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3. cvičenie
ADR. EBM.
• Each pharmacotherapy means
risk akceptation,
each drug can have potential
risk for patient
benefit
• Risk of pharmacotherapy
should never exceed risks
of not treating particular
disease!!!
risk
Pharmacovigilance
Includes all aspects of postmarketing
development:
- monitoring of clinical safety
- identification of new threats
- estimation of risk and contribution
- action and communication
Goal: to prove product safety
Pharmacovigilance
• We take into consideration during drug selection:
–
–
–
–
EFFICACY
SAFETY
PRICE
SUITABILITY
• in 60th after talidomid scandal, WHO established
monitoring focused to early detection of ADR
• WHO created system of spontanneous ADR
monitoring with center in Uppsala (Sweden)
TALIDOMID
• 1959-1961: sedative, hypnotic drug for
pregnant women (marketed in Germany, England,
Canada..., never in USA)
• Born were > 12 000 children with
phocomelia
• Now: new indications – imunomodulatory,
antiangiogenic and antiinflammatory
properties:
– skin lupus erythematodes
– skin form of lepra
– Kaposi´s sarcoma at AIDS ...
ADVANTAGES of
pharmacovigilance
at worldwide cooperation
• Large number of treated patients
• Detection of possible race variations
• Detection of rare ADR
• Possibility of soon warning of particular
drug risk all over the world
SIDE EFFECT
Each unintend drug effect, occuring at normal
doses used for patients, which is in relation to
pharmacologic properties of drug.
(antihypertensive effect of
minoxidil
+
hypertrichosis)
ADVERSE EVENT Each noxious health event,
which can occur during therapy, but doesn´t have
to have relation with this therapy.
(patient takes ATB and breaks his leg)
ADVERSE DRUG REACTION =
ADR
• Reaction to drug which is noxious and unintended
and occurs at doses of drugs normally used for
prophylaxis, diagnosis or treatment of disease or to
modify physiologic functions
• Detection of ADR at targeted monitoring 10-30%.
• At spontanneous monitoring < than 1%.
• Intoxications and mistakes in therapy don´t belong
here
 UNEXPECTED ADVERSE REACTION
Adverse reaction whose character or intensity isn´t in
concordance with domestic informations about drug
or isn´t expected according to drug characteristic.
 SIGNAL
Reported information about possible causal
relationship between adverse event and, this
relationship was yet unknown or incompletely
documented. Usually more than 1 report is required for
signal.
Risk factors of ADR
Drug
Pacient
• nonselective and nonspecific
• with narrow therapeutics range
• lipophilic
Prescription
• Wrong selection of drug, drug
combination, dose, route of
administration, therapy length
• polymorbidity
• diseases of organs of
elimination
• age, women
• pharmacokinetic variability
(etnic group, genetic
polymorphism)
• compliance
Number of drugs
0-5
6-10
11-15
> 16
ADR
4%
10%
28%
54%
I. ADR according to mechanism of
origin
1.
Type A („augmented“)
• these ADR are expected
• they can be predicted on the base of
pharmacodynamic properties of drug
• they depend on drug dose, they appear at higher
doses
• frequency is high > than 1%
• mortality is low
• therapy consists in dose adjustment
• e.g.: cough after ACEI, bleeding from GIT after
NSA, aspirin, corticoids ...
rash
2.
Type B („bizard“)
• idiosyncratic reactions
• these ADR are not expected
• they can be hardly predicted
• doesn´t depend on dose
• frequency is low < than 0,1%
• mortality is high
• treatment consists in stopping drug administration
• e.g.: haemolytic anaemia after metyldopa,
hepatitis induced by isoniazid,
allergic reaction after PNC ...
TYPE A
TYPE B
Predictability
+
–
Dosage
dependence
Occurrence
+
–
high
low
Mortality
low
high
dose
adjustment
stopping
administration
Treatment
1 drug – different types of ADR
DRUG
Type A reaction
Type B reaction
Ampicillin
Pseudomembr.
colitis
Intersticial
nephritis, allergy
Chlorpropamid
Sedation
Hepatotoxicity
Naproxen
GIT haemorrhage Agranulocytosis
Warfarin
Bleeding
Breast necrosis
3.
Type C („continous“)
• this type of ADR increases number of
“spontanneous“ diseases
• they occur usually after long-lasting
administration
• they are often serious and persistant
• mechanism of genesis is unclear
• they are unexpected, not predictable
• they can´t be verified experimentally
• e.g.: oral contraceptives and increased
occurrence of thromboembolia, analgetic
nephropaty
4. Type D („delayed“)
•
•
•
•
•
late ADR (years resp. generations)
teratogenity
carcinogenity
mutagenity
e.g.: ca. of vagina at daughters of mothers treated
with dietylstilbestrol
5. Type E („End of use“)
• after therapy ending (syndrom from omitting)
• rebound phenomenon
• e.g.: beta blockers, opioids, corticosteroids,
nitrates ...
II. ADR according to intensity
• mild – don´t require to stop or to change treatment
• moderate – require to change therapy, but don´t
threat life of the patient
• serious – death, hospitalization, invalidization,
teratogenity
III. ADR according to
frequency
Frequency
• frequent
>1,0 % (sedative effect after
promethazin)
• seldom
>0,1% (rhabdomyolysis after statins)
• rare
> 0,01% (agranulocytosis after
metamizol)
Determination of causality
Basic categories:
A. High probability of causality
B. No sufficient proof of causality
0. Isn´t possible to evaluate causality
ACTIONS AT PROOF OF
CAUSALITY
•
•
•
•
•
warning
methodic direction
limitation of indication
change of dose
deregistration of the drug
Deregistered drugs
•
•
•
•
•
•
•
troglitazon
benaxoprofen
terfenadin
mibefradil
cerivastatin – 2001-2002
rofekoxib, vadekoxib – 2004-2005
group with the highest risk NSA
(> 30% of deregistrations)
• % of ADR reported at active monitoring :
10-30% (mostly done by
pharmaceutical companies
during clinical trials)
at pasive monitoring < 1%
• Type A ADR: - 80%
• Treatment of ADR represents 13-15% of
therapy costs
• ADR occurs mostly between 1-10 day from
beginning of therapy
EBM (Evidence based medicine )
• EBM brings proofs about efficacy and safety
from large clinical studies
• Applied are relevant statistic methods,
metaanalysis
• These results are used for creating
recommandations for therapy (guidelines)
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