
information on 
severity and 
causality re-
assessments 
- 
 All causality and severity assessments will 
be reassessed by Lareb to independently 
validate these assessments. These 
assessors will be blinded to patient’s arm 
allocation. The methods used by the 
assessors will be described in a Standard 
Operating Procedures 4.8 and 4.9. 
45,46 
 
 
Addition of 
information on 
drug-genotype 
association 
assessment 
- 
The drug-genotype association assessment 
will be performed by an expert panel, once 
the study is completed. The assessor is 
blinded to patient’s arm allocation. The 
methods used by the assessors are 
described in a Standard Operating 
Procedure 4.10. 
48 
 
 
Addition of  
information on 
drug-drug-gene 
sub-study 
- 
See Chapter 6.3.3. on page 40. 
50 
 
 
Revised sample 
collection when a 
patient endures a 
serious ADR 
Patients who endure an ADR 
which is categorized as an 
“extreme phenotype” will be 
asked to provide an 
additional blood spot sample 
within 24 hours of the ADR. 
Patients who endure an ADR which is 
categorized as an “extreme phenotype” 
will be asked to provide an additional 
blood sample (10mL EDTA) within 24 hours 
of the ADR. 
54 
5.0 
June 2017 
Incidence of drug 
adherence 
questions 
increased 
Asked at baseline and end of 
study 
Asked at baseline, 4 weeks, 12 weeks and 
end of study 
22 
 
 
Incidence of PGx 
knowledge 
questions 
increased 
Asked at baseline and end of 
study 
Asked at baseline, 12 weeks and end of 
study 
22 
 
 
Windows for 4 
week and 12 
week survey 
expanded 
± 1 week 
± 2 weeks 
21 
 
 
ADE report and 
data collection 
 
Patients must be contacted by the 
research team withtin the described time 
windows for data collection. However, 
47 

 
 
 
 
 
 
PREPARE  
 
 
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GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
described in more 
detail 
patients and physicians may also report 
ADEs outside these time windows. ADEs 
may also be derived from (electronic) 
medical records  
6.0 
March 
2018 
Addition of 
specific criteria 
for withdrawal 
- 
Patient does not use index drug for a 
minimum of 7 consecutive days 
32 
 
 
Adjustment of 
primary 
composite 
endpoint 
definition 
regarding 
oncological 
patients 
- 
For oncology patients receiving 5-FU, 
capecitabine, tegafur or irinotecan, only 
hematological toxicities of NCI-CTCAE 
grade 4-5 and non-hematological toxicities 
of NCI-CTCAE grade 3-5 will be considered 
clinically relevant.    
40 
 
 
Adjustment of 
extreme 
phenotype 
definition 
1.Experience a serious ADR 
which is not expected on the 
basis of the pre-emptive PGx 
testing results.   
2.Experience a serious ADR 
(already known to be 
associated with the drug in 
the DPWG guidelines, Table 
7) even though the patient 
had received an altered drug 
or dose selection as a result 
of an actionable genotype. 
See Figure 10 on page 49 
49 
 
 
Removal of 
carbamazepine 
from index drug 
list 
- 
Removal of carbamazepine from index 
drug list.  
28 
 
 
Removal of HLA-
B*1502 and 
HLA-A*3101 from 
panel 
50 variants in 13 
pharmacogenes 
46 SNPs (to determine 44 variants) in 12 
pharmacogenes 
34 
 
 
Decrease the 
number of 
severity and 
causality 
assessments for 
validation 
All causality and severity 
assessments will be 
reassessed by Lareb to 
independently validate these 
assessments.  
10% of causality and severity assessments 
will be reassessed by Lareb to 
independently validate these assessments.  
41, 43 
 
 
Completion of 
appendix by 
addition of 
warfarin DPWG 
recommendations 
- 
Addition of recommendations related to 
warfarin. 
85 
6.0 
February 
2019 
Windows for 12 
week survey 
expanded 
± 2 weeks 
± 3 weeks 
21 
 
 
Enrolment 
logistics 
surrounding 
cross-over 
It is anticipated that the study 
will start in January 2017 and 
end in December 2019. 
It was anticipated that the study would 
start in January 1st 2017 and end in 
December 31st 2019. Due to a delay, the 
study started in March 6th 2017 and the 
cross-over was performed on October 1st 
2018. 
30 
 
 
Update of 
recruiting centers 
and their 
corresponding 
areas of focus 
- 
See Table 4 
31 
 
 
Removal of 
oxycodone from 
index drug list  
- 
DPWG guidelines are periodically updated 
and these changes need to be reflected in 
the protocol. As of February 20th 2018, 
the DPWG guideline for oxycodone was 
updated. The updated version no longer 
had an actionable recommendation for 
any phenotype. As a result, oxycodone 
33, 34, 
42 

 
 
 
 
 
 
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GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
was removed as an index drug as per May 
15th 2018. 
 
 
Timing of drug-
genotype 
association 
assessment 
The drug-genotype 
association assessment will 
be performed by an expert 
panel once the study is 
completed. 
The drug-genotype association assessment 
will be performed by an expert panel in 
bulk. 
51 
 
 
Addition of 
CYP2B6*5 and 
NUDT15 *3, *6 
and *9 to panel 
 
CYP2B6*5 (rs3211371), NUDT15*3 
(rs116855232), NUDT15*6 (rs869320766) 
and NUDT15*9 (rs746071566).  
39 
7.0 
March 
2020 
Extension of time-
block 2 enrolment 
with 3 months 
The first time block will 
encompass an 19 month 
enrolling period (and an 
additional 3 months follow-
up) and the second time block 
will encompass an 18 month  
enrolling period (and an 
additional 3 months follow-
up), where a new set of 
patients is recruited in each 
arm. 
The first time block will encompass an 19 
month enrolling period (and an additional 
3 months follow-up) and the second time 
block will encompass an 21 month  
enrolling period (and an additional 3 
months follow-up), where a new set of 
patients is recruited in each arm. 
20 
 
 
 
It was anticipated that the 
study would start in January 
1st 2017 and end in 
December 31st 2019. Due to 
a delay, the study started on 
March 6th 2017 and the 
cross-over was performed on 
October 1st 2018.  
It was anticipated that the study would 
start in January 1st 2017 and end in 
December 31st 2019. Due to a delay, the 
study started on March 6th 2017 and the 
cross-over was performed on October 1st 
2018. The second time-block is extended 
with a 3 month enrolment period from 
April 1st 2020 to July 1st 2020. 
29 
8.0 
March 
2022 
Details on the 
primary endpoint 
and statistical 
analysis are 
removed from 
the protocol and 
specified in a 
separate 
Statistical Analysis 
Plan (SAP) version 
3.0 
 
6.1 figure 8 was updated 
6.1.3. Drug-genotype association was 
removed 
7 for the statistical analyses a refence is 
made to the SAP 3.0 
53 
 
 

 
 
 
 
 
 
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CONFIDENTIAL 
GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
CLINICAL STUDY PROTOCOL:  
PREemptive Pharmacogenomic testing for Preventing Adverse drug REactions 
(PREPARE) 
Protocol ID 
Grant Agreement No 668353 (U-PGx) 
Protocol Name 
PREPARE 
Version 
7.0 
Date 
March 27th 2020 
Coordinating investigator 
Jesse J. Swen, PharmD, PhD 
Associate Professor of Pharmacogenetics 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Center 
P.O. Box 9600 
NL 2300 RC  Leiden 
The Netherlands 
Tel.: +31 (0)71 526 2790 
Fax: +31 (0)71 526 6980 
E-mail: J.J.Swen@lumc.nl 
National Principal investigator(s): 
Leiden University Medical Center: (LUMC) 
University of Liverpool: (PHUL) 
Medical University of Vienna: (MUWV) 
Centro di Riferimento Oncologico: (CROA) 
Servicio Andaluz de Salud: (SASG) 
University of Patras: (UPAT) 
University of Ljubljana: (ULMF) 
(see Appendix 18.1 for contact information) 
Jesse J. Swen 
Munir Pirmohamed 
Gere Sunder-Plassmann 
Giuseppe Toffoli 
Cristina Lucía Davila Fajardo 
George P. Patrinos 
Vita Dolzan 
Sponsor  
Leiden University Medical Center 
Albinusdreef 2, 2333 ZA, Leiden 
Subsidising party 
European Commission, Horizon 2020 
Grant Agreement No668353 (U-PGx) 
Independent expert  
Dr. Gijs Santen 
Klinisch Geneticus, LUMC 
Albinusdreef 2 
2333 ZA Leiden 
Tel: 071 5268033 
E-mail: g.w.e.santen@lumc.nl 
Laboratory sites  
FARMACOGENOMIC TESTING: 
LUMC: Department of Clinical Pharmacy and 
Toxicology, Albinusdreef 2, 2223 ZA, Leiden 
Building 1 
Tel: (071) 526 2790 Fax: (071) 526 6866 
E-mail: KFTsecretariaat@lumc.nl 
 
NEXT GENERATION SEQUENCING OF ‘EXTREME 
PHENOTYPES’: 

 
 
 
 
 
 
PREPARE  
 
 
CONFIDENTIAL 
GA No 668353 (U-PGx) 
Horizon 2020 Research and Innovation  
 
  
Section of pharmacogenetics/ Department of 
Physiology and Pharmacology, Karolinska Institutet, 
Nanna Svartz vag 2, SE 171 77 Stockholm, Sweden 
Tel: +46852487735 
Contact: Prof. Dr. Magnus Ingelman-Sundberg 
E-mail: Magnus.Ingelman-Sundberg@ki.se 
 
DRUG-DRUG-GENE INTERACTION SUB-STUDY: 
Dr. Margarete Fischer-Bosch-Institute of Clinical 
Pharmacology 
Auerbachstr. 112 
D-70376 Stuttgart, Germany 
Tel: ++49-711-8101 3700 
Fax: ++49-711-859295 
Contact: Prof. Dr. Matthias Schwab 
E-mail: Matthias.Schwab@ikp-stuttgart.de 
 
The clinical study will be conducted, and essential documentation archived, in compliance with EU 
Directives, which incorporate the requirements of the ICH Guideline for Good Clinical Practice. 
 
 

 
 
 
 
 
 
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Horizon 2020 Research and Innovation  
 
  
PROTOCOL SIGNATURE PAGE 
 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. Henk-Jan Guchelaar  
Professor of Clinical Pharmacy 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Center 
 
04-03-2022 
Coordinating Investigator/Project 
Leader: 
Jesse J. Swen, PharmD, PhD 
Section Head Laboratory 
Associate Professor of Pharmacogenetics 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Center 
 
04-03-2022 
Principal Investigator NL: 
Jesse J. Swen, PharmD, PhD 
Section Head Laboratory 
Associate Professor of Pharmacogenetics 
Section Chair Laboratory 
Dept. Clinical Pharmacy & Toxicology 
Leiden University Medical Center 
 
04-03-2022 

 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
 
Rationale: In recent years, multiple randomized controlled trials for a variety of drug-gene 
combinations have strongly indicated that pharmacogenomics (PGx) testing prior to prescribing, to 
guide the dose and drug selection, can improve patient outcomes. Almost 15% of medicinal products 
evaluated by the European Medicines Agency between 1995 and 2014 contain PGx information in 
their product label. PGx-guided therapeutic dose and drug selection recommendations have also 
been created and published by the Dutch Pharmacogenetics Working Group (DPWG). However, 
despite these major scientific and clinical advances in PGx, and the availability of several 
commercially available PGx tests, the application of PGx into routine care remains very limited. 
PREPARE will implement pre-emptive genotyping of an entire panel of clinically relevant PGx markers 
(for which DPWG guidelines are available: ‘pharmacogenes’) across seven countries within the 
European Union, in a prospective clinical study and investigate its collective impact on patient 
outcomes and cost-effectiveness.  
 
Objective: To determine whether implementing pre-emptive PGx testing of an entire panel of 
clinically relevant PGx markers, to guide the dose and drug selection for 39 commonly prescribed 
drugs, will result in an overall reduction in the number of clinically relevant drug-genotype associated 
adverse drug reactions (ADRs). We hypothesize that the implementation of PGx-guided drug 
prescribing will reduce both the occurrence and severity of drug-genotype associated ADRs in 
comparison to patients receiving standard of care treatment.  
 
Study design: A multi-center, open, randomized, cross-over implementation study conducted in 
seven countries across Europe. Countries will be randomised to start with enrolling either patients 
receiving PGx-guided prescribing (study arm) or standard of care (control arm) for 19 months. After 
this period, a new set of patients will be recruited and the opposite strategy will implemented for 21 
months. All study patients will be followed-up for a minimum of 12 weeks; maximum follow-up is 
limited to 22 months per patient. 
 
Study population: Patients of any ethnicity who are at least 18 years old and receive a first 
prescription for a drug for which a DPWG guideline is available, as part of routine care, are eligible to 
participate. 4,050 patients will receive PGx-guided drug and dose selection (study group) and 4,050 
patients will receive standard of care (control group).  
 

 
 
 
 
 
 
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Intervention: All patients will donate a DNA sample that will be genotyped for a panel of 48 genetic 
variants in 13 pharmacogenes. For patients within the study arm, their results will be: 1) recorded in 
the (electronic) medical record and 2) provided to the patient in the form of plastic card, akin to a 
credit card. Genetic results and DPWG guidelines can used by physicians and pharmacists to guide 
the dose and drug selection for the initial drug of inclusion, and for the prescription of any 
subsequent drugs that are newly started during follow-up and are on the list of drugs eligible for 
inclusion in PREPARE (i.e. a DPWG guideline  is available for the drug). Physicians and pharmacists are 
given PGx test results but are not forced to adhere to the DPWG guidelines.    
 
Main study parameters/endpoints:  
The primary endpoint of PREPARE is a composite endpoint of clinically relevant drug-genotype 
associated ADRs. Secondary outcomes include other clinical outcome measures (e.g. total number of 
ADEs, dose changes, drug cessations etc.), a cost-effectiveness evaluation, and process metrics for 
implementation; the latter includes physician and pharmacist adherence to the DPWG guidelines, 
and the acceptance of PGx-informed prescribing to health care professionals and patients.  
 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
When a patient chooses to participate in this study, genetic information concerning 48 genetic 
variants in 13 pharmacogenes will be determined. Burdens to the patient are: 1) the supply of a 
blood or saliva sample for DNA collection, 2) being contacted four times at regular intervals by a 
research nurse (at baseline, four weeks and 12 weeks and at the end of the arm’s follow-up period), 
and 3) being asked to complete online surveys (at two weeks, and eight weeks). Patients who endure 
an ADR which is categorized as an “extreme phenotype” will be asked to provide an additional blood 
sample within 24 hours of the ADR. In a sub-study, patients included in the study for a first 
prescription of voriconazole, metoprolol, simvastatin, atorvastatin, fluorouracil or capecitabine will 
be asked to provide additional blood spot samples at multiple time points. Benefits to patients in the 
study arm include a potential reduced risk of ADRs. Overall, minimal risks are expected for included 
patients due to the fact that all of the drugs included within this study have previously been licensed 
for routine use and thus have been evaluated as having a positive benefit/risk ratio. 
 
 
 
 

 
 
 
 
 
 
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TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE .................................................................................................. 16 
2. 
STUDY OBJECTIVES ........................................................................................................................ 19 
2.1. 
Primary Objective .................................................................................................................. 19 
2.2. 
Secondary Objectives ............................................................................................................ 19 
3. 
STUDY PLAN AND PROCEDURES .................................................................................................... 20 
3.1. 
Overall study design .............................................................................................................. 20 
3.2. 
Data collection procedures ................................................................................................... 22 
3.2.1. 
Data collection summary matrix ................................................................................... 24 
3.2.2. 
Study arm patient journey............................................................................................. 26 
1.1.1 
Standard of care arm patient journey ........................................................................... 27 
1.1 
DNA sample collection .......................................................................................................... 28 
1.2 
Randomisation and Blinding .................................................................................................. 28 
3.2.3. 
Randomisation ............................................................................................................... 28 
3.2.4. 
Blinding .......................................................................................................................... 29 
3.3. 
Study timetable ..................................................................................................................... 29 
4. 
STUDY POPULATION ...................................................................................................................... 30 
4.1. 
Population ............................................................................................................................. 30 
4.2. 
Inclusion criteria .................................................................................................................... 31 
4.3. 
Exclusion criteria ................................................................................................................... 32 
4.4. 
Patient recruitment and inclusion ......................................................................................... 33 
4.5. 
Patient log and screening ...................................................................................................... 34 
4.6. 
Sample size calculation .......................................................................................................... 34 
4.7. 
Withdrawal of individual subjects ......................................................................................... 35 
4.7.1. 
Specific criteria for withdrawal ..................................................................................... 35 
4.7.2. 
Replacement of individual subjects after withdrawal ................................................... 36 
4.7.3. 
Follow-up of subjects withdrawn from treatment ........................................................ 36 
5. 
TREATMENT OF SUBJECTS ............................................................................................................. 36 
5.1. 
Investigational strategy ......................................................................................................... 36 
5.1.1. 
Variant Selection and Platform ..................................................................................... 36 
5.1.2. 
The DPWG Guidelines ................................................................................................... 39 
5.1.3. 
“Safety-Code” Card ........................................................................................................ 41 
6. 
ENDPOINT ASSESSMENT ............................................................................................................... 44 
6.1. 
Primary endpoint ................................................................................................................... 44 
6.1.1. 
Severity Classification .................................................................................................... 45 
6.1.2. 
Causality Assessment .................................................................................................... 46 

 
 
 
 
 
 
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6.1.3. 
Drug-genotype association ................................................ Error! Bookmark not defined. 
6.2. 
Procedure of data collection ................................................................................................. 48 
6.3. 
Secondary endpoints ............................................................................................................. 48 
6.3.1. 
Cost-effectiveness ......................................................................................................... 49 
6.3.2. 
Implementation and adoption of guidelines ................................................................. 49 
6.3.3. 
Drug-Drug-Gene Interaction Sub-study......................................................................... 49 
6.3.4. 
Extreme phenotypes ..................................................................................................... 52 
7. 
STATISTICAL ANALYSIS ................................................................................................................... 53 
7.1. 
Primary analysis ......................................................................... Error! Bookmark not defined. 
7.2. 
Secondary analyses ................................................................... Error! Bookmark not defined. 
8. 
ASSESSMENT OF SAFETY ............................................................................................................... 54 
8.1. 
Definition SAEs ...................................................................................................................... 54 
1.1 
Methods for recording and follow-up of ADEs...................................................................... 54 
8.2. 
Reporting of SAEs .................................................................................................................. 54 
8.3. 
Safety Committee .................................................................................................................. 55 
8.4. 
Premature termination of the study ..................................................................................... 55 
9. 
STRUCTURED RISK ANALYSIS ......................................................................................................... 56 
9.1. 
Potential issues of concern.................................................................................................... 56 
10. 
DATA HANDLING AND RECORD KEEPING .................................................................................. 59 
10.1. 
Electronic Case Report Forms ........................................................................................... 59 
10.2. 
Data security and subject privacy ...................................................................................... 60 
10.3. 
Access to source data and record retention ..................................................................... 60 
10.4. 
Storage of human material ................................................................................................ 60 
10.5. 
Data management ............................................................................................................. 60 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................................ 61 
11.1. 
Monitoring ......................................................................................................................... 61 
11.2. 
Direct access to documents ............................................................................................... 61 
12. 
TEMPORARY HALT AND PREMATURE TERMINATION OF THE STUDY ....................................... 62 
12.1. 
Temporary halt of study .................................................................................................... 62 
12.2. 
Premature termination of study ....................................................................................... 62 
13. 
ETHICS ........................................................................................................................................ 63 
13.1. 
Ethical conduct of the study .............................................................................................. 63 
13.2. 
Independent ethics committee ......................................................................................... 63 
1.1 
Patient information and informed consent .......................................................................... 63 
13.2.1. 
Recruitment in community pharmacies ........................................................................ 63 
13.2.2. 
Informed Consent and Patient Brochure ...................................................................... 63 
13.3. 
Changes to the study protocol .......................................................................................... 64 

 
 
 
 
 
 
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13.4. 
Annual progress report ..................................................................................................... 64 
14. 
INSURANCE ................................................................................................................................ 65 
15. 
STUDY REPORT .......................................................................................................................... 65 
16. 
PUBLIC DISCLOSURE AND PUBLICATION POLICY ....................................................................... 65 
17. 
REFERENCES .............................................................................................................................. 66 
18. 
APPENDICIES .............................................................................................................................. 67 
18.1. 
National Coordinators and Principal Investigators ............................................................ 67 
18.2. Flow Charts of Patient Journey................................................................................................. 68 
18.2.1. 
General Flow Chart of Patient Journey ......................................................................... 68 
18.2.2. 
Site Specific Flow Chart of Patient Journey ................................................................... 69 
18.3. 
DPWG Guidelines .............................................................................................................. 71 
18.4. 
Scientific Advisory Board ................................................................................................... 89 
18.5. 
Organogram of U-PGx Consortium .................................................................................... 91 
 
 
 

 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
ADR 
ADE 
ADL 
AE 
Adverse Drug Reaction 
Adverse Drug Event 
Activities of Daily Living 
Adverse Event 
AR 
Adverse Reaction 
CDS 
CROA 
CV 
Clinical Decision System 
Centro di Riferimento Oncologico  
Curriculum Vitae 
DPWG 
eCRF 
EMA 
Dutch Pharmacogenomics Working Group 
Electronic Case Report Form 
European Medicines Agency 
EU 
European Union 
EQ5D 
European Quality of Life – Five Dimensions 
GCP 
IB 
Good Clinical Practice 
Investigator’s Brochure 
IC 
ICH 
Informed Consent 
International Council of Harmonization 
LCAT 
LIM 
LUMC 
MAF 
MSC 
MUWV 
NCI-CTCAE 
PGx 
PHUL 
PREPARE 
QAC 
QoL 
(S)AE 
Liverpool Causality Assessment Tool 
Lareb Intensive Monitoring  
Leiden University Medical Center 
Minor Allele Frequency 
Medication Safety Code 
Medical University of Vienna 
Common Toxicity Criteria Adverse Events 
Pharmacogenomic(s) 
University of Liverpool 
PREemptive Pharmacogenomic testing for Preventing Adverse drug REactions 
Quality Assurance Committee 
Quality of Life 
(Serious) Adverse Event  
SASG 
SPC 
Servicio Andaluz de Salud 
Summary of Product Characteristics 
ULMF 
UPAT 
 
University of Ljubljana 
University of Patras 
 

 
 
 
 
 
 
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1. INTRODUCTION AND RATIONALE 
 
Pharmacogenomics is the study of genetic variability affecting an individual’s response to a drug. It is 
one of the first clinical applications of the post-genomic era and allows personalized medicine rather 
than the established ‘one size fits all’ approach to prescribing drugs. The expected reduction in ‘trial 
and error’ drug prescribing will result in safer and more cost-effective drug therapy. 
 
