Iran ADR Center

Detection, Assessment&

Prevention of ADRs in Human.

Ref: World Health Organization.

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.

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

percentage of hospital admissions due to adverse drug reactions:

USA 28%UK 15.6%France 12.6%Norway 11.5%

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

Since 1995 the costs associated with drug-related problems (DRPs) have

more than doubled.

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

The cost of adverse drug events: estimated lost patient activity days per year in hospitalised patients

Country Serious ADRs Lost Activity Days

US 700,000 1,218,000 Germany 206,000 358,440 UK 148,000 257,520 Australia 48,000 83,520 Sweden 22,000 38,280

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

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.

و دارو،وزارت بهداشت درمان دفتر تحقيق و توسعه-معاونت غذا ومركز ثبت و بررسي عوارض ناخواسته داروها، آموزش پزشكي

Incidence of ADRs to be detected

Spontaneous background incidence

Minimum number of patients to be exposed

1 in100 0 360

1 in 10000 520

1 in 1000 730

1 in 100 2000

1 in 1000 0 3600

1 in 10000 7300

1 in 1000 20300

1 in 100 136400

1 in 5000 0 18200

1 in 10000 67400

1 in 1000 363000

1 in 100 3255000

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

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

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

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

History of drug safety (1)

2003 - 155 years of pharmacovigilance

29.01.1848 15 year old Hannah Greener died in course of routine anaesthesia with chloroform (problem: ingrown nail of toe; fibrillation of ventricles?). Lancet’i initiated foundation of a (required, that the pharmaceuticals should be “pure” and “free of any contamination”, nothing was said about the efficacy)

1936 - USA-s 107 lethal cases (diethylenglycol was used to solubilize sulphanilamides); the law was amended in 1938

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

Drug Classes Responsible for ADRs

Drug Class FrequencyAntibiotics Most frequent

Antitumor agents

Anticoagulants

Cardiovascular agents

Anticonvulsant agents

Antihypertensives

Analgesics

Antiasthmatics

Sedative/hypnotics

Antidepressants

Antipsychotics

Peptic ulcer therapy Least frequentRef: J. Russell May. Adverse Drug Reactions and Interactions, In: Pharmacotherapy, A pathophysiologic Approach. 1997,

Appleton & Lange.

Types of Drug-Related Effects by Frequency

Type of adverse event Frequency Marrow suppression Most frequentBleeding Central nervous systemAllergic/cutaneousMetabolicCardiacGastrointestinalRenalRespiratory Least frequent

Ref: J. Russell May. Adverse Drug Reactions and Interactions, In: Pharmacotherapy, A pathophysiologic Approach. 1997, Appleton & Lange.

Preventing ADR

Over 75% of all ADR are dose-dependent

Many ADR arise from failure to tailor the dosage of drugs to widely different

individual needs.

Ref:World Health Organization

• Patient’s specification • Patient’s drug history• Pharmacology of prescribed drugs• Prescription of minimum effective

dosage

Sex Age (weight) Genetic (PHARMACOGENOMICS) Drug allergy Lack of knowledge in patientsConcomitant drugs

Factors related to patient:

Essential factors causing ADRs:

• Non-compliance - underestimated

• Route of Administration - bioavailability

• Food - protein malnutrition

• Pollutants - smoking/herbicide residues

• Timing - chronopharmacology

Factors related to patient:

Essential factors causing ADRs:

Route of administration Dosage Duration of treatment Problems with drug:

1-Formulation

2-Problems with preparing of drug

Factors related to drug:

1936

• USA : 107 lethal cases diethylenglycol was used to solubilize sulphanilamides

Drugs cause hospitalization

Digoxin 41 Aspirin 25

Aspirin 24 Digoxin 24

Prednisone 15 Warfarin 12

Warfarin n 9 HCTZ 11

Guanethidine 5 Prednisone 8

Type of Alerting Order

• One time stat dose

• PRN orders• Short course therapy

• Abrupt decrease in dose Followed by a stat• Serum level

• State laboratory tests

Example Sub-cutaneous epinephrine, corticosteroids,

dextrose 50%, sodium polystyrene sulfate

Antihistamins, topical corticosteroids Oral corticosteroids (eg.20 mg prednisone p.o 7 days) aminoglycosides, antiarrhythmic agents,

anticonvulsants Theophylline, phenytoin, aminoglycosides, Drug interactions (eg. Digoxin-verapamil,

cimetidine-theophylline) Stool guiac, prothrombin time

فوايد وجود ADR در بيمارستان برنامه

افزايش كيفيت درمان -1جلوگيري از شكايات حقوقي -2

ارزيابي مشكالت دارويي -3ارزيابي مشاهدات پزشكان و ديگر حرف -4

پزشكيارتقاء دانش دارويي دست اندركاران -5

درمان

ADRداليلي كه باعث كاهش گزارشات ميگردد:

