Charles University in Prague, Third Faculty of Medicine
Cycle II, Subject: General Pharmacology
Lecture: 12th December 2012
8:00-9:30 Burian Hall, Ruská 87, Prague
ADVERSE DRUG REACTIONS
PHARMACOVIGILANCE
Prof. M. Kršiak
Department of Pharmacology, Third Faculty of Medicine, Charles University
in Prague
Teaching Unit No. 21: Adverse drug reactions
http://vyuka.lf3.cuni.cz/
Risk - benefit evaluation
Benefit/Risk ratio
Exposure to personal risk is recognized as
a normal aspect of everyday life. We
accept a certain level of risk in our lives as
necessary to achieve certain benefits.
Adverse drug reaction (ADR) =
any harmful effect caused by
administration of a drug at a normal
dosage during normal use
Types of Adverse Drug Reactions (A-B-C-D-E):
Type A: Augmented pharmacologic effects - dose
dependent and predictable (e.g. hypoglycaemia with
insulin, bleeding after anticoagulants, drowsiness after
opioids)
They are common but often not severe, they are usually
caused by too high dosage or alered pharmacokinetics
(genetic factors, age, reduced renal or hepatal elimination)
most often with drugs that have a steep dose-response curve
and/or a low therapeutic index
Type B: Bizarre effects (or idiosyncratic) - dose
independent and unpredictable are relatively rare and may
occur with very low doses (e.g. drug allergy – skin rashes –
anaphylaxis, blood dyscrasias)
Types of Adverse Drug Reactions (A-B-C-D-E):
Type C: Chronic effects after chronic administration (e.g.
analgesic nephropathy after some analgesics or tardive
dyskinesia after antipsychotics)
Type D: Delayed effects (e.g. teratogenic effects –
thalidomide , cancerogenic effects – stilbestrol during
pregnancy > vaginal carcinoma in daughters 20+years
later)
Type E: End-of-treatment effects (e.g. withdrawal effects
opioids, antiepileptics, anxiolytics, rebound phenomenonhypnotics)
Examples of adverse effects associated
with specific medications
Bleeding in GIT
NSAIDs
Thrombosis
hormonal contraceptives
Ototoxicity,
nephrotoxicity
Parkinsonism
aminoglycoside antibiotics
Aplastic anaemia
chloramphenicol
Agranulocytosis
clozapine (atypical antipsychotic)
Hair loss
anticancer drugs
1st generation (typical) antipsychotics
Pharmacovigilance
collecting, monitoring, researching, assessing
and evaluating information from healthcare
providers and patients on the adverse effects of
drugs
Major goal of pharmacovigilance is to detect
a signal on an unknown serious adverse drug
reaction as soon as possible
Limits of detecting rare ADRs before drug registration/marketing
Pharmaceutical companies are
required by law in all countries to
report ADRs during clinical trials,
testing new drugs on people before
they are made generally available.
Because these pre-registration clinical
trials involve only several thousand
patients at most,
less-common ADRs are often unknown
when a drug enters the market.
Pharmacovigilance after drug registration/marketing
Postmarketing surveillance
Major sources of information on ADRs:
1.
Spontaneous reporting of suspected ADRs
by healthcare professionals
2.
Reporting of ADRs by pharmaceutical companies
(marketing authorisation holders)
3.
ADRs reported in medical journals
Spontaneous reporting
Spontaneous reporting of suspected ADRs
by healthcare professionals
to their national pharmacovigilance center
(or to the manufacturer)
is indispensable in data-generating
system of pharmacovigilance
Spontaneous reporting of ADRs by physicians
is legally obligatory in many countries
Origin of spontaneous reporting of ADRs by physicians:
Yellow Card Scheme founded in the UK in 1964 –
forms to fill in, sent by post or electronically to the UK pharmacoviligance center
The sort of ADRs that should be reported are:
Yellow Card Scheme
• ADRs that have caused
death or a serious illness
• Any ADR, however minor, if associated
with a new medicine or one that is under
continued monitoring (highlighted in the
British National Formulary (BNF) with a ▼
black triangle)
• Any ADR, however minor, if associated
with a child (under 18 years of age) or in
pregnancy
The sort of ADRs that should be reported are:
The American Food and Drug Administration :
• Death
• Life-threatening
• Hospitalization (initial or prolonged)
• Disability - significant, persistent, or permanent change,
impairment, damage or disruption in the patient's body
function/structure, physical activities or quality of life.