Indeed, in recent years a number of studies have shown that genetic variation in genes encoding 
drug transporters and drug metabolic enzymes affect drug disposition, and can lead to under-dosing 
or overdosing in affected individuals. Furthermore, variation in genes encoding drug targets has also 
been shown to have a major influence on a drug’s effect, influencing both efficacy and safety. The 
results of five randomized clinical trials strongly indicate that PGx testing prior to prescribing, with 
subsequent genotype-informed treatment stratification,  can be associated with improved patient 
outcomes (Table 1).  
 
In addition, almost 15% of medicinal products evaluated by the EMA between 1995 and 2014 contain 
PGx information in their product label (1). PGx-based therapeutic dose and drug selection 
recommendations have also been created and published by the DPWG (2). 
 
Table 1 Randomized clinical trials supporting PGx testing prior to prescribing with clinical outcome endpoints. 
Drug 
Endpoint 
Genetic variants 
Reference 
Abacavir 
Hypersensitivity 
HLA-B *5701 
N Engl J Med 2008 Feb 
7;358(6):568-579. 
Acenocoumarol/ 
Phenprocoumon 
% of time in therapeutic 
INR 
VKORC1/CYP2C9 
N Engl J Med 2013 Dec 
12;369(24):2304-2312. 
Warfarin 
% of time in therapeutic 
INR 
VKORC1/CYP2C9 
N Engl J Med 2013 Dec 
12;369(24):2294-2303. 
Risk of bleeding 
VKORC1/CYP2C9 
Lancet 2015 Jun 
6;385(9984):2231-2232. 
Mercaptopurine/ 
Azathioprine 
Incidence of leukopenia 
TPMT 
Gastroenterology 2015 
Oct;149(4):907-17.e7. 
 

 
 
 
 
 
 
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Importantly, over 95% of the population carry at least one actionable genotype for one of the genes 
covered by the DPWG guidelines (Figure 1). 
However, despite major scientific and clinical advances in PGx and the availability of several 
commercially available PGx tests, the application of PGx into routine patient care remains very 
limited.  We have described the barriers for implementation of clinical PGx into routine patient care 
and recognized the following obstacles (3): 
 
• 
Lack of guidelines directing the clinical use of PGx test results; 
• 
Lack of selection of a panel of clinically relevant PGx tests; 
• 
Lack of data on diagnostic test criteria (e.g. specificity, sensitivity) of PGx testing; 
• 
Need for training and educating health care professionals and patients about the potential 
and practicalities of PGx; 
• 
Lack of information on cost-effectiveness and cost-consequences of PGx testing; 
• 
Lack of appropriate ICT technologies and infrastructure to implement routine PGx testing.  
This requires data storage and clinical interpretation aids, and the incorporation of PGx  into 
the workflow patterns of physicians and pharmacists. 
 
PREPARE will address these major challenges and obstacles for implementing PGx testing into routine 
care, taking into account the diversity of healthcare systems and citizens across Europe. To achieve 
successful implementation, PREPARE will provide an extensive training and education programme to 
prepare recruiting physicians and pharmacists for pre-emptive PGx-based prescribing and dispensing. 
The effectiveness of this training and education programme will be evaluated by performing pre- and 
post-programme surveys in the participating countries. Additionally, novel ICT tools will be created to 
integrate the PGx results into (electronic) medical records before initiation of the study.  
Figure 1 The frequency of actionable pharmacogenes. Over 95% of the population carry at least one actionable genotype for 
one of the genes covered by the DPWG guidelines (4). 

 
 
 
 
 
 
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Following this, PREPARE will primarily determine if pre-emptive genotyping of an entire panel of 
clinically relevant PGx markers (for which DPWG guidelines are available: ‘pharmacogenes’) results in 
better outcomes for patients (i.e. reduces the number of clinically relevant drug-genotype associated 
ADRs) and is more cost-effective than standard care. Furthermore, both quantitative and qualitative 
indicators of implementation success will be monitored and evaluated. In a sub-study, the drug-drug-
gene interactions of voriconazole, metoprolol, simvastatin, atorvastatin, fluorouracil and 
capecitabine will be investigated in more detail by sampling additional plasma blood levels through 
bloodspots. Finally, explorative data analysis will be performed to associate novel variants identified 
by NGS techniques with extreme phenotypes, and elucidate novel drug-drug-gene interactions, and 
so advance the field of PGx. 
 
 
 
 

 
 
 
 
 
 
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2. STUDY OBJECTIVES 
2.1. Primary Objective 
To determine whether the implementation of pre-emptive PGx testing of an entire panel of clinically 
relevant PGx markers, to guide the dose and drug selection for 39 commonly prescribed drugs, will 
result in an overall reduction in the number of clinically relevant drug-genotype associated ADRs 
which are causally related to the initial drug of inclusion (referred to as ‘index drug’).  
 
2.2. Secondary Objectives 
To determine whether the implementation of PGx-guided drug and dose selection: 1) reduces the 
total number ADRs (causally related to both the index drug and subsequent newly prescribed drugs), 
2) reduces the total number of ‘serious’ ADRs (causally related to  the index drug), 3) reduces the 
number of dose changes for the index drug, 4) reduces the number of drug cessations for the index 
drug and 5) is cost-effective compared to standard of care. Additionally, the attitudes towards PGx 
and knowledge of PGx among healthcare providers and patients will be evaluated. Process metrics 
for implementation among physicians and pharmacists will also be monitored. These metrics include: 
adherence to DPWG guidelines, and the acceptance of PGx testing. Explorative data analysis will be 
performed to associate novel variants identified through NGS techniques with extreme phenotypes, 
and elucidate novel drug-drug-gene interactions, and so advance the field of PGx. Six drug-drug-gene 
interactions will be investigated extensively by sampling additional plasma blood levels (voriconazole, 
metoprolol, simvastatin, atorvastatin, fluorouracil and capecitabine) in a sub-study. 
 
 

 
 
 
 
 
 
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3. STUDY PLAN AND PROCEDURES 
3.1. Overall study design 
This study is a multi-center, open, randomized, cross-over study conducted in seven countries across 
Europe (Figure 2). The sequence of study and control arm is randomized per country to minimize the 
influence of time dependent variables. To avoid bias and account for differences between countries, 
countries will serve as their own controls. The countries will be randomized to start with: 1) 
implementing pre-emptive PGx testing to guide drug and dose selection (study arm), or 2) providing 
standard clinical care (control arm). The first time-block will encompass an 19 month enrolling period 
(and an additional 3 months follow-up) and the second time block will encompass an 21 month 
enrolling period (and an additional 3 months follow-up), where a new set of patients is recruited in 
each arm. All patients will be followed up for a minimum of 12 weeks, and up to a maximum of 22 
months (first time block), and 21 months (second time block). 4,050 patients in the study arm and 
4,050 patients in the control arm will be recruited prospectively in Austria, Greece, Italy, Slovenia, 
Spain, The Netherlands, and United Kingdom. Each implementation country will focus on, but is not 
limited to, recruiting patients within a specific therapeutic area.  
 
Figure 2 Study design of the multi-center open randomized cross-over trial. 
A patient who receives a first prescription for any drug listed in Table 5 (i.e. essentially all drugs that 
have a DPWG PGx guideline available) will be eligible for inclusion. This is further defined as the 
‘index drug’. T=0 is defined as the day the patient initiates the index drug. All included patients (both 
study and control arm patients) will donate DNA by a blood or saliva sample and will be genotyped 
for our panel of 48 genetic variants in 13 pharmacogenes. Patients in the control arm will receive the 
usual prescription, without PGx-guided drug or dose selection and a mock “Safety-Code” card (see 
Section 5.1.3). In the study arm only, a patient’s DNA test results will be: 1) recorded in the 
(electronic) medical record and 2) handed to the patient on a “Safety-Code” card (see Section 5.1.3). 
PGx results will be returned to the physicians and pharmacists within seven days of initiating the 
index drug guide the patient’s drug and dose selection as per the DPWG guidelines. Health care 

 
 
 
 
 
 
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providers are not forced to adhere to the DPWG guidelines, but are simply provided with all the tools 
necessary to implement PGx-guided prescribing. Patients in the study arm may start with the usual 
prescription, to bridge the lag-time, and will be contacted by their physician or pharmacist if their 
PGx results recommend a prescription alteration. 
 
Data on ADEs, costs and implementation process parameters will be collected during follow-up (at 
baseline, four weeks and 12 weeks after initiation of the index drug and a cross-sectional collection 
at the end of their time block). Data on patient reported outcomes ADEs are collected at two and 
eight weeks (Figure 3). All patients who receive a subsequent new prescription for another drug 
during the their time block will be asked to report this to the research nurse. Patients in the study 
arm will also be asked to present their PGx results (on their “Safety-Code” card) to the prescribing 
physician or dispensing pharmacist so that they may use these to guide drug and dose selection. It is 
recognized that these health care providers may be outside the realm of the study and may therefore 
not have received training in incorporating pharmacogenomics in clinical care. The research nurse 
will establish whether this newly prescribed drug is on the list of drugs eligible for PREPARE (Table 5).  
If the drug is indeed eligible, additional data on ADEs, costs and implementation process parameters 
regarding this drug will be collected. This prescription is further defined as the ‘subsequent drug’ 
(Figure 3). This data will be used for the secondary analyses. 
 
 
 
Figure 3 Timeline of data collection 
The minimum follow-up time is 12 weeks; the follow-up of all patients recruited in the first time 
block will cease at the end of the time block in which they were recruited (Figure 3). 
 
PGx test results will be recorded in the patient’s (electronic) medical record and a system will be 
developed to generate (automated) alerts whenever a relevant drug (listed in Table 5) is prescribed 
or dispensed to the patient by the physician or pharmacist, respectively. In this way, alerts will be 

 
 
 
 
 
 
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fully integrated into the regular workflow (prescribing and dispensing) of physicians and pharmacists. 
Since the genotype results will be recorded in the (electronic) medical record, they can be used for 
PGx-guided prescribing of subsequent newly started drugs listed in Table 5.  
 
In parallel to this, the DNA of patients who endure an ADE categorized as an “extreme phenotype” 
during follow-up will be analyzed through NGS sequencing of 150-200 ADME genes, to find new 
variants associated with this phenotype. Six drug-drug-gene interactions will also be further 
investigated by sampling additional plasma blood levels through blood spots (voriconazole, 
metoprolol, simvastatin, atorvastatin, fluorouracil and capecitabine) in a sub-study.  
3.2. Data collection procedures 
T=0 is defined as the day the patient initiates the index drug. During the follow-up period trained 
research nurses will contact patients at baseline (t=0) (± one week), four weeks (± two weeks) and 12 
weeks (± three weeks), to go through a standardized questionnaire and to collect data on the 
occurrence of any ADEs (Figures 4 and 5).Inpatient participants will be visited by the research nurse. 
Outpatient participants will be contacted by telephone. The research nurses will acquire information 
about the occurrence and severity of all ADEs by asking an open question regarding the occurrence 
of any ADEs, followed by various specific questions related to the patient’s answers. In addition, all 
patients will be contacted by the research nurse at the end of the time block (± four weeks from the 
end of each time block) to complete the questionnaire for a final time. Research nurses additionally 
will collect required lab and or test results from patients’ (electronic) medical records. If a patient 
discontinues the index drug during the 12 week follow-up period, follow-up will continue as initially 
anticipated.  
Complementary to this, patients will be followed up by receiving online surveys at two weeks and 
eight weeks after initiation of the index drug. Patients are requested to complete the surveys within 
two weeks. The questions within this survey will be used to assess the occurrence and severity of any 
ADEs experienced by the patients. These surveys will be filled in by the patients online using the web-
based Lareb Intensive Monitoring (LIM) tool (see Section 6.1.1). If patients do not have an email 
address or are not able to fill in an online survey, then the LIM tool will not be used. This data will be 
used for secondary analyses. Research nurses will register patients for the LIM tool at baseline. Their 
study-ID number, e-mail address, date of birth, drug of inclusion and initiation date will be reported 
in the LIM registration portal. An automated e-mail will be sent to the patient at week two and eight 
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the LIM portal using their e-mail address and a standard password. Patients will be asked to change 
this password once they log in. This will give patients access to the LIM surveys.  
 
All patients who receive a subsequent prescription for another drug during follow-up will be asked to 
report this to the research nurse. For all drugs newly started during the time block which are eligible 
for inclusion (listed in Table 5), follow-up will be in the same manner that was used to follow-up  the 
index drug. This data will be used for the secondary analyses. 
 
Collected data is summarized in Table 2. All data will be entered into an electronic Case Report Form 
(eCRF) provided, which will guarantee consistency of data collection procedures. Data will be used 
exclusively in a pseudonymous fashion and data protection will be guaranteed according to 
international regulations . An independent Contract Research Organization (CRO) will guarantee data 
integrity and data homogeneity across all seven implementation countries by risk based monitoring 
of a random sample of 10% of the collected data (Section 11.1).  
Research nurses will collect and store patient contact information (e-mail address, telephone 
number, name and study-ID number) in a separate, local file (national subject identification code 
list).  
 
 

 
 
 
 
 
 
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3.2.1. Data collection summary matrix  
Table 2 Summary of prospective data collection  
All in yellow is ONLY collected in the study arm 
 
Research Nurse 
Lareb Intensive Monitoring 
Variable Domains 
Baseline 
4 
weeks 
12 weeks 
End of Study (cross-
sectional at the end of 
each time-block) 
2 
weeks 
8 
weeks 
PATIENTS 
Personal Characteristics 
1.1 General information 
X 
 
 
 
 
 
1.2 In- and exclusion criteria 
X 
 
 
 
 
 
1.3 Demographics 
X 
 
 
 
 
 
1.4 Recruitment Information 
X 
 
 
 
 
 
1.5 Health behaviours 
X 
 
 
 
 
 
1.6 DNA sample collection 
X 
 
 
 
 
 
1.7.1  PGx testing results 
X 
 
 
 
 
 
1.7.2  Safety-code card 
X 
 
 
 
 
 
1.8.1  Index drug 
prescription 
X 
 
 
 
 
 
1.8.2  Action ability 
X 
 
 
 
 
 
1.8.3  Index drug 
prescription change 
X 
 
 
 
 
 
1.8.3.1  Contact information 
HCP 
X 
 
 
 
 
 
1.8.3.1   Adherence to DPWG 
guidelines 
X 
 
 
 
 
 
1.9 Control for logistics 
X 
 
 
 
 
 
Clinical Monitoring 
3. Comorbidities and 
allergies 
X 
X 
X 
X 
 
 
4. Co-medication and herbal 
remedies 
X 
X 
X 
X 
 
 
Nurse Assessment : Clinical Outcome 
2.1 General information 
X 
X 
X 
X 
 
 
2.2 Index drug changes 
 
X 
X 
X 
 
 
2.3 Drug adherence 
X 
X 
X 
X 
 
 
2.4 Global Health Score 
X 
X 
X 
X 
 
 
2.5 Quality of Life 
X 
X 
X 
X 
X 
X 
2.6 Attitudes and knowledge 
X 
 
X 
X 
X 
X 
Adverse events 
5. Adverse drug events  
 
 
 
 
X 
X 
5.1 Patient perception of 
ADE 
 
X 
X 
X 
 
 
5.2 Healthcare costs 
associated with ADE 
 
X 
X 
X 
 
 
5.3 Identifying the extreme 
phenotype 
 
X 
X 
X 
 
 
5.4 ADE assessment of 
severity 
 
X 
X 
X 
 
 
5.5 ADE assessment of 
causality 
 
X 
X 
X 
 
 
5.6 ADE assessment of drug-
genotype association 
 
X 
X 
X 
 
 
Those who are defined as ‘Extreme Phenotypes’ and their controls 
Identifying the ‘Extreme 
Phenotype’ 
 
X 
X 
X 
 
 
Plasma blood level of PGx 
drug (blood sample) 
At time of serious ADR 
Those included within the sub study (voriconazole, atorvastatin, simvastatin, capecitabine, fluorouracil and metoprolol) 
Routine plasma levels (blood 
spots) 
At multiple time points – see Table 9 
 

 
 
 
 
 
 
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SUBSEQUENT DRUGS: 
When a patient reports a subsequent prescription, and the nurse confirms it is a prescription of a drug of interest, the following will 
happen: 
1. The nurse registers the subsequent index drug in 1.8.. Only in the study arm will 1.8.3 be registered. 
2. Register the new index drug with LIM to initiate the 2w and 8w follow-up 
3. New follow-up regarding the following “repeated measures” is initiated: 
- 
Index drug changes (repeated measure at 4w, 12w) 
o 
Drug specific -> always ask 
- 
Global health score (repeated measure – at BL 4w, 12w) 
o 
Time specific -> only asked if the previous collected global health score is at least 1 week old 
- 
Quality of life (repeated measure – at BL, 4w,12w) 
o 
Time specific-> only asked if the previous collected quality of life is at least 1 week old 
 
Research Nurse 
Lareb Intensive Monitoring 
Variable Domains 
Baseline 
4 
weeks 
12 weeks 
End of Study (cross-
sectional at the end of 
each time-block) 
2 
weeks 
8 
weeks 
PATIENTS 
Personal Characteristics 
1.1 General information 
 
 
 
 
 
 
1.2 In- and exclusion criteria 
 
 
 
 
 
 
1.3 Demographics 
 
 
 
 
 
 
1.4 Recruitment Information 
 
 
 
 
 
 
1.5 Health behaviours 
 
 
 
 
 
 
1.6 DNA sample collection 
 
 
 
 
 
 
1.7.1 PGx testing results 
 
 
 
 
 
 
1.7.2 Safety code card 
 
 
 
 
 
 
1.8.1  Index drug 
prescription 
X 
(add the 
subsequent 
drug) 
 
 
 
 
 
1.8.2  Action ability 
X 
 
 
 
 
 
1.8.3  Index drug 
prescription change as a 
result of PGx 
X 
 
 
 
 
 
1.8.3.1 Contact information 
HCP 
X 
 
 
 
 
 
1.8.3.2  Adherence to DPWG 
guidelines 
X 
 
 
 
 
 
1.9 Control for logistics 
 
 
 
 
 
 
Clinical Monitoring 
3. Comorbidities and 
allergies 
X 
X 
X 
 
 
 
4. Co-medication and herbal 
remedies 
X 
X 
X 
 
 
 
Nurse Assessment : Clinical Outcome 
2.1 General information 
X 
X 
X 
 
 
 
2.2 Index drug changes 
 
X 
X 
 
 
 
2.3 Drug adherence 
 
 
 
 
 
 
2.4 Global Health Score 
X 
X 
X 
 
 
 
2.5 Quality of Life 
X 
X 
X 
 
X 
X 
2.6 Attitudes and knowledge 
 
 
 
 
X 
X 
Adverse events 
5. Adverse drug events 
 
X 
X 
 
X 
X 
5.1 Patient perception of 
ADE 
 
X 
X 
 
 
 
5.2 Healthcare costs 
associated with ADE 
 
X 
X 
 
 
 
5.3 Identifying the extreme 
phenotype 
 
X 
X 
 
 
 
5.4 ADE assessment of 
severity 
 
X 
X 
 
 
 

 
 
 
 
 
 
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5.5 ADE assessment of 
causality 
 
X 
X 
 
 
 
5.6 ADE assessment of drug-
genotype association 
 
X 
X 
 
 
 
Plasma blood level of PGx 
drug (blood sample) 
At time of serious ADR 
 
 
 
PHYSICIANS AND PHARMACISTS 
PGx knowledge and attitudes 
Attitudes 
Before study initiation and after study completion 
Knowledge 
Before study initiation and after study completion 
Adoption of guidelines 
Guideline adoption 
Directly after every first and subsequent prescription 
Reason for (not) 
adopting 
Directly after every first and subsequent prescription 
 
3.2.2. Study arm patient journey 
Figure 4 shows a general overview of the patient journey in the study arm. A detailed flowchart of the 
site-specific patient journey can be found in Appendix 18.2. 
Patients in the study arm will start with the usual prescription, to bridge the lag –time before the PGx 
results are ready, and will be contacted by their physician or pharmacist if their prescription is 
recommended to be changed due to their PGx test results. 

