ADR. EBM.ADR. EBM.

3. cvičenie3. cvičenie

• 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!!!

risk

benefit

pharmacotherapy

PharmacovigilancePharmacovigilance

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 safetyto prove product safety

PharmacovigilancePharmacovigilance• We take into consideration during drug selection:

– EFFICACY– SAFETY– PRICE– SUITABILITY

• in 60th after talidomid scandal, WHO established monitoring focused to earlyearly dete detection of ADRction of ADR

• WHO created system of spontanneous ADR monitoring with center in Uppsala (Sweden)

TALIDOMIDTALIDOMID

• 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 ADVANTAGES of pharmacovigilancepharmacovigilance

at at worldwideworldwide cooperation 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 ADRRisk factors of ADRDrugDrug

• nonselective and nonspecific

• with narrow therapeutics range

• lipophilic

Prescription• Wrong selection of drug, drug

combination, dose, route of administration, therapy length

PacientPacient• 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 I. ADR according to mechanism of mechanism of originorigin

1.     Typ1.     Typee A („augmented“) 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. 2. TypTypee B („bizard“) 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 ...

TYPTYPEE A A TYPTYPEE BBPredictability + –

Dosage dependence

+ –

Occurrence high low

Mortality

low high

Treatment dose adjustment

stopping administration

1 drug – different types of ADR1 drug – different types of ADR

DRUGDRUG Type A reactionType A reaction Type B reactionType B reaction

Ampicillin Pseudomembr. colitis

Intersticial nephritis, allergy

Chlorpropamid Sedation Hepatotoxicity

Naproxen GIT haemorrhage Agranulocytosis

Warfarin Bleeding Breast necrosis

3. 3. TypTypee C („continous“) 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. 4. TypTypee D („delayed“) D („delayed“)

• late ADR (years resp. generations)• teratogenity• carcinogenity• mutagenity• e.g.: ca. of vagina at daughters of mothers treated

with dietylstilbestrol 

5. 5. T Typypee E („End of use“) E („End of use“) • after therapy ending (syndrom from omitting) • rebound phenomenon• e.g.: beta blockers, opioids, corticosteroids, nitrates ...

II. ADR according to II. ADR according to intensityintensity

• mild –mild – don´t require to stop or to change treatment

• moderate –moderate – require to change therapy, but don´t

threat life of the patient

• serious – serious – death, hospitalization, invalidization,

teratogenity

III. ADR according to III. ADR according to frequencyfrequency

Frequency

• frequent >1,0 % (sedative effect after

promethazin)

• seldom >0,1% (rhabdomyolysis after statins)

• rare > 0,01% (agranulocytosis after

metamizol)

Determination of causalityDetermination of causality

Basic categories:

A. High probability of causality

B. No sufficient proof of causality

0. Isn´t possible to evaluate causality

AACTIONS AT PROOF OF CTIONS AT PROOF OF CAUSALITYCAUSALITY

•          warning

•          methodic direction

•          limitation of indication

•          change of dose

•          deregistration of the drug

Deregistered drugsDeregistered 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 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)

PREDP

ÍŠTE

RECEPT