• Congenital anomaly
• Requires intervention to prevent permanent
impairment or damage
Pharmaceutical companies* continually monitor and
assess ADRs in their medicines and are expected to
report of them to authorisation agencies and/or to
certain pharmacovigilance centers
* marketing authorisation holders
Periodic Safety Update Reports (PSURs)
PSUR is an update report, at defined time points after authorisation, of the
worldwide safety experience of a medicinal product. The PSUR is to be
submitted to the authorisation agency (e.g. to the European Medicines Agency)
by a marketing authorisation holder. PSUR provides succinct summary
information together with a critical evaluation of the benefit/risk balance of the
product in the light of new or changing post-authorisation information. This
evaluation should ascertain whether further investigations need to be carried
out and whether changes should be made to the marketing authorisation
(e.g. to the product information).
International collaboration in the field of pharmacovigilance:
WHO International Drug Monitoring Programm
Spontaneous reports of suspected ADRs are sent
from national pharmacovigilance centers (n ≈100)
to the Uppsala Monitoring Centre
where they are processed, evaluated and entered into
the WHO International Database
This may lead to the detection of a signal – an alert
about a possible hazard communicated to members
countries.
Pharmacovigilance in EU:
European Medicines Agency (EMA)
EudraVigilance the system of collecting all suspected serious ADRs
Pharmacovigilance in USA:
Postmarketing surveillance is overseen by the
Food and Drug Administration (FDA),
which operates a system called MedWatch,
to which doctors or the general public can
voluntarily report adverse reactions to drugs
Solid sources of information on ADRs
ADRs in general:
SPC (/Summary of Product Characteristics:
frequency
solid Drug Databases e.g. Micromedex, UpToDate,
BNF, AISLP etc
ADRs recently reported:
e.g. Bulletin of European Medicines Agency (EMA):
PhVWP monthly report on safety concerns, guidelines and
general matters
PhVWP = The CHMP Pharmacovigilance
Working Party
CHMP = Committee for Medicinal Products
for Human Use
Frequency of adverse drug reactions
• Very common (>10%)
>= 1/10
• Common (frequent) (1-10%) > = 1/100 and < 1/10
• Uncommon (infrequent) (0,1 - 1 %) >= 1/1000 and < 1/100
• Rare (0,001-0,1%) >= 1/10000 and < 1/1000
• Very rare (< 0,001 %) < 1/10000
Example: frequency of ADRs in NicotineTransdermal Patches (from SPC):
Psychiatric
Very common 1/10 Sleep disorders including abnormal dreams and
insomnia
Common 1/100; <1/10 Nervousness
Nervous system disorders
Very Common 1/10 Headache, dizziness
Common 1/100;<1/10 Tremor
Cardiac Disorders
Common 1/100;<1/10: Palpitations
Uncommon 1/1000; <1/100 Tachycardia
Respiratory, Thoracic and Mediastinal Disorders
Common 1/100; <1/10 Dyspnoea, pharyngitis, cough
Gastrointestinal Disorders
Very Common 1/10 Nausea, vomiting
Common 1/100;<1/10 Dyspepsia, abdominal pain upper, diarrhoea ,
dry mouth, constipation
Skin and Subcutaneous Tissue Disorders
Common 1/100; <1/10 Sweating increased
Very rare <1/10000 Dermatitis allergic, dermatitis contact,
photosensitivity
Musculoskeletal and Connective Tissue Disorders
Common 1/100; <1/10 Arthralgia, myalgia
Summary – „a message to take home“:
Spontaneous reporting of suspected ADRs
by healthcare professionals
to their national pharmacovigilance center
(or to the manufacturer)
is essential in pharmacovigilance