 
 
 
 
 
 
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Figure 4 Timeline describing procedures within the study arm 
 
3.2.3 Standard of care arm patient journey 
Figure 5 shows a general overview of the patient journey in the standard of care arm. A flowchart of 
the site-specific patient journey can be found in Appendix 18.2. Genotyping is performed once the 
respective time-block is completed. 

 
 
 
 
 
 
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Figure 5 Timeline describing procedures within the standard of care arm 
3.3 DNA sample collection 
Inpatients will provide a 10 mL blood sample (EDTA) for DNA collection and outpatients will provide a 
2mL saliva sample for DNA collection.  
Blood samples will be stored at 2-8OC before DNA isolation. 
Saliva samples will be collected using the ORAGENE DNA 500 collection kit and stored at room 
temperature. 
 
3.4 Randomisation and Blinding 
3.4.1 Randomisation 
The PHUL is unable to start with the study arm due to practical reasons (relocation of the hospital 
and the genetic laboratory). Therefore, PHUL has been excluded from the randomization and has 
been assigned to start the study with the standard of care approach. The remaining six sites have 

 
 
 
 
 
 
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been randomized. Randomization has been performed by medical statistician Dr. Ron Wolterbeek 
(LUMC) see Table 3 for the results of the randomization.  
Table 3 Randomization schedule of 6 study site, excluding PHUL 
Site 
Starting Strategy 
LUMC 
Standard of care 
SASG 
PGx-guided Prescription 
MUWV 
Standard of care 
UPAT 
PGx-guided Prescription 
ULMF 
PGx-guided Prescription 
CROA 
Standard of care 
 
3.4.2 Blinding 
This is an open study. Recruiting physicians/pharmacists cannot be blinded within this study because 
they must use the patients’ PGx results to guide drug and dose selection. Research nurses cannot be 
blinded within this study because they must manage study logistics. Patients cannot be blinded as 
those in the study arm as PGx results are available on the “Safety-Code” card.   
A 10% random sample of causality and severity assessments of recorded ADEs will be re-assessed by 
a second independent, blinded (unaware of patient allocation) assessor. 
100% of drug-genotype association assessments as per the Dutch Pharmacogenomics Working Group 
guideline will be assessed by a blinded (unaware of patient allocation) review committee. 
3.5 Study timetable 
It was anticipated that the study would start in January 1st 2017 and end in December 31st 2019. Due 
to a delay, the study started on March 6th 2017 and the cross-over was performed on October 1st 
2018. The second time-block is extended with a 3 month enrolment period from April 1st 2020 to 
July 1st 2020. 
 
 

 
 
 
 
 
 
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4. STUDY POPULATION 
 
4.1. Population 
Patients of any ethnicity who are at least 18 years old and receive a first prescription for a drug for 
which a DPWG guideline is available (Table 5), within the realm of routine care, are eligible to 
participate. 
The participating hospitals each will concentrate on, but are not limited to, recruiting within a 
specific therapeutic area encompassing both in- and out-patient settings (see Table 4): 
 
Table 4 Recruiting centers and their corresponding therapeutic areas of focus 
Site 
Center name 
Therapeutic focus for recruitment 
Country/ 
Language 
LUMC 
28 community pharmacies  
 
Primary care patients  
The 
Netherlands/ 
Dutch 
Leiden University Medical Center: 
Department of Neurology 
Neurology in- and outpatients  
 
SASG 
San Cecilio University Hospital: 
Departments of Pharmacy and Cardiology  
 will enroll patients with -Patients with unstable angina 
and acute coronary syndrome patients undergoing 
percutaneous coronary intervention with stent, 
patients with peripheral vascular disease and neurology 
patients 
Spain/ 
Spanish 
MUWV 
Medical University of Vienna: 
Division of Nephrology and Dialysis 
Patients receiving kidney transplantation  
Austria/ 
German 
UPAT 
University of Patras Medical School 
Psychiatric, oncology and cardiology patients  
Greece/ 
Greek 
 
Attikon University Hospital in Athens 
Psychiatric patients 
Psychiatric Hospital of Attica in Athens 
Psychiatric patients 
Psychiatric 
Hospital 
of 
Attica 
in 
Athens 
“DROMOKAITEION" 
Psychiatric patients 
ULMF 
University Medical Centre Ljubljana:  
Department of Nephrology (Transplantation 
centre) 
Department of Abdominal Surgery 
Department of Neurology 
 
Neurology, renal transplantation and abdominal 
surgery patients 
Slovenia/ 
Slovenian 
 
University Psychiatric Hospital Ljubljana (3 
divisions) 
Psychiatric patients 
Community Health Centre Ljubljana (8 units) 
Primary care patients 
Community Health Centre Litija 
Primary care patients 
Community Health Centre Kocevje 
Primary care patients 
Institute of Oncology Ljubljana 
Oncology Patients 
University Medical Center Maribor: 
Department of Psychiatry 
Psychiatric patients 
Sevnica Hospital 
General medicine patients and psychiatric patients 
Community Health Center Domzale 
Primary care patients 
Community Health Center Ivančna Gorica 
Primary care patients 
PHUL 
University of Liverpool Royal Liverpool University 
Hospital: 
Dept. of Molecular & Clinical Pharmacology  
. General medicine inpatients. 
 
  
United 
Kingdom/ 
English 
Fulwood Medical Practice 
Primary care patients 
United 
Kingdom/ 
English 
 
Clatterbridge Cancer Centre 
Primary care patients 
CROA 
Centro di Riferimento Oncologico, National 
Cancer Institute in Aviano 
Oncology patients  
 
Italy/ 
Italian 

 
 
 
 
 
 
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Centro di Riferimento Oncologico, National 
Cancer Institute in Treviso 
Oncology patients 
 
Medical Oncology department of the San Filippo 
Neri Hospital in Rome 
Oncology and cardiology patients 
4.2. Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 
1. Subject must be ≥ 18 years old 
2. Subject must receive a 1st prescription (meaning no known prescription for this drug in the 
preceding 12 months) for a drug included in Table 5, which is prescribed to them in routine 
care. 
3. Subject is able and willing to take part and be followed-up for at least 12 weeks  
4. Subject is able to donate blood or saliva 
5. Subject has signed informed consent 
 
When 10% of total patients on any specific drug have been included in the study or control arm, 
recruitment of new patients on that drug into that particular arm will no longer be permitted. In 
other words, the inclusion of patients with a first prescription for the same drug is limited to 5% of 
the control arm and 5% of the study arm. More specifically, of this 2.5%,in the control arm and 2.5% 
in the study arm in the first time block, and likewise in the second time block. 
Table 5 List of drugs eligible for inclusion (n=39) 
Antiarrhythmic 
Flecainide 
 
Propafenon 
Analgesic 
Codeine 
 
 
 
Tramadol 
Anticancer 
Capecitabine 
 
Fluorouracil 
 
Irinotecan 
 
Tamoxifen 
 
Tegafur 
Anticoagulation 
Acenocoumarol 
 
Clopidrogel  
 
Phenprocoumon 
 
Warfarin 
Antidepressant 
Citalopram  
 
Escitalopram 
 
Paroxetine 
 
Sertraline 
 
Venlafaxine 
Antidepressant (TCA) 
Amitriptyline 
 
Clomipramine 
 
Doxepine 
 
Imipramine 
 
Nortryptiline 

 
 
 
 
 
 
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Antiepileptic 
 Phenytoin 
Antihypertensive 
Metoprolol 
Anti-infective 
Efavirenz 
 
Flucloxacillin 
 
Voriconazole 
Antipsychotic 
Aripiprazole 
 
Haloperidol 
 
Pimozide 
 
Zuclopenthixol 
Cholesterol-lowering 
Atorvastatin 
 
Simvastatin 
Immunosuppressive 
Azathioprine 
 
Mercaptopurine 
 
Tacrolimus 
 
Thioguanine 
Psychostimulant 
Atomoxetine 
 
Table 5 includes all drugs for which an actionable gene-drug interaction is present according to the 
DPWG recommendations with the exception of abacavir, omeprazole, esomeprazole, lansoprazole, 
pantoprazole, rabeprazole, oxycodone and oestrogen containing oral contraceptives. Abacavir is 
excluded because PGx-guided prescribing is part of routine care. Proton pump inhibitors are 
excluded because they are only associated with a difference in efficacy among aberrant genotypes. 
The primary outcome of this study is however a reduction in drug-genotype specific ADRs. 
Oxycodone was initially included as an index drug but removed after the DPWG guideline was 
updated to be non-actionable. Oestrogen containing drugs will only be included in the study as a 
subsequent prescription.  
4.3. Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in this 
study: 
1. Previous (direct-to-consumer, or clinical) genetic testing for a gene important to the index 
drug  
2. Pregnancy or lactating 
3. Life expectancy estimated to be less than three months by treating clinical team 
4. Duration of index drug total treatment length is planned to be less than seven 
consecutive days. A drug whose route of administration changes during the first seven 
days (e.g. intravenous to oral flucloxacillin) but whose total treatment duration is seven 
days or longer, is still eligible.  
5. For inpatients: hospital admission is expected to be less than 72 hours (to facilitate acting 
upon the PGX results) 
6. Unable to consent to the study 
7. Unwilling to take part 
8. Subject has no fixed address 

 
 
 
 
 
 
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9. Subject has no current general practitioner 
10. Subject is, in the opinion of the Investigator, not suitable to participate in the study  
11. Patient has existing impaired hepatic or renal function for which a lower dose or alternate 
drug selection are already part of current routine care.  This would not apply to any drugs 
specifically given to manage liver/renal impairment/transplantation.  
12. Estimated glomerular filtration rate (MDRD) of less than 15 ml/min per 1,73m2 in a 
subject with a functioning graft 
13. Patients with advanced liver failure (stage Child-Pugh C) 
 
 
4.4. Patient recruitment and inclusion 
Patients who receive a first prescription for a drug listed in Table 5 will be identified by a ‘trigger’, 
and will be eligible for inclusion. Patients who are planned to receive a first prescription for a drug 
listed in Table 5 are also eligible for inclusion and may be recruited in the study. The time of the first 
dose of the index drug (t=0) will be noted in the eCRF.  
 
The recruiting physician, pharmacist or nurse will check the in- and exclusion criteria and determine 
whether the patient is eligible for participation. If so, the patient will be asked if they would like to 
participate in the study. Patients will be informed about the aims of the study both verbally and in 
writing. Patients will have the opportunity to ask questions and refuse participation. Patients who 
consent to participate in the study will sign an informed consent form in duplicate. These forms will 
be co-signed by the recruiting physician/nurse/pharmacist. One signed consent form will be kept in 
the Investigator Site File, one given to the patient. Information regarding the informed consent will 
be noted in the eCRF.  
 
Regarding patients in the study arm: 
PGx-results regarding the gene of interest must be reported to the physician/pharmacist within one 
week of index drug initiation. For example, if a patient starts with the first dose of the index drug on 
Monday, then the PGx results must be returned to the physician/pharmacist on or before the 
following Monday. In the meantime, informed consent must be obtained, the DNA sample must be 
collected and the PGx test must be run. The PGx test will have a turnaround time of three working 
days. The “Safety-Code card” may be provided after this week. If this is not complied then the patient 
will be excluded from the data set in a sensitivity analysis. 
 
Regarding patients in the control arm: 
Patients must provide informed consent and provide a DNA sample within one week of index drug 
initiation. For example, if a patient starts with the first dose of the index drug on Monday, then 

 
 
 
 
 
 
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informed consent and a DNA sample must be provided on or before the following Monday. The mock 
“Safety-Code card” may be provided after this week. If this is not complied then the patient will be 
excluded from the data set in a sensitivity analysis. 
 
4.5. Patient log and screening 
The recruiting physicians and pharmacists shall note all patients (including their age, sex, index drug 
and indication) that are considered for participation in their study logbook. Reasons for excluding 
patients from entering the study should be stated in each case. Reasons given by patients who do not 
want to participate in the study will be noted in each case. This procedure will be used to assess 
whether included patients reflect the general target patient population and to establish that the 
subject population was selected without bias. 
4.6. Sample size calculation 
The sample size calculation is based on showing a significant reduction of clinically relevant drug-
genotype associated ADRs among the subgroup of patients carrying an actionable drug-genotype 
combination. 
 
The drug-genotype associated ADRs which are derived from the DPWG guidelines are shown in Table 
7. All ADRs categorized as grade 2 or higher are considered clinically relevant and combined in the 
composite endpoint: grade2,3,4,5. To quantify the incidence of drug-genotype associated ADRs listed 
in Table 7, the EMA frequency classification of ADRs in drug labels was used. For example, an ADR of 
class 1 is common and has a frequency of ≥ 1/100 to < 1/10 (see Table 7). 
 
Sample size calculation for subgroup of patients carrying an actionable index drug-genotype 
combination  
The frequency of the composite endpoint grade 2,3,4,5 is estimated to be 0.04. We however 
hypothesize that this frequency is higher among those with an aberrant genotype and could range 
between 0.04 and 0.10.  
We hypothesize that implementing PGx-guided drug and dose selection among those carrying an 
actionable index drug-gene combination will lead at least a 30% reduction in occurrence of these 
clinically relevant drug-genotype associated ADRs. If the frequency of the grade 2,3,4,5 endpoint is 
0.10 and the true frequency for the carriers of an actionable index drug-gene combination PGx-
guided subjects is 0.0683 a sample size of 1,200 subjects in the study arm and 1,200 subjects in the 

 
 
 
 
 
 
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control is still sufficient to reject the null hypothesis with a probability (power) 0.8 and a Type I error 
probability of 5%.  
Preliminary data from a pilot experiment among 200 patients indicate approximately 30% of included 
patients will carry an actionable genotype for the index drug. Therefore, 4,000 subjects of unknown 
genotype in the study arm and 4,000 subjects of unknown genotype in the control arm are needed.  
To compensate for a 1.25% dropout rate, 100 extra patients will be included in the study. This equals 
a total inclusion of 8,100 patients, as shown in Table 4. 
 
4.7. Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The National Principal Investigators can decide to withdraw a subject from the study 
for urgent medical reasons.  
The eCRF will have a specific page that enables the type of withdrawal to be classified precisely, and 
where possible the individual reason to be documented. Types of withdrawal from which can be 
selected: 
• 
Complete withdrawal (none of the patient’s data can be used, e.g. because the subject wants 
to fully withdrawal/wrong initial drug etc.) 
• 
Withdrawal from remaining follow-up only (patient consents for the study to use their data 
which has already been collected, but they decline to continue to be followed-up OR patient 
did not use index drug for at least 7 consecutive days) 
• 
Lost to follow-up (the subject does not specify that they decline further follow-up, they are 
unable to be contacted)  
• 
Partial withdrawal (e.g. withdraw from ever using the patient-reported online monitoring 
system, but happy to be contacted by research team) 
• 
Death 
4.7.1. Specific criteria for withdrawal  
The subject may be withdrawn from the study if one of the following criteria is met: 
 
• 
Voluntary discontinuation by the patient, who is at any time free to discontinue their 
participation in the study  
• 
Incorrect enrolment of the patient  
• 
Patient does not use index drug for a minimum of 7 consecutive days 
• 
Patient experiences adverse events that contraindicate continuing the study (as judged by 
the National Principal Investigators) 
• 
Patient’s general condition contraindicates continuing in the study (as judged by the National 
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4.7.2. Replacement of individual subjects after withdrawal 
Since 8,100 patient will be recruited and only 8,000 patients are necessary as calculated by the 
power calculation, individuals will not be replaced after withdrawal. The withdrawal is not expected 
to succeed 100 patients.  
4.7.3. Follow-up of subjects withdrawn from treatment 
If a patient does not attend scheduled visits or replies to attempts of contact, every effort will be 
made to contact the patient. If a patient wishes to withdraw, the reason for discontinuation will be 
noted, if the patient agrees. The date and reason (if disclosed) will be noted in the eCRF. How missing 
data is handled in the analyses is described in the statistical analysis plan. 
 
5. TREATMENT OF SUBJECTS 
 
5.1. Investigational strategy 
The intervention in this study is the use of PGx testing to guide drug and dose selection according to 
the DPWG guidelines. The control arm will receive standard of care, without routine PGx testing. The 
intervention thus consists of two parts: 1) the panel of pharmacogenes, and 2) the clinical 
interpretation of the genetic data according to the DPWG guidelines. Physicians and pharmacists are 
not forced to adhere to the DPWG guideline, but are simply provided with all tools necessary to 
implement PGx-guided prescribing and dispensing. In order to facilitate implementation of this 
intervention, physicians and pharmacists will receive education on PGx through an extensive e-
learning study initiation of the study arm. 
5.1.1. Variant Selection and Platform 
The pre-emptive PGx test consists of a panel of 50 PGx SNPs (=48variants) within 13 pharmacogenes. 
The panel of pharmacogenes includes the variants listed in Table 6 and originates from the DPWG 
guidelines (1). The criteria for variant inclusion were: 
• 
A DPWG guideline with therapeutic recommendations for the specific genotype exists 
• 
The effect of the variant on the gene is established (e.g. Is the enzyme inactive if the variant 
is present?) 
• 
Is the overall MAF1 ≥ 1%? 
• 
If not, is the MAF in selected populations (European/Asian/African) 2 ≥ 1%? 
• 
If the MAF is below 1% in all cases, selection of certain variants is possible if at least one of 
the implementation sites already determines the allele in patient care. 
 
1. 
MAF = minor allele frequency. For the determination of the MAF we used www.ensembl.org and received input from Karolinksa 
Institutet and the DPWG. A MAF of 1% or greater is considered to be common. We restricted allele selection above this selected 
MAF cut off. 

 
 
 
 
 
 
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2. 
The selected populations are the most common populations in Europe. Besides the Europeans, Asians and Africans are present 
in Europe due to migration. 
 
Variants included in the panel will be updated regularly, in parallel to the development of new 
guidelines by the DPWG. See Section 5.1.2. 
 
All patients included in the study will be asked to provide informed consent for additional NGS 
sequencing of the most relevant regions of 150-200 ADME genes (i.e. genes involved in the 
metabolism and distribution of drugs) with respect to the drug treatment in question, encompassing 
6-10 Mb of sequence. The chance of finding secondary findings is negligible within ADME genes. This 
data will only be used for exploratory analysis and not be implemented in clinical care or returned to 
the patient. 
 
 

 
 
 
 
 
 
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Table 6 The panel of pharmacogenes and respective variants (RS number included) selected. All patients enrolled in PREPARE 
will be tested for these variants. 
Genes 
Allele 
Major Nucleotide 
Variation 
dbSNP RS ID 
CYP2B6 
*6/*9 
516G>T 
rs3745274  
CYP2B6 
*4/*16 
785A>G 
rs2279343 
CYP2B6 
*18 
983T>C 
rs28399499 
CYP2B6 
*5 
1459C>T 
rs3211371 
CYP2C9 
*2 
430C>T 
rs1799853 
CYP2C9 
*3 
1075A>C 
rs1057910 
CYP2C9 
*5 
1080C>G 
rs28371686 
CYP2C9 
*11 
1003C>T 
rs28371685 
CYP2C19 
*2 
681G>A 
rs4244285 
CYP2C19 
*3 
636G>A 
rs4986893  
CYP2C19 
*4A/B 
1A>G 
rs28399504  
CYP2C19 
*5 
1297C>T 
rs56337013  
CYP2C19 
*6 
395G>A 
rs72552267  
CYP2C19 
*8 
358T>C 
rs41291556 
CYP2C19 
*9 
431G>A 
rs17884712  
CYP2C19 
*10 
680C>T 
rs6413438 
CYP2C19 
*17 
-806C>T3 
rs12248560 
CYP2D6 
*xN 
Gene duplication or 
multiplication 
X 
CYP2D6 
*3 
2549delA 
rs35742686 
CYP2D6 
*4 
1846G>A 
rs3892097 
CYP2D6 
*5 
Gene deletion 
X 
CYP2D6 
*6 
1707delT 
rs5030655 
CYP2D6 
*8 
1758G>T 
rs5030865 
CYP2D6 
*9 
2615delAAG 
rs5030656 
CYP2D6 
*10 
100C>T 
rs1065852 
CYP2D6 
*14A/B 
1758G>A 
rs5030865 
CYP2D6 
*17 
1023C>T 
rs28371706 
CYP2D6 
*41 
2988G>A 
rs28371725 
CYP3A5 
*3 
6986A>G 
rs776746 
CYP3A5 
*6 
14690G>A 
rs10264272 
CYP3A5 
*7 
27131_27132insT 
rs41303343 
DPYD 
*2A 
IVS14 + 1G>A 
(1905+1G>A) 
rs3918290  
DPYD 
*13 
1679T>G 
rs55886062 
DPYD 
X 
2846A>T 
rs67376798 
DPYD 
X 
1236G>A 
rs56038477 
F5 
X 
1691G>A 
rs6025 
HLA-B 
*5701 
T>G 
rs2395029 

 
 
 
 
 
 
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NUDT15 
*3 
7973C>T 
rs116855232 
NUDT15 
*6 
55_56insGAGTCG 
rs869320766 
NUDT15 
*9 
49delGGAGTC 
rs746071566 
SLCO1B1 
*5/*15/*17 
521T>C 
rs4149056 
TPMT 
*2 
238G>C 
rs1800462 
TPMT 
*3B 
460G>A 
rs1800460 
TPMT 
*3C 
719A>G 
rs1142345 
UGT1A1 
*6 
211(G>A) 
rs4148323 
UGT1A1 
*27 
686(C>A) 
rs35350960  
UGT1A1 
*28/*37 
A(TA)6TAA>A(TA)7TA
A/A(TA)8TAA 
rs8175347 
VKORC1 
X 
1173C>T (C6484T) 
rs9934438 
 
All implementation sites will be provided with an identical genotyping platform so that samples can 
be analysed locally but in a standardised manner. To reflect the different backgrounds of local 
infrastructure and expertise, centres will be offered a suitable implementation process including staff 
training. Scaling and batch effects will be accounted for and test results will have a turnaround time 
of three working days.  
The SNPline workflow, by LGC Group will be used to perform all genotyping assays. (See 
https://www.lgcgroup.com/products/genotyping-instruments/snpline/#.V_Ni1fl95aQ for 
specifications)  
5.1.2. The DPWG Guidelines 
In 2005, the KNMP established the DPWG with the objective to develop PGx-based therapeutic 
recommendations based on a systematic review of the literature. The DPWG consists of 12 members 
including clinical pharmacists, a general practitioner, physicians, clinical chemists, epidemiologists 
and a toxicologist. Currently, the database consists of 80 gene -drug-combinations comprising 13 
genes.  
 
