Side effects of drugs annual volume 38

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Contributors

Alexander Accinelli School of Pharmacy and Health
Professions, University of Maryland at Eastern Shore,
Princess Anne, MD, USA

Teresa DeLellis Department of Pharmacy Practice, College of
Pharmacy, Natural and Health Sciences, Manchester
University, Fort Wayne, IN, USA

Asima N. Ali Campbell University CPHS, Buies Creek; Wake
Forest Baptist Health—Internal Medicine OPD Clinic,
Winston-Salem, NC, USA

Rahul Deshmukh Department of Pharmaceutical Sciences,
College of Pharmacy, Rosalind Franklin University of
Medicine and Science, North Chicago, Il, USA

Laura J. Baumgartner Department of Clinical Sciences, Touro
University California College of Pharmacy, Vallejo, CA, USA

Sujana Dontukurthy
NY, USA

Robert D. Beckett Manchester University College of
Pharmacy, Natural, and Health Sciences, Fort Wayne, IN,
USA

Kirk Evoy College of Pharmacy, The University of Texas at
Austin, Austin; School of Medicine, University of Texas
Health Science Center San Antonio, Pharmacotherapy
Education and Research Center, San Antonio, TX, USA

Renee A. Bellanger Department of Pharmacy Practice,
University of the Incarnate Word, Feik School of Pharmacy,
San Antonio, TX, USA

New York Methodist Hospital, Brooklyn,

Jingyang Fan Department of Pharmacy Practice, SIUE School
of Pharmacy, Edwardsville, IL, USA

Nicholas T. Bello Department of Animal Sciences, School of
Environmental and Biological Sciences, Rutgers, The State
University of New Jersey, New Brunswick, NJ, USA

Elizabeth Flockton Royal Liverpool Hospital, Liverpool,
United Kingdom
Cynthia E. Franklin Department of Pharmaceutical Sciences,
University of the Incarnate Word, Feik School of Pharmacy,
San Antonio, TX, USA

Skye Bickett Medical Librarian. Assistant Director of Library
Services, PCOM, Suwanee, GA, USA

Lynn Frendak Department of Pharmacy, Johns Hopkins
Bayview Medical Center, Baltimore, MD, USA

Adrienne T. Black 3E Company, Warrenton, VA, USA
Alison Brophy Ernest Mario School of Pharmacy, Rutgers, The
State University of New Jersey, Piscataway; Saint Barnabas
Medical Center, Livingston, NJ, USA

Jason C. Gallagher

Temple University, Philadelphia, PA, USA

Nidhi Gandhi Department of Pharmacy Practice, PCOM
School of Pharmacy, Suwanee, GA, USA

Maria Cardinale Ernest Mario School of Pharmacy, Rutgers,
The State University of New Jersey, Piscataway; Saint Peter’s
University Hospital, New Brunswick, NJ, USA

Tatsuya Gomi Department of Radiology, Ohashi Medical
Center, Toho University, Tokyo, Japan

Saira B. Chaudhry Ernest Mario School of Pharmacy, RutgersThe State University of New Jersey, Piscataway, NJ, USA

Joshua P. Gray Department of Science, United States Coast
Guard Academy, New London, CT, USA

James Chue Clinical Trials and Research Program, Edmonton,
AB, Canada

Andrew L. Griffiths Asthma & Allergy Group, Swansea
University Medical School, Institute of Life Science 1,

Swansea University, Swansea, United Kingdom

Pierre Chue University of Alberta, Edmonton, AB, Canada
Karyn I. Cotta Department of Pharmaceutical Sciences, South
University School of Pharmacy, Savannah, GA, USA

Kristopher G. Hall Department of Pharmaceutical Sciences,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA

Bryony Coupe Asthma & Allergy Group, Swansea University
Medical School, Institute of Life Science 1, Swansea
University, Swansea, United Kingdom

Makoto Hasegawa Department of Radiology, Ohashi Medical
Center, Toho University, Tokyo, Japan

Kendra M. Damer Butler University College of Pharmacy and
Health Sciences, Indianapolis, IN, USA

Christopher S. Holaway Department of Pharmacy Practice,
PCOM School of Pharmacy, Suwanee, GA, USA

Gwyneth A. Davies Asthma & Allergy Group, Swansea
University Medical School, Institute of Life Science 1,
Swansea University, Swansea, United Kingdom

Sandra L. Hrometz Department of Pharmaceutical Sciences,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA

v


vi

CONTRIBUTORS

I-Kuan Hsu Department of Clinical Sciences, Touro
University California College of Pharmacy, Vallejo, CA, USA

Cassandra Maynard Department of Pharmacy Practice, SIUE
School of Pharmacy, Edwardsville, IL, USA

Eric J. Ip Department of Clinical Sciences, Touro University
California College of Pharmacy, Vallejo, CA, USA

Renee McCafferty Department of Pharmacy Practice,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA

Jason Isch PGY2 Ambulatory Care, Saint Joseph Health
System, Mishawaka, IN, USA
Abhishek Jha Royal Liverpool Hospital, Liverpool,
United Kingdom

Dayna S. McManus Department of Pharmacy Services, YaleNew Haven Hospital, Yale University, New Haven, CT, USA

Carrie M. Jung Butler University College of Pharmacy and
Health Sciences; Eskenazi Health, Indianapolis, IN, USA

Calvin J. Meaney Department of Pharmacy Practice, School of
Pharmacy and Pharmaceutical Sciences, State University of
New York at Buffalo, Buffalo, NY, USA

Allison Kalstein
USA

Philip B. Mitchell School of Psychiatry, University of New
South Wales; Black Dog Institute, Sydney, NSW, Australia

New York Methodist Hospital, Brooklyn, NY,

Spinel Karas Department of Pharmacy Practice, School of
Pharmacy and Pharmaceutical Sciences, State University of
New York at Buffalo, Buffalo, NY, USA
Sipan Keshishyan Department of Pharmacy Practice,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA
Madan K. Kharel School of Pharmacy and Health Professions,
University of Maryland at Eastern Shore, Princess Anne, MD,
USA
Nicole Kiehle Department of Pharmacy, Johns Hopkins
Bayview Medical Center, Baltimore, MD, USA
Vladlena Kovalevskaya Department of Pharmaceutical
Sciences, Manchester University College of Pharmacy,
Natural and Health Sciences, Fort Wayne, IN, USA
Justin G. Kullgren Department of Pharmacy, The Ohio State
University Wexner Medical Center, Columbus, OH, USA
Dirk W. Lachenmeier Chemisches und

Veterin€aruntersuchungsamt (CVUA) Karlsruhe, Karlsruhe,
Germany
Bonnie Lau Department of Clinical Sciences, Touro University
California College of Pharmacy, Vallejo; Department of
Emergency Medicine, Kaiser Permanente Santa Clara
Medical Center, Santa Clara; Department of Emergency
Medicine, Stanford University School of Medicine, Palo Alto,
CA, USA
Tina C. Lee University of the Incarnate Word Feik School of
Pharmacy, San Antonio, TX, USA
Linda Lim College of Pharmacy, The University of Texas at
Austin, Austin; School of Medicine, University of Texas
Health Science Center San Antonio, Pharmacotherapy
Education and Research Center, San Antonio, TX, USA
Tristan Lindfelt Department of Clinical Sciences, Touro
University California College of Pharmacy, Vallejo,
CA, USA
Mei T. Liu

Jersey City Medical Center, Jersey City, NJ, USA

Megan E. Maroney Rutgers University Ernest Mario School of
Pharmacy, Piscataway, NJ, USA
Ashley Martinelli Department of Pharmacy, Johns Hopkins
Bayview Medical Center, Baltimore, MD, USA
Mark Martinez Department of Pharmacy Practice, PCOM
School of Pharmacy, Suwanee, GA, USA
Dianne May University of Georgia College of Pharmacy on
Augusta University Campus, Augusta, GA, USA

Vicky V. Mody Department of Pharmaceutical Sciences,
PCOM School of Pharmacy, Suwanee, GA, USA
Kaitlin Montagano Department of Pharmaceutical Sciences,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA
Toshio Nakaki Department of Pharmacology, Teikyo
University School of Medicine, Tokyo, Japan
Anjan Nan Department of Pharmaceutical Sciences,
University of Maryland Eastern Shore School of Pharmacy,
Princess Anne, MD, USA
Diane Nguyen Department of Pediatrics, Baylor College of
Medicine, Houston, TX, USA
John D. Noti Allergy and Clinical Immunology Branch,
Health Effects Laboratory Division, National Institute for
Occupational Safety and Health, Centers for Disease Control
and Prevention, Morgantown, WV, USA
Igho J. Onakpoya Nuffield Department of Primary Care
Health Sciences, Oxford, United Kingdom
Michael G. O’Neil Department of Pharmacy Practice, Drug
Diversion, Pain Management and Substance Abuse Specialist,
South College School of Pharmacy, Knoxville, TN, USA
Yekaterina Opsha Ernest Mario School of Pharmacy, Rutgers,
The State University of New Jersey, Piscataway; Saint
Barnabas Medical Center, Livingston, NJ, USA
Sreekumar Othumpangat Allergy and Clinical Immunology
Branch, Health Effects Laboratory Division, National
Institute for Occupational Safety and Health, Centers for
Disease Control and Prevention, Morgantown, WV, USA
Harish Parihar Department of Pharmacy Practice, PCOM
School of Pharmacy, Suwanee, GA, USA

Deepa Patel Department of Pharmacy Practice, PCOM School
of Pharmacy, Suwanee, GA, USA
Punam B. Patel Department of Clinical Sciences, Touro
University California College of Pharmacy, Vallejo, CA, USA
Michelle M. Peahota Infectious Diseases, Thomas Jefferson
University Hospital, Philadelphia, PA, USA
Alan Polnariev College of Pharmacy, University of Florida,
Gainesville, FL, USA
Hanna Raber College of Pharmacy, The University of Utah,
Salt Lake City, UT, USA
Sushma Ramsinghani Department of Pharmaceutical Sciences,
University of the Incarnate Word, Feik School of Pharmacy,
San Antonio, TX, USA


vii

CONTRIBUTORS

Sidhartha D. Ray Department of Pharmaceutical Sciences,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA
David Reeves Department of Pharmacy Practice, College of
Pharmacy and Health Sciences, Butler University;
Department of Pharmacy, St. Vincent Indianapolis Hospital,
Indianapolis, IN, USA

