Iranian Pharmacovigilance Center 4/6/2019 Iranian Pharmacovigilance Center Research & Development Office Undersecretary for Food & Drug Ministry of Health & Medical Education

Adverse drug reaction (ADR) = any harmful effect caused by administration of a drug at a normal dosage during normal use

Adverse Drug Reaction WHO definition: Any response to a drug which is Noxious and Unintended, and which occurs at doses used in men of prophylaxis, diagnosis or treatment.

Types of Adverse Drug Reactions (A-B-C-D-E): Type A: Augmented pharmacologic effects Dose dependent and predictable (e.g. hypoglycaemia with insulin, bleeding after anticoagulants, drowsiness after opioids) Common but often not severe Usually caused by too high dosage or alered pharmacokinetics (genetic factors, age, reduced renal or hepatal elimination) Most often with drugs that have a steep dose-response curve and/or a low therapeutic index Steep means saturable

Types of Adverse Drug Reactions (A-B-C-D-E): Type B: Bizarre effects (or idiosyncratic) dose independent and unpredictable are relatively rare and may occur with very low doses (e.g. drug allergy – skin rashes – anaphylaxis, blood dyscrasias) Bizarre means very strange or unusual

Types of Adverse Drug Reactions (A-B-C-D-E): Type C: Chronic effects after chronic administration analgesic nephropathy after some analgesics tardive dyskinesia after antipsychotics Type D: Delayed effects teratogenic effects – thalidomide cancerogenic effects – stilbestrol during pregnancy (vaginal carcinoma in daughters 20+years later) Type E: End-of-treatment effects (withdrawal effects) opioids, antiepileptics, anxiolytics, rebound phenomenon- hypnotics

Examples of adverse effects associated with specific medications Bleeding in GIT NSAIDs Thrombosis hormonal contraceptives Ototoxicity, nephrotoxicity aminoglycoside antibiotics Parkinsonism 1st generation (typical) antipsychotics Aplastic anaemia chloramphenicol Agranulocytosis clozapine (atypical antipsychotic) Hair loss anticancer drugs

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Specific ADR Cases

Troglitazone (Rezulin™) Indication: Antidiabetic agent used in combination with insulin or sulfonylurea for Type II diabetes ADR Problem: Hepatotoxicity Indicated by increased liver transaminase levels Some cases of liver transplantation, and a few deaths reported Withdrawn: Rezulin™ recalled from market in 2000 References: http://www.fda.gov/bbs/topics/ANSWERS/ANS00831.html Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

Grepafloxacin (Raxar™) Indication: Oral fluoroquinolone antibiotic ADR Problem: Linked to prolongation of the heart’s QT interval, leading to ventricular arrhythmia Withdrawn: Raxar™ removed from the market in 1999 References: http://www.who.int/medicines/organization/qsm/activities/drugsafety/orgqsmalerts.shtml Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

Cerivastatin (Baycol™) Indication: Oral statin to lower cholesterol ADR Problem: Rhabdomyolysis (injury to skeletal muscle) Muscle weakness and myalgia very common Many cases seen in combination with gemfibrazil Deaths reported with cerivastatin, although no definitive link Withdrawn: Baycol™ removed from the market in 2001 References: Psaty BM, et al, JAMA, 2004 Dec 1; 292 (21), 2622-31 Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

Incidence of adverse drug reactions HOSPITAL IN-PATIENTS:10-20% suffer an adverse drug reaction DEATHS IN HOSPITAL IN-PATIENTS: 0.24-2.9% are due to adverse drug reactions. HOSPITAL ADMISSIONS: 0.3-5% of hospital admissions are due to adverse drug reactions.

quality of life while Minimizing patient risk 4/6/2019 The goal of drug therapy is the achievement of defined therapeutic outcomes that improve a patient’s quality of life while Minimizing patient risk SAFETY EFFICACY

Limitations of Clinical Trials

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

Adverse Drug Reaction Adverse Drug Reaction Pharmacovigilance

Pharmacovigilance in EU: European Medicines Agency (EMA) EudraVigilance - the system of collecting all suspected serious ADRs

Pharmacovigilance in USA: Postmarketing surveillance is overseen by the Food and Drug Administration (FDA), which operates a system called MedWatch, to which doctors or the general public can voluntarily report adverse reactions to drugs

Frequency of adverse drug reactions • 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

Annual death rates in USA AIDS 16,516 Breast cancer 42,297 Highway accidents 43,458 ADR 100,000

percentage of hospital admissions due to adverse drug reactions: USA 28% UK 15.6% France 12.6% Norway 11.5%

exceeds the cost of the medications themselves The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9

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 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.

Incidence of ADRs to be detected Spontaneous background incidence مركز ثبت و بررسي عوارض ناخواسته داروها، دفتر تحقيق و توسعه-معاونت غذا و دارو،وزارت بهداشت درمان و آموزش پزشكي Incidence of ADRs to be detected Spontaneous background incidence Minimum number of patients to be exposed 1 in100 360 1 in 10000 520 1 in 1000 730 1 in 100 2000 3600 7300 20300 136400 1 in 5000 18200 67400 363000 3255000

Adverse reaction Drug Time lag(yr) Pulmonary embolism Oral contraceptive 3 Myocardial infarction Oral contraceptive 5 Death fro asthma Sympathomimetic 4 Jaundice Halothane 7 Colitis Lincomycin 6 Colitis Clindamycin 5 Aplastic anemia Phenylbutazone 6 Ref: J.Russel May.Adverse Drug Reactions and interactions,In:Pharmacotherapy, a pathophysiologic approach.1997, Appleton & Lange.

“yellow cards”

Spontaneous Reporting Large population All medicines Hospital and out-patient care Long perspective Patient analysis possible Non-interventional Not Expensive

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

Pharmacovigilance concerns have been widened to include: Drugs Vaccines Blood products Traditional and complementary medicines herbals Food additives Medical devices Biologicals Biotechnology products cosmetics

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

The sort of ADRs that should be reported are: The American Food and Drug Administration : Death Life-threatening Hospitalization (initial or prolonged) Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life. Congenital anomaly Requires intervention to prevent permanent impairment or damage

ADR Effects (Erythema Multiforme) Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

ADR Effects (Gingival Enlargement due to Ca2+-Channel Blockers) Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005

ADR Effects (Coumadin Necrosis of the Leg) Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

Frequency of ADRs reported during 2004-2010 Year Frequency Percentage P-value 2004 16 2 0.001 2005 10 1.3 2006 12 1.5 2007 162 20.4 2008 82 10.3 2009 229 28.9 2010 237 29.9 Year Unknown 45 5.7 Total 793 100

ADR reporters

Frequency of ADRs with different rout of administration Route of administration Frequency Percentage P-value INJECTION 586 73.9 0.001 ORAL 172 21.7 ORAL& INJECTION 12 1.5 TOPICAL 11 1.4 RESPIRATORY 4 0.5 INTRASPINAL 3 0.4 RECTAL OPHTHALMIC 2 0.3 Total 793 100