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Pharmacovigilance MK Farmasi Komunitas Bagian Farmasi Klinik dan Komunitas Fak Farmasi Univ Jember.

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Presentasi berjudul: "Pharmacovigilance MK Farmasi Komunitas Bagian Farmasi Klinik dan Komunitas Fak Farmasi Univ Jember."— Transcript presentasi:

1 Pharmacovigilance MK Farmasi Komunitas Bagian Farmasi Klinik dan Komunitas Fak Farmasi Univ Jember

2 Defined by WHO, pharmacovigilance is – The science and activities relating to detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. Spontaneous ADR reporting system Pharmacovigilance is not only a science of adverse drug effects!

3 A response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Problems: – Including minor adverse reactions, e.g.? – Excluding error as a source of adverse effects ADR Definition (WHO 1972)

4 Exclude minor adverse reactions A harmful or significantly unpleasant effect caused by a drug at doses intended for therapeutic effect (or prophylaxis or diagnosis) which warrants reduction of dose or withdrawal of the drug and/or foretells hazard from future administration. Problems: – Excluding error as a source of adverse effects ADR Definition (Laurence & Carpenter, 1998, A dictionary of pharmacology and allied topics)

5 Proposed definition of adverse drug reaction: An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product. ADR Definition (Edwards & Aronson, 2000)

6 An adverse drug reaction (ADR) is ‘a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man’. It concerns: – the response of a patient, in which individual factors may play an important role, – the phenomenon is noxious (an unexpected therapeutic response, for example, may be a side effect but not an adverse reaction). Currently accepted international terminology of ADR Main goal: improving pharmacovigilance communication, integrated with other WHO’s project: International Classification of Diseases (ICD, 10 th version) – And, there still have a problems: combining the terminology with bibliographic databases (Uppsala Monitoring Centre) WHO’s Adverse Drug Reaction Terminology (WHO-ART), 1992

7 WHO, 1992: A side effect is ‘any unintended effect of a pharmaceutical product occurring at doses normally used by a patient which is related to the pharmacological properties of the drug’. Essential elements – the pharmacological nature of the effect, that the phenomenon is unintended – there is no deliberate overdose, at normal dose Side Effect and Toxic Effect?

8 So, the differences are... Side Effect Occured in normal dose Not always dose-dependent Not via therapeutic effect Maybe beneficial E.g. – Anaphylaxis of penicillins – Anticholinergic activity of tricyclic antidepressants – Beta-blocker activity for hypertension and angina Toxic Effect Occured in overdose Always dose-dependent Via therapeutic effect Always harmful E.g. – a headache due to a calcium antagonist is a toxic effect (vasodilatation)

9 ADR, Side Effect, and Toxic Efect Side Effect Toxic Effect Adverse Effect Adverse Effect  from point of view of the drug Adverse Drug Reaction  from point of view of patient

10 Adverse Effect: always drug- related Adverse Event: not always drug-related But, we have to distinguish ADVERSE EFFECT and ADVERSE EVENT


12 Dose dependent Predictable from the known pharmacology of the drug Common and low mortality Case: – Digoxin toxicity – Serotonine syndrome with SSRIs – Anticholinergic effects of tricyclic antidepressants A (Augmented) BCDEF - Mnemonic

13 Non dose dependent Unpredictable from the known pharmacology of the drug Uncommon and high mortality Case: – Penicillin hypersensitivity – Acute porphyria – Malignant hyperthermia AB (Bizarre) CDEF

14 Dose-related and time-related Uncommon Related to the cummulative dose Case: – Hypothalamic-pituitary-adrenal axis supression by corticosteroids ABC (Chronic) DEF

15 Time-related and usually dose-related Uncommon Occurs or become apparent after some time the use of the drug Case: – Vaginal adenocarcinoma with diethylstilbestrol – Carcinogenesis – Tardive dyskinesia ABCD (Delayed) EF

16 Withdrawal Uncommon Occurs soon after withdrawal of the drug Case: – Opiate withdrawal syndrome – Myocardial ischaemia (beta-blocker withdrawal) ABCDE (End of Use) F

17 Unexpected failure of therapy Common Dose-related Often caused by drug interactions Case: – Inadequate dosage of an oral contraceptive when used with specific enzyme inducers ABCDEF (Failure)

