گودرزیان فرهاد دکتراصفهان ADRنماینده وداروی غذا معاونت

• In the early 1900s Paul Ehrlich described an ideal drug as a magic bullet. magic bullet. Such a drug would be aimed precisely at a disease site and would not harm healthy tissues.

What is an ideal drug?

04/19/23

Risk

• No medicinal product is entirely or absolutely safe for all people, in all places, at all times. We must always live with some measure of uncertainty.

We Must Always Ask:

• Do the potential benefits outweigh the potential risks for this individual?

ACHP

Adverse Drug Reaction

WHO definition:Any response to a drug which is Noxious and Unintended, and which occurs at doses

used in man for prophylaxis, diagnosis or treatment.

:تعريف

عارضه نا خواسته WHOمطابق تعريف دارويی عبارتست از:

هرگونه پاسخ ناخواسته وزيان آور که در

مقادير مصرفمعمول دارو جهت تشخيص، پيشگيری و

.درمان بيماری ايجاد شود

History of drug safety after thalidomide eradication

1961 :

Dr William McBride (Australia)( thalidomide 4000 cases)

1964 :

UK started “yellow cards” system

1968 :

start of WHO Programme for International Drug Monitoring

Why Should We Learn about Adverse Drug Reactions (ADR)?

Over 2 MILLION serious ADRs yearly

100,000 DEATHS yearly

6.7% of hospitalized patients have an ADR with a fatality of 0.32,

Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Annual death rates in USA

AIDS 16,516 Breast cancer 42,297 Highway accidents 43,458 ADR 100,000

Costs Associated with ADRs

$ 136 BILLION yearly (related to morbidity and mortality)

Greater than total costs of cardiovascular or diabetic care.

Mean length of stay, cost and mortality ADR patients are DOUBLE that for control group of patients without ADR.

ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients.

Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

ADR has financial and social effects:

1- Unreliability on manufacturer 2- Unreliability on health system (Physician, Pharmacist & Nurse) 3- Unreliability on governments in saving the social safety 4- Causing mortality & morbidity

So many prescriptions!

Tow-thirds of patients visits result in a prescription

2.8 BILLION outpatients prescriptions were filled in the year 2000 (about 10 prescriptions per person in the U.S.)

ADRs increase exponentially with 4 or more medications

Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Who might get an ADR?

• Anyone who takes a medicine – Differential diagnosis should include the

possibility of an ADR if the patient is taking any form of medication

Who is most at risk from ADRs?

Patients who;

• are young, or old or female

• are taking multiple therapies – 50% of patients on 5 drugs or more

• have more than one medical problem

• have a history of allergy or a previous reaction to drugs

Older Adults and Medications

• Older adults make up 13% of population

• Account for:– About 30% of prescribed

medications – About 40% of over-the-counter

medications

• At least 90% take at least one prescription medication

• 12% use ten or more per weekACHP

Even more, dramatic situation with drug safety is in developing countries (IRAN)

• They often have older, cheaper drugs which may be more toxic.

• Health professional have less opportunity for post-graduate education on clinical pharmacology.

• Useful,easily available, balanced information on adverse effects and their management is absent or not enough.

• Ref:World Health Organization

Assessment the quality of medications

Assessment of drug safety

Detection of occurrence rate of ADR

Decreasing the risk of occurrence of adverse events

How Knowledge About ADRs Is Created?

1-Animal experiments2- Clinical trials3- Epidemiological methods

Spontaneous reporting Cohort studies Case-control studies

Limitations of Clinical Trials

Limited size Narrow population Narrow indications Short duration

• Ref: J. Russell May. Adverse drug Reactions and interaction, In: Pharmacotherapy, A pathophysiologic Approach. 1997, Appleton &

Lange.

How many patients one needs to treat to see with high probability the reaction?