Briefly, for development of the DWPG guidelines, clinical effects of different severities observed in 
patients with aberrant genotypes were classified on a seven-point scale derived from the National 
Cancer Institute's Common Toxicity Criteria (5). These clinical endpoints are ranked from non-
significant changes classified as AA (lowest impact), through clinical effects of increasing severity up 
to the most extreme phenotypes (e.g. death) that are classified as F (highest impact) (Table 7). For 
each of the drugs included in the DPWG guidelines, specific drug-genotype associated ADRs (i.e. QTc 
prolongation related to the use of amitriptyline, or leukopenia related to the use of azathioprine) or 
other effects are systematically categorized into their clinical effect class (i.e. AA to F - Table 7). 

 
 
 
 
 
 
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Table 7 For development of the DWPG guidelines clinical effects observed in patients with aberrant genotypes were 
classified on a seven-point scale derived from the National Cancer Institute's Common Toxicity Criteria (CTC AE). 
Class  
(Grade 
NCI-
CTCAE) 
EMA ADE 
frequency  
Clinical Effect 
AA# 
 
Positive clinical effect (NS) 
AA 
 
Clinical effect (NS): no change or a non-significant change of clinical parameters 
Kinetic effect (NS): no change or a non-significant change of kinetic parameters. 
A 
Common  
≥ 1/100 to 
< 1/10 
Minor clinical effect (S): QTc prolongation (<450 ms  , <470 ms  ); QTc time 
increase < 60ms; INR increase < 4.5 
Kinetic effect (S): significant change of kinetic parameters 
B 
(Grade 1) 
Common  
≥ 1/100 to 
< 1/10 
Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. 
reduced decrease in resting heart rate; reduction in exercise tachycardia; 
decreased pain relief from oxycodone; ADE resulting from increased 
bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance, 
depressive mood, etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; 
thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; 
reduced glucose increase following oral glucose tolerance test; muscle 
complaints creatine kinase <3 times normal upper limit 
C 
(Grade 2) 
Common  
≥ 1/100 to 
< 1/10 
Clinical effect (S): long-standing discomfort (48-168 hr) without permanent 
injury e.g. failure of therapy with tricyclic antidepressants, atypical antipsychotic 
drugs; extrapyramidal side effects; parkinsonism; ADE resulting from increased 
bioavailability of tricyclic antidepressants, metoprolol, propafenone (central 
effects e.g. dizziness); increased INR 4.5-6.0; neutropenia 1.0-1.5x109/l; 
leucopenia 2.0-3.0x109/l; thrombocytopenia 50-75x109/l; muscle complaints 
creatine kinase 3-10 times normal upper limit  
D 
(Grade 3) 
Uncommon 
 ≥ 1/1,000 
to< 1/100 
Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or 
invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous 
thromboembolism; decreased effect of clopidogrel on inhibition of platelet 
aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; 
neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-
50x109/l; severe diarrhea; myopathy (muscle complaints creatine kinase ≥10 
times normal upper limit)  
E 
(Grade 4) 
Uncommon 
 ≥ 1/1,000 
to< 1/100 
Clinical effect (S): Failure of lifesaving therapy e.g. anticipated myelosuppression; 
prevention of breast cancer relapse; arrhythmia; neutropenia < 0.5x109/l; 
leucopenia < 1.0x109/l; thrombocytopenia < 25x109/l; life-threatening 
complications from diarrhea; rhabdomyolysis 
F 
(Grade 5) 
Rare  
≥ 1/10,000 
Clinical effect (S): death; arrhythmia; unanticipated myelosuppression 
NS: not statistically significant difference; S: statistically significant difference; INR: international normalized ratio; EMA: 
European Medicines Agency; ADE: adverse drug event.  
 
Before initiation of this study, the DPWG guidelines will be translated into all local languages to 
facilitate interpretation by local physicians and pharmacists. The guidelines will be maintained and 
updated regularly to ensure all available scientific information is included and recommendations are 
based on the latest literature. The DPWG will update each gene-drug interaction every two years. The 

 
 
 
 
 
 
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DPWG also expects to develop four new gene drug-interactions per year. These drugs will not be added 
to the list of drugs for inclusion (Table 5), as this would result in a difference in the study and control 
arms. These guidelines will still be available for physicians and pharmacists once the study is 
completed. Additionally, the CPIC guidelines can also be consulted by physicians and pharmacists 
through the www.PharmGKB.org. These too are updated regularly and will remain available once the 
study is completed. The original version of the DPWG guidelines are attached in Appendix 18.3. DPWG 
guidelines are periodically updated and these changes are directly implemented in the study protocol. 
As of February 20th 2018, the DPWG guideline for oxycodone was updated. The updated version no 
longer had an actionable recommendation for any phenotype. As a result, oxycodone was removed as 
an index drug as per May 15th 2018. 
5.1.3. “Safety-Code” Card  
Patients in the study arm will receive their PGx results on a “Safety-Code” card (see Figure 6 and 
Figure 7). This card is part of a mobile-based clinical decision support system called the ‘Medication 
Safety Code’ (MSC) system that is independent of existing IT infrastructures, and enables the quick 
retrieval of patient-relevant PGx drug dosing guidelines. The MSC system does not require central 
patient data storage. Instead, the “Safety-Code” card contains a QR code that stores the patient’s 
encoded PGx results. It can be decoded and interpreted by common smartphones and other devices. 
After scanning the QR code, the medical professional is led to a website that provides drug dosing 
recommendations customized to the PGx profile of the patient. 
 
In the context of PREPARE, the MSC system is aimed to serve as an auxiliary tool to maximize the 
accessibility and sharing of PGx results within and between different health care settings and health 
care professionals.  Patients will be asked to show their “Safety-Code” card to physicians and 
pharmacists who prescribe or dispense drugs to them during the follow-up period of the study. These 
providers can thus use the patient’s PGx results to guide drug and dose selection. Concomitantly, 
patients will be asked to report additional drug prescriptions to the research nurse during the follow-
up period.   
 
The “Safety-Code” card will include the following information: 
• 
Study patient ID number 
• 
Phenotypic PGx results 
• 
List of drugs that are critical for the card owner, and for which a DPWG guideline is available 
(Table 5) 

 
 
 
 
 
 
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• 
QR code which will direct the physician to the DPWG guidelines applicable for the patients 
results  
• 
URL which will direct the physician to the DPWG guidelines applicable for the patients results  
• 
Patient name and date of birth 
• 
PREPARE research team contact details 
 
 
Figure 7 Back of the ‘Safety-Code’ card 
 
Patients in the control arm will also receive a mock safety code card. This card will not contain any 
PGx information, but only include a list of drugs of interest to the study (Table 5) and PREPARE 
research team contact details.  
 
Figure 6 Front of the ‘Safety-Code’ card 

 
 
 
 
 
 
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Local card logistics 
The mock “Safety-Code” card will be provided to patients once they have provided the DNA sample. 
The “Safety-Code” card including the patient’s PGx results will be provided to patients once PGx 
results have been provided to the treating physician/pharmacist. 
 
Study completion and card disposal 
At the end of the study arm the participating patients in the study arm will have the choice to keep or 
dispose of the card. If they wish to dispose of the card, they will be asked to return the card and it 
will be destroyed. If they wish to keep the card, they may continue to use it in clinical care. 
 
Participants in the control arm may receive their “Safety-Code” card once the study is completed. 
They are able to opt-in for this option during the informed consent and may change their mind at any 
time. Again, they may continue to use it in clinical care once the study is completed. 
 
 
 

 
 
 
 
 
 
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6. ENDPOINT ASSESSMENT 
  
6.1. Primary endpoint 
The primary outcome is the occurrence of at least one causal (definite, probable or possible), 
clinically relevant (classified as NCI-CTCAE grade 2, 3, 4, or 5), attributable to the index drug, within 
12 weeks of follow-up. For oncology patients receiving 5-FU, capecitabine, tegafur or irinotecan, only 
hematological toxicities of NCI-CTCAE grade 4-5 and non-hematological toxicities of NCI-CTCAE grade 
3-5 will be considered clinically relevant.   
All collected ADEs during the follow-up period will be assessed with regard to causality, severity and 
the association with genotype (Figure 8). The severity of the ADE is classified using the CTCAE 
classification scale (5) for primary analysis and the WHO classification (serious/non-serious) for 
secondary analysis. Following this, a causality assessment (Section 6.1.2) will be performed using the 
Liverpool Causality Assessment Tool (LCAT) (6). Once an ADE has been assessed regarding causality it 
is referred to as an ADR.. Only clinically relevant adverse events, categorized as definitely, probably 
or possibly caused by the drug (i.e. now constituting an ADR), will contribute to the primary 
endpoint, as highlighted in green in Figure 8. 
 
Figure 8 Funnel plot of classification of ADEs which contribute to the primary endpoint.*For oncology patients only 
hematological toxicities of grade 4-5 and non-hematological toxicities of grade 3-5 will be considered clinically relevant. 
LCAT: Liverpool Causality Assessment Tool 
 

 
 
 
 
 
 
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6.1.1. Severity Classification  
All ADEs will be classified using both the National Cancer Institute's Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE) scale (primary outcome) and the WHO classification (secondary 
outcomes). 
The NCI-CTCAE scale is a descriptive terminology that can be utilized for ADE reporting. A grading 
(severity) scale is provided for each ADE term. The current CTCAE (version 4.0) consists of 790 
individual ADE items, which often occur as a result of cancer treatment. Each item represents a 
discrete event which is graded for severity on a five point scale based on clinical criteria. Since this 
study also measures ADEs outside the realm of cancer treatment the ADEs which cannot be classified 
using the NCI-CTCAE (such as bleeding events) will be classified using the pre-specified DPWG 
classification as listed in Table 7. In fact the DPWG classification is an expanded version of the CTCAE 
including all ADRs identified by the DPWG during the systematic literature review of gene-drug pairs. 
If an ADE occurs which cannot be classified using either of these scales, the ADE will be classified 
using the general definition of the NCI-CTCAE as described in Table 8. 
Table 8 Equivalence of DPWG ADR classification and CTCAE classification 
DPWG 
Classification 
CTCAE 
General definition of the CTCAE 
A 
- 
- 
B 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
C 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living*. 
D 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living**. 
E 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
F 
Grade 5 
Death related to AE. 
Activities of Daily Living (ADL) *Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. **Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
NCI-CTCAE version 4.0  will be used by clinicians and research nurses to grade severity of all ADEs 
reported at baseline, four weeks, 12 weeks and at the end of the time block (cross-sectional). If data 
from patients’ medical records are be used to classify severity, this data will be recorded in the eCRF. 
The methods used by the assessors will be described in a Standard Operating Procedure (4.9). 
10% of severity assessments will be reassessed by Lareb (www.lareb.nl) to independently validate 
the severity assessments. These assessors will be blinded to patient’s arm allocation. 
 

 
 
 
 
 
 
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For secondary analyses the Lareb Intensive Monitoring (LIM) tool will be used to measure the 
frequency and severity of patient reported ADEs at two weeks and eight weeks. The LIM tool is a 
web-based intensive monitoring system and has previously been validated in several clinical trials as 
a feasible and accurate method to collect adverse drug event data (7, 8). The LIM surveys will be 
translated to local languages before study initiation. 
 
The WHO classifies (secondary analysis) SAEs as: 
An adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of an existing inpatient hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; or 
- 
is any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the Principal Investigator. 
 
An elective hospital admission will not be considered a SAE. Any ADE which is not classified as being 
serious is classified as being non-serious. 
 
6.1.2. Causality Assessment  
The Liverpool Causality Assessment Tool has been developed by the University of Liverpool. It assigns 
the full range of causality categories and has demonstrated a good inter-rater reliability (6). The tool 
is shown in Figure 9. Once ADEs are assessed with regard to causality they are referred to as ADRs. 
Only ADRs classified as definitely, probably or possibly will contribute to the primary endpoint. The 
methods used by the assessors will be described in a Standard Operating Procedure (4.8). 
 
A health care professional assigned by the National Principal Investigators will perform the causality 
assessments. To reduce inter-observer variability, providers performing the causality assessments 
will receive a two-hour training session, provided by the Royal Liverpool Hospital to ensure similar 
assessments.  
 
10% of causality assessments will be  reassessed by Lareb (www.lareb.nl) to independently validate 
the causality assessments, once data collection is complete. These assessors will be blinded to 
patient’s arm allocation. 

 
 
 
 
 
 
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Figure 9 Flow-chart of Liverpool Causality Assessment Tool 
 

 
 
 
 
 
 
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6.2. Procedure of data collection  
Patients must be contacted by the research team for data collection within the time window as 
described in section 3.2. This is purely to manage logistical and practical data collection issues. 
However, both patients and physicians may report ADEs outside these time windows, by contacting 
the research team (for example in the case of serious ADEs). In both cases (contact by the research 
team in the time window or contact by the patient or physician outside the time window), the start 
date (and end date) of each reported ADE must be entered into the ADE record (chapter 5.1). 
Additionally, if the research team notices an ADE in the (electronic) medical record which was not 
reported by either patients or physicians, the research team may enter this as an ADE in the eCRF. 
 
The results of additional tests (e.g. leukocyte count) may be necessary to be able to classify the 
severity of the ADE according to the NCI-CTCAE. These tests will not be additionally performed if they 
have not been performed within the realm of clinical care. Results of available tests will be collected 
from the medical record by the research nurse. These test results will be recorded in the eCRF.  
6.3. Secondary endpoints  
The secondary analyses of PREPARE are aimed at evaluating clinical outcome, cost-effectiveness, 
quantitative and qualitative indicators of successful implementation strategies, finding novel variants 
associated with extreme phenotypes and elucidating drug-drug-gene interactions.  These will be 
collected during follow-up  as stipulated in Table 2. 
Baseline demographics and clinical monitoring:  
• 
Demographic measurements  
• 
Current and past medical history  
• 
Smoking status  
• 
Alcohol consumption  
• 
Self-perceived level of exercise  
• 
Existing drug allergies  
• 
Comorbidities  
• 
Global Health Score  
• 
Co-medication  
• 
Renal function 
• 
Liver function 
 
Secondary clinical outcome: 
• 
Total number of ADEs (related to index and subsequent drugs) 
• 
Dose adjustments to index drug 
• 
Drug cessation (and reason for discontinuation) 
• 
Additional drugs that are prescribed during follow-up 
• 
Routine drug levels (only those that are collected routinely) as a proxy for exposure 
• 
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6.3.1. Cost-effectiveness 
• 
Quality of life 
• 
Measurement of effectiveness (QALY) 
• 
Total cost estimation (healthcare consumption, cost of drugs, cost of hospitalization, cost of 
ADEs, cost of genetic testing etc.) 
 
6.3.2. Implementation and adoption of guidelines 
Among patients:  
• 
Beliefs, knowledge and usability of PGx 
 
Among implementing physicians and pharmacists: 
• 
Process indicators for implementation (e.g. guideline compliance, extent of adoption, 
number of tests) 
• 
Effectiveness of the training and education programme will be evaluated by performing pre- 
and post-programme surveys in the participating countries 
• 
When health care professionals do not comply with the DPWG guidelines, they will be asked 
to report the reason(s) for not doing so. 
 
A generic trigger in the electronic prescribing system will alert the physician or pharmacist that PGx 
results are available in the patient’s medical record.  When prescribing (or dispensing), the software 
will ask the prescribing physician or dispensing pharmacist to write whether they complied with the 
DPWG guidance, and if not, why not. 
 
A sub-analysis will be performed among physicians and pharmacists who did receive extensive 
pharmacogenomics training before initiation of the study, and those who did not. Additionally the 
adherence of physicians will be compared to those of pharmacists. 
 
6.3.3. Drug-Drug-Gene Interaction Sub-study 
 
Through a systems pharmacology approach, PGx and non-genetic determinants of drug response 
(such as gender, age, and concomitant drug intake) are integrated to create novel, powerful and 
practice-oriented models of personalized medicine. This work will strive toward assessing the relative 
contribution of PGx to the variability in drug response by utilizing pharmacometric models that 
integrate PGx with other sources of variability. The models will describe the events from dose to the 
drug response, thus including effects of PGx on pharmacokinetics and pharmacodynamics. 

 
 
 
 
 
 
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Population and physiologically-based pharmacokinetic models will be utilised to predict the impact of 
genetic variability on pharmacokinetic and pharmacodynamic variables. 
 
The aim of this sub-study is to collect multiple drug levels per patient at different time points, as well 
as measurements of the relevant pharmacodynamic/clinical endpoints. The models developed will be 
applied to the assembled data (drug levels, endpoints, demographic information, PGx, and non-
genetic factors) to elucidate the agreement of model predictions with the observed real-world data 
(i.e. model qualification). If sufficient amount of data (drug levels, endpoints) will be collected in this 
sub-study  this approach also allows to assess population pharmacokinetic parameters of the target 
drug in the study population, to further investigate the sources of variability and to potentially 
improve models already developed. 
 
Therefore, patients included in the primary study for a first prescription of voriconazole, metoprolol, 
simvastatin, atorvastatin, fluorouracil or capecitabine are eligible to participate in the sub study and 
will be asked to provide additional blood samples.  
Patients will need to provide informed consent for this sub-study before additional blood sampling 
can occur. Patients may choose not to provide consent for the sub study and still participate in the 
general study. 
 
A population phamacokinetic sampling design will be used, i.e. a limited number of blood samples 
will be drawn from subjects at various time points following drug administration. Four to five blood 
samples for each patient will be collected using the dried blood spots (DBS) method at one day. The 
number of samples to be collected from each patient depends on the target drug (for details see 
Table 9). Five sample collection windows will be used as followed: t0=pre-dose, t1=0.5-1.5, t2=2-4, 
t3=5-8 and t4=9-12 hours after a medication intake. In addition, patients will be asked to provide a 
blood sample within 24 hours after a serious ADR. For each blood sample, descriptive data, including 
sample ID, collection time window, target drug and dosage as well as dose history must be 
documented. The dose history contains information about the last (when applicable, at least three 
and up to five) previous drug administrations, including dose amounts as well as route, date and time 
of drug administrations. Clinical endpoint data, demographic information as well as clinically relevant 
drug-drug interactions will be extracted from the general study (PREPARE).  
 
The dried blood samples can easily be collected using a Whatman Protein Saver Card, which holds a 
maximum of 80uL of blood per spot. Blood samples must be wrapped and stored at -20oC. The 

 
 
 
 
 
 
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advantage of using DBS, compared with venipuncture,  includes the relative ease and low cost of 
sample collection and storage. They can easily be shipped and analytically analyzed using HPLC. 
Furthermore, there is only minor discomfort associated with this minimally invasive method for the 
patients.Outpatients are asked to document their drug administrations (date, time, and dose 
amount) in a checklist and bring it to the study center at the visit for the blood sampling procedure.  
 
 
 
 
Table 9  Summary of drug-specific data collection and blood sampling in the drug-drug-gene sub-study 
Drugs for 
inclusion to 
sub-study 
Blood sampling time windows 
 
Endpoints 
t0* 
t1 
[0.5-
1h] 
t2 
[2-
4h] 
t3 
[5-8h] 
t4 
[9-12h] 
tADR** 
Atorvastatin 
x 
x 
x 
x 
x 
x 
Lipid panels (TC, HDL-C, LDL-
C, and TG) 
Capecitabine 
x 
x 
x 
x 
 
x 
-5-FU related ADRs, e.g. 
hand-and-foot syndrome; 
leucopenia, neutropenia, 
thrombocytopenia. (Tumor 
response) 
Fluorouracil 
x 
x 
x 
x 
 
x 
-5-FU related ADRs, e.g. 
hand-and-foot syndrome; 
leucopenia, neutropenia, 
thrombocytopenia. (Tumor 
response) 
Metoprolol 
x 
x 
x 
x 
 
x 
-Resting blood pressure 
-Heart rate 
Simvastatin 
x 
x 
x 
x 
x 
x 
Lipid panels (TC, HDL-C, LDL-
C, and TG) 
Voriconazole 
x 
x 
x 
x 
 
x 
-clinical symptoms and signs 
(e.g., body temperature, CT 
scans, MRI ﬁndings),  
-microbiological response, 
(e.g. -microscopic 
examination, the cultivation 
result) 
-serological tests (b-D-glucan 
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* pre-dose. 
**not later than 24h after event. 
 
