ADVERSE DRUG REACTION & ITS

MONITORING (Pharmacovigilance)

Suharti K Suherman
Dept of Pharmacology & Therapeutic
Medical Faculty, Univ. of Indonesia
 CUR’D YESTERDAY OF MY
DISEASE I DIED LAST NIGHT OF
MY PHYSICIAN ( from : The remedy
worse than disease. Matthew Prior,
1664 – 1721)

• Nature is neutral, i.e.it has no

“intervention” towards humans, though
it is often unfavorable to them.
• It is mankind, in its desire to avoid
suffering & death, people go
to ask drug to their doctor.
• But you have to remember that some of
the biological effects of drugs
are desirable (therapeutic
effect) & others are
undesirable (adverse effect)
 Pharmacovigilance

= also known as Drug Safety, is the

pharmacological science
relating to the collection,
detection, assessment, &
prevention of adverse effects
with pharmaceutical products
• is defined by the WHO as
“the science & activities relating
to the detection, assessment,
understanding & prevention of
adverse effects or any other
drug-related problem
• In the last decade, problem caused by
ADRs & DI is  due to the  of :

* poor doctor–patient communication

* misuse of medication
*  new drugs in the market, with <
informations
*  self medication, incl herbal drugs
* over-prescriptions
* additional drugs to treat side-effects
* polypharmacy  DI  ADRs
• Pharmacoepidemiology
= the study of the incidence of
ADRs in patient populations using
drug agents

• Pharmacogenetics
is generally regarded as the study
/ clinical testing of genetic variation
that gives rise to differing
responses to drugs, including
ADRs
• It is hoped that pharmacogenetics will
eventually provide information
as to which genetic profiles in
patients will place those
patients at greatest risk, or
provide the greatest
benefit, for using a particular
drug or drugs
• adverse effect =
rx yg tidak diingini (diharapkan,
yg timbul saat menggunakan obat
 dapat merupakan efek toksik / efek
samping (= adverse drug rx)

• toxic effects  rxs yg merugikan

akibat penggunaan obat dg dosis
yg > dosis terapi / profilaksis /
diagnostik
• an adverse event = an unwanted rx
that appeared during the
th/ of a patient.
It may occur as a consequence
of the disease, a procedure, or
an adverse drug reaction

• this term is usually use in phase I ,

II , III clinical trials of a new
drug
 drug + receptor DR complex 
modifying biological processes 
therapeutic / prophylactic / diagnos
tic effect  intended effect , but it
may + side effect  unintended
effect (ADR)
 ADRs 
unintended response to a drug
which occurs at dose normally
used for prophylaxis / diagnosis /
treatment of a disease
• More skilful prescribing will 
adverse effects & this means
that doctors, among all the
other claims on their time,
must find time better to
understand drugs, as well as
understanding patients & their
diseases
 Incidence of ADRs (%)
• < 6 drugs  5% ; drugs > 15  40%
• 2 – 3% ambulatory patients are due to
ADRs
• 6.5% of all hospitalizations are due to
ADRs
• 20 – 30% of hospital in-patients suffer an
ADRs,
& 5 – 20%  are allergic reaction
• 0.3 – 3% of death in hospital in-patients
are due to ADRs
•  2 – 3% abnormal babies  from women
using drugs during
pregnancy

• Cost  developed country US$ 30–130

billion for ambulatory patients with
ADRs
• : obat yg sering dilaporkan di negara
berkembang :
aspirin, NSAID, anti-influenza,
digoxin, warfarin, diuretik,
antimikroba, glukokortikoid,
antineoplasma, anti- DM
 Incidence of ADRs (%)
• UK from a large study  prevalence of
ADRs as a cause of hospital
admission = 6.5% ; with
median bed stay 8 days 
• most rxs were definitely or possibly
avoidable; the commonest drugs
were : low dose aspirin,
diuretics, warfarin, NSAIDs, & the
commonest adverse rx was
GI bleeding.
• Overall incidence in hospital inpatients is
10 – 20%, with possible
prolongation of hospital stay in
2 – 10% of patients in acute
medical words.
• ADRs cause 2 – 3 % of consultations in
general practice
• Drugs < 5 incidence ADR  5% ; > 5
drugs  40%
International prevalence of adverse drug events in hospitals:
an analysis of routine data from England, Germany, and the
USA (Jürgen Stausberg)