18 Erythromycin and nausea-vomitting Case

19 The DoTS Classification

20 Supratherapeutic doses  toxic dose Collateral effects, at standard/ normal therapeutic dose  commonly named side effect Hypersusceptibility reactions Do (Dose relatedness) TS

21 Time independent reactions Time dependent reactions – Rapid reactions, e.g. the red man syndrome with vancomycin – First dose reactions, e.g. Hypotension after the first dose of an ACE-inhibitor Type I hypersensitivity reactions – Early reactions, e.g. Nitrate induced headache – Intermediate reactions, e.g. Type II-IV hypersensitivity reactions – Late reactions, e.g. Adverse effects of corticosteroids, tardive dyskinesia with dopamine receptor antagonists – Delayed reactions, e.g. Teratogenesis due to thalidomide DoT (Time relatedness) S

22 Genetic, e.g. – Porphyria – Malignant hyperthermia – CYP isoenzyme polymorphism Age, e.g. – Neonates and chloramphenicol – Elderly people with hypnotics DoTS (Susceptibility sources)

23 Sex, e.g. – Alcohol intoxication – Mefloquine and neuropsychiatric effect – ACE-inhibitor and cough – Lupus-like syndrome Physiology altered, e.g. – Phenytoin in pregnancy DoTS (Susceptibility sources)

24 Exogenous factors, e.g. – Drug interactions – Interactions of GJ with drugs metabolized by CYP3A4 Disease, e.g. – Renal insufficiency with lithium – Hepatic chirrosis with morphine DoTS (Susceptibility sources)

25 Signal detection Evaluation and investigation Taking action Communication Crisis management Process in Pharmacovigilance

26 Signal is – Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report, depending upon: – the seriousness of the event and – the quality of the information Signal Detection What is signal?

27 The data source may be associated with: – Previously unrecognised hazard – Known hazard that may be different from existing knowledge Quantitatively  more frequent Qualitatively  more serious Tiaprofenic acid and cystitis in mid-1990s Signal Detection What is signal?

28 Number of reports to generate a signal: When the suspected ADR is a disease which is rare in the general population (e.g. aplastic anaemia, toxic epidermal necrolysis) a very small number of cases associated with a single drug is unlikely to be a chance phenomenon, even if the drug has been used quite widely. Except for certain types of event that are particularly important and likely to be drug related (e.g. anaphylaxis)  three cases Signal Detection Processes for signal detection

29 “Profiling” to create “ADR profile” and to find the “disproportionality” Profiling – Creating the proportions of all ADRs for a particular drug that are of a specific type – perhaps within an organ system class of reactions (e.g. gastrointestinal or cutaneous). Signal Detection Processes for signal detection

30 Example of profiling process UK Yellow Card, mid-1990s: ± 600,000 suspected reactions in 30 years  ± 800 classified as ‘uveitis’ – about 0.13% rifabutin  some 41 cases of uveitis from total 55 reactions in that time (i.e. 75% of them were uveitis). Signal Detection Processes for signal detection

31 Signal Detection Uveitis

32 Signal Detection Processes for signal detection PRR: Proportional Reporting Ratio

33 Example of profiling process Cut-off points for a minimum signal: – PRR > 3 – Chi-squared > 4 (roughly 5% of statistical significance) – N = 3 or more Visualisation of data (ADR profiles) Signal Detection Processes for signal detection

34 Number of reports (N) as the symbol


36 Another measure of disproportionality: – Reporting Odds Ratio (ROR)  Netherlands – Information Component (IC, Bayesian)  WHO – US FDA  Multi-Item Gamma Poisson Shrinker (MGPS, Bayesian) Signal Detection Processes for signal detection

37 Overview of Pharmacovigilance Programmes Tujuh negara yang tidak memiliki program farmakovigilans: Banglades, Ekuador, Liberia, Malawi, Mauritius, Timor Leste, Uni Emirat Arab Kedudukan struktural: – Tergabung dalam Drug Regulatory Agency: 70% (n=31) – Tergabung dalam Ministry of Health: 20% – Tergabung dengan universitas atau lembaga akademis: 10% Pusat kegiatan: – 60% (n=28) tersentralisasi – 40% (n=20): regional center atau sentinel sites