6.3.4. Extreme phenotypes  
Extreme phenotypes are identified from patients who have consented to the main study. Extreme 
phenotypes are defined as those patients who: 
 
 
Figure 10: Flow-chart used to identify extreme phenotypes 
 
Extreme phenotypes will be flagged and contacted by the research nurse to obtain an additional 
blood sample (10mL EDTA) within 24 hours of the ADR, if possible, to be able to determine the 
plasma blood level of the index drug and other concurrent drugs. The last dose and time of both 
index drug and co-medications  must be recorded in the eCRF .  This sample collection will be 
described in Standard Operating Procedure (9.1). A maximum of 35mL of blood (intended for 
research purposes) will be collected within a four week period. 
 
 
To identify a possible genetic origin of the extreme phenotype, all patients included in the study will 
be asked to provide informed consent for additional NGS sequencing of the most relevant regions of 
150-200 ADME genes (i.e. genes involved in the metabolism and distribution of drugs) with respect 

 
 
 
 
 
 
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to the drug treatment in question, encompassing 6-10 Mb of sequence, in an anonymous analysis. 
The chance of finding secondary findings is negligible within ADME genes. This data will only be used 
for exploratory analysis and not be implemented in clinical care or returned to the patient. 
Once the identity of the subject has been removed, it will not be able to be reconnected to the 
subject. Therefore no secondary findings will be returned to the patients. NGS sequencing will be 
performed to search for novel variants associated with the extreme phenotype, only if the patient 
provided consent for anonymised NGS. 
 
 
7. STATISTICAL ANALYSIS 
 
All analyses are pre-specified in detail in the statistical analysis version 3.0  
 
 

 
 
 
 
 
 
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8. ASSESSMENT OF SAFETY 
All drugs included within this study have previously been registered for use in humans. Therefore, no 
additional safety issues are expected in the study arm. However, to support and stimulate 
spontaneous reporting of ADEs, SAEs will be reported to national spontaneous reporting systems 
which are connected to the Eudravigilance Database.  
8.1. Definition SAEs  
Only adverse events related to the study procedures (i.e. blood draws, saliva collection, blood spot 
sampling, or PGx tests) will be regarded as SAEs.  
 
A Serious Adverse Event (SAE) is an AE occurring during any study phase and at any dose of the 
investigational product, comparator or placebo that fulfils one or more of the following criteria: 
- 
results in death 
- 
is life-threatening 
- 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
- 
results in persistent or significant disability/incapacity 
- 
results in a congenital anomaly/birth defect 
- 
is an important medical event that may jeopardise the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
Any adverse event leading to hospitalization or prolongation of hospitalization will be considered as 
‘serious’, unless at least one of the following exceptions are met: 
- 
the admission is pre-planned (e.g. elective or scheduled surgery arranged prior to the start of 
the study, documented in the patient’s file); 
- 
prolonged hospitalization for technical, practical or social reasons, in the absence of an 
adverse event. 
8.2   
 
8.2. Methods for recording and follow-up of ADEs 
All AEs will be followed up until they have abated, or until a stable situation has been reached, as 
done within the realm of routine clinical care. Recording and ADEs is the primary outcome of this 
study. ADEs will be monitored by both a trained research nurse and via patient reporting through an 
online spontaneous reporting system as further explained in Section 6.1. 
 

 
 
 
 
 
 
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8.3. Reporting of SAEs 
All National Principal Investigators will have the responsibility for safety within their own country. 
The local Investigators will report SAEs to the National Principal Investigators who will report it to 
their national spontaneous reporting system. 
8.4. Safety Committee 
Since the study is not blinded, and health care providers may choose to implement PGx testing 
results in their prescriptions, no additional safety issues are expected. Therefore a Data Safety 
Monitoring Board would be superfluous and not provide any additional safety benefit.  
8.5. Premature termination of the study 
 
No additional safety issues are expected in the study arm, and therefore no criteria have been 
defined for premature termination of the study.  
 
 

 
 
 
 
 
 
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9. STRUCTURED RISK ANALYSIS  
 
9.1. Potential issues of concern 
Recruitment of sufficient numbers of patients 
Successful recruitment of sufficient numbers of patients is crucial for the success of PREPARE. The 
consortium therefore includes multiple institutions with large number of patients (see Table 4), 
excellent logistics to effectively include patients, collect outcome data and extensive experience with 
clinical PGx research. In addition, similar to the situation in clinical trials, institutions will receive a fee 
per included patient as coverage of costs and as a motivation. Physicians and pharmacists will be 
offered an education program to improve knowledge and appreciation and to stimulate PGx 
implementation. Close collaboration with patient associations will be established and a patient 
representative is a member of the Advisory Board. The recruitment rate will be closely monitored 
during the project. If recruitment rate appears to slow additional centers will be included by the 
Principal Investigator of the respective country. To this end the Principal Investigators already 
contacted collaborating centers in their countries that have shown interest in including patients in 
the unlikely events that this is needed. Although we do not foresee that more centers will be needed 
this contingency plan removes the main potential threat for PREPARE. 
To prevent overrepresentation of a single drug, the number of prescriptions for any drug included in 
the study will be capped at 10% of the total population. 
 
Collection of clinical data 
Poor collection of clinical data would be detrimental for the success of PREPARE. To remove this 
possible threat we will implement a central web-based database including eCRFs and extensive 
resources are allocated for dedicated research assistants for each implementation site. 
 
Ethics 
The risk that ethical aspects cannot be managed within the project is extremely low as we will be 
proactive and managing the ethical issues prospectively in a separate work package. As soon as a 
potential problem would appear, it will be managed by open discussion within the consortium and 
finding external advice. In addition, we are aware that a change in ethical and legal regulations in the 
EU and member states may be enforced soon and that possibly adaptations in the project are 
warranted. We have specifically addressed these changing ethical and legal regulations by Anne 

 
 
 
 
 
 
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Cambon-Thomsen, who is closely involved in EU ethical and legal regulations by representation in 
several European working parties. Additionally, a Scientific Advisory Board has been commissioned to 
advise on the development of the protocol to ensure a scientifically sound method (see Appendix 
18.4). 
 
Changes over time 
A potential threat is that during the project the panel of drugs and genetic variants will change. For 
example, new drugs for which genetic testing is recommended may be marketed, drugs may be 
removed from the market, or a genetic test may become mandatory. In addition new genetic 
variants may be identified that are not in the current panel. At this moment it is difficult to judge if 
and how fast these developments will proceed. However, the  PREPARE can cope with these 
developments since maintenance and development of guidelines are responsibility of the DPWG. The 
discovery of novel genetic variants can easily be addressed by incorporating them in the genotyping 
platform which is open and flexible by design. 
In addition, institutions which were randomized to start with PGx-guided prescribing in the first time 
block may be reluctant to start the standard of care control period (see Figure 2) since they have had 
experience with PGx-guided prescribing and may be more aware of pharmacological issues. To 
ameliorate this risk, and also for scientific reasons (i.e. minimize risk of physician carry over effect), 
patients will be blinded for the study outcome until the end of the inclusion period. 
 
Clinicians‘ acceptance of clinical decision support tools  
A potential risk is that CDS tools will not be (properly) used by clinicians at the participating sites. To 
address this issue, clinicians will receive extensive training and education. In addition acceptance of 
CDS will be closely monitored throughout the entire project and CDS tools will be improved through 
an iterative process based on clinician and patient feedback.  
 
Differences in health care settings 
Obviously, the differences in health care settings across the EU are a challenge for the project. 
Indeed, differences in languages, level of use of IT in health care, standards of care, regulatory issues 
etc. will differ considerably. However, in this H2020 project, implementation of personalised 
medicine taking into account the diversity in health care settings is an explicit aim. We have chosen 
the participating countries and settings in a way that the diversity is covered maximally. In this way, 
models for effective PGx implementation emerging form the PREPARE project can be extrapolated 
across Europe. However, the design of the project is chosen in a way that assessment of clinical 

 
 
 
 
 
 
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outcome and cost-effectiveness is not hampered by the differences in health care settings. To this 
end, a prospective cross-over design was chosen and every institution serves as its own control. 
 
Management of the project 
No threats are foreseen with work that deals with management issues. The study coordinator has 
ample experience with managing large international projects. A detailed and clear organizational 
structure has been set up and clear decision-making procedures have been described (see Appendix 
18.5).  
 
 
 
 
 
 

 
 
 
 
 
 
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10. DATA HANDLING AND RECORD KEEPING 
 
10.1. Electronic Case Report Forms 
An electronic case report form (eCRF) will be completed for each included subject. The subject’s 
identity will always remain confidential. The database will only contain the patient study ID code and 
never the name of the patient.  The completed eCRFs are property of the PREPARE study and should 
not be made available to third parties (except for authorised representatives of appropriate 
regulatory authorities) without written permission from the PREPARE study. All data in the eCRFs will 
be in English. If necessary, the monitor should translate any information or comments recorded in 
another local language. The National Principal Investigator is responsible for ensuring the accuracy, 
completeness and timeliness of the data recorded in the electronic CRFs. 
 
A TRE (Trial Related Events) section will be incorporated within the eCRF. This will record the 
occurrence of causal (definite, probable or possible), clinically relevant (Grade 2, 3,4, or 5) ADEs 
which are associated with a drug-genotype. This filtered data will be used for the primary analysis.  
 
The eCRF database software ProMISe (Project Manager Internet Server)  (see Section 10.5) has the 
following specifications: 
• 
Central and secure storage of the study data in a central study database. The database server 
is situated at Leiden University Medical Center 
• 
Participating centres have access to the eCRF through a log-in 
• 
Access levels and restrictions to the central database, to the participating centres and to the 
subject data is configured and managed centrally. 
• 
Allows quality control and data quality checks  
• 
Allows central monitoring as well as local monitoring and source data verification. 
• 
Allows inclusion of all sites to me monitored. Through this tool, the 10% capping if index 
drugs will be monitored by LUMC  
• 
All changes to the data in the database, starting from the moment of creation of the data 
item, will be stored in an audit trail and will be time, date and user stamped by the system 
without any user intervention. 
• 
The data in the database will be available for easy but quality controlled export to other 
applications to allow statistical analysis. 
 

 
 
 
 
 
 
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10.2. Data security and subject privacy  
Data on subjects collected in eCRFs will be documented in an pseudonymous fashion such that a 
patient will not be identifiable from the information recorded on the eCRF. The confidentiality of 
those documents which could identify the patients must respect the subjects’ privacy and the norms 
of confidentiality in accordance with the applicable national regulatory requirements. The National 
Principal Investigator will maintain a subject identification code list. 
 
10.3. Access to source data and record retention 
The National Principal Investigator is responsible for archiving all source documents and the study 
documentation as required by national laws and regulations. The Investigator will retain all study 
records for 15 years if not instructed otherwise by the sponsor.  
 
10.4. Storage of human material 
• 
Blood and saliva samples used to collect DNA will be stored until they are used up.  
• 
The blood  sample at the time of an “extreme phenotype” ADR will be kept until they are 
used up. 
• 
The blood spot samples used to elucidate a drug-drug-gene interaction (sub-study) will be 
kept until used up. 
• 
Other samples of human material which are collected within the realm of routine care will be 
kept in accordance to national laws and regulations.  
 
10.5. Data management 
ProMISe (https://www.msbi.nl/promise/) is a web-based relational database management system 
for the design and maintenance of clinical data management. ProMISe is developed within the Leiden 
University Medical Center (LUMC) Section of Advanced Data Management (ADM) who work closely 
with the department of Biostatistics and Bioinformatics. The ADM is NEN7510 certified and ProMISe 
meets the requirements for data-safety and privacy as set by the international legislations. ProMISe 
facilitates storage, exchange and retrieval of data according to the security conditions demanded by 
the GCP. 
 
 
 

 
 
 
 
 
 
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11. QUALITY CONTROL AND QUALITY ASSURANCE  
 
11.1. Monitoring 
A professional clinical research organization (CRO) will be subcontracted to perform the monitoring of 
PREPARE. The monitors are required to have a health related background training and specific GCP 
training. Trial monitors will visit all sites during the study. Trial monitors will oversee the progress of 
the study, ensure the wellbeing of study subjects, ensure accuracy, completeness of study data and 
monitor compliance with the study protocol, SOPs, ICH-GCP and the Declaration of Helsinki, EU 
directives and applicable regulatory requirements. A monitoring plan will be written before study 
initiation. 
The monitor will visit each site three times during the study (two monitoring visits and once close-out 
visit). The monitor will check that each subject has provided written informed before participating in 
the study. The monitor will follow the patient inclusion and patient withdrawal frequencies, confirm 
the completeness of the trial master file and the investigator file, verify 100% of all informed consent 
procedures and paperwork, check 10% of eCRFs and all source files. Any discrepancies of data will be 
documented and explained in the monitoring reports. If necessary, the data in the database can be 
changed in order to match with the source data, by a person with sufficient access rights to the 
database to make changes of this type. Additionally, the monitor will control compliancy to the study 
protocol. 
 
11.2. Direct access to documents 
By signing the study protocol the participating centres confirm that they will provide source data 
during monitoring and inspection by regulatory agencies or local ethics committees. The 
investigational sites will give permission for trial-related monitoring, audits and provide direct access 
to source data and hospital records required.  
 
 

 
 
 
 
 
 
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12. TEMPORARY HALT AND PREMATURE TERMINATION OF THE STUDY  
 
The investigator will notify the accredited ethical committee of the end of the study within a period 
of 8 weeks. The end of the study is defined as the last patient’s last visit/telephone contact.  
The sponsor will notify the ethical committee immediately of a temporary halt of the study, including 
the reason of such an action. In case the study is ended prematurely, the sponsor will notify the 
accredited ethical committee within 15 days, including the reasons for the premature termination. 
Within one year after the end of the study, the investigator/sponsor will submit a final study report 
with the results of the study, including any publications/abstracts of the study, to the accredited 
ethical committee.  
 
12.1. Temporary halt of study 
The sponsor will suspend the study if there is sufficient ground that continuation of the study will 
jeopardise subject health or safety.  The sponsor will notify the accredited Ethical Committee without 
undue delay of a temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited Ethical Committee. The investigator will be 
responsible for keeping all patients informed. The sponsor will notify each country’s ethics 
committee immediately of a temporary halt of the study, including the reason of such an action.  
 
12.2. Premature termination of study 
The U-PGx Consortium reserves the right to discontinue the study prior to inclusion of the intended 
number of subjects, but intends to exercise this right only for valid scientific or administrative 
reasons, and only after consultation with the National Principal Investigators. After such a decision, 
all study-related materials must be collected without delay and all eCRFs must be completed as far as 
possible. 
 
 
 
 

 
 
 
 
 
 
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13. ETHICS 
 
13.1. Ethical conduct of the study 
The PREPARE study will be conducted according to the study protocol, applicable regulatory 
requirements, ICH/GCP, the ethical principles of the Declaration of Helsinki (latest version 2013, 
www.wma.net) and in accordance to national laws and legislation. 
13.2. Independent ethics committee 
It is the responsibility of the National Principal Investigators to obtain ethical approval or favourable 
opinion in writing of the study protocol and protocol amendments, the patient information 
leaflet and the informed consent form from the before enrolment of any subject into the study. 
1.1 Patient information and informed consent 
Before any site can begin recruitment, they must receive approval of the study by the regulatory 
authority (if required) and accredited ethical committee, as well as other country-specific required 
approvals. Recruiters (treating physicians of pharmacists) will be provided with a checklist of 
inclusion and exclusion criteria and a recruitment study log book. To participate in the study, eligible 
patients must give written, informed consent 
13.2.1. Recruitment in community pharmacies 
Patients receiving a first prescription for at least one drug for which a DPWG guideline is available 
(Table 5) will be recognized  by the treating pharmacist by a newly developed automated trigger. This 
trigger will invite the pharmacist to check eligibility criteria for this particular patient in the PREPARE 
study in real time.  
13.2.2. Informed Consent and Patient Brochure  
Informed consent will be obtained by recruiting pharmacists and research nurses who are informed 
of patient eligibility by the recruiting pharmacist and trained to answer questions about the protocol 
and consent forms.  
 
The consent process will begin with a verbal description of the study as outlined by the consent form. 
This process includes a verbal description of what the patient would be asked to do if he or she 
participated in the study, the risks and benefits of participating in the study, confidentiality of health 
information while in the study, and his or her right to refuse or withdraw participation without 
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Informed consent forms signed in twofold by the patient and the Investigator or delegate shall be 
filed in the Investigator’s File for possible future audits and inspections. A copy of the patient 
information leaflet and an originally signed informed consent form will be given to the subject.  
13.3. Changes to the study protocol  
Amendments are changes made to the research after a favourable opinion by the accredited Ethical 
Committee has been given. All amendments will be notified to the ethical committee that gave a 
favourable opinion.  All substantial amendments will be notified to the ethical committee. Non-
substantial amendments will not be notified to the accredited ethical committee, but will be 
recorded and filed by the sponsor.  
13.4. Annual progress report 
The National Principal Investigator will submit a summary of the progress of the study to the 
accredited ethical committee once a year. Information will be provided on the date of inclusion of 
the first subject, numbers of subjects included and numbers of subjects that have completed the 
study, SAEs, other problems, and amendments.  
 
 
 

 
 
 
 
 
 
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14. INSURANCE 
 
The sponsor/investigator has received exemption for patient insurance for this protocol.  
 
15. STUDY REPORT 
 
The study report is sent to each national regulatory agency (if applicable), independent ethics 
Committees and to the European Commission. 
 
16. PUBLIC DISCLOSURE AND PUBLICATION POLICY 
 
The clinical study report will form of manuscripts intended for publication in a medical/scientific 
journal. Publication policy details are presented in the U-PGx Consortium Agreement.  

 
 
 
 
 
 
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17. REFERENCES 
1. Ehmann F. et al. Pharmacogenomic information in drug labels: European Medicines Agency 
perspective. Pharmacogenomics J. 2015 Feb 24;15(3):201-10  
2. Swen JJ. et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin 
Pharmacol Ther. 2011 May;89(5):662-73.  
3. Swen JJ. et al. Translating pharmacogenomics: challenges on the road to the clinic. PLoS Med. 
2007 Aug;4(8):e209.  
4. Dunnenberger HM. et al. Preemptive clinical pharmacogenetics  implementation: current 
programs in five US medical centers. Annu Rev Pharmacol Toxicol. 2015;55:89-106. 
5. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
6. Gallagher RM, et al. Development and inter-rater reliability of the Liverpool adverse drug 
reaction causality assessment tool. PLoS One 2011;6(12):e28096. 
7. van Balveren-Slingerland L. et al. Web-based intensive monitoring of adverse events 
following influenza vaccination in general practice. Vaccine. 2015 [Epub ahead of print]  
8. Härmark L, et al. Intensive monitoring of pregabalin: results from an observational, Web-
based, prospective cohort study in the Netherlands using patients as a source of information. 
Drug Saf. 2011 1;34(3):221-31.  
 
 
 

 
 
 
 
 
 
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18. APPENDICIES 
18.1. National Coordinators and Principal Investigators  
Appendix Table 1 National Coordinators and Principal Investigators 
Country 
Name Institute 
 
National 
Principal 
Investigator 
Email address 
The 
Netherlands 
Leiden University 
Medical Center 
 
Jesse J. Swen 
j.j.swen@lumc.nl 
United 
Kingdom 
University of 
Liverpool 
 
Munir 
Pirmohamed 
munirp@liverpool.ac.uk 
Austria 
Medical University 
of Vienna 
 
Gere Sunder-
Plassmann 
gere.sunder-
plassmann@meduniwien.ac.at 
Italy 
Centro di 
Riferimento 
Oncologico 
 
Giuseppe 
Toffoli 
gtoffoli@cro.it 
Spain 
Servicio Andaluz de 
Salud 
 
Cristina Davila 
Fajardo 
cristinal.davila.sspa@juntadeandalucia.es 
Greece 
University of Patras 
 
George P. 
Patrinos 
gpatrinos@upatras.gr 
Slovenia 
University of 
Ljubljana 
 
Vita Dolzan 
vita.dolzan@mf.uni-lj.si 
 
 

 
 
 
 
 
 
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18.2. Flow Charts of Patient Journey  
18.2.1. General Flow Chart of Patient Journey 
Study arm - logistics for index drug 
 
 
Standard of care arm - logistics for index drug 
 
 
 
 

 
 
 
 
 
 
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18.2.2. Site Specific Flow Chart of Patient Journey 
 

 
 
 
 
 
 
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18.3. DPWG Guidelines 
The DPWG recommendations below have initially translated from Dutch to English by a certified 
translation company. The validated translations into all local languages will be completed in 
December 2016.  
 
Drug-gene interaction 
Recommendation 
1480
 
CYP2D6 PM: 
CLOMIPRAMINE 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity. This can cause the 
plasma concentrations of clomipramine and the active metabolite to increase, while reducing those of 
the potentially cardiotoxic hydroxy metabolites. 
 
