دکتر فرهاد گودرزیان نماینده ADR معاونت غذا وداروی اصفهان

What is an ideal drug? 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.

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. 4/22/2017

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: مطابق تعريف WHO عارضه نا خواسته دارويی عبارتست از: هرگونه پاسخ ناخواسته وزيان آور که در مقادير مصرف معمول 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

Why Are There So Many ADRs? So many prescriptions!

Why Are There So Many ADRs? 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 Things to say Not all ADRs will be apparent to the patient or the health care professional as ADRs can mimic any disease process. Always be alert to the possibility of ADRs as a cause of the patients symptoms. Useful information Quote taken from Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000; 356: 1255-1259

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 Things to say Age – The very old and the very young are more susceptible to ADRs. In children, systems for handling drugs are not developed and in the elderly these systems may be slowing with age. The elderly are also likely to have multiple and often chronic diseases. E.g. Elderly patients much more susceptible to the effects of benzodiazepines leading to drowsiness the next day. Gender – Women appear to be at a higher risk of suffering ADRs. The reason is not clear. Multiple therapies – The incidence of ADRs increases sharply with the number of drugs taken, 50% patients on 5 drugs are likely to experience an ADR. Intercurrent diseases – Drug handling may be altered in patients with renal, hepatic, and cardiac disease. Allergy – patients with a history of allergic disorders are at the greatest risk of experiencing an allergic reaction. Useful information Specific diseases predispose to ADRs eg in HIV positive patients there is an increased frequency of idiosyncratic toxicity with anti-infective drugs such as co-trimoxazole (50% vs 3% in HIV negative patients).

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 week ACHP

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

Why Should We Report ADRs?! 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 experiments 2- Clinical trials 3- 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

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 population All medicines Hospital and out-patient care Long perspective Patient analysis possible Non-interventional Cheap

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

Prevention of ADRs in Human. Pharmacovigilance Detection, Assessment & Prevention of ADRs in Human. Ref: World Health Organization.

فارماکوويژيلانس به تمام شيوه وروش های ارزيابی و پيشگيری از ADRs گويند. شناسايی ، ارزيابی ، گزارش عوارض ناخواسته دارويی و پيشگيری از وقوع آنها در انسان رافارماکوويژيلانس 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 پ-م خانم 38 ساله با وزن 55 کیلوگرم است که به علت سردرد شدید به همراه تهوع واستفراغ به اورژانس بیمارستان مراجعه نموده است.در شرح حال بیمار عنوان می نماید که سردردش ازحدود 8روز پیش آغاز گردیده وبه تدریج میزان سردرد افزایش یافته به طوری که دیگر قابل تحمل نبوده است. در سابقه مصرف دارو بیمار تنها سابقه مصرف قرص LD را جهت پیشگیری از بارداری از 9 ماه پیش اعلام می دارد وسابقه ای از عارضه دارویی قبلی یا بیماری خاصی را ذکر نمی نماید.با توجه به اینکه بیمار از زرین شهر مراجعه نموده و از قرص شرکت بهبود با شماره ساخت 132895 استفاده نموده فرم زرد را تکمیل نمایید.

OCPعوارض شایع ترین: سردرد- سرگیجه - تهوع – بی نظمی در خونریزی قاعد گی مهم ترین: ترومبوآمبولی – آمبولی ریه – ایست قلبی عروقی – پانکراتیت – تومور کبدی – انفارکتوس میوکارد – ترومبوز کرونر – خونریزی مغزی – هیپرتانسیون – بیماریهای صفراوی – تومور کبدی نیاز به تماس به پزشک : احساس درد یا فشار در قفسه سینه – بی حسی یا سفت شدن پا – درد در پا یا باسن – تنگی نفس – سردرد شدید – اختلا ل بینایی – ترشح یا خونریزی غیر عادی از واژن – احساس وجود تود ه درسینه ها یا درد شدید شکم

The FDA Safety Information and Adverse Event Reporting Program: MedWatch The FDA Safety Information and Adverse Event Reporting Program: www.fda.gov/medwatch/ Safety alerts Recalls Withdrawals Important labeling changes Biologicals, Drugs, Dietary supplements

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