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16 Methods to Detect, Predict, and Prevent Adverse Drug Reactions in Pharmacovigilance and Clinical…
379
(c) Drug-induced gene expression proles
This is a novel genomic prediction
technique that compares drug-induced
gene expression (DIGE) proles after
invitro incubation of a drug with a culture of tumor cells or primary cell line
with that of a normal condition. DIGE
proles can be obtained from three major
public sources: Gene Expression
Omnibus, Comparative Toxicogenomics
Database, and Connectivity Map.
(d) Phenotypic features from primary cell
cultures
The predened set of phenotypic features relevant to toxic pathways can be
used to predict ADR mechanisms. For
instance, in silico validated hybrid models were developed based on a set of 156
drug- induced liver injury (DILI)-positive
and 136 DILI-negative compounds
screening to predict hepatotoxicity [46].
5.2 Preventability and
Predictability of Adverse Drug
Reactions in Clinical Practice
In clinical practice, ADRs could be prevented by
ensuring rational medication use (the right
patient, the right drug, the right time, the right
dose, and the right route), evaluating for the risk
factors, availability of alternative safer options,
taking a thorough concomitant medication history and history of allergies, allergy testing,
deprescribing, giving preventive medications,
and likewise [47]. Inappropriate prescription is
considered asone of the most important risk factors for ADRs, especially in the elderly. It
includes a wide spectrum ranging from potentially inappropriate medications (PIMs) to potential prescribing omissions (PPOs). To tackle this,
the screening tool of older people’s prescriptions
(STOPP) and screening tool to alert to right treatment (START) criteria have been developed to
address PIMs and PPOs, respectively [48]. It is to
be noted that the STOPP/START criteria, when
applied as an intervention within 72h of hospital
admission, signicantly reduced ADRs (absolute
risk reduction = 9.3%; number needed to
treat = 11) and the average length of stay by
3 days in elderly who were admitted with any
acute illness [49]. Preventability of an ADR from
already reported individual ADR reports could
also be assessed using validated scales such as
the Schumock and Thornton preventability scale
[50].Details of the mentioned scale is provided
in Case 2 of the chapter.
Predictability, on the other hand, refers to
the ability to forecast the likelihood of occurrence of an ADR based on certain factors or
indicators. Type A ADRs are more predictable, and a good knowledge of the drug with a
good medical history elicited from the patient
would help predict ADRs better. Further, the
Council for International Organizations of
Medical Sciences (CIOMS) scale can also be
used to assess the frequency of ADRs and
help predict and categorize ADRs based on
their frequency of occurrence. The following
are the categories of CIOMS scale: (a) very
rare: < 1 in 10,000 patients, (b) rare: ≥1 in
10,000 to <1in 1000 patients, (c) uncommon:
≥1in 1000 to <1in 100 patients, (d) common:
≥1 in 100 to <1 in 10 patients, and (e) very
common: ≥ 1in 10 patients. The frequency of
ADRs is usually identified through clinical
trials, post-marketing surveillance, and other
pharmacovigilance methods described previously in this chapter. By using the CIOMS
scale for frequency of ADRs, healthcare professionals can better understand the likelihood and potential impact of ADRs associated
with a particular drug. However, the downside
is that the frequency of ADRs can vary
depending on the patient population, dose,
and duration of treatment, among many other
factors [51].
6 Seriousness andSeverity
ofAdverse Drug Reactions
As per the ICH, a serious adverse event (SAE) is
dened as “any untoward medical occurrence
that at any dose results in death; or is life threatening or requires inpatient hospitalisation or
380
J. P. Raj et al.
Table 16.1 Modied version of Hartwig et al.’s severity
assessment scale
Level Description
1 An ADR occurred but required no change in
treatment with the suspected drug
2 The ADR required that treatment with the
suspected drug be held, discontinued, or
otherwise changed. No antidote or other
treatment requirement was required. No
increase in length of stay (LOS)
3 The ADR required that treatment with the
suspected drug be held, discontinued, or
otherwise changed. AND/ORan antidote or
other treatment was required. NO increase in
LOS
4 (A) Any level 3 ADR which increases LOS
by at least 1 day
OR:
(B) The ADR was the reason for admission
5 Any level 4 ADR which requires intensive
medical care
6 The adverse reaction caused permanent harm
to the patient
7 The adverse reaction either directly or
indirectly led to the death of the patient
Mild = levels 1 and 2, moderate = levels 3 and 4, severe = 5,
6, and 7 as represented in the second table of Q 3 of Case 2.