عدم اطالع از مكانيزم موجود براي ارسال گزارش -1

عدم دسترسي به فرم مربوطه -2عدم اهميت عارضه از نظر گزارشگر -3

نداشتن وقت -4در رابطه با فرم مربوطه -5

اجتناب از درگيري در كارهاي اداري -6ترس از شكايات حقوقي, كيفري -7عدم اطمينان از -ADR 8توسط دارو

بوجود آمدن

Misconceptions about ADR Reporting

All serious ADRs are documented by the time a drug is marketed

About patient receiving multiple medications,it is difficult

to determine if a drug is responsible for the ADR

ADRs should only be reported if absolutely certain

One reported case can’t make a different

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

Report of Iranian ADR monitoring center

The numbers of reports, registered in ADR center of Iran

The numbers of reports, registered in ADR center of Iran

•From the year 1377 to Mordad 83 , 5861 cases of Adverse Drug Reaction have been sent to Iranian ADR Center

Pharmacovigilance Activities in Iran

Accepted as a full member of WHO International Drug Monitoring Program in July 1998.

Implemented Spontaneous Reporting System in Iran.

Collected more than 6000 ADR reports from different parts of the country.

Issued 38 Alert Letters on drug safety sending to the health professionals.

Pharmacovigilance Activities in Iran

Has published 24 monthly reports in Razi journal.

Has published 9 issues of national ADR Bulletin.

Has over 150 workshops and seminars all over the country.

Has trained over 8000 health professionals on ADRs.

1837 1793

734671

446

17 7

276

730

200

400

600

800

1000

1200

1400

1600

1800

2000

Pharm

acis

t

Genera

l pra

ctiti

oner

Special

ist

Nurse

Patie

nts

Dentist

Clinic

al p

harm

acis

t

Oth

ers

Unknown

Reporters

Official member countriesAssociate member countries

WHO Drug Monitoring ProgrammeParticipating countries 1999

58 countries have joined the programme

-

International Vigilance

Every healthcare professional in the world should be constantly alert for adverse effects or potentional new

hazards and reporting them to their National Centers.

Countries with the best reporting rates generate:

• Over 200 reports per 1,000,000 inhibitants per year.

• Over 150 reports per 1000 physicians per year.

1720

1502

601

469 448

281 235 205112

63 61 57 49 45

0

200

400

600

800

1000

1200

1400

1600

1800

Adverse Drug Reaction vs Drug classes

From:

1377

To

Mordad 83

691

352

223 212

96 90 88 8252 49 40 40 25

0

100

200

300

400

500

600

700

CNS

GI

Body as a whole

Skin & apprndages

Application site

Cardiovascular

Psychiatric

Respiratory

Autonomic

Musculoskeletal

Urinary

Vision

Heart rate & rhythm

Site of Reaction (CNS agents )

From:

77

To

Mordad 83

Site of Reaction (Antibiotics)

596

347

179 167

71 6126 21 18

0

100

200

300

400

500

600

Skin &

Appendag

es GI

Body as

a whole

CNS

Respira

tory

Liver &

bili

ary

Visio

n

Coagula

ting S

ys

Reproduct

ive

From:

77

To

Mordad 83

Diclofenac Na Above 100 Cases of Foot drop

Withdrawal from Iranian Pharmacopoeia

Streptokinase

Bupivacaine

4 Cases of Para-plegia following IT injection

2 of them led to Death

Tramadol?

