ADR. EBM.

1. 3. cvičenie ADR. EBM.

2. pharmacotherapy • 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!!! 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 • in60thaftertalidomid scandal, WHO established monitoring focused to early detection of ADR • WHO createdsystem of spontanneousADR monitoringwith centerin Uppsala (Sweden)

5. 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 ...

7. ADVANTAGES of pharmacovigilanceat 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

8. SIDE EFFECT Eachunintenddrug effect, occuring at normal doses used for patients, which is in relation to pharmacologic properties of drug. (antihypertensive effect of minoxidil + hypertrichosis) • ADVERSE EVENTEach noxious health event, which can occur during therapy, but doesn´t have to have relation with this therapy. (patienttakes ATB and breaks his leg)

9. ADVERSE DRUG REACTION = ADR • Reaction to drug which is noxious and unintended and occurs at dosesof drugs normally used for prophylaxis, diagnosis or treatment of disease or to modify physiologic functions • Detection of ADR attargeted monitoring 10-30%. • Atspontanneous monitoring< than 1%. • Intoxications and mistakes in therapy don´t belong here

10. UNEXPECTED ADVERSE REACTION Adverse reaction whose character or intensity isn´t in concordance with domestic informations about drugor isn´t expected according to drug characteristic. • SIGNAL Reported information about possible causal relationshipbetween adverse event and, this relationship was yet unknown or incompletely documented. Usually more than 1 report is required for signal.

11. Drug 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% Risk factors of ADR

12. I. ADR according to mechanism of origin 1.     Type A („augmented“) • these ADRare expected • they can bepredictedon the base ofpharmacodynamic properties of drug • they dependon drug dose, they appear at higher doses • frequencyishigh> than 1% • mortalityis low • therapyconsistsindose adjustment • e.g.:cough after ACEI, bleeding from GIT after NSA, aspirin, corticoids ...

13. rash

14. 2. Type B („bizard“) • idiosyncratic reactions • these ADR arenot expected • they can behardly predicted • doesn´t depend on dose • frequencyis low< than 0,1% • mortality is high • treatment consists instopping drug administration • e.g.: haemolytic anaemia after metyldopa, hepatitis induced by isoniazid, allergic reaction after PNC ...

16. 1 drug – different types of ADR

17. 3. Type C („continous“) • this type of ADR increasesnumberof“spontanneous“ diseases • theyoccurusuallyafterlong-lastingadministration • they are oftenserious and persistant • mechanismofgenesisisunclear • they areunexpected, notpredictable • theycan´tbeverifiedexperimentally • e.g.: oral contraceptives and increasedoccurrenceofthromboembolia, analgeticnephropaty

18. 4. Type D („delayed“) • late ADR (years resp. generations) • teratogenity • carcinogenity • mutagenity • e.g.:ca.ofvaginaatdaughtersofmotherstreatedwithdietylstilbestrol 5. Type E („End ofuse“) • aftertherapyending (syndromfromomitting) • reboundphenomenon • e.g.:beta blockers, opioids, corticosteroids, nitrates ...

19. II. ADR according to intensity • mild –don´trequire to stop or to changetreatment • moderate –require to changetherapy, butdon´tthreatlifeofthepatient • serious – death, hospitalization, invalidization, teratogenity

20. 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)

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

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

23. Deregistered drugs • troglitazon • benaxoprofen • terfenadin • mibefradil • cerivastatin – 2001-2002 • rofekoxib, vadekoxib – 2004-2005 • group with the highest risk NSA (> 30% of deregistrations)

24. % 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

25. 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)

26. P R E D P Í Š T E R E C E P T