Thus, not all SAEs are severe in grade. For instance, let us
consider a patient on a new drug who develops a rash, and
he/she gets admitted to the hospital for observation or
treatment for just 1day and gets discharged. This would
qualify as an SAE due to hospitalization but will not qualify as a severe grade SAE as ascertained by themodied
version of Hartwig et al.’s severity assessment scale. The
SAE will be considered as a moderate-grade ADR
prolongation of existing hospitalisation; or
results in persistent or signicant disability/
incapacity or is a congenital anomaly/birth
defect.” Severity, on the other hand, is graded
using the Hartwig et al. severity assessment scale
which categorizes ADRs into seven levels. The
modied version of the scale available in literature further combines these levels into three
grades of severity: mild, moderate, and severe.
Mild = Levels 1 and 2; Moderate = Levels 3 and
4; Severe = Levels 5, 6, and 7 [47] (Table16.1).
On a little different note, the “severity” of an
ADR also represents a measure of the “extent” to
which the adverse effect develops and the same
concept is discussed in Chap. 1.
7 Broad Principles Regarding
Management ofAdverse
Drug Reactions
Although the best way to manage ADRs is to prevent them from occurring, patients do suffer from
ADRs due to myriad reasons. The main aim of
ADR management is therefore to mitigate harm
to the patient through various strategies. These
include the following:
(a) Early detection: Close monitoring and increas-
ing the awareness of patients to watch out for
known ADRs would help identify ADRs early,
thereby prompting appropriate medical attention and preventing it from becoming severe.
(b) Documentation: Documentation of ADRs in
patient les and providing alert cards is critical for tracking and monitoring adverse events
and informing clinical decision-making.
(c) Treatment: Treating the presenting clinical
symptoms is key to keeping the patient comfortable and minimizing the impact on the patient’s
quality of life. This may involve providing an
antidote, providing supportive care, or using
other therapies to manage specic symptoms.
(d) Discontinuation or switching medications: In
some cases, ADRs may require discontinuation of the offending medication, reducing the
dose, or switching to an alternative therapy.
(e) Follow-up and monitoring: This is the nal step
in the management wherein patients who had
experienced an ADR are closely monitored
and followed up for any further symptoms or
complications that may require ongoing care
to manage/prevent any long- term effects or
complications associated with the ADR.
8 Summary andConclusions
While detecting ADRs is relatively easy, predicting and preventing them is more challenging.
Over the years, a lot of thrust has been given to
the prevention approaches and some of this has
found its way into patient care and mitigated and
minimized ADR burden. As the knowledge base
16 Methods to Detect, Predict, and Prevent Adverse Drug Reactions in Pharmacovigilance and Clinical…
381
evolves, it is hoped that as more and more predictive and preventative tools become available that
are not too expensive, the clinician will be able to
deliver better quality patient care. This will be
particularly impactful for developing countries.
9 Case Studies
9.1 Case Study 1
A 79-year-old male patient who is a known case
of cerebral amyloid angiopathy developed headache and seizures. He was diagnosed to have subarachnoid hemorrhage. He was started on Tab.
Phenytoin 100mg twice daily. However, he had
an episode of seizure 2weeks later, and hence the
evening dose of phenytoin was increased to
150mg. He continued to have seizures and within
2days of the dose hike, he developed altered sensorium and was admitted to the hospital. At
admission, his plasma phenytoin level was
30.8 μg/ml (normal range: 10–20 μg/ml).
Pharmacogenetic testing for CYP2C9 polymorphism revealed a diplotype of *2/*3. Tab.
Phenytoin was thus replaced with Tab. Clobazam
10mg twice daily and the plasma phenytoin levels normalized within 4days and the patient was
relieved of his symptoms.
1. What is the interpretation of the pharmacoge-
netic test in this patient?
*3 is a no function allele and *2 is a
decreased function allele. Therefore, this
patient’s phenotype may be considered as
poor metabolizer [49].
2. Name the other pharmacogenetic test that is
recommended to be done along with
CYP2C9 in patients prescribed with
phenytoin.
HLA-B *15:02
3. Describe the clinical application of these
pharmacogenetic tests while prescribing
phenytoin.
The following are excerpts from the Clinical
Pharmacogenetics Implementation Consortium
(CPIC) guidelines for phenytoin [49].