Pre-marketing studies are carried out in limited number of patients: “The law of three”– In order to detect for sure SAE that occurs as 1 event per

2000 patients treated we need to treat • 6000 patients for 1 case• 9600 patients for 2 cases• 13000 patients for 3 cases

• The number of patients involved in pre-marketing studies has been increasing but is still limited in comparison with the exposure to the drug in post-marketing phase

Drug Development

Phase IVPost-approval studies to

determine specific safety issues

Clinical development of medicines

Animal experiments for acute toxicity, organ

damage, dose dependence, metabolism, kinetics,

carcinogenicity, mutagenicity/teratogenicity

PreclinicalAnimal Experiments

Phase I Phase II

Development Post Registration

Phase III Phase IVPost-approval

SpontaneousReporting

Reg

istr

atio

n

Phase I

20 – 50 healthy volunteers to gather preliminary data

Phase II150 – 350 subjects with disease - to determine

safety and dosage recommendations

Phase III250 – 4000 more varied

patient groups – to determine short-term safety

and efficacy

Some drugs cause serious ADRs at very low frequencies

bromfenac hepatotoxicity

1 in 20,000 patients,

removed from the market in 1998, less than 1 year after it was

introduced).• Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Examples of product recalls due to toxicity

• Medicine Year

• Thalidomide 1965• Practolol 1975• Clioquinol 1970• Benoxaprofen 1982• Terfenadine 1997• Rofecoxib 2004• Veralipride 2007

• Examples of serious and unexpected adverse events leading to withdrawal of medicine

• Phocomelia• Sclerosing peritonitis• Subacute nephropathy• Nephrotoxicity, cholestatic

jaundice• Torsade de pointes• Cardiovascular effects• Anxiety, depression,

movement disorders

Spontaneous Reporting

Large populationAll medicinesHospital and out-patient careLong perspectivePatient analysis possibleNon-interventionalCheap

Pharmaco - Vigilance

• Pharmaco = medicine

• Vigilare = to watch

– alert watchfulness– forbearance of sleep; wakefulness– watchfulness in respect of danger; care;

caution; circumspection– the process of paying close and continuous

attention

Detection, Assessment&

Prevention of ADRs in Human.

Ref: World Health Organization.

فارماکوويژيالنس

از • پيشگيری و ارزيابی های وروش شيوه تمام بهADRs. گويند

ارزيابی شناسايی • ناخواسته ، عوارض گزارش ،و دارويی

رافارماکوويژيالنس انسان در آنها وقوع از پيشگيری گويند.

Recent trends: enlarging the scope of pharmacovigilance

Pharmacovigilance concerns have been widened to include:– herbal medicines

– traditional and complementary medicines

– blood products

– biologicals

– vaccines

– medical devices

Pharmacovigilance Major Aims

Early detection of unknown reactions and interactions

Detection of increase in frequency Identification of risk factors Quantifying risks Preventing patients from being

affected unnecessarily RATIONAL AND SAFE USE OF

DRUGS

Ref: World Health organization.

The ultimate goal of pharmacovigilance is

improving pharmacotherapy

Ref:World Health Organization

CASE STUDY 6

– - خانم م وزن 38پ با علت 55ساله به که است کیلوگرماورژانس به واستفراغ تهوع همراه به شدید سردرد

. عنوان بیمار حال شرح در است نموده مراجعه بیمارستانازحدود سردردش که نماید وبه 8می گردیده آغاز پیش روز

قابل دیگر که طوری به یافته افزایش سردرد میزان تدریج. است نبوده سابقه تحمل تنها بیمار دارو مصرف سابقه در

قرص از LDمصرف بارداری از پیشگیری جهت پیش 9را ماهبیماری یا قبلی دارویی عارضه از ای وسابقه دارد می اعالم . شهر زرین از بیمار اینکه به توجه با نماید نمی ذکر را خاصی

ساخت شماره با بهبود شرکت قرص از و نموده مراجعه132895. نمایید تکمیل را زرد فرم نموده استفاده

OCPعوارض

: ترین در- - – شایع نظمی بی تهوع سرگیجه سردردگی قاعد خونریزی

: ترین عروقی – – مهم قلبی ایست ریه آمبولی ترومبوآمبولیترومبوز– – – – میوکارد انفارکتوس کبدی تومور پانکراتیت

بیماریهای – – – هیپرتانسیون مغزی خونریزی کرونرکبدی – تومور صفراوی

پزشک : به تماس به سینه نیاز قفسه در فشار یا درد احساستنگی– – – باسن یا پا در درد پا شدن سفت یا حسی بی

خونریزی – – – یا ترشح بینایی ل اختال شدید سردرد نفسدرد – یا ها درسینه ه تود وجود احساس واژن از عادی غیر

شکم شدید

The FDA Safety Information and Adverse Event Reporting Program:

Safety alerts Recalls WithdrawalsImportant labeling changesBiologicals, Drugs, Dietary supplements

MedWatch

www.fda.gov/medwatch/www.fda.gov/medwatch/

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