38 Overview of Pharmacovigilance Programmes Sumber daya manusia pada setiap pusat: – 1 petugas : 6 negara – 2-4 petugas : 17 negara – 5-9 petugas : 14 negara – petugas: 3 negara – petugas: 2 negara – >30 petugas : 3

39 TI, Dukungan Internet dan Akses thd Referensi Hampir semua (n=46 dari 48) mengakses komputer Komputer yg didisain spesifik unt farmakovigilans: 11 negara Komputer tdk begitu mendukung kebutuhan farmakovigilans: 11 negara 32 negara mengeklaim memiliki akses cukup thd referensi ttg keamanan obat dari perpustakaan lokal atau internet

40 Spontaneous Reporting Macam-macam Aktivitas Hanya farmakovigilans: 6 negara (13%) + informasi obat: 63% + promosi keamanan obat: 52% + penggunaan obat rasional: 46% + informasi keracunan: 15%

41 Spontaneous Reporting Macam-macam Aktivitas

42 Spontaneous Reporting Who Reports Di 33 negara (67%): menjadi persyaratan legal untuk pemegang izin edar obat 8 negara (17%): persyaratan legal untuk tenaga kesehatan All (n=48): dokter 98% (n=47): farmasis 90%: perawat 79%: produsen 58%: pasien 38%: traditional therapist

43 Spontaneous Reporting What is Reported Di 33 negara (67%): menjadi persyaratan legal untuk pemegang izin edar obat 8 negara (17%): persyaratan legal untuk tenaga kesehatan All (n=48): dokter 98% (n=47): farmasis 90%: perawat 79%: produsen 58%: pasien 38%: traditional therapist


45 Kegunaan MESO BADAN PENGAWASAN OBAT Menilai hubungan kausal obat dengan gejala yang dicurigai sebagai keluhan efek samping obat → berdampak pada peredaran dan penandaan obat PERUSAHAAN FARMASI Pengamanan investasi yang telah ditanamkan dalam pengembangan dan penelitian obat baru → berdampak pada keamanan obat SISI AKADEMIK Menguji suatu hipotesis → analisa struktur kimia obat atau golongan obat Misal: MESO Cimetidine dilakukan karena struktur kimianya mirip dengan Methiamide yang telah ditarik karena menyebabkan agranulositosis

46 Form dan Buletin MESO POM Form MESO nasional Buletin MESO POM – Terbit 1 tahun 2 kali – Tersedia dalam bentuk elektronik – Tips: Via  buletin berita eso

47 Cara MESO LAPORAN INSIDENTAL – biasanya dikemukakan pada pertemuan-pertemuan di RS atau laporan kasus di majalah – tidak dapat tersebar dengan cepat karena tidak ada organisasi nasional yang mengatur – pengendalian ESO yang diduga, sangat tergantung pada motivasi masing-masing klinikus LAPORAN SUKARELA – dikoordinir oleh pusat – disebut “laporan spontan” – diminta melaporkan ESO pada praktek sehari-hari

48 Cara MESO LAPORAN INTENSIF di RS – kelompok dokter, perawat terlatih, ahli farmasi mencari dan mengumpulkanESO – populasi tertentu dan terbatas di RS – data yang terkumpul dianalisa oleh tim ahli

49 Cara MESO LAPORAN LEWAT CATATAN MEDIK – pengumpulan data melalui riwayat penyakit serta pengobatan yang diterima dari bermacam sumber – mungkin dikerjakan di tempat di mana pelayanan medik yang lengkap, terorganisir baik dan fasilitas komputer yang canggih LAPORAN WAJIB – ada peraturan yang mewajibkan setiap petugas kesehatan melaporkan ESO di tempat tugas atau praktek sehari-hari

50 References Aronson JK, Ferner RE, 2003, Joining the DoTS: new approach to classifying adverse drug reactions, BMJ, 327, p Edwards, IR, Aronson, JK, 2000, Adverse drug reactions: definitions, diagnosis, and management, The Lancet, 356, p Olsson S, Pal SN, Stergachis A, Couper M. Pharmacovigilance activities in 55 low- and middle-income countries: a questionnaire-based analysis, Drug Saf, 2010 Aug 1;33(8):689–703. Waller, P., 2010, An Introduction to Pharmacovigilance, John Wiley and Sons: West Sussex

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