Recommendation:  
* Indication DEPRESSION:  
- Reduce the dose to 50% of the normal dose, and monitor the plasma concentrations of clomipramine 
and N-desmethylclomipramine  
* Indication ANXIETY DISORDERS: 
 - Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. If no alternative is possible and adverse effects occur:  
- Reduce the dose by 50%, and monitor the plasma concentrations of clomipramine and N-
desmethylclomipramine. It is not known whether it is possible to reduce the dose to a point at which 
the adverse effects disappear while efficacy is maintained. Clomipramine and N-
desmethylclomipramine both contribute to these adverse effects. Efficacy, however, is due solely to 
clomipramine. 
1481
 
CYP2D6 IM: 
CLOMIPRAMINE 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity. This can cause the 
plasma concentrations of clomipramine and the active metabolite to increase, while reducing those of 
the potentially cardiotoxic hydroxy metabolites. 
 
Recommendation:  
- Reduce the dose to 70% of the normal dose, and monitor the plasma concentrations of clomipramine 
and desmethylclomipramine. For the indication of obsessive compulsive disorder and other anxiety 
disorders only clomipramine is relevant. For toxicity and the indication of depression, both are relevant.  
1482
 
CYP2D6 UM: 
CLOMIPRAMINE 
 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity. This can cause the 
plasma concentrations of clomipramine and the active metabolite to decrease, while increasing those of 
the potentially cardiotoxic hydroxy metabolites. 
 
Recommendation:  
- Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. If no alternative is possible:  
- Increase the dose to 150% of the normal dose, and monitor the plasma concentrations of 
clomipramine and desmethylclomipramine.     
For the indication of obsessive compulsive disorder and other anxiety disorders only clomipramine is 
relevant. For toxicity and the indication of depression, both are relevant.  
1538
 
CYP2D6 PM: 
VENLAFAXINE 
 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity. This can cause the 
plasma concentration of venlafaxine to increase, while reducing that of the active metabolite O-
desmethylvenlafaxine. There are indications that the efficacy of venlafaxine is decreased in depressive 
patients with this genetic polymorphism.  
 
Recommendation:    
Based on the literature, it is not possible to make a sufficiently well substantiated recommendation with 
regard to dose adjustment.  
- Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline.  
If no alternative is possible and adverse effects occur:  
- Reduce the dose, check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. It is 
not known whether it is possible to reduce the dose to a point at which the adverse effects disappear 
while efficacy is maintained. In general, it is assumed that efficacy is determined by the sum of the 
plasma concentrations of venlafaxine and O-desmethylvenlafaxine. The adverse effects, however, do 
not seem to be related to this sum.     
In addition, observations have shown that the efficacy of venlafaxine is decreased in depressive patients 
with this genetic polymorphism. 
1539
 
CYP2D6 IM: 
VENLAFAXINE  
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity. This can cause the 
plasma concentration of venlafaxine to increase, while reducing that of the active metabolite O-
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Recommendation:    
Based on the literature, it is not possible to make a sufficiently well substantiated recommendation with 
regard to dose adjustment.  
- Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. If no alternative is possible and adverse effects occur: - reduce the dose, 
check the plasma concentrations of venlafaxine and O-desmethylvenlafaxine.     
It is not known whether it is possible to reduce the dose to a point at which the adverse effects 
disappear while efficacy is maintained. In general, it is assumed that efficacy is determined by the sum 
of the plasma concentrations of venlafaxine and O-desmethylvenlafaxine. The adverse effects, however, 
do not seem to be related to this sum.  
1540
 
CYP2D6 UM: 
VENLAFAXINE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity. This can cause the 
plasma concentration of venlafaxine to decrease, while increasing that of the active metabolite O-
desmethylvenlafaxine.  
 
Recommendation: 
- Be alert to a possible reduction in the sum of the plasma concentrations of venlafaxine and its active 
metabolite O-desmethylvenlafaxine. If necessary, increase the dose to 150% of the normal dose. If dose 
adjustment based on therapeutic drug monitoring is not possible, an alternative should be selected.    
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. 
1542
 
CYP2D6 PM: 
ARIPIPRAZOL 
 
 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the sum of the plasma concentrations of aripiprazole and the active metabolite.  
 
Recommendation:     
- Advise the prescriber to prescribe no more than 10 mg/day or 300 mg/month (67%-75% of the normal 
maximum dose of aripiprazole). 
1544
 
CYP2D6 PM: 
IMIPRAMINE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of imipramine and the active metabolite.  
 
Recommendation:  
- Reduce the dose to 30% of the normal dose, and monitor the plasma concentrations of imipramine 
and desipramine for the purpose of setting the maintenance dose. 
1545
 
CYP2D6 IM: IMIPRAMINE 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of imipramine and desipramine.  
 
Recommendation:  
- Reduce the dose to 70% of the normal dose, and monitor the plasma concentrations of imipramine 
and desipramine for the purpose of setting the maintenance dose.  
1546
 
CYP2D6 UM: 
IMIPRAMINE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentrations of imipramine and desipramine, and an increase in that of the 
hydroxy metabolites.  
 
Recommendation: 
- Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline.  
If no alternative is possible:  
- Increase the dose to 170% of the normal dose, and monitor the plasma concentrations of imipramine 
and desipramine for the purpose of setting the maintenance dose. 
1547
 
CYP2D6 PM: 
ZUCLOPENTHIXOL 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of zuclopenthixol.  
 
Recommendation:  
- Advise the prescriber to reduce the dose to 50% of the normal dose or to prescribe an alternative, in 
accordance with existing guidelines.     
Some examples of antipsychotics that are only partially metabolized by CYP2D6, or not at all, are 
flupentixol, quetiapine, olanzapine and clozapine.  
1548
 
CYP2D6 IM: 
ZUCLOPENTHIXOL 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of zuclopenthixol.  
 
Recommendation:  
- Advise the prescriber to reduce the dose to 75% of the normal dose or to prescribe an alternative, in 
accordance with existing guidelines.     
Some examples of antipsychotics that are only partially metabolized by CYP2D6, or not at all, are 
flupentixol, quetiapine, olanzapine and clozapine.  

 
 
 
 
 
 
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1549
 
CYP2D6 UM: 
ZUCLOPENTHIXOL 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of zuclopenthixol.  
 
Recommendation:    
No data from studies into the pharmacokinetics and effects of zuclopenthixol in this phenotype have 
been published.  
- Advise the prescriber, as a precaution, to be alert to a decrease in the plasma concentration of 
zuclopenthixol and, if necessary, to increase the dose based on the clinical effect or to prescribe an 
alternative, in accordance with existing guidelines.     
Some examples of antipsychotics that are only partially metabolized by CYP2D6, or not at all, are 
flupentixol, quetiapine, olanzapine and clozapine. 
1552
 
CYP2D6 PM: 
HALOPERIDOL 
 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of haloperidol and the active metabolite.  
 
Recommendation:  
Advise the prescriber to:  
- Either reduce the starting dose to 50% of the normal starting dose, and to adjust the dose based on 
the effect 
- Or prescribe an alternative.     
Some examples of antipsychotics that are only very partially metabolized by CYP2D6, or not at all, are 
flupentixol, flufenazine, quetiapine, olanzapine and clozapine.  
1553
 
CYP2D6 UM: 
HALOPERIDOL 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentrations of haloperidol and reduced haloperidol.  
 
Recommendation:     
Based on the limited amount of literature available, it is not possible to make a sufficiently well 
substantiated recommendation with regard to dose adjustment.  
Advise the prescriber to:  
- Either be alert to a possible decrease in the plasma concentrations of haloperidol and reduced 
haloperidol and to increase the dose based on therapeutic drug monitoring 
- Or to prescribe an alternative, in accordance with existing guidelines.     
Some examples of antipsychotics that are only very partially metabolized by CYP2D6, or not at all, are 
flupentixol, flufenazine, quetiapine, olanzapine and clozapine.  
1554
 
CYP2D6 IM: 
METOPROLOL 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of metoprolol.  
 
Recommendation:  
* HEART FAILURE:  
- Advise the prescriber, if possible, to prescribe an alternative, in accordance with existing guidelines or, 
when setting the dose, to make allowance for the fact that, as a result of the gene polymorphism, it may 
be necessary to reduce the required dose to 50% of the normal dose.     
Possible alternatives are bisoprolol or carvedilol.  
Bisoprolol: advantage: it is not metabolized by CYP2D6; disadvantage: elimination is dependent on renal 
function.  
Carvedilol: advantage: elimination is not dependent on renal function; disadvantage: is metabolized by 
CYP2D6 (albeit to a lesser extent than metoprolol). If no alternative is selected: advise patients that, 
should their heart failure symptoms worsen, or if they should experience adverse effects such as 
bradycardia and cold extremities, they should contact the prescriber.  
 
* OTHER INDICATIONS:     
No dose adjustment is necessary, as there are no indications in the literature that an increase in the 
area under the curve (AUC) or in the plasma concentration has a major effect in terms of blood pressure 
change.  
- Draw the prescriber’s attention to the potential increase in plasma concentration, and to the 
possibility of an increased risk of adverse effects, such as bradycardia. If necessary, as a precaution, an 
alternative can be selected. Some examples of β-blockers that are only partially metabolized by CYP2D6, 
or not at all, are atenolol and bisoprolol. If no alternative is selected: advise patients that, if they should 
experience adverse effects such as bradycardia and cold extremities, they should contact the prescriber. 
1555
 
CYP2D6 PM: 
METOPROLOL 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of metoprolol.  
 
Recommendation:  
* HEART FAILURE:  
- Advise the prescriber to prescribe an alternative, in accordance with existing guidelines or, when 
setting the dose, to make allowance for the fact that, as a result of the gene polymorphism, it may be 
necessary to reduce the required dose to 25% of the normal dose.  
Possible alternatives are bisoprolol or carvedilol. 
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function. 
Carvedilol: advantage: elimination is not dependent on renal function; disadvantage: is metabolized by 
CYP2D6 (albeit to a lesser extent than metoprolol). If no alternative is selected: advise patients that, 
should their heart failure symptoms worsen, or if they should experience adverse effects such as 
bradycardia and cold extremities, they should contact the prescriber.  
 
* OTHER INDICATIONS:     
No dose adjustment is necessary, as there are no indications in the literature that an increase in the 
area under the curve (AUC) or in the plasma concentration has a major effect in terms of blood pressure 
change.  
- Draw the prescriber’s attention to the potential increase in plasma concentration, and to the 
possibility of an increased risk of adverse effects, such as bradycardia. If necessary, as a precaution, an 
alternative can be selected. Some examples of β-blockers that are only partially metabolized by CYP2D6, 
or not at all, are atenolol and bisoprolol. If no alternative is selected: advise patients that, if they should 
experience adverse effects such as bradycardia and cold extremities, they should contact the prescriber.  
1556
 
CYP2D6 UM: 
METOPROLOL 
 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of metoprolol. 
 
 Recommendation:  
- Advise the prescriber to prescribe an alternative, in accordance with existing guidelines.     
Possible alternatives are:  
- HEART FAILURE: bisoprolol or carvedilol.  
Bisoprolol: advantage: it is not metabolized by CYP2D6; disadvantage: elimination is dependent on renal 
function.  
Carvedilol: advantage: elimination is not dependent on renal function; disadvantage: is metabolized by 
CYP2D6 (albeit to a lesser extent than metoprolol).  
- OTHER INDICATIONS: atenolol or bisoprolol. Neither are metabolized by CYP2D6.  
If no alternative is possible: advise the prescriber to increase the dose, based on efficacy and adverse 
effects, to 250% of the normal dose. 
1557
 
CYP2D6 IM: 
NORTRIPTYLINE 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of nortriptyline.  
 
Recommendation:  
- Reduce the dose to 60% of the normal dose, and monitor the plasma concentrations of nortriptyline 
for the purpose of setting the maintenance dose.  
1558
 
CYP2D6 PM: 
NORTRIPTYLINE 
 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of nortriptyline.  
 
Recommendation:  
- Reduce the dose to 40% of the normal dose, and monitor the plasma concentration of nortriptyline for 
the purpose of setting the maintenance dose.  
1559
 
CYP2D6 UM: 
NORTRIPTYLINE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of nortriptyline, and an increase in that of the active metabolite E-
10-OH-nortriptyline. 
 
Recommendation:  
- Select an alternative     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline.  
If no alternative is possible:  
- Increase the dose to 160% of the normal dose, monitor the plasma concentration of nortriptyline, and 
be alert to an anticipated increase in the plasma concentration of the potentially cardiotoxic, active 
metabolite E-10-hydroxynortriptyline.  
1565
 
CYP2D6 UM: 
PAROXETINE 
Genetic variation results in increased conversion of paroxetine by the enzyme CYP2D6. This can reduce 
efficacy.  
 
Recommendation:     
Based on the literature, it is not possible to make a recommendation with regard to dose adjustment.  
If possible, select an alternative.     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram or sertraline. 
1566
 
FACT. V LEIDEN 
HOMOZYG: CONTRACEP. 
WITH OESTR. 
Homozygosity for the Factor V Leiden genetic polymorphism causes an increased tendency for blood to 
clot, resulting in an increased risk of venous thromboembolism. Oestrogen-containing contraceptives 
may increase this risk still further.  
 
Recommendation:  
* In the event of NUMEROUS CASE HISTORIES in a family OR a previous case of VENOUS THROMBOSIS:  
- Advise the prescriber to avoid the use of oestrogen-containing contraceptives and, as an alternative, to 

 
 
 
 
 
 
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prescribe a non-hormone-containing contraceptive, such as a copper-bearing intrauterine device (IUD). 
Another option is a contraceptive method that only uses progestogens, such as the birth control 
injection, an IUD with levonorgestrel or etonogestrel implant.  
 
* OTHER CASES:  
- Advise patients to avoid additional risk factors for thrombosis (obesity, smoking, etc.). 
1567
 
FACT. V LEIDEN 
HETEROZYG: CONTRACEP. 
WITH OESTR. 
 
Heterozygosity for the Factor V Leiden genetic polymorphism causes an increased tendency for blood to 
clot, resulting in an increased risk of venous thromboembolism. Oestrogen-containing contraceptives 
may increase this risk still further.  
 
Recommendation:  
* In the event of NUMEROUS CASE HISTORIES in a family OR a previous case of VENOUS THROMBOSIS:  
- Advise the prescriber to avoid the use of oestrogen-containing contraceptives and, as an alternative, to 
prescribe a non-hormone-containing contraceptive, such as a copper-bearing intrauterine device (IUD). 
Another option is a contraceptive method that only uses progestogens, such as the birth control 
injection, an IUD with levonorgestrel or etonogestrel implant.  
 
* OTHER CASES:  
- Advise patients to avoid additional risk factors for thrombosis (obesity, smoking, etc.). 
1583
 
CYP2D6 PM: CODEINE 
The genetic polymorphism reduces the conversion of codeine into morphine. This can lead to a 
reduction in pain relief.  
 
Recommendation:  
* In the event of COUGHING:      
- No action required   
 
* In the event of PAIN:    
Based on the limited amount of literature, it is not possible to make a sufficiently well substantiated 
recommendation with regard to dose adjustment for this phenotype.  
- Select an alternative     
In this connection, do not select tramadol as this is also metabolized by CYP2D6.    
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects. If no alternative is possible: advise patients that, in the event 
of inadequate pain relief, they should contact the prescriber.  
1584
 
CYP2D6 IM: CODEINE 
The genetic polymorphism reduces the conversion of codeine into morphine. This can lead to a 
reduction in pain relief.  
 
Recommendation:  
* In the event of COUGHING:  
- No action required  
 
* In the event of PAIN:     
Based on the limited amount of literature, it is not possible to make a sufficiently well substantiated 
recommendation with regard to dose adjustment for this phenotype.  
- Be alert to reduced efficacy in the event of inadequate efficacy:  
- Try increasing the dose; if this does not work select an alternative.     
In this connection, do not select tramadol as this is also metabolized by CYP2D6.     
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects.  
If no alternative is selected: advise patients that, in the event of inadequate pain relief, they should 
contact the prescriber. 
1585
 
CYP2D6 UM: CODEINE
 
 
The genetic polymorphism increases the conversion of codeine into morphine. This can lead to an 
increase in adverse effects. Mortality has occurred in children.  
 
Recommendation:     
Codeine is contraindicated with CYP2D6 UM.  
If possible, select an alternative.     
In the event of PAIN: do not select tramadol as this is also metabolized by CYP2D6.     
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects.  
1586
 
CYP2D6 PM: 
OXYCODONE 
The genetic polymorphism reduces the conversion of oxycodone into the more active metabolite 
oxymorphone. However, when setting the dose based on pain, an adequate degree of pain relief is 
usually achieved.  
 
Recommendation:  
- Be alert to reduced pain relief  
1587
 
CYP2D6 IM: OXYCODONE 
The genetic polymorphism reduces the conversion of oxycodone into the more active metabolite 
oxymorphone. However, when setting the dose based on pain, an adequate degree of pain relief is 

 
 
 
 
 
 
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usually achieved.  
 
Recommendation:  
- Be alert to reduced pain relief  
1588
 
CYP2D6 UM: 
OXYCODONE 
The genetic polymorphism increases the conversion of oxycodone into the more active metabolite 
oxymorphone. However, when setting the dose based on pain, an adequate degree of pain relief is 
usually achieved without any increase in adverse effects.  
 
Recommendation:  
- Be alert to the occurrence of adverse effects (such as drowsiness, confusion, constipation, nausea and 
vomiting, respiratory depression or urinary retention) and/or advise patients that, if they should 
experience any adverse effects they should contact the prescriber.  
1589
 
CYP2D6 PM: TRAMADOL 
The genetic polymorphism reduces the conversion of tramadol into a more active metabolite. This can 
lead to a reduction in pain relief.  
 
Recommendation:     
It is not possible to make a sufficiently well substantiated recommendation with regard to dose 
adjustment, as the total analgesic effect changes when the ratio between the parent compound and the 
active metabolite changes.  
- Be alert to reduced efficacy in the event of inadequate efficacy  
- Try increasing the dose; if this does not work select an alternative     
In this connection, do not select codeine as this is also metabolized by CYP2D6.     
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects.  
* If no alternative is selected: advise patients that, in the event of inadequate pain relief, they should 
contact the prescriber. 
1590
 
CYP2D6 IM: TRAMADOL 
The genetic polymorphism reduces the conversion of tramadol into a more active metabolite. This can 
lead to a reduction in pain relief.  
 
Recommendation:     
It is not possible to make a sufficiently well substantiated recommendation with regard to dose 
adjustment, as the total analgesic effect changes when the ratio between the parent compound and the 
active metabolite changes.  
- Be alert to reduced efficacy in the event of inadequate efficacy  
- Try increasing the dose; if this does not work select an alternative     
In this connection, do not select codeine as this is also metabolized by CYP2D6.     
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects.  
If no alternative is selected: advise patients that, in the event of inadequate pain relief, they should 
contact the prescriber. 
1591
 
CYP2D6 UM: TRAMADOL 
The genetic polymorphism increases the conversion of tramadol into a metabolite with stronger opioid 
activity. This can lead to an increase in adverse effects.  
 
Recommendation:     
The effect of a dose reduction cannot be predicted with any certainty as the total analgesic effect 
changes when the ratio between the parent compound and the active metabolite changes.  
- Reduce the dose to 20%-40% of the normal dose  
If a dose reduction fails to have the desired effect: select an alternative.     
In this connection, do not select codeine as it is contraindicated with CYP2D6 UM.     
Oxycodone is also metabolized by CYP2D6, but can usually be adjusted to give adequate pain relief 
without giving rise to any adverse effects.  
If no alternative is selected: advise patients that, if they should experience adverse effects (such as 
drowsiness, confusion, constipation, nausea and vomiting, respiratory depression or urinary retention) 
they should contact the prescriber. 
1592 
CYP2D6 PM: FLECAINIDE  
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of flecainide.  
 
Recommendation:  
- Reduce the dose to 50% of the normal dose, perform an ECG, and monitor the plasma concentration. 
1593
 
CYP2D6 IM: FLECAINIDE 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of flecainide.  
 
Recommendation:  
- Reduce the dose to 75% of the normal dose, perform an ECG, and monitor the plasma concentration. 
1594
 
CYP2D6 UM: FLECAINIDE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of flecainide.  
 
Recommendation:    

 
 
 
 
 
 
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No data from studies into the pharmacokinetics and/or effects of flecainide in this phenotype have been 
published.  
- As a precaution, monitor the plasma concentration and perform an ECG or select an alternative.     
Some examples of antiarrhythmics that are only partially metabolized by CYP2D6, or not at all, are 
sotalol, disopyramide, quinidine and amiodarone. 
1595
 
CYP2D6 PM: 
PROPAFENONE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of propafenone, and a decrease in that of the active metabolite 5-
hydroxypropafenone.  
 
Recommendation:  
- Reduce the dose to 30% of the normal dose, perform an ECG, and monitor the plasma concentration. 
1596
 
CYP2D6 IM: 
PROPAFENONE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of propafenone, and a decrease in that of the active metabolite 5-
hydroxypropafenone.  
 