• Hospital data for England & USA & German were

obtained in year 2006
•  6 - (England), 7 - (USA), & 16 million (Germany)
inpatients could be included. ADEs were
identified through a list of codes used in the
national diagnosis classifications.
• BMC Health Services Research 2014, 14:125
• Results: The overall prevalence rate ( 95% CI)
of coded ADEs was :
3.22% (3.20–3.23%) for England,
4.78% (4.73–4.83%) for Germany, &
5.64% (5.63–5.66%) for the USA
Most of the English ADE cases occurred in
patients admitted as emergency
A non-surgical status & a longer length of stay
were consistently associated with the
occurrence of an ADE.
Enterocolitis caused by Clostridium difficile
was the most frequent ADE in all
 Assessing ADRs
• most commonly used : Naranjo algorithm,
1981  often used when
reporting suspected ADRs as
case reports in published literature
• It contains 10 items with 3 possible
responses (“yes,” “no” or “do not
know or not done”) & points are
assigned for each response.
• The items are based on certain criteria
such as temporal relationship,
objective evidence (e.g., drug
levels), dechallenge/rechallenge
 conclusion : “definite,”
“possible,” “probable” or “doubtful”
based on the cumulative score.
• Another example of an adverse event
scoring system is the WHO Upsalla
Monitoring Centre Causality Assessmt
• This scale ranks adverse events as
certain,
probable/likely,
possible &
unlikely
based on criteria such as laboratory
parameters & biological effect
• Recent examples of pharmacovigilance
* Health Canada continues to release
advisories of suspected ADRs that have
been discovered through pharmacovigilance
* these include the risk of bladder Ca with
pioglitazone, Clostridium difficile–
associated diarrhea &
bone fractures with PPIs,
DM with statins,
Cancer with prolonged use of calcitonin
& cardiac dysrhythmias with
domperidone, & azithromycin.2
 The role of the pharmacist

• Pharmacists are ideally situated to play a

key role in the identification &
reporting of suspected drug-related
adverse effects due to our
accessibility & knowledge of drug
therapy
• As stated, the reporting of suspected
ADRs does not mandate that a
direct cause-and-effect relationship
be established.
• All that is required is to document the
reaction itself & the circumstances
around how it occurred (relevant
history, investigations, concurrent
medications, etc
• In 2012, pharmacists submitted only 10%
of Health Canada ADRs reports
very low. As a profession, we need
to accept responsibility to ensure
this activity is performed systematically
& consistently for all suspected ADRs.
Pharm Pract (Granada),2012 Jan;10(1):40-4. Days lost due to disability of diclofenac-
induced adverse drug reactions.Thomas D1, Mathew M, Raghavan CV, Mohanta GP,
Reddy YP., Karpagam Univ , Coimbatore, ( India ).
 Classification of seriousness / severity
Severity
# mild : aspirin, ampicillin  ..............
# moderate: edema  ..................
# severe: hypertension ..............
 serious :
 may fatal, persistent disability,
, hospitalisation or prolongation of
existing hospitalisation :................
 Classification of ADRs (mechanism)
• Type A (augmented)  rx will occur in
everyone if enough of the drug is
given, due to excess of bloodlevel,
predictable, dose-related, pharma
codynamic effect
• Type B (bizarre)  rx will occur only in
some people; are not part of the
normal phar’logical effect, dose-
unrelated, an unusual rx of the
patient, unpredictable, immunolo
gical processes
• Type C (chronic)  rx due to long-term
exposure; …?… nephropathy,
corticost ………..?