Jonathan Smithson School of Psychiatry, University of New
South Wales; Black Dog Institute, Sydney, NSW, Australia
Brian Spoelhof Department of Pharmacy, Johns Hopkins

Bayview Medical Center, Baltimore, MD, USA
Lisa V. Stottlemyer Wilmington VA Medical Center,
Wilmington, DE; Pennsylvania College of Optometry, Elkins
Park, PA, USA

Lucia Rivera Lara Departments of Neurology,
Anesthesiology, and Critical Care Medicine, Johns Hopkins
Medicine, Baltimore, MD, USA

Kalee Swanson Department of Pharmaceutical Sciences,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA

Nicholas Robinson Manchester University College of
Pharmacy, Natural, and Health Sciences, Fort Wayne, IN,
USA

Fred R. Tejada School of Pharmacy and Health Professions,
University of Maryland at Eastern Shore, Princess Anne, MD,
USA

Lauren K. Roller Department of Clinical Sciences, Touro
University California College of Pharmacy, Vallejo,
CA, USA

Kelan L. Thomas Touro University California College of
Pharmacy, Vallejo, CA, USA

Lucia Rose Infectious Diseases, Cooper University Hospital,
Camden, NJ, USA

Sonia Thomas Department of Pharmacy Practice, PCOM
School of Pharmacy, Suwanee, GA, USA

Audrey Rosene Manchester University College of Pharmacy,
Natural, and Health Sciences, Fort Wayne, IN, USA

Sara N. Trovinger Department of Pharmacy Practice,
Manchester University College of Pharmacy, Natural and
Health Sciences, Fort Wayne, IN, USA

Christina Seeger University of the Incarnate Word, Feik
School of Pharmacy, San Antonio, TX, USA

Kirby Welston AU Medical Center/University of Georgia
College of Pharmacy, Augusta, GA, USA

Mona U. Shah Department of Pharmacy, Falls Church, VA,
USA

Andrea L. Wilhite Manchester University College of Pharmacy,
Natural, and Health Sciences, Fort Wayne, IN, USA

Ajay N. Singh Department of Pharmaceutical Sciences, South
University School of Pharmacy, Savannah, GA, USA

Zhiqian Wu Department of Pharmaceutical Sciences, PCOM
School of Pharmacy, Suwanee, GA, USA

Michel R. Smith School of Pharmacy and Health Professions,

University of Maryland at Eastern Shore, Princess Anne, MD,
USA

Joel Yarmush
USA

Thomas Smith Manchester University College of Pharmacy,
Fort Wayne, IN, USA

New York Methodist Hospital, Brooklyn, NY,

Matthew R. Zahner Drug Safety and Research Development,
Pfizer, Groton, CT, USA


Preface
Side Effects of Drugs: Annual (SEDA) is a yearly publication focused on existing, new and evolving side effects
of drugs encountered by a broad range of healthcare professionals including physicians, pharmacists, nurse practitioners, and advisors of poison control centers. This 37th
edition of SEDA includes analyses of the side effects of
drugs using both clinical trials and case-based principles
which include encounters identified during bedside clinical practice over the 18 months since the previous edition. SEDA seeks to summarize the entire body of
relevant medical literature into a single volume with dual
goals of being comprehensive and of identifying emerging trends and themes in medicine as related to side
effects and adverse drug effects (ADEs).
With a broad range of topics authored by practicing
clinicians and scientists, SEDA is a comprehensive and
reliable reference to be used in clinical practice. The
majority of the chapters include relevant case studies that
are not only peer-reviewed but also have a forwardlooking, learning-based focus suitable for practitioners
as well as students in training. The nationally known contributors believe this educational resource can be used to

stimulate an active learning environment in a variety of
settings. Each chapter in this volume has been reviewed
by the editor, experienced clinical educators, actively
practicing clinicians and scientists to ensure the accuracy
and timeliness of the information. The overall objective is
to provide a framework for further understanding the
intellectual approaches in analyzing the implications of
the case studies and their appropriateness when dispensing medications, as well as interpreting adverse drug
reactions (ADRs), toxicity and outcomes resulting from
medication errors.
This issue of SEDA is the first to include perspectives
from pharmacogenomics/pharmacogenetics and personalized medicine. Due to the advances in science, the
genetic profiles of patients must be considered in the etiology of side effects, especially for medications provided
to very large populations. This marks the first phase of
genome-based personalized medicine, in which side
effects of common medications are linked to polymorphisms in one or more genes. A focus on personalized
medicine should lead to major advances for patient care

and awareness among clinicians to deliver the most
effective medication for the patient. This modality should
considerably improve ‘appropriate medication use’ and
enable the clinicians to pre-determine “good versus the
bad responders”, and help reduce ADRs. Overall, clinicians will have a better control on ‘predictability and preventability’ of ADEs induced by certain medications.
Over time, it is anticipated that pharmacogenetics and
personalized medicine will become an integral part of
the practice sciences. SEDA will continue to highlight
the genetic basis of side effects in future editions.
The collective wisdom, expertise and experience of the
editor, authors and reviewers were vital in the creation of
a volume of this breadth. Reviewing the appropriateness,

timeliness and organization of this edition consumed an
enormous amount of energy by the authors, reviewers
and the editor, which we hope will facilitate the flow of
information inter-professionally among health practitioners, professionals in training, and students, and will
ultimately improve patient care. Scanning for accuracy,
rebuilding and reorganizing information between each
edition is not an easy task; therefore, the editor had the
difficult task of accepting or rejecting information. The
editor will consider this undertaking worthwhile if this
publication helps to provide better patient care; fulfills
the needs of the healthcare professionals in sorting out
side effects of medications, medication errors or adverse
drug reactions; and stimulates interest among those
working and studying medicine, pharmacy, nursing,
physical therapy, chiropractic, and those working in the
basic therapeutic arms of pharmacology, toxicology,
medicinal chemistry and pathophysiology.
Editor of this volume gratefully acknowledge the leadership provided by the former editor Prof. J.K. Aronson,
all the contributors and reviewers, and will continue to
maintain the legacy of this publication by building on
their hard work. The editor would also like to extend special thanks for the excellent support and assistance provided by Ms. Zoe Kruze (Publisher, serials and series)
and Ms. Shellie Bryant (Editorial Project Manager) during
the compilation of this work.
Sidhartha D. Ray
Editor

xvii


Special Reviews in SEDA 38

1. Chapter 3 – Lithium
Susceptibility Factors
2. Chapter 8 – Anti-Inflammatory and Antipyretic Analgesics and Drugs Used in Gout
Special Review – New Drug Approval: Lesinurad
3. Chapter 11 – Neuromuscular Blocking Agents and Skeletal Muscle Relaxants
Neuromuscular Blockers: Reversal Agents
4. Chapter 12 – Drugs That Affect Autonomic Functions or the Extrapyramidal System
Dopamine Receptor Agonists
• Piribedil and impulse control disorders
5. Chapter 14 – Antihistamines (H1 Receptor Antagonists)
Special Review – RX: Pharmacogenetics
• Rupatadine & other antihistamines

26
83
108
119

144

6. Chapter 15 – Drugs That Act on the Respiratory Tract
Olodaterol
Monoclonal Antibodies in the Treatment of Asthma
7. Chapter 25 – Antifungal Drugs
Special Review – Drug–Drug Interactions and Pharmacogenomics of the Azoles
Antifungal

157,161

8. Chapter 33 – Drugs that Affect Blood Coagulation, Fibrinolysis and Hemostasis

Special Review – Idarucizumab

375

9. Chapter 34 – Gastrointestinal Drugs
Proton-Pump Inhibitors (PPIs)
10. Chapter 36 – Drugs That Act on the Immune System: Immunosuppressive
and Immunostimulatory Drugs
Special Review – Association of Genetic Factors and Adverse Effects of Thiopurines
11. Chapter 43 – Cytostatic Agents—Tyrosine Kinase Inhibitors Utilized in the Treatment
of Solid Malignancies
Special Review – Skin
12. Chapter 44 – Radiological Contrast Agents and Radiopharmaceuticals
Special Review – B-Raf Inhibitors
• Vemurafenib and Dabrafenib
13. Chapter 45 – Drugs Used in Ocular Treatment
Special Review on Pharmacogenetics
• Gadolinium accumulation

xix

249

379

418

487
498

509


Table of Essays, Annuals 1–37
SEDA

Author

Country

Title

1

M.N.G Dukes

The Netherlands

The moments of truth

2

K.H. Kimbel

Germany

Drug monitoring: why care?

3

L. Lasagna

USA

Wanted and unwanted drug effects: The need for perspective

4

M.N.G. Dukes

The Netherlands

The van der Kroef syndrome

5

J.P. Griffin, P.F. D’Arcy

UK

Adverse reactions to drugs—the information lag

6

I. Bayer

Hungary

Science vs practice and/or practice vs science

7

E. Napke

Canada

Adverse reactions: some pitfalls and postulates

8

M.N.G. Dukes

Denmark

The seven pillars of foolishness

9

W.H.W. Inman

UK

Let’s get our act together

10

S. Van Hauen

Denmark

Integrated medicine, safer medicine and “AIDS”

11

M.N.G. Dukes

Denmark

Hark, hark, the fictitious dogs do bark

12

M.C. Cone

Switzerland

Both sides of the fence

13

C. Medawar

UK

On our side of the fence

14

M.N.G. Dukes, E. Helsing

Denmark

The great cholesterol carousel

15

P. Tyrer

UK

The nocebo effect—poorly known but getting stronger

16

M.N.G. Dukes

Denmark

Good enough for Iganga?