(a) Assignment of HLA-B phenotypes based
on genotypes
HLA
phenotype Genotype
HLAB*15:02
negative
HLAB*15:02
positive
Homozygous for
an allele other
than
HLA-B*15:02
Heterozygous or
homozygous
variant
Examples of
diplotypes
*X/*X
Where *X=any
HLA-B allele other
than HLA-B*15:02
*15:02/*X,
*15:02/*15:02
Where *X=any
HLA-B allele other
than HLA-B*15:02
(b) Assignment of CYP2C9 phenotypes
based on genotypes
Examples
CYP2C9
phenotype
Normal
metabolizer
Intermediate
metabolizer
Poor
metabolizer
Activity
score Genotypes
2 An individual
carrying two
normal function
alleles
1.5 An individual
carrying one
normal function
allele and one
decreased
function allele
OR
1 One normal
function allele
plus one no
function allele
OR two
decreased
function alleles
0.5 An individual
carrying one no
function allele
and one
decreased
function allele
OR
0 Two no function
alleles
of
diplotypes
*1/*1
*1/*2
*1/*3,
*2/*2
*2/*3
*3/*3
382
(c) Algorithm for phenytoin prescription
HLA –B* 15:02 Genotype
J. P. Raj et al.
HLA –B* 15:02 Positive
If patient is Phenytoin-
,
navie do not use
Phenytoin
CYP2C9 NM and IM AS 1.5
No adjustment for typical
dosing strategies. Subsequent
doses to be adjusted as per
TDM, response, and adverse
effects.
HLA –B* 15:02 Negative
CYPC2C9 genotype
CYP2C9 IM AS 1.0
Typical initialor loading
dose to be used followed
subsequently by 25% less
dose of a typical
maintenance dose.
Subsequent doses to be
adjusted as per TDM,
response, and adverse
effects.
CYP2C9 PM
Typical initial or
loading dose to be used
followed subsequently
by 50% less dose of a
typical maintenance
dose. Subsequent doses
to be adjusted as per
TDM, response, and
adverse effects.
HLA human leukocyte antigen, NM normal metabolizer, IM intermediate metabolizer, PM poor
metabolizer, AS activity score, TDM therapeutic drug monitoring
9.2 Case Study 2
A 54-year-old male patient who is a known person living with HIV infection was started on antiretroviral treatment (ART) regimen containing
tenofovir, lamivudine, atazanavir, and ritonavir.
Within 6months of starting the ART, the patient
developed pufness of the face and pitting pedal
edema during his routine follow- up. There was
no change in the ART regimen recommended
then, and in the subsequent 1month, he was diagnosed to have high blood pressure and severe pitting pedal edema, new onset pleural effusion
requiring intensive care unit admission.
1. Identify the ADR and name the drug that is
likely to have caused this. What is the possible
mechanism of this ADR?
Tenofovir-induced nephrotoxicity [56].
The major pathway of renal elimination of
tenofovir is glomerular ltration. However,
approximately 20–30% gets eliminated by
tubular secretion through the human organic
anion transporter-1 (hOAT-1) transporter. But
cellular accumulation through increased entry
from the OAT and decreased efux into tubular lumen results in cytotoxicity secondary to
mitochondrial dysfunction of the proximal
tubular cells [56].
16 Methods to Detect, Predict, and Prevent Adverse Drug Reactions in Pharmacovigilance and Clinical…
383
2. Name the other drugs that interfere with the
renal tubular function similar to the offending drug?
Drug
Transporter
hOAT-1 Probenecid
MRP-4 NSAIDs and
MRP-2 Ritonavir gets
hOAT-1 human organic anion transporter- 1,MRP multidrug resistance protein
interaction Effect [56]
Probenecid may
inhibits
hOAT- 1
acyclovir and
didanosine
compete with
tenofovir
acyclovir group
of drugs inhibit
MRP-4
transported by
MRP-2
decrease the incidence
of nephrotoxicity by
tenofovir.
Acyclovir increases
serum tenofovir
concentrations, while
tenofovir increases
didanosine
concentrations
Increased risk of
tenofovir associated
nephrotoxicity
Ritonavir increases
tenofovir concentration
and thereby increases
the risk of
nephrotoxicity
3. Could this ADR have been prevented? Assess
using the Schumock and Thornton criteria and
also grade the severity using themodied version
of Hartwig et al.’s severity assessment scale.
Preventable ADR of severe grade.There is
a reported interaction between tenofovir and
ritonavir which increases the risk of nephrotoxicity with tenofovir.
Schumock and Thornton
Sr. no.
criteria [54] Ye s No
1. Was the drug involved in the
ADR not considered
appropriate for the patient’s
clinical condition?
2. Was the dose, route, and
frequency of administration
not appropriate for the
patient’s age, weight and
disease state?
Schumock and Thornton
Sr. no.
criteria [54] Ye s No
3. Was therapeutic drug
monitoring or other
necessary laboratory test not
performed?