• Type D (delayed)  effects following

prolonged used of a drug, the rx +
 after the drug has been stop:
.................
• Type E (ending of use)  withdrawal
effects aft longterm or rebound
phenomenon:..........................
 Classification of ADRs
• Type A (augmented)  rx will occur in
everyone if enough of the drug is
given, due to excess of bloodlevel,
predictable, dose-related, pharma
codynamic effect
• Type B (bizarre)  rx will occur only in
some people; are not part of the
normal phar’logical effect, dose-
unrelated, an unusual rx of the
patient, unpredictable, immunolo
gical processes
• Type C (chronic)  rx due to long-term
exposure; …?… nephropathy,
corticost ………..?

• Type D (delayed)  effects following

prolonged used of a drug, the rx +
 after the drug has been stop

• Type E (ending of use)  withdrawal

effects aft longterm or rebound
phenomenon
 dose–related / dose–dependent
 > frequent  80% of all rxs
 predictable  maybe avoidable
 usually an excess of a known phar’cologi
cal effect  due to kinetic or
dynamic abnormality ; ie.insulin
hypoglycaemia ;
or other effect occuring with the
th/ effect ie. -blocker nonselective
in the lung  asthmatic attact
 Non-dose-related
• mechanisms of ADRs : immunological &
pharmacogenetic

• immunological reactions  drug allergy or

hypersensitivity rxs
* usually > serious
* usually unpredictable
* unpreventable
• Characteristic of drug allergy :
* there is a latent periode between the
initial exposure & the rx
* once an allergic state has been
established  the rx can be + by
small amounts of the drug
* the rx does not resemble the pharma-
cological effect of the drug
* symptoms are of some form of allergic
respons : skin rash, urticaria,
anaphylactic, Steven J Syndr
 Classification of drug allergy
• Type I (immediate rx; IgE) hypersensitivity
 anaphylactic shock ,
bronchospasm
• Type II (cytotoxic) a. IgG  Hapten-cell rx
: hemolytic anemia
b. IgM  Immune complex rx :
granulocytopenia,
thrombo cytopenia,
neutropenia
• Type III (immune complex ; & Ig)
hypersensivity   of antigen-
antibody complexes in the
circulation deposit on basement
membranes in tissues & vessels ,
 vascular damage : glomerulo-
nephritis, serum sickness with
fever , arthritis, joint & muscle pain
; hydralazine , penicillins
• Type IV (delayed) hypersensitivity 
unlike types I, II, & III,
 type iV is cell- mediated, &
responses occur 2 – 3 days after
exposure of to the sensitizing
antigen  fixed drug eruptions or
allergy to topical drugs
Immunologically mediated reaction

Tipe Reaksi Jenis reaksi Obat

I IgE-dependent Urtikaria, NSAID, penisilin,

reactions angioedema,
anafilaksis, hay
fever
II Cytotoxic Hemolisis, Penisilin, sefalosporin,
reactions, Ig G purpura sulfonamid, rifampisin
III Immune complex Vasculitis, Quinidin, salisilat,
reactions serum sickness chlorpromazine, sulfonamid
IV Delayed-type Dermatitis tersering
reaction/ contact, reaksi Banyak obat (topikal &
Cell mediated exanthematous sistemik)
hypersensitivity , reaksi
photoallergic
• Pseudoallergic rxs  rx that clinicaly
resemble allergic rxs, but for
which no immunological basis
can found
• In a proportion of asthmatic patient,
aspirin may triggers an
attack of asthma
Efek samping yg spesifik pd or pd organ yg
spesifik

