ADR. EBM.

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

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)

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

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 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%

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 („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 ...

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

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

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“) 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 ...

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 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

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

Determination of causality Basic categories: High probability of causality 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)