1. ADR. EBM.

2. Each pharmacotherapy means risk akceptation,
each drug can have potential
risk for patient
Risk of pharmacotherapy
should never exceed risks
of not treating particular
disease!!!
pharmacotherapy
benefit
risk

3. 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

4. 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)

5. to the Uppsala Monitoring Centre
In European Union spontaneous reports of suspected ADRs are sent from national pharmacovigilance centers
to the Uppsala Monitoring Centre
where they are processed, evaluated and entered into the WHO International Database

6. TALIDOMID
: sedative, hypnotic drug for pregnant women (marketed in Germany, England, Canada..., never in USA)
Born were > children with phocomelia
Now: new indications – imunomodulatory, antiangiogenic and antiinflammatory properties:
skin lupus erythematodes
skin form of lepra
Kaposi´s sarcoma at AIDS ...

8. 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

9. 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)

10. 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

11. 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.

12. Risk factors of ADR Drug Prescription Pacient Number of drugs 0-5 6-10
nonselective and nonspecific
with narrow therapeutics range
lipophilic
Prescription
Wrong selection of drug, drug combination, dose, route of administration, therapy length
Pacient
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%

13. 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 ...

14. rash

15. 2. Type B („Bizzare“) 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 ...

16. stopping administration
TYPE A
TYPE B
Predictability + –
Dosage dependence
Occurrence
high
low
Mortality
Treatment
dose adjustment
stopping administration

17. 1 drug – different types of ADR
Type A reaction
Type B reaction
Ampicillin
Pseudomembr. colitis
Intersticial nephritis, allergy
Chlorpropamid
Sedation
Hepatotoxicity
Naproxen
GIT haemorrhage
Agranulocytosis
Warfarin
Bleeding
Breast necrosis

18. 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

19. 4. Type D („Delayed“) 5. Type E („End of Use“)
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 ...

20. 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

21. III. ADR according to frequency
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

22. III. ADR according to frequency
frequent >1,0 % (sedative effect after promethazin)
infrequent >0,1% (rhabdomyolysis after statins)
rare > 0,01% (agranulocytosis after
metamizol)

23. Determination of causality
Basic categories:
High probability of causality
No sufficient proof of causality
0. Isn´t possible to evaluate causality

24. ACTIONS AT PROOF OF CAUSALITY
         warning
         methodic direction
         limitation of indication
         change of dose
         deregistration of the drug

25. Deregistered drugs
troglitazon
benaxoprofen
terfenadin
mibefradil
cerivastatin –
rofekoxib, vadekoxib –
group with the highest risk NSA
(> 30% of deregistrations)

26. % 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

27. 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)