• Fluoroquinolon  # paracetamol 
• Aminoglikosida  # Kloramfenikol
• Tetracyclin  # Sulfasalazine 
• NSAID  # captopril 
• Kontrasepsi oral kombinasi 
• PTU/ MMI  # Bisfosfonat
• Glukokortikoid 
• Metronidazole 
• Banyak ESO tidak dpt dicegah , dng mengi ngat
bbrp faktor deteminat  usaha maksi mal agar
ESO timbul seminimal mungkin
• Faktor determinant :
** usia , ekstrim muda / dlm kandungan &
usia lanjut , kehamilan
** kelainan genetik (defisiensi enzim G-6-PD);
variasi genetik ( isozim CYP) #
** penyakit  dahulu & sekarang
** dosis – cara pemberian obat – lama
** gaya hidup perokok, alkoholism
** interaksi pd polifarmasi
• # kelainan genetik: defisiensi enzim G6-PD 
antimalaria (primakuin),sufametok
sazol  anemia hemolitik
• # variasi genetik oksidasi obat oleh CYP (2D6
, 2C9, 2C19)
metabolisme obat  variasi interindividual
 variasi kadar obat dlm darah.
Bbrp jenis enzim ini bersifat polimorfisme
genetik  akibat me  aktivitas metabolism
enzim tsb  menimbulkan concentration –
dependent toxicity
• Mis : # glipizid di metabolisme CYP2C9,
pemberian glipizid dg dosis terapeutik
pd penderita dg genetic CYP2C9 poor
metabolizer  akan terjadi hipoglikemia
berlebihan
# penformin lactic acidosis, sekarang
diketahui obat tsb dimetabolisme oleh
CYP2D6  DM dg aktivitas 2D6
rendah  resiko lactic acidosis
Surveillance methods  in detecting
ADRs
• Anecdotal reporting
• Voluntary–organized reporting  UK,
Indonesia  “yellow card” , for
voluntary reporting of
suspected ADRs
• Intensive – event recording / hospital
monitoring
• Record linkage
• Prospective cohort studies
• Case-control study (retrospective study)
INDONESIA : VOLUNTARY MONITORING
• MINIMAL REPORTS
• LOW ATTENTION FROM MEDICAL
PROFESION
• RESULT :
REKAP LAPORAN ESO TAHUN 2007

GOLONGAN OBAT YANG DIDUGA

MENIMBULKAN ESO

5% 5% 5%
5% 31%
5%

9%
9%
9% 17%

Antibiotik Analgesik&Antipiretik NSAID

Anti Tuberculosa Anti Histamin Costicosteroid
Neuroleptikum Anti Hipertensi Anti Epilepticum
Antiviral
 Efek Samping Obat yang Dilaporkan Terjadi