17

M.N.G. Dukes

Denmark

The mists of tomorrow

18

R.D. Mann

UK

Databases, privacy, and confidentiality—the effect of proposed legislation on
pharmacoepidemiology and drug safety monitoring

19

A. Herxheimer

UK

Side effects: Freedom of information and the communication of doubt

20

E. Ernst

UK

Complementary/alternative medicine: What should we do about it?

21

H. Jick

USA

Thirty years of the Boston Collaborative Drug Surveillance Program in relation to

principles and methods of drug safety research

22

J.K. Aronson, R.E. Ferner

UK

Errors in prescribing, preparing, and giving medicines: Definition, classification,
and prevention

23

K.Y. Hartigan-Go, J.Q. Wong

Philippines

Inclusion of therapeutic failures as adverse drug reactions

24

IPalmlund

UK

Secrecy hiding harm: case histories from the past that inform the future

25

L. Marks

UK

The pill: untangling the adverse effects of a drug

26

D.J. Finney

UK

From thalidomide to pharmacovigilance: a Personal account

26

L.L.Iversen

UK

How safe is cannabis?

27

J.K. Aronson

UK

Louis Lewin—Meyler’s predecessor

27

H. Jick

USA

The General Practice Research Database

28

J.K. Aronson

UK

Classifying adverse drug reactions in the twenty-first century

29

M. Hauben, A. Bate

USA/Sweden

Data mining in drug safety

30

J.K. Aronson

UK

Drug withdrawals because of adverse effects

31

J. Harrison, P. Mozzicato

USA

MedDRA®: The Tale of a Terminology

32

K. Chan

Australia

Regulating complementary and alternative medicines

xxi


xxii

TABLE OF ESSAYS, ANNUALS 1–37

SEDA

Author

Country

Title

33

Graham Dukes

Norway

Third-generation oral contraceptives: time to look again?

34

Yoon K. Loke

UK

An agenda for research into adverse drug reactions

35

J.K. Aronson

UK

Observational studies in assessing benefits and harms: Double standards?

36

J.K. Aronson

UK

Mechanistic and Clinical Descriptions of Adverse Drug Reactions
Definitive (Between-the-Eyes) Adverse Drug Reactions

37

Sidhartha D. Ray

USA

ADRs, ADEs and SEDs: A Bird’s Eye View


Abbreviations
The following abbreviations are used throughout the SEDA series.
2,4-Dimethoxyamfetamine
3,4-Dimethoxyamfetamine
Lamivudine (dideoxythiacytidine)
Attention deficit hyperactivity disorder
Adenosine diphosphate
Antinuclear antibody
Antineutrophil cytoplasmic antibody
Acellular pertussis
Acute physiology and chronic health evaluation (score)
Activated partial thromboplastin time
American Society of Anesthesiologists
Anti-Saccharomyces cerevisiae antibody
The area under the concentration versus time curve from zero to infinity
The area under the concentration versus time curve from zero to time x

The area under the concentration versus time curve from zero to the time of the last sample
The area under the concentration versus time curve during a dosage interval
Anthrax vaccine adsorbed
Zidovudine (azidothymidine)
Bacillus Calmette Guérin
Twice a day (bis in die)
Bispectral index
Body mass index
Continuous ambulatory peritoneal dialysis
Cluster of differentiation (describing various glycoproteins that are expressed on the surfaces of T cells, B cells and
other cells, with varying functions)
CI
Confidence interval
Maximum (peak) concentration after a dose
Cmax
Maximum (peak) concentration after a dose at steady state
Css.max
Minimum (trough) concentration after a dose at steady state
Css.min
COX-1 and COX-2
Cyclo-oxygenase enzyme isoforms 1 and 2
CT
Computed tomography
CYP (e.g. CYP2D6, CYP3A4) Cytochrome P450 isoenzymes
D4T
Stavudine (didehydrodideoxythmidine)
DDC
Zalcitabine (dideoxycytidine)
DDI
Didanosine (dideoxyinosine)

DMA
Dimethoxyamfetamine; see also 2,4-DMA, 3,4-DMA
DMMDA
2,5-Dimethoxy-3,4-methylenedioxyamfetamine
DMMDA-2
2,3-Dimethoxy-4,5-methylenedioxyamfetamine
DTaP
Diphtheria + tetanus toxoids + acellular pertussis
DTaP-Hib-IPV-HB
Diphtheria + tetanus toxoids + acellular pertussis + IPV + Hib + hepatitis B (hexavalent vaccine)
DT-IPV
Diphtheria + tetanus toxoids + inactivated polio vaccine
DTP
Diphtheria + tetanus toxoids + pertussis vaccine
DTwP
Diphtheria + tetanus toxoids + whole cell pertussis
eGFR
Estimated glomerular filtration rate
ESR
Erythrocyte sedimentation rate
FDA
(US) Food and Drug Administration
Forced expiratory volume in 1 s
FEV1
FTC
Emtricitabine
FVC
Forced vital capacity
G6PD
Glucose-6-phosphate dehydrogenase

GSH
Glutathione
GST
Glutathione S-transferase
HAV
Hepatitis A virus
Hemoglobin A1c
HbA1c
HbOC
Conjugated Hib vaccine (Hib capsular antigen polyribosylphosphate covalently linked to the nontoxic diphtheria
toxin variant CRM197)
HBV
Hepatitis B virus
2,4-DMA
3,4-DMA
3TC
ADHD
ADP
ANA
ANCA
aP
APACHE
aPTT
ASA
ASCA
AUC
AUC0!x
AUC0!t
AUCτ
AVA

AZT
BCG
bd
BIS
BMI
CAPD
CD [4, 8, etc]

xxiii


xxiv
HDL, LDL, VLDL
Hib
HIV
hplc
HPV
HR
HZV
ICER
Ig (IgA, IgE, IgM)
IGF
INN
INR
IPV
IQ [range], IQR
JE
LABA
MAC
MCV4

MDA
MDI
MDMA
MenB
MenC
MIC
MIM
MMDA
MMDA-2
MMDA-3a
MMR
MMRV
MPSV4
MR
MRI
NMS
NNRTI
NNT, NNTB, NNTH
NRTI
NSAIDs
od
OMIM
OPV
OR
OROS
PCR
PMA
PMMA
PPAR
ppb

PPD
ppm
PRP-CRM
PRP-D-Hib
PT
PTT
QALY
qds
ROC curve
RR
RT-PCR
SABA
SMR
SNP
SNRI
SSRI

ABBREVIATIONS

High-density lipoprotein, low-density lipoprotein, and very low density lipoprotein (cholesterol)
Haemophilus influenzae type b
Human immunodeficiency virus
High-performance liquid chromatography
Human papilloma virus
Hazard ratio
Herpes zoster virus vaccine
Incremental cost-effectiveness ratio
Immunoglobulin (A, E, M)
Insulin-like growth factor
International Nonproprietary Name (rINN ¼ recommended; pINN ¼ provisional)

International normalized ratio
Inactivated polio vaccine
Interquartile [range]
Japanese encephalitis vaccine
Long-acting beta-adrenoceptor agonist
Minimum alveolar concentration
4-valent (Serogroups A, C, W, Y) meningococcal Conjugate vaccine
3,4-Methylenedioxyamfetamine
Metered-dose inhaler
3,4-Methylenedioxymetamfetamine
Monovalent serogroup B meningoccocal vaccine
Monovalent serogroup C meningoccocal conjugate vaccine
Minimum inhibitory concentration
Mendelian Inheritance in Man (see />3-Methoxy-4,5-methylenedioxyamfetamine
2-Methoxy-4,5-methylendioxyamfetamine
2-Methoxy-3,4-methylendioxyamfetamine
Measles + mumps + rubella
Measles + mumps + rubella + varicella
4-Valent (serogroups A, C, W, Y) meningococcal polysaccharide vaccine
Measles + rubella vaccine
Magnetic resonance imaging
Neuroleptic malignant syndrome
Non-nucleoside analogue reverse transcriptase inhibitor
Number needed to treat (for benefit, for harm)
Nucleoside analogue reverse transcriptase inhibitor
Nonsteroidal anti-inflammatory drugs
Once a day (omne die)
Online Mendelian Inheritance in Man (see />Oral polio vaccine
Odds ratio
Osmotic-release oral system

Polymerase chain reaction
Paramethoxyamfetamine
Paramethoxymetamfetamine
Peroxisome proliferator-activated receptor
Parts per billion
Purified protein derivative
Parts per million
See HbOC
Conjugated Hib vaccine(Hib capsular antigen polyribosylphosphate covalently Linked to a mutant polypeptide of
diphtheria toxin)
Prothrombin time
Partial thromboplastin time
Quality-adjusted life year
Four times a day (quater die summendum)
Receiver-operator characteristic curve
Risk ratio or relative risk
Reverse transcriptase polymerase chain reaction
Short-acting beta-adrenoceptor agonist
Standardized mortality rate
Single nucleotide polymorphism
Serotonin and noradrenaline reuptake inhibitor
Selective serotonin reuptake inhibitor


ABBREVIATIONS

SV40
Td
Tdap:
tds

TeMA
TMA
TMA-2
tmax
TMC125
TMC 278
Vmax
wP
VZV
YF
YFV

Simian virus 40
Diphtheria + tetanus toxoids (adult formulation)
Tetanus toxoid + reduced diphtheria toxoid + acellular pertussis
Three times a day (ter die summendum)
2,3,4,5-Tetramethoxyamfetamine
3,4,5-Trimethoxyamfetamine
2,4,5-Trimethoxyamfetamine
The time at which Cmax is reached
Etravirine
Rilpivirine
Maximum velocity (of a reaction)
Whole cell pertussis
Varicella zoster vaccine
Yellow fever
Yellow fever virus

xxv

ADRs, ADEs and SEDs: A Bird’s Eye View
Sidhartha D. Ray*,1, Kelan L. Thomas†, David F. Kisor*
*Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences,
Fort Wayne, IN, USA
†
Department of Clinical Sciences, Touro University California College of Pharmacy, Vallejo, CA, USA
1
Corresponding author:

INTRODUCTION
Adverse drug events (ADEs), drug-induced toxicity
and side effects are a significant concern. ADEs are
known to pose significant morbidity, mortality, and cost
burden to society; however, there is a lack of strong evidence to determine their precise impact. The landmark
Institute of Medicine (IOM) report To Err is Human
implicated adverse drug events in 7000 annual deaths
at an estimated cost of $2 billion [1]. However, the US
Department of Health and Human Services estimates
770 000 people are injured or die each year in hospitals
from ADEs, which costs up to $5.6 million each year
per hospital excluding the other accessory costs (e.g.,
hospital admissions due to ADEs, malpractice and litigation costs, or the costs of injuries). Nationally, hospitals spend $1.56–5.6 billion each year, to treat patients
who suffer ADEs during hospitalization [2]. A second
landmark study suggests that approximately 28% of
ADEs are preventable, through optimization of medication safety and distribution systems, provision and
dissemination of timely patient and medication information, and staffing assignments [3]. Subsequent recent
investigations suggest these numbers might be conservative estimates of the morbidity and mortality impact
of ADEs [4].

drug events (i.e., any injury, whether minor or significant, caused by a medication or lack thereof ). Another
significant ADE generating category that can be added
to the list is: lack of incorporation of pre-existing
condition(s) or pharmacogenetic factors. This work
focuses on adverse drug events; however, it should be
noted that adverse drug events may or may not occur
secondary to a medication error.
The lack of more up to date epidemiological data
regarding the impact of ADEs is largely due to challenges
with low adverse drug event reporting. ASHP recommends that health systems implement adverse drug reaction (ADR) monitoring programs in order to (i) mitigate
ADR risks for specific patients and expedite reporting to
clinicians involved in care of patients who do experience
ADRs and (ii) gather pharmacovigilance information
that can be reported to pharmaceutical companies and
regulatory bodies [7]. Factors that may increase the risk
for ADEs include polypharmacy, multiple concomitant
disease states, pediatric or geriatric status, female sex,
genetic variance, and drug factors, such as class and route
of administration. The Institute for Safe Medication
Practices (ISMP) defines high-alert medications as those
with high risk for harmful events, especially when used
in error [8]. Examples include antithrombotic agents, cancer chemotherapy, insulin, opioids, and neuromuscular
blockers.

Analysis of ADEs, ADRs, Side Effects
and Toxicity

Terminology

A recent report suggested that ADEs and/or side

effects of drugs occur in approximately 30% of
hospitalized patients [5]. The American Society of
Health-System Pharmacists (ASHP) defines medication
misadventures as unexpected, undesirable iatrogenic
hazards or events where a medication was implicated
[6]. These events can be broadly divided into two categories: (i) medication errors (i.e., preventable events that
may cause or contain inappropriate use), (ii) adverse

ADEs may be further classified based on expected
severity into adverse drug reactions (ADRs) or adverse
effects (also known as side effects). ASHP defines ADRs
as an “unexpected, unintended, undesired, or excessive
response to a drug” resulting in death, disability, or
harm [7]. The World Health Organization (WHO) has
traditionally defined an ADR as a “response to a drug
which is noxious and unintended, and which occurs at
doses normally used”; however, another proposed

xxvii


xxviii

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

definition, intended to highlight the seriousness of
ADRs, is “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use
of a medicinal product, which predicts hazard from
future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or
withdrawal of the product” [9]. Under all definitions,

ADRs are distinguished from side effects in that they
generally necessitate some type of modification to the
patient’s therapeutic regimen. Such modifications could
include discontinuing treatment, changing medications,
significantly altering the dose, elevating or prolonging
care received by the patient, or changing diagnosis or
prognosis. ADRs include drug allergies, immunologic
hypersensitivities, and idiosyncratic reactions. In contrast, side effects, or adverse effects, are defined as
“expected, well-known reaction resulting in little or no
change in patient management” [7]. Side effects occur
at predictable frequency and are often dose-related,
whereas ADRs are less foreseeable [9,10].
Two additional types of adverse drug events are druginduced diseases and toxicity. Drug-induced diseases are
defined as an “unintended effect of a drug that results in
mortality or morbidity with symptoms sufficient to
prompt a patient to seek medical attention, require hospitalization, or both” [11]. In other words, a drug-induced
disease has elements of an ADR (i.e., significant severity,
elevated levels of patient care) and adverse effects
(i.e., predictability, consistent symptoms). Toxicity is a

less precisely defined term referring to the ability of a substance “to cause injury to living organisms as a result of
physicochemical interaction” [12]. This term is applied to
both medication and non-medication types of substances,
while “ADRs,” “side effects,” and “drug-induced
diseases” typically only refer to medications. When
applied to medication use, toxicity typically refers to
use at higher than normal dosing or accumulated
supratherapeutic exposure over time, while ADRs, side
effects, and drug-induced diseases are associated with
normal therapeutic use.

Although the title of this monograph is “Side Effects of
Drugs,” this work provides emerging information for all
adverse drug events including ADRs, side effects, druginduced diseases, toxicity, and other situations less
clearly classifiable into a particular category, such as
effects subsequent to drug interactions with other drugs,
foods, and cosmetics. Pharmacogenetic considerations
have been incorporated in several chapters as appropriate and subject to availability of literature.
Adverse drug reactions are described in SEDA using
two complementary systems, EIDOS and DoTS [13–15].
These two systems are illustrated in Figures 1 and 2
and general templates for describing reactions in this
way are shown in Figures 3–5. Examples of their use have
been discussed elsewhere [16–20]. As the clinicians are
becoming more cognizant about different types of ADRs,
reports in this arena are growing faster than one can imagine; few recent articles are listed for reference [21].

FIGURE 1

Describing adverse drug
reactions—two complementary systems.
Note that the triad of drug–patient–
adverse reaction appears outside the
triangle in EIDOS and inside the triangle
in DoTS, leading to Figure 2.

Drug

Extrinsic
2. DoTS: A clinical description

Dis
t

rib

uti

on

Dose-relatedness

Extrinsic

tio
n

Adverse reaction

rib
u

Patient

Outcome

Dis
t

Intrinsic

Intrinsic
Susceptibility factors

Outcome
Time course


xxix

INTRODUCTION

EIDOS

DOSE: RELATION
BENEFIT: HARM

The EIDOS mechanistic description of adverse drug
reactions [15] has five elements:

Drug

•
•
•
•

the Extrinsic species that initiates the reaction (Table 1);
the Intrinsic species that it affects;
the Distribution of these species in the body;
the (physiological or pathological) Outcome (Table 2),

which is the adverse effect;
• the Sequela, which is the adverse reaction.

Dis

trib

uti

on

Extrinsic

Outcome

Intrinsic

Sequela

Patient

Adverse reaction

SUSCEPTIBILITY

TIME COURSE

FIGURE 2 How the EIDOS and DoTS systems relate to each other.
Here the two triangles in Figure 1 are superimposed, to show the relation between the two systems. An adverse reaction occurs when a drug
is given to a patient. Adverse reactions can be classified mechanistically (EIDOS) by noting that when the Extrinsic (drug) species and

an Intrinsic (patient) species are co-Distributed, a pharmacological
or other effect (the Outcome) results in the adverse reaction (the
Sequela). The adverse reaction can be further classified (DoTS) by considering its three main features—its Dose-relatedness, its Time-course,
and individual Susceptibility.

Extrinsic species: This can be the parent compound, an
excipient, a contaminant or adulterant, a degradation
product, or a derivative of any of these (e.g. a metabolite)
(for examples see Table 1).
Intrinsic species: This is usually the endogenous molecule with which the extrinsic species interacts; this can be
a nucleic acid, an enzyme, a receptor, an ion channel or
transporter, or some other protein.
Distribution: A drug will not produce an adverse
effect if it is not distributed to the same site as the target
species that mediates the adverse effect. Thus, the pharmacokinetics of the extrinsic species can affect the occurrence of adverse reactions.
Outcome: Interactions between extrinsic and intrinsic
species in the production of an adverse effect can result
in physiological or pathological changes (for examples
see Table 2). Physiological changes can involve either
increased actions (e.g. clotting due to tranexamic acid)
or decreased actions (e.g. bradycardia due to β(beta)adrenoceptor antagonists). Pathological changes can

Intrinsic species (I)

Extrinsic species (E)

EIDOS
Distribution

Manifestations (test results)

Hazard

Outcome (the adverse effect)

Variable
predictive power

Modifying factor
(e.g., trauma)

Sequela (the adverse reaction)
Manifestations (clinical)

DoTS

Dose responsiveness

Hazard

Time course

Harm

Susceptibility factors

FIGURE 3 A general form of the EIDOS and DoTS template for describing an adverse effect or an adverse reaction.


xxx

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

Extrinsic species (E)

Intrinsic species (1)

EIDOS

Harm

Intrinsic species (2)

Distribution 1

Distribution 2

Outcome (1)

Outcome (2)

Sequela 1

Sequela 2

Dose responsiveness

Benefit

Susceptibility factors

Time course

DoTS

FIGURE 4 A general form of the EIDOS and DoTS template for describing two mechanisms of an adverse reaction or (illustrated here) the balance
of benefit to harm, each mediated by a different mechanism.

Intrinsic species (2)

Extrinsic species (E)

EIDOS

Extrinsic
species (E)

Intrinsic
species (I)

Distribution
Distribution

Outcome 2 (the normal effect)

Manifestations
(clinical)

Sequela 2 (the adverse reaction)

Sequela 1 (the adverse reaction)

Hazard
alters the
normal effects

Harm

DoTS

Outcome 1 (the adverse effect)

Dose responsiveness

Time course

Susceptibility factors

FIGURE 5 A general form of the EIDOS and DoTS template for describing an adverse drug interaction.

involve cellular adaptations (atrophy, hypertrophy,
hyperplasia, metaplasia and neoplasia), altered cell function (e.g. mast cell degranulation in IgE-mediated anaphylactic reactions) or cell damage (e.g. cell lysis,
necrosis or apoptosis).
Sequela: The sequela of the changes induced by a drug
describes the clinically recognizable adverse drug

reaction, of which there may be more than one. Sequelae
can be classified using the DoTS system.