Recommendation: 
Based on the literature, it is not possible to make a sufficiently well substantiated recommendation with 
regard to dose adjustment.  
- Either set the dose based on therapeutic drug monitoring, perform an ECG, and be alert to the 
occurrence of adverse effects, 
- Or select an alternative.     
Some examples of antiarrhythmics that are only partially metabolized by CYP2D6, or not at all, are 
sotalol, disopyramide, quinidine and amiodarone. 
1597
 
CYP2D6 UM: 
PROPAFENONE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of propafenone, and an increase in that of the active metabolite 
5-hydroxypropafenone.  
Recommendation: 
Based on the literature, it is not possible to make a sufficiently well substantiated recommendation with 
regard to dose adjustment.  
- Either monitor the plasma concentration, perform an ECG and be alert to reduced therapeutic efficacy, 
- Or select an alternative.     
Some examples of antiarrhythmics that are only partially metabolized by CYP2D6, or not at all, are 
sotalol, disopyramide, quinidine and amiodarone. 
1598
 
CYP2D6 PM: 
ATOMOXETINE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentration of atomoxetine and a decrease in that of the active metabolite.  
 
Recommendation:  
- Start with the normal starting dose, but make allowance for the fact that it will probably not be 
necessary to increase this dose. Advise patients that, if they should experience adverse effects (such as 
decreased appetite, vomiting, abdominal pain, constipation, insomnia, early awakening, drowsiness, 
irritability, pupil dilation and itching) they should contact the prescriber. 
1600
 
CYP2D6 UM: 
ATOMOXETINE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentration of atomoxetine and an increase in that of the active metabolite.  
 
Recommendation:    
There are no known data from studies into the pharmacokinetics and/or effects of atomoxetine in this 
phenotype.  
- As a precaution, be extra alert to reduced therapeutic efficacy. Advise patients that, in the event of 
inadequate therapeutic efficacy, they should contact the prescriber. If necessary, as a precaution, an 
alternative can be selected.     
Methylphenidate and clonidine are only partially metabolized by CYP2D6, or not at all.  
1601
 
CYP2D6 PM: TAMOXIFEN
 
 
This genetic variant reduces the conversion of tamoxifen into its active metabolite endoxifen. This can 
reduce efficacy.  
 
Recommendation:  
- Select an alternative or increase the dose to 40 mg/day and monitor the endoxifen concentration. 
Studies have shown that PM can achieve an adequate endoxifen concentration when the dose is 
increased to 40-60 mg/day.     
For post-menopausal women, aromatase inhibitors are a potential alternative.  
1602
 
CYP2D6 IM: TAMOXIFEN 
This genetic variant reduces the conversion of tamoxifen into its active metabolite endoxifen. This can 
reduce efficacy.  
 
Recommendation:  
- Select an alternative or measure the endoxifen concentration and, if necessary, increase the dose by a 
factor of 1.5-2.     
For post-menopausal women, aromatase inhibitors are a potential alternative. 
- If TAMOXIFEN is selected: avoid concomitant therapy with CYP2D6 inhibitors, such as paroxetine or 
fluoxetine.  

 
 
 
 
 
 
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1676
 
CYP2C9 IM: PHENYTOIN
 
 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 75% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber. 
1677
 
CYP2C9 PM: PHENYTOIN 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 50% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber. 
1678 CYP2C9*1/*2: 
PHENYTOIN 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 75% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber.  
1679 
CYP2C9*1/*3: PHENYTOIN
 
 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 75% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber.  
1680 
CYP2C9*2/*2: PHENYTOIN 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 50% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber. 
1681 
CYP2C9*2/*3: PHENYTOIN 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 50% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber.  
1682 
CYP2C9*3/*3: PHENYTOIN 
The genetic polymorphism leads to a reduction in CYP2C9’s metabolic capacity, which can result in an 
increase in the plasma concentration of phenytoin.  
 
Recommendation:  
- A loading dose does not need to be adjusted. Reduce remaining doses to 50% of the normal dose, and 
assess the dose based on the effect and the serum level after 7-10 days. Advise patients that, if they 
should experience adverse effects (such as ataxia, nystagmus, speech disorder, sedation) they should 
contact the prescriber.  
1683 
CYP2C19 IM: VORICONAZOL 
The genetic polymorphism leads to a reduction in CYP2C19’s metabolic capacity, which can result in an 
increase in the plasma concentration of voriconazol.  
 
Recommendation:  
- Monitor the plasma concentration  
1684 
CYP2C19 PM: VORICONAZOL 
The genetic polymorphism leads to a reduction in CYP2C19’s metabolic capacity, which can result in an 
increase in the plasma concentration of voriconazol.  
 
Recommendation:  
- Monitor the plasma concentration  

 
 
 
 
 
 
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1692
 
UGT1A1 PM: 
IRINOTECAN 
 
This genetic variant reduces the conversion of irinotecan to inactive metabolites. This increases the risk 
of severe, life-threatening adverse effects.  
 
Recommendation:  
- Reduce the starting dose by 30%     
If the patient tolerates this starting dose, if necessary, the dose can be increased based upon the 
neutrophil count.  
1694
 
UGT1A1 *28/*28: 
IRINOTECAN 
 
This genetic variant reduces the conversion of irinotecan to inactive metabolites. This increases the risk 
of severe, life-threatening adverse effects.  
 
Recommendation:  
- Reduce the starting dose by 30%     
If the patient tolerates this starting dose, if necessary, the dose can be increased based upon the 
neutrophil count. 
1820 
CYP2C19 UM: 
ESCITALOPRAM 
 
The genetic polymorphism leads to an increase in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of escitalopram.  
 
Recommendation:  
- Be alert to a possible reduction in the plasma concentration of citalopram and, if necessary, increase 
the dose to 175% of the normal dose. If dose adjustment based on therapeutic drug monitoring is not 
possible, an alternative should be selected.     
Some examples of antidepressants that are only partially metabolized by CYP2C19, or not at all, are 
fluoxetine and paroxetine. 
1821 
CYP2C19 IM: ESCITALOPRAM 
The genetic polymorphism leads to an increase in the plasma concentrations of citalopram. This 
increases the risk of QT prolongation and torsades de pointes.  
 
Recommendation:  
- Prescribe up to the following maximum dose levels (50% of the normal maximum dose): adults up to 
the age of 65: 10 mg/day, and those over the age of 65: 5 mg/day.  
While monitoring the ECG, the dose can be increased to the normal maximum dose, if necessary.   
1822 
CYP2C19 PM: 
ESCITALOPRAM 
 
The genetic polymorphism leads to an increase in the plasma concentrations of citalopram. This 
increases the risk of QT prolongation and torsades de pointes.  
 
Recommendation:  
- Prescribe up to the following maximum doses (50% of the normal maximum dose): adults up to the 
age of 65: 10 mg/day, and those over the age of 65: 5 mg/day. 
1826 
CYP2C19 UM: 
ESOMEPRAZOLE 
The genetic polymorphism leads to an increase in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of esomeprazole.  
 
Recommendation:  
In ERADICATION THERAPY for Helicobacter pylori:  
- Increase the dose to 150-200% of the normal dose and advise patients to contact the prescriber if the 
dyspepsia problems persist.  
* OTHER INDICATIONS:  
- Look out for signs of reduced efficacy. If present, increase the dose to 150-200% of the normal dose. 
Advise patients to contact the prescriber if the dyspepsia problems persist. 
1833 
CYP2C19 UM: 
LANSOPRAZOLE 
 
The genetic polymorphism leads to an increase in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of lansoprazole.  
 
Recommendation:  
In ERADICATION THERAPY for Helicobacter pylori:  
- Increase the dose to 300% of the normal dose and advise patients to contact the prescriber if the 
dyspepsia problems persist.  
* OTHER INDICATIONS:  
- Look out for signs of reduced efficacy. If present, increase the dose to 300% of the normal dose. Advise 
patients to contact the prescriber if the dyspepsia problems persist.  
1841 
CYP2C19 UM: OMEPRAZOLE 
The genetic polymorphism leads to an increase in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of omeprazole.  
 
Recommendation:  
In ERADICATION THERAPY for Helicobacter pylori:  
- Increase the dose to 200-300% of the normal dose.  
Advise patients to contact the prescriber if the dyspepsia problems persist.  
* OTHER INDICATIONS:  
- Look out for signs of reduced efficacy. If present, increase the dose to 200-300% of the normal dose. 
Advise patients to contact the prescriber if the dyspepsia problems persist. 

 
 
 
 
 
 
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1849 
CYP2C19 UM: 
PANTOPRAZOLE 
 
The genetic polymorphism leads to an increase in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of pantoprazole.  
 
Recommendation:  
In ERADICATION THERAPY for Helicobacter pylori:  
- Increase the dose to 500% of the normal dose and advise patients to contact the prescriber if the 
dyspepsia problems persist.  
* OTHER INDICATIONS: 
 - Look out for signs of reduced efficacy. If present, increase the dose to 500% of the normal dose. 
Advise patients to contact the prescriber if the dyspepsia problems persist.  
1905
 
TPMT IM: 
AZATHIOPRINE / 
MERCAPTOPURINE 
The genetic variant reduces the conversion of azathioprine and mercaptopurine to largely inactive 
metabolites. This increases the risk of severe, life-threatening adverse effects, such as bone marrow 
suppression.  
 
Recommendation:  
- Reduce the starting dose to 50% of the normal dose.     
Base the adjustment of the starting dose on toxicity (blood picture monitoring) and efficacy.    
The frequency of monitoring should be increased.     
If the current dose does not exceed azathioprine 1.5 mg/kg per day or mercaptopurine 0.75 mg/kg per 
day, no dose adjustment is necessary. 
1906
 
TPMT PM: 
AZATHIOPRINE / 
MERCAPTOPURINE 
The genetic variant reduces the conversion of azathioprine and mercaptopurine to largely inactive 
metabolites. This increases the risk of severe, life-threatening adverse effects, such as bone marrow 
suppression.  
 
Recommendation: 
Reduce the starting dose to 10% of the normal dose or select an alternative.     
Base any adjustment of the starting dose on toxicity (blood picture monitoring) and efficacy.    
The frequency of monitoring should be increased.  
If the dose is reduced: advise patients to contact the prescriber if symptoms of bone marrow depression 
(e.g. sore throat in combination with elevated temperature, frequent nosebleeds and easy bruising) 
occur. 
1907
 
TPMT IM: TIOGUANINE 
The genetic variant reduces the conversion of tioguanine to inactive metabolites. This increases the risk 
of severe adverse effects, such as bone marrow suppression.  
 
Recommendation: 
 - Reduce the starting dose to 75% of the normal dose.     
Base the adjustment of the starting dose on toxicity (blood picture monitoring) and efficacy.     
The frequency of monitoring should be increased. 
1908
 
TPMT PM: TIOGUANINE 
The genetic variant reduces the conversion of tioguanine to inactive metabolites. This increases the risk 
of severe, life-threatening adverse effects, such as bone marrow suppression.  
 
Recommendation:  
- Reduce the starting dose to 6-7% of the normal dose or select an alternative.     
Base any adjustment of the starting dose on toxicity (blood picture monitoring) and efficacy.     
The frequency of monitoring should be increased. If the dose is reduced: advise patients to contact the 
prescriber if symptoms of bone marrow depression (e.g. sore throat in combination with elevated 
temperature, frequent nosebleeds and easy bruising) occur. 
1910
 
VKORC1 TT: 
ACENOCOUMAROL 
The genetic variant leads to increased sensitivity to acenocoumarol.  
 
Recommendation:  
* Examination by the THROMBOSIS CLINIC:  
- Recommend reducing the starting dose to 50% of the normal starting dose. 
* OTHERWISE:  
- Recommend reducing the starting dose to 50% of the normal starting dose. 
- Recommend checking the INR more frequently. *     
The starting dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. 
1912
 
VKORC1 TT: 
FENPROCOUMON 
 
The genetic variant leads to a lower dose being required. However, if the patient is regularly examined 
by the thrombosis clinic, there is no significant increase in the haemorrhage risk.  
 
Recommendation:  
* Examination by the THROMBOSIS CLINIC:  
- Recommend reducing the starting dose to 50% of the normal starting dose. 
* NO examination by the thrombosis clinic:  
- Recommend reducing the starting dose to 50% of the normal starting dose. 
- Check the INR more frequently. *      
The starting dose and maintenance dose can be calculated using an algorithm, as used in EU-PACT. 

 
 
 
 
 
 
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1914
 
CYP2C19 PM: 
IMIPRAMINE 
The genetic polymorphism leads to a reduction in CYP2C19’s metabolic capacity, which can result in an 
increase in the plasma concentration of imipramine.  
 
Recommendation:  
- Reduce the dose to 70% of the normal dose and monitor the plasma concentration of imipramine and 
desipramine, or select an alternative.     
Some examples of antidepressants that are only partially metabolized by CYP2C19, or not at all, are 
fluvoxamine and mirtazapine. 
1920
 
CYP2D6 IM: 
AMITRIPTYLINE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline, and a 
decrease in the plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH-
nortriptyline.  
 
Recommendation:  
If possible, select an alternative.    
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline.  
If no alternative is possible: reduce the dose to 60% of the normal dose and monitor the plasma 
concentrations of amitriptyline and nortriptyline.     
Because the adverse effects are related to the nortriptyline plasma concentration and the efficacy is 
related to the plasma concentration of amitriptyline plus nortriptyline, which is not influenced as 
strongly by CYP2D6, it is not known whether it is possible to reduce the dose to a point at which the 
adverse effects disappear while efficacy is maintained.  
1921
 
CYP2D6 PM: 
AMITRIPTYLINE 
The genetic polymorphism leads to a decrease in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of amitriptyline and its active metabolite nortriptyline, and a 
decrease in the plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH-
nortriptyline.  
 
Recommendation: 
If possible, select an alternative.     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. 
If no alternative is possible:  
- Reduce the dose to 50% of the normal dose and monitor the plasma concentrations of amitriptyline 
and nortriptyline.     
Because the adverse effects are related to the nortriptyline plasma concentration and the efficacy is 
related to the plasma concentration of amitriptyline plus nortriptyline, which is not influenced as 
strongly by CYP2D6, it is not known whether it is possible to reduce the dose to a point at which the 
adverse effects disappear while efficacy is maintained.  
1922
 
CYP2D6 UM: 
AMITRIPTYLINE 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentrations of amitriptyline and its active metabolite nortriptyline, and an 
increase in the plasma concentrations of the active metabolites E-10-OH-amitriptyline and E-10-OH-
nortriptyline.  
 
Recommendation:  
If possible, select an alternative.     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline.  
If no alternative is possible:  
- Increase the dose to 125% of the normal dose, monitor the plasma concentration and be alert to the 
possibility of therapy failing due to a reduction in the plasma concentrations of amitriptyline and 
nortriptyline and an increase in the plasma concentration of the potentially cardiotoxic, active hydroxy 
metabolites. 
2008
 
CYP2C19 IM: 
SERTRALINE 
The genetic polymorphism leads to a reduction in CYP2C19’s metabolic capacity, which can result in an 
increase in the plasma concentrations of sertraline and desmethylsertraline.  
Recommendation:  
- Do not use a dose higher than 100 mg/day. Adjust the dose on the basis of the response and adverse 
effects and/or on the basis of the plasma concentration of sertraline plus desmethylsertraline. 
2009
 
CYP2C19 PM: 
SERTRALINE 
The genetic polymorphism leads to a reduction in CYP2C19’s metabolic capacity, which can result in an 
increase in the plasma concentrations of sertraline and desmethylsertraline.  
 
Recommendation:  
- Do not use a dose higher than 50 mg/day. Adjust the dose on the basis of the response and adverse 
effects and/or on the basis of the plasma concentration of sertraline plus desmethylsertraline. 
2015
 
CYP2D6 IM: DOXEPIN
 
 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of doxepin and nordoxepin.  
 

 
 
 
 
 
 
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Recommendation:  
- Reduce the dose to 80% of the normal dose and monitor the plasma concentrations of doxepin and 
nordoxepin for the purpose of setting the maintenance dose.  
2016
 
CYP2D6 PM: DOXEPIN
 
 
The genetic polymorphism leads to a reduction in CYP2D6’s metabolic capacity, which can result in an 
increase in the plasma concentrations of doxepin and nordoxepin.  
 
Recommendation: 
- Reduce the dose to 40% of the normal dose and monitor the plasma concentrations of doxepin and 
nordoxepin for the purpose of setting the maintenance dose. 
2017
 
CYP2D6 UM: DOXEPIN 
The genetic polymorphism leads to an increase in CYP2D6’s metabolic capacity, which can result in a 
decrease in the plasma concentrations of doxepin and nordoxepin, and an increase in the plasma 
concentrations of the hydroxy metabolites.  
 
Recommendation: 
- Select an alternative.     
Some examples of antidepressants that are only partially metabolized by CYP2D6, or not at all, are 
citalopram and sertraline. If no alternative is possible, increase the dose to 200% of the normal dose 
and monitor the plasma concentrations of doxepin and nordoxepin for the purpose of setting the 
maintenance dose. 
2357
 
CYP3A5 HOMOZYGOUS 
EXPRESSOR: TACROLIMUS 
The genetic variant leads to increased conversion of tacrolimus to inactive metabolites, making a higher 
dose necessary. Adjustment of the starting dose increases the probability of the tacrolimus 
concentration being within the target range prior to the start of therapeutic drug monitoring on day 3. 
However, there is no direct evidence of that leading to better clinical outcomes.  
 
Recommendation:  
* Indications OTHER than liver transplantation: 
 - Increase the starting dose to 250% of the starting dose associated with the desired outcome in non-
expressors.    
Subsequent adjustment of the dose should be based on therapeutic drug monitoring.     
NB: The starting dose associated with the desired outcome in non-expressors may be lower than the 
normal starting dose. In the example below, the starting dose associated with the desired outcome in 
non-expressors was 75% of the normal starting dose. Therefore, increasing the starting dose to 250% of 
the starting dose associated with the desired outcome in non-expressors implies increasing it to 200% of 
the normal starting dose. Example: After 3 days, Thervet et al. observed a median trough tacrolimus 
concentration of 14.0 ng/ml at a starting dose of 0.15 mg/kg 2x per day in 4 renal transplant patients 
who were homozygous expressors. At a starting dose of 0.1 mg/kg 2x per day, the concentration was 
5.6 ng/ml (n = 6). Their target value was 10-15 ng/ml. That is lower than the target value sought in the 
Netherlands in the first 2-4 weeks following renal transplantation (15-20 ng/ml). In the reference group 
of non-expressors, median trough concentrations of 16.6 ng/ml and 12,0 ng/ml were observed at doses 
of, respectively 0.1 mg/kg 2x per day and 0.075 mg/kg 2x per day. In this hospital, the first dose is 
administered to patients whose CYP3A5 genotype is not known. The second dose is a reduced dose 
based on the patient’s genotype.  
 
* LIVER transplantation:     
The metabolism of tacrolimus is influenced not only by the patient’s genotype, but also by the genotype 
of the transplanted liver.  
* LIVER genotype is also HOMOZYGOUS EXPRESSOR:  
- Increase the starting dose to 250% of the normal starting dose.     
Subsequent adjustment of the dose should be based on therapeutic drug monitoring.  
* LIVER is ANOTHER genotype:     
The literature provides insufficient information to support a dosage recommendation.     
2358
 
CYP3A5 HETEROZYGOUS 
EXPRESSOR: TACROLIMUS 
The genetic variant leads to increased conversion of tacrolimus to inactive metabolites, making a higher 
dose necessary. Adjustment of the starting dose increases the probability of the tacrolimus 
concentration being within the target range prior to the start of therapeutic drug monitoring on day 3. 
However, there is no direct evidence of that leading to better clinical outcomes.  
 
* Indications OTHER than liver transplantation:  
- Increase the starting dose to 175% of the starting dose associated with the desired outcome in non-
expressors.     
Subsequent adjustment of the dose should be based on therapeutic drug monitoring.     
NB: The starting dose associated with the desired outcome in non-expressors may be lower than the 
normal starting dose. In the example below, the starting dose associated with the desired outcome in 
non-expressors was 75% of the normal starting dose. Therefore, increasing the starting dose to 175% of 
the starting dose associated with the desired outcome in non-expressors implies increasing it to 130% of 
the normal starting dose. Example: After 3 days, Thervet et al. observed a median trough tacrolimus 
concentration of 12.3 ng/ml at a starting dose of 0.15 mg/kg 2x per day in heterozygous renal transplant 
patients. Their target value was 10-15 ng/ml. That is lower than the target value sought in the 
Netherlands in the first 2-4 weeks following renal transplantation (15-20 ng/ml). In the reference group 
of non-expressors, median trough concentrations of 16.6 ng/ml and 12,0 ng/ml were observed at doses 

 
 
 
 
 
 
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of, respectively 0.1 mg/kg 2x per day and 0.075 mg/kg 2x per day. In this hospital, the first dose is 
administered to patients whose CYP3A5 genotype is not known. The second dose is a reduced dose 
based on the patient’s genotype.  
 
* LIVER transplantation:     
The metabolism of tacrolimus is influenced not only by the patient’s genotype, but also by the genotype 
of the transplanted liver.  
* LIVER genotype is also HETEROZYGOUS EXPRESSOR:  
- Increase the starting dose to 175% of the normal starting dose.     
Subsequent adjustment of the dose should be based on therapeutic drug monitoring.  
* LIVER is ANOTHER genotype:     
The literature provides insufficient information to support a dosage recommendation.   
2447
 
CYP2D6 PM: PIMOZIDE
 
 
The genetic variant leads to an increase in the plasma concentration of pimozide. That increases the risk 
of potentially life-threatening QT prolongation.  
 