4% 4% 2% 10%

25%

49%
6%

Steven Johnson Syndrom Urtikaria Udema

Drug Eruption Headache Angioedema
Lain-lain
 Profesi Pelapor ESO

6%
24%

70%

Dokter Rumah Sakit Dokter PKM Dokter Umum

REKAP LAPORAN ESO TAHUN 2008

Profesi Pelapor ESO

6%
24%

70%

Dokter Rumah Sakit Dokter PKM Dokter Umum

 EFEK SAMPING OBAT YANG DILAPORKAN TERJADI
10%
Rash makulo-papular
4%
4% 31% Rash

5% Steven's Johnson
Syndrome
Fixed eruption

14% Udema

Urticaria

Lain-lain
32%
 PROFESI PELAPOR ESO

1% 1%
16%

82%

Dokter RS Apoteker Dokter PKM Dokter Umum

REKAP LAPORAN ESO TAHUN 2008

Profesi Pelapor ESO

6%
24%

70%

Dokter Rumah Sakit Dokter PKM Dokter Umum

 54
ESO yg dilaporkan terjadi selama th 2012

Rash

Extrapyramidal disorder
3% 3% 3% 25% Pruritus
5%

8% Steven Johnson Syndrome

Nausea
8% Rash Maculopapular

Oedema periorbital
13%
8% Headache

11% 13% Fever

Tachycardia

Vomiting

54
Gol Obat yg diduga sebg penyebab ESO Selama Tahun
55 2012

SYSTEMIC ANTIBIOTICS

TUBERCULOSTATICS, EXCL
4% STREPTOMYCIN
6% 27%
6% ANTACIDS, ANTIFLATULENTS AND
ANTI-PEPTIC ULCERANTS

7% ANALGESICS

NSAIDs

7% VITAMIN&MINERALS

9% 13% CENTRAL NERVOUS SYSTEM

10% 11% CARDIAC THERAPY

PSYCHOLEPTICS

SYSTEMIC ANTIVIRALS

55
 Profesi Pelapor ESO Selama Tahun 2012

2%
Apoteker
2% 1%

Dokter RS

43% 52% Dokter

Puskesmas

Perawat

Dokter praktek
swasta
 Bisphosphonates  osteonecrosis of the
jaw (ONJ)
• Med Oral Patol . 2008 May1; 13(5) :318-24. Osteochemo
necrosis of the Jaws due to Bisphosphonate Treatments.
Update
• drugs that seem to have the highest
incidence of ONJ are: zoledronate,
pamidronate, alendronate , risendronate
& ibandronate, from the greatest to the
least.
• the risk of osteonecrosis being produced is
accumulative & may reach 21% in the
3rd year of IV BIS use.
Idiosyncratic drug reactions are a significant cause of
morbidity & mortality for patients; they also
markedly  the uncertainty of drug development.
The major targets are skin, liver, & bone marrow.
Clinical characteristics suggest IDRs are immune
mediated, & there is substantive evidence that
most, but not all, IDRs are caused by chemically
reactive species. However, rigorous mechanistic
studies are very difficult to perform, especially in
the absence of valid animal models. Models to
explain how drugs or reactive metabolites interact
with the MHC/T-cell receptor complex include the
hapten and P-I models,
• & most recently it was found that abacavir can
interact reversibly with MHC to alter the endogenous
peptides that are presented to T cells. The discovery
of HLA molecules as important risk factors for some
IDRs has also significantly contributed to our
understanding of these adverse reactions, but it is
not yet clear what fraction of IDRs have a strong
HLA dependence
 Pediatric Adverse Drug Events in the Outpatient
Setting: An 11-Year National Analysis

• ADEs  are common complication of

medical care, but few pediatric
data are available describing the
frequency or epidemiology of these
events
• Obj: to estimate the national incidence of
pediatric ADEs

• PEDIATRICS Vol. 124 No. 4 October 2009, pp. e744-e750

• Methods: data were obtained from the
National Center for Health
Statistics, which collects
information on patient visits to
outpatient clinics & emergency
departs throughout the US
• analyzed were done on data for children 0
to 18 yrs of age, seeking medical
th/ for an ADE between 1995 &
2005
• RESULTS: mean annual number of ADE-
related visits was 585.922
(95% CI: 503.68 - 668.156) 
78% from in outpatient clinics
& 12% in emergency departs.
Children 0 to 4 years of age had the
highest incidence of ADE-
related visits, accounting for
43.2% (95% CI: 35.6%–
51.2%) of visits.
 The most common symptom
manifestations were
dermatologic conditions
(45.4% [95% CI: 36.9%–
54.1%]) & GI symptoms
(16.5% [95% CI: 11.1%–
23.8%]).
• The medication classes most frequently
implicated in an ADE were
a. AB (27.5% [95% CI: 21.5% –
34.5%]),
b. CNS agents (6.5% [95% CI:
4.0% –10.5%]), &
c. hormones (6.1% [95% CI: 3.1%
– 11.6%]).
• While ADEs related to
AB  most common among
children 0 to 4 yrs old &
 in frequency among older
children,
ADEs caused by CNS agents &
hormones  in frequency
among children 5 to 11 & 12
to 18 yrs old.
 Contoh resep :