DoTS

In the DoTS system (SEDA-28, xxvii–xxxiii; 1,2)
adverse drug reactions are described according to the


xxxi

INTRODUCTION

TABLE 1

The EIDOS Mechanistic Description of Adverse Drug Effects and Reactions

Feature

Varieties

Examples

E. Extrinsic species

1. The parent compound

Insulin

2. An excipient

Polyoxyl 35 castor oil

3. A contaminant

1,1-Ethylidenebis[1-tryptophan]

4. An adulterant

Lead in herbal medicines

5. A degradation product formed before the drug enters
the body

Outdated tetracycline

6. A derivative of any of these (e.g. a metabolite)

Acrolein (from cyclophosphamide)

I. The intrinsic species and the nature of its interaction with the extrinsic species
(a) Molecular

1. Nucleic acids
(a) DNA

Melphalan

(b) RNA

Mitoxantrone

2. Enzymes
(a) Reversible effect

Edrophonium

(b) Irreversible effect

Malathion

3. Receptors
(a) Reversible effect

Prazosin

(b) Irreversible effect

Phenoxybenzamine

4. Ion channels/transporters

Calcium channel blockers; digoxin and Na+–K+–
ATPase

5. Other proteins
(a) Immunological proteins

Penicilloyl residue hapten

(b) Tissue proteins

N-acetyl-p-benzoquinone-imine (paracetamol
[acetaminophen])

1. Water

Dextrose 5%

2. Hydrogen ions (pH)

Sodium bicarbonate

3. Other ions

Sodium ticarcillin

(c) Physical or
physicochemical

1. Direct tissue damage

Intrathecal vincristine

2. Altered physicochemical nature of the extrinsic species

Sulindac precipitation

D. Distribution

1. Where in the body the extrinsic and intrinsic species
occur (affected by pharmacokinetics)

Antihistamines cause drowsiness only if they
affect histamine H1 receptors in the brain

O. Outcome (physiological or
pathological change)

The adverse effect (see Table 2)

S. Sequela

The adverse reaction (use the Dose, Time, Susceptibility
[DoTS] descriptive system)

(b) Extracellular

Dose at which they usually occur, the Time-course over
which they occur, and the Susceptibility factors that make
them more likely, as follows:
• Relation to dose
 Toxic reactions (reactions that occur at
supratherapeutic doses)

 Collateral reactions (reactions that occur at standard
therapeutic doses)
 Hypersusceptibility reactions (reactions that occur
at subtherapeutic doses in susceptible individuals)
• Time course
 Time-independent reactions (reactions that occur at
any time during a course of therapy)


xxxii

TABLE 2

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

Examples of Physiological and Pathological Changes in Adverse Drug Effects (Some Categories Can Be Broken Down Further)

Type of change

Examples

1. Physiological changes
(a) Increased actions

Hypertension (monoamine oxidase inhibitors); clotting (tranexamic acid)

(b) Decreased actions

Bradycardia (beta-adrenoceptor antagonists);
QT interval prolongation (antiarrhythmic
drugs)

2. Cellular adaptations
(a) Atrophy

Lipoatrophy (subcutaneous insulin); glucocorticosteroid-induced myopathy

(b) Hypertrophy

Gynecomastia (spironolactone)

(c) Hyperplasia

Pulmonary fibrosis (busulfan); retroperitoneal fibrosis (methysergide)

(d) Metaplasia

Lacrimal canalicular squamous metaplasia (fluorouracil)

(e) Neoplasia
– Benign

Hepatoma (anabolic steroids)

– Malignant
– Hormonal

Vaginal adenocarcinoma
(diethylstilbestrol)

– Genotoxic

Transitional cell carcinoma of bladder (cyclophosphamide)

– Immune suppression

Lymphoproliferative tumors (ciclosporin)

3. Altered cell function

IgE-mediated mast cell degranulation (class I immunological reactions)

4. Cell damage
(a) Acute reversible damage
– Chemical damage

Periodontitis (local application of methylenedioxymetamfetamine [MDMA, ‘ecstasy’])

– Immunological reactions

Class III immunological reactions

(b) Irreversible injury
– Cell lysis

Class II immunological reactions

– Necrosis

Class IV immunological reactions; hepatotoxicity (paracetamol,
after apoptosis)

– Apoptosis

Liver damage (troglitazone)

5. Intracellular accumulations
(a) Calcification

Milk-alkali syndrome

(b) Drug deposition

Crystal-storing histiocytosis (clofazimine)
Skin pigmentation (amiodarone)

• Time-dependent reactions
 Immediate or rapid reactions (reactions
that occur only when drug administration is
too rapid)
 First-dose reactions (reactions that occur after the
first dose of a course of treatment and not
necessarily thereafter)
 Early tolerant and early persistent reactions
(reactions that occur early in treatment then either
abate with continuing treatment, owing to
tolerance, or persist)

 Intermediate reactions (reactions that occur
after some delay but with less risk during longer
term therapy, owing to the ‘healthy survivor’ effect)
 Late reactions (reactions the risk of which increases
with continued or repeated exposure)
 Withdrawal reactions (reactions that occur when,
after prolonged treatment, a drug is withdrawn or
its effective dose is reduced)
 Delayed reactions (reactions that occur at some time
after exposure, even if the drug is withdrawn before
the reaction appears)

REFERENCES ON ADVERSE DRUG REACTIONS

• Susceptibility factors
 Genetic (Ex. Variations in expression of certain
drug-metabolizing enzymes)
 Age (newborn, pediatric, young adult, adult and
old age)
 Sex (gender differences—hormonal variations)
 Physiological variation (e.g. weight, pregnancy)
 Exogenous factors (for example the effects of other
drugs, devices, surgical procedures, food,
phytochemicals & nutraceuticals, alcoholic
beverages, smoking)
 Diseases (ongoing but latent with no clinical signs,
pre-existing and obvious)
 Environmental factors (drinking water containing
trace chemicals; breathing polluted air)

WHO Classification
Although not systematically used in Side Effects of
Drugs Annual, the WHO classification, used at the Uppsala Monitoring Center, is a useful schematic to consider
in assessing ADRs and adverse effects. Possible classifications include:
• Type A (dose-related, “augmented”), more common
events that tend to be related to the pharmacology of
the drug, have a mechanistic basis, and result in lower
mortality;
• Type B (non-dose-related, “bizarre”), less common,
unpredictable events that are not related to the
pharmacology of the drug;
• Type C (dose-related and time-related, “chronic”),

events that are related to cumulative dose received
over time;
• Type D (time-related, “delayed”), events that are
usually dose-related but do not become apparent until
significant time has elapsed since exposure to the drug;
• Type E (withdrawal, “end of use”), events that occur
soon after the use of the drug;
• Type F (unexpected lack of efficacy, “failure”),
common, dose-related events where the drug
effectiveness is lacking, often due to drug interactions;

REFERENCES ON ADVERSE DRUG
REACTIONS
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xxxiii

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[8] Institute for Safe Medication Practices. ISMP list of
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[9] Edwards IR, Aronson JK. Adverse drug reactions:
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[11] Tisdale JE, Miller DA, editors. Drug-Induced
Diseases: Prevention, Detection, and Management.
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Health-System Pharmacists; 2010.
[12] Wexler P, Abdollahi M, Peyster AD, et al., editors.
Encyclopedia of Toxicology. 3rd edition. Burlington,
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PHARMACOGENOMIC
CONSIDERATIONS
Introduction
Advances in genomic medicine have fostered an
increased public interest in precision (personalized) medicine, while the field of pharmacogenomics provides an
opportunity to identify clinically important genetic variants that alter drug efficacy or ADR risk. However, the
cost and turn-around-time of genetic tests have slowed
the routine use of pharmacogenetic testing for clinical
decision-making. It is anticipated that clinicians’ education and attitudes toward pharmacogenetic testing may
be vital to the success of health system implementation.

It has been suggested that pharmacogenetic profiles of
patients be analyzed when administering and tailoring
drug therapy.
The past decade has witnessed an explosion in the
development, implementation and availability of genetic
testing. Compelling statistics on ADRs remain a primary
component for driving such testing. In the United States,

ADRs occur in nearly 10% of patients taking prescription
medications in the ambulatory setting and cause estimated 100 000 deaths annually in hospitalized patients
[1,2]. Although many nongenetic factors, such as age,
organ function, concomitant therapy, drug interactions,
and pathophysiology of the disease, influence the effects
of medications, it has been projected that genetics can
account for 20–95% of variability in drug disposition
and effects [3]. More than one-fourth of primary care
patients take a medication commonly implicated in
ADRs and metabolized by enzymes with a known
“poor metabolizer” genetic variant [4]. The United States
Food and Drug Administration (FDA) has made considerable efforts to inform prescribers about drugs with
pharmacogenomic information in their labeling [5]. Information pertaining to pharmacogenomics is indicated on
the labels of over 150 drugs, and it has been estimated
that 25% of outpatients take at least one drug with pharmacogenomic information in the labeling [5,6].