4. Was there a history of allergy
or previous reactions to the
drug?
5. Was a drug interaction
involved in the reaction?
6. Was a toxic serum drug level
documented?
7. Was poor compliance
involved in the reaction?
Answering “yes” to one or more of the above questions
suggests that the ADR in question may indeed have been
preventable
Modied version of Hartwig et al.’s
Level
severity assessment scale
1 An ADR occurred but required no
change in treatment with the
suspected drug
2 The ADR required that treatment
with the suspected drug be held,
discontinued, or otherwise changed.
No antidote or other treatment
requirement was required. No
increase in length of stay (LOS)
3 The ADR required that treatment
with the suspected drug be held,
discontinued, or otherwise changed.
AND/OR An Antidote or other
treatment was required. NO increase
in LOS
4 (A) Any level 3 ADR which
increases LOS by at least 1 day
OR:
(B) The ADR was the reason for
admission
5 Any level 4 ADR which requires
intensive medical care
6 The adverse reaction caused
permanent harm to the patient
7 The adverse reaction either directly
or indirectly led to the death of the
patient
Mild = levels 1 and 2, moderate = levels 3 and 4,
severe=5, 6, and 7
✓
Choose
the right
level
✓
384
J. P. Raj et al.
Acknowledgments Both the case studies were reported
to an ADR monitoring center (AMC), West Zone, established under the aegis of the Pharmacovigilance Program
of India and were also discussed in the monthly causality
assessment meeting held at this AMC.
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Information Sources forDrug
Safety andCommunicating Risks
inPractice
VivienTong, MathiasMøllebæk, andParisaAslani
17
Abstract
Drug safety is an important goal of clinical
practice, where healthcare professionals must
balance the benets versus harms of medication use to optimize treatment outcomes. To
facilitate this decision-making process and
subsequent communication of drug safety
issues to patients and their families, identifying
and utilizing appropriate health and medicines
information sources are critical. Drug safetyrelated information can be obtained from
numerous sources, including government/regulatory bodies, non-government sources such
as drug sponsors and other academic, commercial, and patient/healthcare professional organizations. These sources contribute toward the
publication of different information types,
including research studies, product information, clinical guidelines, safety advisories, and
patient information leaets, intended for
healthcare professionals and/or patients/consumers. Healthcare professionals should
V. Tong (*) · P. Aslani
The University of Sydney School of Pharmacy,
Faculty of Medicine and Health, The University of
Sydney, Camperdown, NSW, Australia
e-mail: vivien.tong@sydney.edu.au
M. Møllebæk
Copenhagen Centre for Regulatory Science,
Department of Pharmacy, University of Copenhagen,
Copenhagen, Denmark
source high-quality drug safety information.
Assessing risk of bias, currency of information, and the reliability and trustworthiness of
information are practical ways to help evaluate
information quality. Harms and benets information is important for safe and effective use
of medicines by patients. They can be
expressed in several ways, and risk information should be carefully appraised, considering
the context in which the data were derived and
communicated, when applying it in clinical
practice and communicating to patients.
Keywords
Drug information · Drug safety · Patient
information · Safety advisories · Risk of bias ·
Trustworthiness of information · Side effect
risk · Risk communication · Medication
harms · Medication benets · Information
sources
Learning Objectives
• Describe the range of sources that are avail-
able through which healthcare professionals
can obtain accurate and up-to-date information about the safety of medicines
• Identify the approaches and methods used to
assess the quality, bias, accuracy, and reliability of drug safety-related information across
the range of information sources
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_17
387
388
V. Tong et al.
• Describe the types of risk of harms and benets information that are available for medicines,
and varioussources of suchinformation
• Utilize the sourced information on risk of
harms and benets to communicate to healthcare professionals and patients/the public
Key Points
• Drug safety-related information can be
obtained from numerous sources,
including government/regulatory bodies, non- government sources such as
drug sponsors and other academic, commercial, and patient/healthcare professional (HCP) organizations
• These sources contribute toward the
publication of different information
types, including research studies, product information, clinical guidelines,
safety advisories, and patient information leaets, intended for HCPs and/or
patients/consumers
• High-quality drug safety information
should be sourced by HCPs for use.
Assessing for risk of bias, recency of
information, and the reliability and
trustworthiness of information are practical ways to help evaluate information
quality
• Harms and benets information can be
expressed in several ways via framing of
information and the use of qualiers
versus numbers. Numerical risk information should be carefully appraised,
considering the context in which the
data was derived and how it has been
communicated, when applying it in clinical practice
1 Introduction
must balance the benets versus harms of medication use to optimize treatment outcomes. To
facilitate this decision-making process and subsequent communication of drug safety issues to
patients and their families, identifying and utilizing appropriate health and medicines information
sources are critical.