• Tn. A, 80 th, D/ DM & cirrhosis; D/ awal stroke

• R/ Ceftazidim 1gr /h * R/ Levo 500mg
• R/ Ranitidin tab * R/ Domperidon
• R/ Captopril * R/ Amlodipin
• R/ Curcumin *R/ Inpepsa ( sucralfat)
• Tn B , 70 th, D/ hipertensi ; arthritis;
pnemonia
* R/ Fitbon (glucosamin)
*R/ Aptor ( as salisilat)
* R/ Biscos (Bisoprolol fumarat)
* R/ Meloxicam *R/ Rantin
*R/ Captopril *R/ Levofloxacin
*R/ Cefadroxyl * R/ Inpepsa
(sucralfat)
• Tn. C , 73 th, D/ CAD, hipertensi, hiperlipidemia
• R/ Clopidogrel
• R/ Captopril
• R/ Amlodipin
• R/ Simvastatin
• R/ Aspirin
• R/ berbagai vitamin
• R/ Omeprazol
• R/ Voltaren
• R/ Inpepsa
ADVERSE DRUG REACTION & ITS
MONITORING (Pharmacovigilance)

Suharti K Suherman
Dept of Pharmacology & Therapeutic
Medical Faculty, Univ. of Indonesia
VigiBase entry
Count
(initial)
VigiBase entry
1975 118 Count
(initial)
1976 479 1996 88
1977 472 1997 0
1978 57 1998 69
1979 77 1999 32
1980 0 2000 0
1981 0 2001 81
1982 156 2002 0
1983 113 2003 72
1984 241 2004 0
1985 211 2005 45
1986 205 2006 26
1987 239 2007 26
1988 72 2008 30 TOTAL
1989 85 2009 111 LAPORAN ESO
1990 58
1991 73
2010 144
 4785
2011 319
1992 55 2012 63
LAPORAN
1993 111 2013 232
1994 41 2014 187
1995 192 2015 205
 Patient age Count

0 - 27 days 12
28 days to 23 months 105
2 - 11 years 429
12 - 17 years 242
18 - 44 years 2 611
45 - 64 years 1 098
65 - 74 years 185
≥ 75 years 60
Unknown 43
 Medication (WHODrug) Count
ATC: A ALIMENTARY TRACT AND METABOLISM 1 252
ATC: B BLOOD AND BLOOD FORMING ORGANS 191
ATC: C CARDIOVASCULAR SYSTEM 395
ATC: D DERMATOLOGICALS 1 188
ATC: G GENITO URINARY SYSTEM AND SEX HORMONES 533
ATC: H SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS 87
ATC: J ANTIINFECTIVES FOR SYSTEMIC USE 2 277
ATC: L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 166
ATC: M MUSCULO-SKELETAL SYSTEM 457
ATC: N NERVOUS SYSTEM 1 494
ATC: P ANTIPARASITIC PRODUCTS, INSECTICIDES AND REPELLENTS 127
ATC: R RESPIRATORY SYSTEM 696
ATC: S SENSORY ORGANS 1 462
ATC: V VARIOUS 159
 Reaction Count
SOC: Blood and lymphatic system disorders 27
SOC: Cardiac disorders 182
SOC: Congenital, familial and genetic disorders 4
SOC: Ear and labyrinth disorders 112
SOC: Endocrine disorders 1
SOC: Eye disorders 112
SOC: Gastrointestinal disorders 720
SOC: General disorders and administration site conditions 470
SOC: Hepatobiliary disorders 52
SOC: Immune system disorders 559
SOC: Infections and infestations 46
SOC: Injury, poisoning and procedural complications 2
SOC: Investigations 23
SOC: Metabolism and nutrition disorders 35
SOC: Musculoskeletal and connective tissue disorders 25
SOC: Neoplasms benign, malignant and unspecified (incl cysts and polyps) 2
SOC: Nervous system disorders 607
SOC: Pregnancy, puerperium and perinatal conditions 3
SOC: Psychiatric disorders 79
SOC: Renal and urinary disorders 49
SOC: Reproductive system and breast disorders 60
SOC: Respiratory, thoracic and mediastinal disorders 194
SOC: Skin and subcutaneous tissue disorders 2 460
SOC: Vascular disorders 154