Definition of Pharmacogenomics
The U.S. Food and Drug Administration defines pharmacogenomics (PGx) as the study of variations of DNA
and RNA characteristics as related to drug response,
whereas pharmacogenetics (PGt), being a subset of
PGx, is defined as the study of variations in DNA
sequence as related to drug response [7]. Pharmacogenomics is also referred to as the study of the scientific area
of drug–gene(s) interaction. The interaction between a
drug and a gene product (e.g., functional protein) affecting an individual’s response to the drug represents a clear
application of the EIDOS mechanism description; an
adverse drug reaction when the drug–gene interaction
produces a collateral reaction due to susceptibility factors
as described using the DoTS system [8].
The gene products affecting individual drug response
include receptors, target enzymes, drug transporters and

drug-metabolizing enzymes [9]. Gene variants, a consequence of single nucleotide polymorphisms (SNPs) or
insertions or deletions (indels), among other DNA alterations or duplications can result in outcomes with deleterious effects. These effects range from an exaggerated
clinical response, e.g. increased bleeding as can be seen
with warfarin in an individual with decreased production of the target enzyme vitamin K epoxide reductase
subunit 1 (VKORC1; A/A genotype), or in an individual


xxxv

REFERENCES ON PHARMACOGENOMIC CONSIDERATIONS

TABLE X

Drug (Extrinsic)–Gene (Intrinsic) Interactions and Example Outcomes with Prescribing Information Recommendations

Drug–
gene(s) interaction

Example
Gene varianta
Diplotype
Metabolizer phenotypeb

Effect on drug
response

Pharmacokinetic
consequencesb

Prescribing information

recommendations

Azathioprine and
6-mercaptopurine–
TPMT [14]

TPMT*2, *3A, *3B, *3C
or *4
*2/*3A
Poor metabolizer (PM)

Increased risk of
severe
myelosuppression

Increased active metabolite
exposure: higher thioguanine
nucleotide metabolite
concentrations

Testing should be considered if
patients develop severe toxicity,
since substantial dose reductions
may be required

Carbamazepine–
HLA-B [12]

HLA-B*15:02 negative/
HLA-B*15:02 positive

HLA-B*15:02 positivec

Increased risk of
severe cutaneous
reactions like SJS and
TEN

None

Testing should be performed in
patients of Asian ancestry before
initiation

Clopidogrel–
CYP2C19 [15,16]

CYP2C19*2 or *3
*2/*2
PM

Increased risk of
adverse
cardiovascular
events like
thrombosis

Decreased active metabolite
exposure: 40% lower AUC for
active metabolite

Testing can be used as an aid to
determine therapeutic strategy

Codeine–CYP2D6
[11,17]

CYP2D6*1xN or *2xN
*1/*2xN
UM

Increased risk of
respiratory
depression

Increased active metabolite
exposure: 1.5-fold higher
AUC for morphine

Codeine is contraindicated for
pain management in pediatric
patients undergoing
adenotonsillectomy due to case
reports of death

Warfarin–CYP2C9
[10,18]

CYP2C9*2 or *3
*3/*3
PM

Increased risk of
over-anticoagulation
and bleeding

Increased drug exposure: 3fold higher AUC for S-warfarin

Decreased daily dosage
recommendations based on
genotypes with variant

a
b
c

“Star” nomenclature [13].
AUC ¼ area under the plasma drug concentration–time curve.
Carrier status.

who is a CYP2C9 poor metabolizer, being exposed to
higher warfarin concentrations to death, e.g. respiratory
arrest due to morphine overdose following the administration of codeine in CYP2D6 ultrarapid metabolizers
[10,11]. Another example of a drug–gene interaction
resulting in a life-threatening adverse effect involves carbamazepine with its increased risk of Stevens–Johnson
Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
for individuals with the human leukocyte antigen
(HLA)-B*15:02 allele, which is a genetic variant that
encodes a cell surface protein involved in presenting antigens to the immune system [12]. These drug–gene interactions may result in collateral reactions, due to intrinsic
susceptibility factors, since the adverse outcomes are seen
at standard therapeutic doses.

Perhaps the most studied drug–gene interactions are
related to the activity of drug-metabolizing gene elements, such as cytochrome P450 enzymes (CYPs) and
thiopurine methyl transferase (TPMT). Variants of these
genes may result in altered drug metabolism and changes
in pharmacokinetic parameters, which may influence the
required maintenance dose of a given drug. Table X presents examples of gene variants and the effects on drug
response, including pharmacokinetic consequences and
prescribing information recommendations.

The intrinsic genetic susceptibility factors can influence
an individual’s response to standard doses of a given drug.
In Table X examples below, the collateral reactions can
potentially result in life-threatening outcomes. As technology allows, preemptive genetic testing of patients may
allow for appropriate drug and dose selection to decrease
the risk of adverse drug reactions.
Readers are advised to refer to specific literature pertaining to a drug or a class of drugs to gain further
insights into this field. Several references are provided
[19–36].

REFERENCES ON PHARMACOGENOMIC
CONSIDERATIONS
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of adverse drug events in ambulatory care: a
systematic review. Ann Pharmacother. 2011;
45(7–8):977–989.
[2] Lazarou J, Pomeranz B, Corey PN. Incidence of
adverse drug reactions in hospitalized patients: a
meta-analysis of prospective studies. JAMA. 1998;
279(15):1200–1205.

xxxvi

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

[3] Evans WE., McLeod HL. Pharmacogenomics: Drug
Disposition, Drug Targets, and Side Effects. N Engl
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[4] Grice GR, Seaton TL, Woodland AM, McLeod HL.
Defining the opportunity for pharmacogenetic
intervention in primary care. Pharmacogenomics.
2006; 7(1):61–65.
[5] U.S. Food and Drug Administration. Table of
pharmacogenomic biomarkers in drug labeling.
Available from: />scienceresearch/researchareas/pharmacogenetics/
ucm083378.htm.
[6] Frueh FW, Amur S, Mummaneni P, et al.
Pharmacogenomic biomarker information in drug
labels approved by the United States food and drug
administration: prevalence of related drug use.
Pharmacotherapy. 2008; 28(8):992–998.
[7] U.S. Food and Drug Administration. Definitions
for Genomic Biomarkers, Pharmacogenomics,
Pharmacogenetics, Genomic Data and
Sample Coding Categories. Available from:
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guidances/ucm073162.pdf.
[8] Aronson JK, Ferner RE. Joining the DoTS. New
approach to classifying adverse drug reactions. BMJ.

2003; 327:1222–5.
[9] Ma Q, Lu AYH. Pharmacogenetics,
pharmacogenomics, and individualized medicine.
Pharmacol Rev. 2011; 63(2):437–459.
[10] Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical
Pharmacogenetics Implementation Consortium
guidelines for CYP2C9 and VKORC1 genotypes and
warfarin dosing. Clin Pharmacol Ther. 2011;
90(4):625–629.
[11] Crews KR, Gaedigk A, Dunnenberger HM, et al.
Clinical Pharmacogenetics Implementation
Consortium guidelines for cytochrome P450
2D6 genotype and codeine therapy: 2014
update. Clin Pharmacol Ther. 2014;
95(4):376–82.
[12] Leckband SG, Kelsoe JR, Dunnenberger HM, et al.
Clinical Pharmacogenetics Implementation
Consortium guidelines for HLA-B genotype and
carbamazepine dosing. Clin Pharmacol Ther. 2013;
94(3):324–8.
[13] Robarge JD, Li L, Desta Z, Nguyen A, Flockhart DA.
The star-allele nomenclature: retooling for
translational genomics. Clin Pharmacol Ther. 2007;
82(3):244–8.
[14] Relling MV, Gardner EE, Sandborn WJ, et al.
Clinical Pharmacogenetics Implementation
Consortium guidelines for thiopurine
methyltransferase genotype and thiopurine dosing.
Clin Pharmacol Ther. 2011; 89(3):387–91.

[15] Scott SA, Sangkuhl K, Stein CM, et al. Clinical
Pharmacogenetics Implementation Consortium
guidelines for CYP2C19 genotype and clopidogrel
therapy: 2013 update. Clin Pharmacol Ther. 2013;
94(3):317–23.
[16] Erlinge D, James S, Duvvuru S, et al. Clopidogrel
metaboliser status based on point-of-care CYP2C19
genetic testing in patients with coronary
artery disease. Thromb Haemost. 2014; 111
(5):943–50.
[17] Kirchheiner J, Schmidt H, Tzvetkov M, et al.
Pharmacokinetics of codeine and its metabolite
morphine in ultra-rapid metabolizers due to
CYP2D6 duplication. Pharmacogenomics J. 2007;
7(4):257–65.
[18] Flora DR, Rettie AE, Brundage RC, Tracy TS.
CYP2C9 Genotype-Dependent Warfarin
Pharmacokinetics: Impact of CYP2C9 Genotype
on R- and S-Warfarin and Their Oxidative
Metabolites. J Clin Pharmacol. 2016; doi: 10.1002/
jcph.813.
[19] Hertz DL, Rae J. Pharmacogenetics of cancer drugs.
Annu Rev Med. 2015; 66:65–81.
[20] Dunnenberger HM, Crews KR, Hoffman JM, et al.
Preemptive clinical pharmacogenetics
implementation: current programs in five US
medical centers. Annu Rev Pharmacol Toxicol. 2015;
55:89–106.
[21] Aithal GP. Pharmacogenetic testing in idiosyncratic
drug-induced liver injury: current role in clinical

practice. Liver Int. 2015; 35(7):1801–8.
[22] Cuzzoni E, De Iudicibus S, Franca R, et al.
Glucocorticoid pharmacogenetics in pediatric
idiopathic nephrotic syndrome.
Pharmacogenomics. 2015; 16(14):1631–48.
[23] Aceti A, Gianserra L, Lambiase L, et al.
Pharmacogenetics as a tool to tailor
antiretroviral therapy: A review. World J Virol.
2015; 4(3):198–208.
[24] Sahu RK, Singh K, Subodh S. Adverse Drug
Reactions to Anti-TB Drugs: Pharmacogenomics
Perspective for Identification of Host
Genetic Markers. Curr Drug Metab. 2015;
16(7):538–52.
[25] Higgins GA, Allyn-Feuer A, Handelman S, et al. The
epigenome, 4D nucleome and next-generation
neuropsychiatric pharmacogenomics.
Pharmacogenomics. 2015; 16(14):1649–69.
[26] Niemeijer MN, van den Berg ME, Eijgelsheim M,
et al. Pharmacogenetics of Drug-Induced QT
Interval Prolongation: An Update. Drug Saf. 2015;
38(10):855–67.
[27] Perwitasari DA, Atthobari J, Wilffert B.
Pharmacogenetics of isoniazid-induced
hepatotoxicity. Drug Metab Rev., 2015; 47(2):222–8.