• From 04.81 to 05.83, 289 cases of adverse effects of Tramadol have reported to ADR center

• Among them :

81 cases have been in Male

&

208 cases have been in Female

0-10 3 11-20 7 21-30 86 31-40 61 41-50 51 51-60 29 61-70 18 71-80 11 >80 3 Unknown 20

Age groups Age groups (Reaction of Tramadol):(Reaction of Tramadol):

84.78%

9.34%5.19%

0.35%

0.35%

IM PO IV ID Unknown

Rout of administration(In patients with Tramadol adverse effects)

Adverse Reaction of Tramadol from 04.81 to 03.83

6 Major Adverse Effects of Tramadol:

•Nausea 125•Vomiting 116•Vertigo 109•Asthenia 57•Dyspnoea 42•Hypotension 41

Adverse effects of Tramadol from 04.81 to 03.83

Reaction Number Reaction Number

Sweating 24 Myalgia 7

Headache 21 Pale 7

Agitation 20 Ataxia 6

Somnolence 17 Vision disorders 6

Pruritus 16 Paraesthesia 6

Rigors 15 Injection site reaction 6

Flushing 11 Delusion 6

Urticaria 11 Tachycardia 6

Bronchospasm 10 Respiratory depression 6

Hallucination 9 Palpitation 5

Convulsion 9 Rash 4

Hypertension 8 Cold extremity 4

Confusion 8 Apnoea 3

Abdominal pain 8 Anxiety 3

Dry mouth 7 Stupor 3

Reaction Number Reaction Number

Cardiac arrest 3 Back pain 1

Anorexia 3 Arrhythmia 1

Shock 3 Bradycardia 1

Allergic reaction 2 Lacrimation abnormal 1

Cyanosis 2 Myocardial Ischemia 1

Constipation 2 Diarrhea 1

GI disorders 2 Depression 1

Leg pain 2 Erythem 1

Dysphagia 2 Coma 1

Speech disorders 2 Edema 1

Urinary retention 2 Hearing decrease 1

Chest pain 2 Facial pain 1

Fever 2 Withdrawal syndrome 1

Syncope 2 Foot drop 1

Insomnia 2 Tremor 1

Adverse effects of Tramadol from 04.81 to 03.83

Sildenafil

•Sildenafil has cardiac related side effect.

•Some cases of myocardial infarction were reported to ADR center due to this

drug.

The following tips must be reminded when using Sildenafil:

• Cardiovascular adverse effects such as atrial fibrillation, cardiomyopathy, flushing, hypotension, myocardial infarction, thrombosis, ventricular tachycardia have been reported with Sildenafil.

• Concomitant use of Sildenafi with following drugs are forbidden:

Organic nitrates (eg. Nitroglycerin) Nitrates & Nitric donors (eg. Nitroproside)

Lamotrigine

Common adverse effects:

Skin reaction: rash ,Steven's Johnson

syndrome, TEN

Women more than men Onset Caution Adverse events causing hospitalization Weight limitation

Age Limitation

• Not effective & safe in children under 16 years old

• Person younger than 16 years old:

• Risk factor for severe skin reactions

Lindane

•*This drug has entered to the world drug market since 1901.

•*Since the year 1990 Lindane has been introduced as a second line treatment.

Suggestion:

Single dose of useSecond line of treatmentLabelingContraindicationPrecaution

•Systemic adverse effects of Lindane•70% of adverse effects have been the CNS adverse events,including:•Seizure,Vertigo,Headache,Parasthesia

•17 cases of death have been reported to FDA,•IN 3 cases an established relationship between the events and using of drug were found

FDA alert (2003)FDA alert (2003)

CelecoxibLabelling Changes

• Celecoxib Long-term Arthritis Safety Study

(Class) did not show a safety advantage of

upper GI events for celecoxib compared with

diclofenac or ibuprofen.

Hypiran

Drug Interaction with:

• Indinavir• OCPs• Antidepressants• Digoxin, Warfarin, Theophylline, Cyclosporin

Risperidone

Extrapyramidal Reactions:

Rabbit Syndrome

1 Case in the USA 2 Cases in the English- Language Literature 4 Cases reported to IADRMC

.

IV IG

2 Cases of Death2 Cases of Death

following Administration of Vials with Unusual Colorfollowing Administration of Vials with Unusual Color

Benzyl benzoate

.