Recommendation:  
- Prescribe up to the following maximum doses (25% of the normal maximum dose): adults 5 mg/day, 
children 0.025 mg/kg per day, up to a maximum of 1 mg/day. 
2448
 
CYP2D6 IM: PIMOZIDE 
The genetic variant leads to an increase in the plasma concentration of pimozide. That increases the risk 
of potentially life-threatening QT prolongation.  
 
Recommendation:  
- Prescribe up to the following maximum doses (60-65% of the normal maximum dose): adults 
12 mg/day, children 0.065 mg/kg per day, up to a maximum of 2.6 mg/day. 
2548
 
CYP2C19 PM: 
CLOPIDOGREL 
The genetic polymorphism leads to a decrease in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of the active metabolite of clopidogrel. Patients with this genetic 
polymorphism are at elevated risk of a poor clopidogrel response.  
 
Recommendation:  
- Consider an alternative.     
Prasugrel and ticagrelor are only partially metabolized by CYP2C19, or not at all. 
2549
 
CYP2C19 IM: 
CLOPIDOGREL 
The genetic polymorphism leads to a decrease in CYP2C19’s metabolic capacity, which can result in a 
decrease in the plasma concentration of the active metabolite of clopidogrel. Patients with this genetic 
polymorphism are at elevated risk of a poor clopidogrel response.  
 
Recommendation:  
- Consider an alternative.     
Prasugrel and ticagrelor are only partially metabolized by CYP2C19, or not at all. 
2551
 
DPD GENACT 0: 
FLUOROURACIL / 
CAPECITABINE 
The genetic variant affects DPD, leading to the reduced conversion of fluorouracil/capecitabine to 
inactive metabolites. This may cause intracellular concentrations of the active metabolite of 
fluorouracil/capecitabine to increase, leading to a greater risk of serious, potentially fatal, toxicity. 
 
Recommendation:  
- Select an alternative. 
Tegafur is not an alternative, as this is also metabolized by DPD.     
NB: If a patient has two different genetic variants that have resulted in an inactive DPD enzyme (e.g. 
*2A and *13), this recommendation will only apply if the variants are located on different alleles. If both 
variants are located on the same allele, the patient will have a gene activity score of 1, and the 
recommendation associated with this score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 
2552
 
DPD GENACT 1: 
FLUOROURACIL / 
CAPECITABINE 
The genetic variant affects DPD, leading to the reduced conversion of fluorouracil/capecitabine to 
inactive metabolites. This may cause intracellular concentrations of the active metabolite of 
fluorouracil/capecitabine to increase, leading to a greater risk of serious, potentially fatal, toxicity. 
 
Recommendation:  
- Reduce the starting dose to 50% of the normal dose or select an alternative.     
Base the adjustment of the starting dose on toxicity and efficacy. Tegafur is not an alternative, as this is 
also metabolized by DPD.    
NB1: Reduction of the dose as described is well-supported for *1/*2A. In patients with 2 alleles 
associated with reduced activity (e.g. 2846T/2846T or 1236A/1236A), the dose reduction is calculated 
from the dose reduction observed for *1/2846T.    
NB2: If a patient has two different genetic variants associated with a less active DPD enzyme (e.g. 2846T 
and 1236A), the recommendation above applies only if the variants are located on different alleles. If 
both variants are located on the same allele, the patient will have a gene activity score of 1.5, and the 
recommendation associated with that score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 

 
 
 
 
 
 
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2553
 
DPD GENACT 0: 
TEGAFUR 
This genetic variant reduces the conversion of tegafur to inactive metabolites. That increases the risk of 
severe, potentially fatal toxicity.  
 
Recommendation:    
Tegafur is contraindicated in patients with a gene activity score of 0 (zero).    
- Select an alternative.    
Do not select fluorouracil or capecitabine, as these are also metabolized by DPD.    
NB: If a patient has two different genetic variants that have resulted in an inactive DPD enzyme (e.g. 
*2A and *13), this recommendation will only apply if the variants are located on different alleles. If both 
variants are located on the same allele, the patient will have a gene activity score of 1, and the 
recommendation associated with this score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 
2554
 
DPD GENACT 1: 
TEGAFUR 
This genetic variant reduces the conversion of tegafur to inactive metabolites. That increases the risk of 
the normal dose leading to severe, potentially fatal toxicity.  
 
Recommendation:    
- Select an alternative or start with a reduced dose and adjust the starting dose on the basis of toxicity 
and efficacy.    
Fluorouracil and capecitabine are not usable alternatives, as they are also metabolized by DPD. The 
literature does not provide an adequate basis on which to make a recommendation regarding dose 
adjustment. It is recommended that the starting doses of fluorouracil and capecitabine be reduced to 
50% of the normal dose.    
NB: If a patient has two different genetic variants associated with a less active DPD enzyme (e.g. 2846T 
and 1236A), the recommendation above applies only if the variants are located on different alleles. If 
both variants are located on the same allele, the patient will have a gene activity score of 1.5, and the 
recommendation associated with that score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 
4055
 
SLCO1B1 521TC: 
SIMVASTATIN 
The genetic polymorphism can lead to reduced transportation of simvastatin to the liver. That can result 
in an elevated simvastatin plasma concentration and thus to an increased risk of myopathy. 
 
Recommendation:  
- Select an alternative.     
When selecting an alternative, consider any additional risk factors for statin-induced myopathy that 
may be present. 
Rosuvastatin and pravastatin are not influenced as strongly by SLCO1B1 polymorphisms. Nor are they 
influenced by CYP3A4 inhibitors, such as amiodarone, verapamil and diltiazem. Fluvastatin is not 
influenced by SLCO1B1 polymorphisms or CYP3A4-inhibitors.  
If no alternative is possible:  
- Avoid simvastatin doses exceeding 40 mg/day and advise patients to contact the prescriber in the 
event of muscle problems. 
4056
 
SLCO1B1 521CC: 
SIMVASTATIN 
The genetic polymorphism leads to reduced transportation of simvastatin to the liver. That results in an 
elevated simvastatin plasma concentration and thus to an increased risk of myopathy.  
 
Recommendation:  
- Select an alternative.     
When selecting an alternative, consider any additional risk factors for statin-induced myopathy that 
may be present. 
Rosuvastatin and pravastatin are not influenced as strongly by SLCO1B1 polymorphisms. Nor are they 
influenced by CYP3A4 inhibitors, such as amiodarone, verapamil and diltiazem. Fluvastatin is not 
influenced by SLCO1B1 polymorphisms or CYP3A4-inhibitors.  
4057
 
SLCO1B1 521TC: 
ATORVASTATIN 
The genetic polymorphism can lead to reduced transportation of atorvastatin to the liver. That can 
result in an elevated atorvastatin plasma concentration and thus to an increased risk of myopathy.  
 
Recommendation:  
* Patient has SIGNIFICANT ADDITIONAL RISK FACTORS for statin-induced myopathy:  
- Select an alternative.     
Rosuvastatin and pravastatin are influenced by SLCO1B1 polymorphisms to a broadly similar extent, but 
they are not influenced by CYP3A4-inhibitors, such as amiodarone, verapamil and diltiazem.     
Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4-inhibitors. If no alternative is 
possible, advise patients to contact the prescriber in the event of muscle problems.  
* Patient has NO significant additional risk factors for statin-induced myopathy:  
- Advise patients to contact the prescriber in the event of muscle problems. 
4058
 
SLCO1B1 521CC: 
ATORVASTATIN 
The genetic polymorphism can lead to reduced transportation of atorvastatin to the liver. That can 
result in an elevated atorvastatin plasma concentration and thus to an increased risk of myopathy.  
 
Recommendation:  
* Patient has SIGNIFICANT ADDITIONAL RISK FACTORS for statin-induced myopathy: 
- Select an alternative.    

 
 
 
 
 
 
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Rosuvastatin and pravastatin are influenced by SLCO1B1 polymorphisms to a broadly similar extent, but 
they are not influenced by CYP3A4-inhibitors, such as amiodarone, verapamil and diltiazem.     
Fluvastatin is not influenced by SLCO1B1 polymorphisms or CYP3A4-inhibitors.  
If no alternative is possible:  
- Advise patients to contact the prescriber in the event of muscle problems.  
* Patient has NO significant additional risk factors for statin-induced myopathy:  
- Advise patients to contact the prescriber in the event of muscle problems. 
4195
 
CYP2C19 IM: 
CITALOPRAM 
 
The genetic polymorphism leads to an increase in the plasma concentrations of citalopram. This 
increases the risk of QT prolongation and torsades de pointes.  
 
Recommendation: 
 - Prescribe up to the following maximum daily doses:  
* Adults up to 65 years old: 20 mg in tablet form or 22 mg in droplet form From 65 years old: 10 mg in 
tablet form or droplet form      
While monitoring the ECG, the dose may if necessary be increased to the normal maximum dose:  
* Adults up to 65 years old: 40 mg in tablet form or 32 mg in droplet form From 65 years old: 20 mg in 
tablet form or 16 mg in droplet form 
4196
 
CYP2C19 PM: 
CITALOPRAM 
The genetic polymorphism leads to an increase in the plasma concentrations of citalopram. That 
increases the risk of QT prolongation and torsades de pointes.  
 
Recommendation: 
 - Prescribe up to the following maximum doses (50% of the normal maximum doses):  
* Adults up to 65 years old: 20 mg in tablet form or 16 mg in droplet form From 65 years old: 10 mg in 
tablet form or 8 mg in droplet form 
4642 
CYP1A2*1C-HETEROZYGOUS: 
CLOZAPINE 
The genetic polymorphism can lead to reduced metabolism of clozapine. That can result in an elevated 
clozapine plasma concentration and thus to an increased risk of adverse effects.  
 
Recommendation:    
The literature does not provide an adequate basis on which to make a recommendation regarding dose 
reduction.  
- Adjust the dose on the basis of the plasma concentration of clozapine.    
The therapeutic range suggested for clozapine is 200-600 ng/ml. 
4643 
CYP1A2*1C/*1C: CLOZAPINE 
The genetic polymorphism can lead to reduced metabolism of clozapine. That can result in an elevated 
clozapine plasma concentration and thus to an increased risk of adverse effects.  
Recommendation:     
The literature does not provide an adequate basis on which to make a recommendation regarding dose 
reduction.  
- Adjust the dose on the basis of the plasma concentration of clozapine.    
The therapeutic range suggested for clozapine is 200-600 ng/ml.  
4652
 
HLA-B*5701: 
FLUCLOXACILLIN 
 
HLA-B*5701-positive patients are at 80 times greater risk of flucloxacillin-induced liver damage. The 
incidence is nevertheless low (1-2 cases per 1000 people).  
 
Recommendation:  
- Check the patient’s liver function regularly and select an alternative if liver enzymes and/or bilirubin 
increase. 
4754
 
CYP2B6 IM: EFAVIRENZ
 
 
The genetic variant can lead to reduced metabolism of efavirenz. This can result in an elevated efavirenz 
plasma concentration and thus to an increased risk of adverse effects. For the majority of the IM, 
however, the efavirenz plasma concentration remains within the therapeutic range. 
 
Recommendation:  
- If adverse effects occur, check the efavirenz plasma concentration and, if necessary, reduce the dose 
to 400 or 200 mg/day.     
The therapeutic range determined for efavirenz is 1000-4000 ng/ml. 
4755
 
CYP2B6 PM: EFAVIRENZ 
The genetic variant can lead to reduced metabolism of efavirenz. This can result in an elevated efavirenz 
plasma concentration and thus to an increased risk of adverse effects.  
 
Recommendation:  
* Efavirenz in MONO preparation form:  
*Body mass index NOT EXCEEDING 25: - Start with a dose of 400 mg/day and thereafter adjust the dose 
as necessary, on the basis of the plasma concentration (reduce further to 200 mg/day or, exceptionally, 
increase to 600 mg/day).     
The therapeutic range determined for efavirenz is 1000-4000 ng/ml.  
* Body Mass Index MORE THAN 25:  
- Start with a dose of 600 mg/day and thereafter adjust the dose as necessary, on the basis of the 
plasma concentration (reduce to 400 or 200 mg/day).     
The therapeutic range determined for efavirenz is 1000-4000 ng/ml. 
 
* Efavirenz in COMBINATION preparation form:  

 
 
 
 
 
 
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- Start with the combination preparation and thereafter adjust the efavirenz dose as necessary, on the 
basis of the plasma concentration (reduce to 400 or 200 mg/day).     
The therapeutic range determined for efavirenz is 1000-4000 ng/ml. 
  
Considerations:     
Excluding studies carried out in Africa, the median of the average plasma concentration for PM is above 
the therapeutic range. A recent study observed a virological response to efavirenz at 400 and 600 
mg/day that was similar to that observed in patients not selected on the basis of genotype. The risk of 
an underdose resulting from reduction of the starting dose to 400 mg/day is very small, therefore. 
Both administration in combination preparation form and the avoidance of unnecessary adverse effects 
associated with an excessive plasma concentration promote therapy adherence.     
With PM, it is not necessary to take account of the possible use of CYP2B6-inductors, such as rifampicin. 
Because CYP2B6’s metabolic capacity is greatly reduced or entirely lacking, induction is of little or no 
relevance. 
4891
 
DPD GENACT 0.5: 
TEGAFUR 
This genetic variant reduces the conversion of tegafur to inactive metabolites. That increases the risk of 
the normal dose leading to severe, potentially fatal toxicity.  
 
Recommendation:    
The literature does not provide an adequate basis on which to make a recommendation regarding dose 
reduction.  
- Select an alternative or start with a low dose and adjust the starting dose on the basis of toxicity and 
efficacy.    
Fluorouracil and capecitabine are not usable alternatives, as they are also metabolized by DPD. The 
literature does not provide an adequate basis on which to make a recommendation regarding dose 
adjustment. It is recommended that the starting doses of fluorouracil and capecitabine be reduced to 
25% of the normal dose.   
NB: This recommendation will only apply if the two genetic variants are located on different alleles. If 
both variants are located on the same allele, the patient will have a gene activity score of 1, and the 
recommendation associated with this score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 
4892
 
DPD GENACT 1.5: 
TEGAFUR 
This genetic variant reduces the conversion of tegafur to inactive metabolites. That increases the risk of 
the normal dose leading to severe, potentially fatal toxicity.  
 
Recommendation:  
- Select an alternative or start with a reduced dose and adjust the starting dose on the basis of toxicity 
and efficacy.   
Fluorouracil and capecitabine are not usable alternatives, as they are also metabolized by DPD.     
The literature does not provide an adequate basis on which to make a recommendation regarding dose 
adjustment. It is recommended that the starting doses of fluorouracil and capecitabine be reduced to 
75% of the normal dose. 
4893
 
DPD GENACT 0.5: 
FLUOROURACIL / 
CAPECITABINE 
The genetic variant affects DPD, leading to the reduced conversion of fluorouracil/capecitabine to 
inactive metabolites. This may cause intracellular concentrations of the active metabolite of 
fluorouracil/capecitabine to increase, leading to a greater risk of serious, potentially fatal, toxicity. 
 
Recommendation:  
- Reduce the starting dose to 25% of the normal dose or select an alternative.     
Base the adjustment of the starting dose on toxicity and efficacy. Tegafur is not an alternative, as this is 
also metabolized by DPD.    
NB: This recommendation will only apply if the two genetic variants are located on different alleles. If 
both variants are located on the same allele, the patient will have a gene activity score of 1, and the 
recommendation associated with this score should be followed. The only way to distinguish between 
these two situations is to measure the activity of the enzyme (phenotyping). 
4894
 
DPD GENACT 1.5: 
FLUOROURACIL / 
CAPECITABINE 
The genetic variant affects DPD, leading to the reduced conversion of fluorouracil/capecitabine to 
inactive metabolites. This may cause intracellular concentrations of the active metabolite of 
fluorouracil/capecitabine to increase, leading to a greater risk of serious, potentially fatal, toxicity. 
 
Recommendation:  
- Reduce the starting dose to 75% of the normal dose or select an alternative.    
 Base the adjustment of the starting dose on toxicity and efficacy. Tegafur is not an alternative, as this is 
also metabolized by DPD. 
6233 - CYP2C9 IM:  
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:     
 
1. use 65% of the standard initial dose 
 
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Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the 
reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed 
as if *1/*2 or *1/*3 is present. See 
https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica for Excel files containing 
calculation modules for oral and equivalent intravenous doses. From day 6 on the standard algorithm 
without genotype information can be used to calculate the dose. 
Modified dose algorithms have been developed for patients of African or (East) Asian heritage. 
6234 - CYP2C9 PM: 
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:     
 
1. use 20% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm. 
Algorithms for Caucasian patients usually contain only the *2 and *3 allele. If the activity of the 
reduced-activity alleles is comparable to the activity of *2 or *3, then the algorithm can be completed 
as if *2 or *3 is present. See https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica 
for Excel files containing calculation modules for oral and equivalent intravenous doses. From day 6 on 
the standard algorithm without genotype information can be used to calculate the dose. 
Modified dose algorithms have been developed for patients of African or (East) Asian heritage. 
6228 - CYP2C9*1/*2: 
WARFARIN 
NO action is required for this gene-drug interaction. 
  
Genetic variation may lead to a decrease in the required maintenance dose. However, there is 
insufficient evidence that this causes problems when therapy is initiated as usual. 
6229 - CYP2C9*1/*3: 
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:     
 
1. use 65% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used 
in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica  
From day 6 on the standard algorithm without genotype information can be used to calculate the dose. 
6230 - CYP2C9*2/*2: 
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:     
 
1. use 65% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used 
in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica 
From day 6 on the standard algorithm without genotype information can be used to calculate the dose. 
6231 - CYP2C9*2/*3:  
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:      
 
1. use 45% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used 
in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica. 
From day 6 on the standard algorithm without genotype information can be used to calculate the dose. 
6232 - CYP2C9*3/*3: 
WARFARIN 
This gene variation reduces the conversion of warfarin to inactive metabolites. This can increase the risk 
of bleeding. 
  
Recommendation:     
 
1. use 20% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used 
in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica 
From day 6 on the standard algorithm without genotype information can be used to calculate the dose. 
6235 – VKORC1 CT: 
WARFARIN 
NO action is required for this gene-drug interaction. 
  

 
 
 
 
 
 
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The genetic variation results in a reduction in the required dose and an increase in the risk of excessively 
severe inhibition of blood clotting during the first month of the treatment. However, the effect is small 
and CT is also the most common genotype, meaning that the standard treatment will primarily be based 
on patients with this genotype. 
6236 – VKORC1 TT: 
WARFARIN 
The genetic variation results in increased sensitivity to warfarin. This results in an increase in the risk of 
excessively severe inhibition of blood clotting (INR >4) during the first month of the treatment. 
  
Recommendation:     
 
1. use 60% of the standard initial dose 
  
The genotype-specific initial dose and maintenance dose can be calculated using an algorithm, as used 
in EU-PACT: see https://www.knmp.nl/patientenzorg/medicatiebewaking/farmacogenetica.    
From day 6 on the standard algorithm without genotype information can be used to calculate the dose. 
 
 

 
 
 
 
 
 
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18.4. Scientific Advisory Board 
 
Prominent clinicians and scientists representing key aspects of the U-PGX proposal have accepted to 
participate in the Scientific Advisory Board (SAB) of U-PGx. Project execution will be continuously 
advised and critically reflected by this strong advisory board. 
 
1. 
Mark J. Ratain, MD (Chair) 
Professor & Chairman of Center for Personalised Therapeutics, University of Chicago Medicine, 
Chicago, USA. Main expertise: Pharmacology 
2. 
Russ Altman, MD 
Kenneth Fong Professor and Professor of Bioengineering of Genetics, of Medicine (General Medical 
Discipline) and, by courtesy, of Computer Science, Stanford University at San Paulo, USA. Main 
expertise: Bioinformatics 
3. 
Dan Roden, MD 
Professor of Pharmacology, Assistant Vice Chancellor for Personalised Medicine, Professor of 
Medicine, William Stokes Chair in Experimental Therapeutics, Vanderbilt University, Nashville, USA. 
Main expertise: Pharmacology 
4. 
Michel Eichelbaum, MD 
Professor & former chair of the Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, 
Stuttgart/Germany, Professor and former chairman of Clinical Pharmacology at the University of 
Tübingen, Germany. Main expertise: Pharmacology/Pharmacogenetics 
5. 
David H.U. Haerry  
David Haerry is a patients’ advocate. He is co-chair of the Patient and Consumer Working Party of the 
European Medicines Agency (EMA).  
6. 
Mary Relling PharmD 
Scientist at St. Jude Children’s Research Hospital where she is a member of the St. Jude Faculty, chair 
of the Pharmaceutical Sciences Department and leader of the Clinical Pharmacogenetics 
Implementation Consortium (CPIC) Initiative. 
 
Tasks: The Scientific Advisory Board will ensure a high standard of research and monitor the progress 
of the project by taking part in the annual General Assembly Meetings. Whenever appropriate, the 

 
 
 
 
 
 
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consortium will consult the Advisory Board for recommendations to improve the performance of the 
consortium. 
 

 
 
 
 
 
 
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18.5. Organogram of U-PGx Consortium