IMMUNOLOGICAL REACTIONS

[28] Roberts RL, Barclay ML. Update on thiopurine

pharmacogenetics in inflammatory bowel disease.
Pharmacogenomics. 2015; 16(8):891–903.
[29] Seripa D, Panza F, Daragjati J, Paroni G, Pilotto A.
Measuring pharmacogenetics in special groups:
geriatrics. Expert Opin Drug Metab Toxicol. 2015;
11(7):1073–88.
[30] Chan SL, Jin S, Loh M, et al. Brunham LR. Progress
in understanding the genomic basis for adverse
drug reactions: a comprehensive review and focus
on the role of ethnicity. Pharmacogenomics. 2015;16
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[31] Jarjour S, Barrette M, Normand V, et al. Genetic
markers associated with cutaneous adverse drug
reactions to allopurinol: a systematic review.
Pharmacogenomics. 2015; 16(7):755–67.
[32] Błaszczyk B, Laso
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drugs and adverse skin reactions: An update.
Pharmacol Rep. 2015 Jun; 67(3):426–34.
[33] Zhou ZW, Chen XW, Sneed KB, et al. Clinical
association between pharmacogenomics
and adverse drug reactions. Drugs. 2015;
75(6):589–631.
[34] Sousa-Pinto B, Pinto-Ramos J, Correia C, et al.
Pharmacogenetics of abacavir hypersensitivity:
A systematic review and meta-analysis of the
association with HLA-B*57:01. J Allergy Clin
Immunol. 2015; 136(4):1092–4.e3.
[35] Pellegrino P, Falvella FS, Perrone V, et al. The first
steps towards the era of personalised vaccinology:

predicting adverse reactions. Pharmacogenomics J.
2015; 15(3):284–7.
[36] Goulding R, Dawes D, Price M, et al. Genotypeguided drug prescribing: a systematic review and
meta-analysis of randomized control trials. Br J Clin
Pharmacol. 2015; 80(4):868–77.

xxxvii

Type III hypersensitivity), and cell-mediated immunity
(delayed-type hypersensitivity or Type IV hypersensitivity). Although Gell and Coomb’s classification was proposed more than 30 years ago, it is still widely used [1–3].

Type I Reactions (IgE-Mediated Anaphylaxis;
Immediate Hypersensitivity)
In type I reactions, the drug or its metabolite interacts
with IgE molecules bound to specific type of cells (mast
cells and basophils). This triggers a process that leads to
the release of pharmacological mediators (histamine,
5-hydroxytryptamine, kinins, and arachidonic acid derivatives), which cause the allergic response. Mounting of
such a reaction depends exclusively upon exposure to
the same assaulting agent (antigen, allergen or metabolite)
for the second time and the severity depends on the level of
exposure. The clinical effects [2] are due to smooth muscle
contraction, vasodilatation, and increased capillary permeability. The symptoms include faintness, light-headedness,
pruritus, nausea, vomiting, abdominal pain, and a feeling
of impending doom (angor animi). The signs include urticaria, conjunctivitis, rhinitis, laryngeal edema, bronchial
asthma and pulmonary edema, angioedema, and anaphylactic shock; takotsubo cardiomyopathy can occur, as can
Kounis syndrome (an acute coronary episode associated
with an allergic reaction). Not all type I reactions are
IgE-dependent; however, under circumstances, adverse
reactions that are mediated by direct histamine release

have conventionally been called anaphylactoid reactions,
but are better classified as non-IgE-mediated anaphylactic
reactions. Cytokines, such as, IL-4, IL-5, IL-6 and IL-13,
either mediate or influence this class of hypersensitivity
reaction. Representative agents that are known to induce
such reactions include: Gelatin, Gentamicin, Kanamycin,
Neomycin, Penicillins, Polymyxin B, Streptomycin and
Thiomersal [1–3].

IMMUNOLOGICAL REACTIONS
The immunological reactions are diverse and varied
but considered specific. Nearly five decades ago, Karl
Landsteiner’s ground-breaking work “The Specificity of
Serological Reactions” set the standard in experimental
immunology. Several new discoveries in immunology in
the twentieth century, such as, ‘CD’ receptors (cluster of differentiation), recognition of ‘self’ versus ‘non-self’, a large
family of cytokines and antigenic specificity became instrumental in describing immunological reactions. The most
widely accepted classification divides immunological reactions (drug allergies or otherwise) into four pathophysiological types, namely, anaphylaxis (immediate type or
Type I hypersensitivity), antibody-mediated cytotoxic reactions (cytotoxic type or Type II hypersensitivity), immune
complex-mediated reactions (toxic-complex syndrome or

Type II Reactions (Cytotoxic Reactions)
Type II reactions involve circulating immunoglobulins G or M (or rarely IgA) binding with cell surface antigens (membrane constituent or protein) and interacting
with an antigen formed by a hapten (drug or metabolite)
and subsequently fixing complement. Complement is
then activated leading to cytolysis. Type II reactions
often involve antibody-mediated cytotoxicity directed
to the membranes of erythrocytes, leukocytes, platelets,
and probably hematopoietic precursor cells in the bone
marrow. Drugs that are typically involved are methyldopa (hemolytic anemia), aminopyrine (leukopenia),

and heparin (thrombocytopenia) with mostly hematological consequences, including thrombocytopenia, neutropenia, and hemolytic anemia [1–3].


xxxviii

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

Type III Reactions (Immune Complex Reactions)
In type III reactions, formation of an immune complex
and its deposition on tissue surface serve as primary initiators. Occasionally, immune complexes bind to endothelial cells and lead to immune complex deposition
with subsequent complement activation in the linings
of blood vessels. Circumstances that govern immune
formation or immune complex disease remain unclear
to date, and it usually occurs without symptoms. The
clinical symptoms of a type III reaction include serum
sickness (e.g., β-lactams), drug-induced lupus erythematosus (eg, quinidine), and vasculitis (e.g., minocycline).
Type III reactions can result in acute interstitial nephritis
or serum sickness (fever, arthritis, enlarged lymph nodes,
urticaria, and maculopapular rashes) [1–3].

[2]

[3]

[4]

[5]

Type IV Reactions (Cell-Mediated or Delayed
Hypersensitivity Reactions)

Type IV reactions are initiated when hapten–protein
antigenic complex-mediated sensitized T lymphocytes
meet the assaulting immunogen for the second time;
usually this leads to severe inflammation. Type IV reactions are exemplified by contact dermatitis. Pseudoallergic reactions resemble allergic reactions clinically
but are not immunologically mediated. Examples
include asthma and rashes caused by aspirin and maculopapular erythematous rashes due to ampicillin or
amoxicillin in the absence of penicillin hypersensitivity.
Few other entities that can initiate this reaction are: sulfonamides, anticonvulsants (phenytoin, carbamazepine, and phenobarbital), NSAIDs (aspirin, naproxen,
nabumetone, and ketoprofen), antiretroviral agents
and cephalosporins [1–4].

Other Types of Reactions
Several types of adverse drug reactions do not easily fit
into Gell and Coomb’s classification scheme. These include
most cutaneous hypersensitivity reactions (such as toxic
epidermal necrolysis), ‘immune-allergic’ hepatitis and
hypersensitivity pneumonitis. Another difficulty is that
allergic drug reactions can occur via more than one mechanism; picryl chloride in mice induces both type I and type
IV responses. Although other classification schemes have
evolved over time, Gell and Coomb’s system remains the
most widely utilized scheme. Several articles are included
in this review to serve as a pointer to this field [4–12].

REFERENCES
[1] Coombs RRA, Gell PGH. Classification of allergic
reactions responsible for clinical hypersensitivity
and disease. In: Gell PGH, Coombs RRA, Lachmann
PJ, editors. Clinical Aspects of Immunology.

[6]

[7]

[8]

[9]

[10]

[11]

[12]

London: Blackwell Scientific Publications; 1975.
pp. 761–81.
Schnyder B, Pichler W. Mechanisms of DrugInduced Allergy. Mayo Clin Proc. Mar 2009; 84(3):
268–272.
Boyman O, Comte D, Spertini F. Adverse reactions
to biologic agents and their medical management.
Nat Rev Rheumatol., 2014 Aug 12. doi: 10.1038/
nrrheum.2014.123. [Epub ahead of print].
Brown SGA. Clinical features and severity grading
of anaphylaxis. J Allergy Clin Immunol 2004; 114(2):
371–6.
Johansson SGO, Hourihane JO, Bousquet J,
Bruijnzeel-Koomen C, Dreborg S, Haahtela T,
Kowalski ML, Mygind N, Ring J, van Cauwenberge
P, van Hage-Hamsten M, W€
uthrich B. A revised
nomenclature for allergy. An EAACI position

statement from the EAACI nomenclature task force.
Allergy 2001; 56(9): 813–24.
Uzzaman A, Cho SH. Chapter 28: Classification of
hypersensitivity reactions. Allergy Asthma Proc.
2012 May–Jun; 33 Suppl 1:S96–9.
Descotes J, Choquet-Kastylevsky G. Toxicology,
2001; 158(1–2):43–9. Gell and Coombs’s
classification: is it still valid?
Corominas M, Andres-López B, Lleonart R. Severe
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hydrochlorothiazide: A persistent old problem. Ann
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Velickovic J, Palibrk I, Miljkovic B, et al. Selfreported drug allergies in surgical population in
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Yip VL, Alfirevic A, Pirmohamed M. Genetics of
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Agúndez JA, Mayorga C, García-Martin E. Drug
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Curr Opin Allergy Clin Immunol. 2015;
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Wheatley LM, Plaut M, Schwaninger JM. et al.
Report from the National Institute of Allergy and
Infectious Diseases workshop on drug allergy.
J Allergy Clin Immunol., 2015; 136(2):262–71.e2.