The overall goals of the chapter are to:
• Provide abroad outlookon the range of information sources that are available to clinicians,
pharmacists, and other HCPs on medicines
and, specically, on the safety aspects of
medicines
• Outline practical approaches to assess the
quality and reliability of information sources
on risk of harms and benets
• Demonstrate how information on risk of
harms and benets obtained from the sources
can be best utilized for communicating to
other HCPs and patients/the public
2 Sources ofDrug Safety-
Related Information
Drug safety information can be communicated
via several means, including spoken, written,
multimedia, and other hybrid communication
formats. HCPs should be aware of the breadth
of information sources that are available that
tailor information intended for their use, as
well as common information sources that
patients or consumers are exposed to. From a
safety perspective, optimal drug safety information can support medication literacy for
both HCPs and consumers, as well as drug
safety. Medication literacy can be dened as:
The degree to which individuals can obtain, comprehend, communicate, calculate and process
patient-specic information about their medications to make informed medication and health decisions in order to safely and effectively use their
medications, regardless of the mode by which the
content is delivered (e.g. written, oral and visual).
(p.801) [1]
Drug safety is an important goal of clinical practice, where healthcare professionals (HCPs) who
prescribe and/or oversee the use of medicines
Effective understanding of drug safety-related
information underpins effective communication
within multidisciplinary healthcare teams about
17 Information Sources forDrug Safety andCommunicating Risks inPractice
389
drug safety. Broadly, from a user perspective,
information sources can be consumer-focused or
targeted toward HCPs. HCPs can acquire information about drugs and drug safety from a wide range
of sources which may differ in multiple ways with
respect to their content and communication style.
The information may be communicated with different intended uses; that is, clinical treatment
guidelines, news bulletins, or safety advisories.
Due consideration should also be given to the provider of the information. For example, organizations that provide information may have nancial
or other interests in the drugs they inform about, or
the provision of information may be a result of
regulatory requirement or may be integrated in an
electronic system or software, such as prescribing
and dispensing software and processes. The following sections go into more detail about potential
information sources relevant to drug safety.
2.1 Government andRegulatory
Agencies
Government agencies and public bodies, such as
drug regulators or health technology assessment
(HTA) bodies (e.g., the National Institute for
Health and Care Excellence (NICE), Finnish
Coordinating Center for Health Technology
Assessment (FinCCHTA)), provide information
about drugs and drug safety as part of their remit
to protect public health and individual consumers
from harm. Importantly, regulators and HTA
bodies have different functions in the regulation
and assessment of drugs, and the information
they provide may differ accordingly. Whereas
HTA bodies provide recommendations on the
value of new health technologies in the context of
existing therapeutic options and healthcare provision more generally, regulators are mandated to
ensure the safety, efcacy, and quality of health
products upon market entry and monitor them
after marketing. While recommendations by
HTA bodies include the harms and benets of
drugs, they typically do not aim to provide a
comprehensive picture of potential safety issues
in clinical practice to the same extent as information from regulators.
Regulators oversee the information provided
by medicine sponsors and available pharmacovigilance data and issue postapproval safety advisories if new safety concerns have emerged and
need to be communicated to HCPs and/or the
public, as appropriate. Regulatory safety advisories may come in the form of information letters
to HCPs, drug safety bulletins, media alerts, and
public website announcements, with different
examples available from regulatory bodies [2].
HTA bodies may include emergent safety concerns in their guidelines, although the degree of
coordination and harmonization between information material from regulatory authorities and
HTA bodies is currently unknown. The adverse
event reporting databases in some countries may
also be accessible by users to see the reporting
that has been received for medicines. Examples
include:
• United States of America: Food and Drug
Administration (FDA) Adverse Event
Reporting System (FAERS) Public Dashboard
[3]
• European Union: EudraVigilance—European
database of suspected adverse drug reaction
reports [4]
• Australia: Database of Adverse Event
Notications (DAEN) for medicines and med-
ical devices [5]
2.2 Professional Organizations
Professional organizations have considerable
inuence in the provision of drug information to
HCPs. Professional organizations typically produce publicly available medical information for
their membership, which may include different
types of healthcare professionals (e.g., physicians, pharmacists, nurses) at varying levels of
speciality (e.g., endocrinologists, diabetes education nurses, diabetes educators). Drug safety
information may be delivered as part of continuing professional development activities spearheaded by the organizations such as
presentations, articles, newsletters, and online
publications, to name a few. Notably, as HCP
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