5 Cases of Sever Systemic Side Effects 5 Cases of Sever Systemic Side Effects following Topical Administration following Topical Administration

3 of them led to Death3 of them led to Death

تزریق از ناشی مرگجای به حیوانی سرم

انسانی سرمآبان- 1381درود

Salmeterol

3 cases of Asthma attack

ماه- بهمن 1382تهران

تزریق 3 از ناشی مرگ موردجای ÷ به کلراید تاسیم اشتباه

مترونیدازولماه 1384تیر

One case of Death

Promethazin + Hyoscin+Dicyclomin

1385اردیبهشت

صفاقی دیالیز محلولهایثامن شرکت ساخت

شیمیایی ÷ 250 ریتونیت مورد1385اردیبهشت

Contribution of Drug Interactions to the Overall Burden of preventable ADRs

Drug interactions represent 3-5% of preventable in-hospital ADRs.

Drug interactions are an important contributor to number of emergency departments visits and hospital admissions.

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

Comparison Type A and Type B

A B

Pharmacologically predictable

Yes No

Dose-dependent Yes No

Incidence and morbidity High Low

Mortality Low High

Treatment Adjust dose

Stop

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/

www.fdo.ir

دارو و غذا معاونت

دبيرخانه تحقيقات كاربردی

مركز ثبت و بررسی عوارض ناخواسته دارويیIranian Adverse Drug Reaction Monitoring

Center

 

• معرفي ADRمركز • ADR فرم

• عضويت • ها اطالعيه

• •خبرنامه مركز گزارشاتADR

• مفيد لينكهای

مركز ثبت و بررسي عوارض ناخواسته داروها

دفتر تحقيق و توسعه-معاونت غذا و دارو

وزارت بهداشت درمان و آموزش پزشكي

6405569تلفن:6417252نمابر:

E-mail: iadrmc@yahoo.com

Case II  

با 35خانم درمان تحت خون فشار و افسردگي سابقه با اي ساله . به ايشان باشد مي هيدروكلرتيازيد و اناالپريل سيپرومين، ترانيلقرارمي پتيدين و هالوتان با بيهوشي تحت اورژانس، جراحي دليل

اطاق. در بيمار براي جراحي از پس خون Recoveryگيرد فشار210/120 . عدم دليل به بيمار شود مي ثبت ميوكلونيك انقباضات و

به اورژانس خون فشار دليل به و كامل تحت ICUهوشياري و منتقل . ويا كاهش به اقدام از پس گيرد مي قرار پروسايد نيترو با درمان . كليه يابد مي افزايش بيمارمجددا خون فشار نيتروپروسايد، قطع

. باشد مي طبيعي بيمار پاراكلينيك آزمايشات 

  چيست؟ : بيمار خون فشار افزايش علت شما نظر به سوال

 

Ccase III 

بچه پسر با 4 بيمار درمان تحت حاد مدياي اوتيت تشخيص با كه است اي ساله . تب بيمار اوليه شكايت است گرفته قرار سيلين بوده –آموكسي گوش درد و قراري بي

. 2است. است شده بهتر عمومي حال و شده قطع بيمار تب دارو شروع از بعد 4روزو بوده خوب عمومي حال ولي است كرده تب دوباره كودك درمان، شروع از بعد روز

Toxic . و است داده موقع به را سيلين آموكسي كه نمايد مي ذكر بيمار مادر باشد نمي. دارد ادامه درمان هنوز

نداشته را سيلين آموكسي به مقاوم اوتيت تجربه كند مي طبابت كه اي منطقه در پزشك. دهد نمي را مكرر اوتيت و اخير ماه يك در بيوتيك آنتي مصرف سابقه نيز بيمار و

. در شود مي مشاهده تنه روي بر ماكولوپاپوالر راشهاي اخير معاينه بيمار :CBCدر اخيرWBC = 9000PMN = 57%L= 30%E=10%M=2%B= 1%

 

پزش¥ك تص¥ميم ب¥ه قط¥ع داروي آموكس¥ي س¥يلين و ادام¥ه درم¥ان ب¥ا اريترومايس¥ين مي گيرد.

س¥اعت بع¥د از قط¥ع آموكس¥ي س¥يلين تب بيم¥ار قط¥ع ش¥ده و راش¥هاي جل¥دي مح¥و 48 مي شود.

لطفا در مورد اين بيمار به سواالت زير پاسخ دهيد: 

تشخيص شما در مورد مشكل بيمار چيست؟  -1چه نكات مثبتي به تشخيص شما كمك مي كند؟  -2تشخيص هاي افتراقي در اين بيمار كدامند؟  -3درمان مشكل اخير بيمار چيست؟  -4