ANALYSIS OF TOXICOLOGICAL
REACTIONS
Potentiation Reactions

This type of reaction occurs only when one non-toxic
chemical interacts with another non-toxic chemical, or
one non-toxic chemical interacts with another toxic chemical at low doses (subtoxic, acutely toxic). An alternate
interpretation could be when two drugs are taken


xxxix

REFERENCES

together and one of them intensifies the action of the
other. In such scenarios, if the final outcome is high toxicity, then the final outcome is called a potentiation
(increasing the toxic effect of ‘Y’ by ‘X’). Theoretically,
it can be expressed as: x + y ¼ M (1 + 0 ¼ 4).
Examples: (i) When chronic or regular alcohol drinkers
consume therapeutic doses of acetaminophen, it can lead
to alcohol-potentiated acetaminophen-induced hepatotoxicity (cause: ethanol-induced massive CYP2E1 induction in the liver); (ii) Avoid iron supplements in patients
on doxorubicin therapy to prevent possible potentiation
of doxorubicin-induced cardiotoxicity (cause: hydroxyl
radical formation and redox cycling of doxorubicin);
(iii) Phenergan®, an antihistamine, when given with a
painkilling narcotic such as Demerol® can intensify its
effect; therefore, reducing the dose of the narcotic is
advised; (iv) Ethanol potentiation of CCl4-induced hepatotoxicity; (v) Use of phenytoin and calcium-channel
blockers combination should be used with caution. Representative references from each category of toxic reactions are provided below:

Synergistic Effect
Synergism is somewhat similar to potentiation. When
two drugs are taken together that are similar in action, such
as barbiturates and alcohol, which are both depressants,

an effect exaggerated out of proportion to that of each drug
taken separately at the given dose may occur (mathematically: 1 + 1 ¼ 4). Normally, taken alone, neither substance
would cause serious harm, but if taken together, the combination could cause coma or death. Another established
example: when smokers get exposed to asbestos.

Additive Effect
Additive effect is defined as a consequence which follows exposure to two or more physicochemical agents
which act jointly but do not interact, or commonly, the
total effect is the simple sum of the effects of separate
exposure to the agents under the same conditions. This
could be represented by 1 + 1 ¼ 2: (i) one example would
be barbiturate and a tranquilizer when given together
before surgery to relax the patient; (ii) toxic effect on bone
marrow that follows after AZT + Ganciclovir or AZT
+ Clotrimazole administration.

Antagonistic Effects
Antagonistic effects are when two drugs/chemicals
are administered simultaneously or one followed by
the other, and the net effect of the final outcome of the
reaction is negligible or zero. This could be expressed
by 1 + 1 ¼ 0. An example might be the use of a tranquilizer
to stop the action of LSD.

Examples: (i) When ethanol is administered to
methanol-poisoned patient; (ii) NSAIDs administered
to diuretics (hydrochlorothiazide/Furosemide): Reduce
diuretics effectiveness; (iii) Certain β-blockers (INDERAL®)
taken to control high blood pressure and heart disease
counteract β-adrenergic stimulants, such as Albuterol®.

REFERENCES
[1] Ray SD, Mehendale HM. Potentiation of CCl4 and
CHCl3 hepatotoxicity and lethality by various
alcohols. Fundam Appl Toxicol. 1990; 15(3):429–40.
[2] Gammella, E., Maccarinelli, F., Buratti, P., et al. The
role of iron in anthracycline cardiotoxicity. Front
Pharmacol. 2014; 5:25. doi: 10.3389/
fphar.2014.00025. eCollection 2014.
[3] NLM’s Toxlearn tutorials: .
gov/Module1.htm.
[4] NLM’s Toxtutor (visit interactions): .
nih.gov/enviro/toxtutor/Tox1/a42.htm.
[5] Smith MA, Reynolds CP, Kang MH, et al.
Synergistic activity of PARP inhibition by
talazoparib (BMN 673) with temozolomide in
pediatric cancer models in the pediatric preclinical
testing program. Clin Cancer Res., 2015;
21(4):819–32.
[6] Niu F, Zhao S, Xu CY, et al. Potentiation of the
antitumor activity of adriamycin against
osteosarcoma by cannabinoid WIN-55,212-2. Oncol
Lett. 2015; 10(4):2415–2421.
[7] Calderon-Aparicio A, Strasberg-Rieber M, Rieber
M. Disulfiram anti-cancer efficacy without copper
overload is enhanced by extracellular H2O2
generation: antagonism by tetrathiomolybdate.
Oncotarget. 2015; 6(30):29771–81.
[8] Zajac J, Kostrhunova H, Novohradsky V, et al.
Potentiation of mitochondrial dysfunction in tumor

cells by conjugates of metabolic modulator
dichloroacetate with a Pt(IV) derivative of
oxaliplatin. J Inorg Biochem. 2016; 156:89–97.
[9] Nurcahyanti AD, Wink M. Cytotoxic potentiation of
vinblastine and paclitaxel by L-canavanine in
human cervical cancer and hepatocellular
carcinoma cells. Phytomedicine. 2015;
22(14):1232–7.
[10] Lu CF, Yuan XY, Li LZ, et al. Combined exposure to
nano-silica and lead-induced potentiation of
oxidative stress and DNA damage in human lung
epithelial cells. Ecotoxicol Environ Saf. 2015;
122:537–44.
[11] Kuchárová B, Mikeš J, Jendželovský R, et al.
Potentiation of hypericin-mediated photodynamic
therapy cytotoxicity by MK-886: focus on
ABC transporters, GDF-15 and redox status.
Photodiagnosis Photodyn Ther. 2015; 12(3):490–503.


xl

ADRs, ADEs AND SEDs: A BIRD’S EYE VIEW

[12] Djillani A, Doignon I, Luyten T, et al.
Potentiation of the store-operated calcium entry
(SOCE) induces phytohemagglutinin-activated
Jurkat T cell apoptosis. Cell Calcium. 2015;
58(2):171–85.

GRADES OF ADVERSE DRUG REACTIONS
Drugs and chemicals may exhibit adverse drug reactions (ADR, or adverse drug effect) that may include
unwanted (side effects), uncomfortable (system dysfunction), or dangerous effects (toxic). ADRs are a form of manifestation of toxicity, which may occur after over-exposure
or high-level exposure or, in some circumstances, after
exposure to therapeutic doses but often with an underlying
cause (pre-existing condition). In contrast, ‘Side effect’ is an
imprecise term often used to refer to a drug’s unintended
effects that occur within the therapeutic range [1]. Risk–
benefit analysis provides a window into the decisionmaking process prior to prescribing a medication. Patient
characteristics such as age, gender, ethnic background,
pre-existing conditions, nutritional status, genetic predisposition or geographic factors, as well as drug factors
(e.g., type of drug, administration route, treatment duration, dosage, and bioavailability) may profoundly influence ADR outcomes. Drug-induced adverse events can
be categorized as unexpected, serious or life-threatening.
Adverse drug reactions are graded according to intensity, using a scheme that was originally introduced by the
US National Cancer Institute to describe the intensity of
reactions to drugs used in cancer chemotherapy [2]. This
scheme is now widely used to grade the intensity of other
types of adverse reactions, although it does not always
apply so clearly to them. The scheme assigns grades as
follows:
•
•
•
•
•

Grade 1  mild;
Grade 2  moderate;
Grade 3  severe;
Grade 4  life-threatening or disabling;

Grade 5  death.

Then, instead of providing general definitions of
the terms “mild”, “moderate”, “severe”, and “lifethreatening or disabling”, the system describes what they
mean operationally in terms of each adverse reaction, in
each case the intensity being described in narrative terms.
For example, hemolysis is graded as follows:
• Grade 1: Laboratory evidence of hemolysis only (e.g.
direct antiglobulin test; presence of schistocytes).
• Grade 2: Evidence of red cell destruction and 2 g/dl
decrease in hemoglobin, no transfusion.
• Grade 3: Transfusion or medical intervention (for
example, steroids) indicated.

• Grade 4: Catastrophic consequences (for example,
renal failure, hypotension, bronchospasm, emergency
splenectomy).
• Grade 5: Death.
Not all adverse reactions are assigned all grades. For
example, serum sickness is classified as being of grade
3 or grade 5 only; i.e. it is always either severe or fatal.
The system is less good at classifying subjective reactions. For example, fatigue is graded as follows:
• Grade 1: Mild fatigue over baseline.
• Grade 2: Moderate or causing difficulty performing
some activities of daily living.
• Grade 3: Severe fatigue interfering with activities of
daily living.
• Grade 4: Disabling.
Attribution categories can be defined as follows:
(i) Definite: The adverse event is clearly related to the

investigational agent(s).
(ii) Probable: The adverse event is likely related to the
investigational agent(s).
(iii) Possible: The adverse event may be related to the
investigational agent(s).
(iv) Unlikely: The adverse event is doubtfully related to
the investigational agent(s).
(v) Unrelated: The adverse event is clearly NOT related
to the investigational agent(s).

REFERENCES
[1] Merck Manuals: />professional/clinical_pharmacology/adverse_drug_
reactions/adverse_drug_reactions.html.
[2] National Cancer Institute. Common Terminology
Criteria for Adverse Events v3.0 (CTCAE). 9 August,
2006. />protocolDevelopment/electronic_applications/
docs/ctcaev3.pdf.

FDA PREGNANCY CATEGORIES/
CLASSIFICATION OF TERATOGENICITY
On June 30, 2015 the FDA implemented the “Pregnancy and Lactation Labeling Rule (PLLR)” that will
apply to new prescription drugs and biologic products
submitted after this date, while labeling approved on
or after June 30, 2001 will be phased in gradually.
Prior to the PLLR the FDA had established five categories to indicate the potential of a drug to cause birth
defects if used during pregnancy. The categories were
determined by the reliability of documentation and the
risk to benefit ratio. They did not take into account any