Iran ADR Centerپارسائيدكتر

گروه فارماكولوژي دانشكده پزشكي

&&

ADR(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.

هر گونه پاسخ داروئي مضر و

نامطلوبي كه با دوز معمولي دارو

در انسان جهت پيشگيري، تشخيص

و يا درمان ايجاد شده باشد

:اصطالحات رايج

*Side Effects عوارض كم اهميت ومختصر

* Adverse Reaction عوارض مهم و كامال ناخوشايند

* Toxicity ( اثرات سمي مستقيم دارو )غالبا دوز باال

* Secondary Effects آثار ثانوي غيرمستقيم

* Intolerance عدم تحمل بدليل آستانه پايينپاسخ دهي

* Idiosyncrasy پاسخ غير نرمال بدليلاختالل ژنتيكي

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 ADR:

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.

The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves.

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

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

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

ADR has financial and social effects:

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

So many prescriptions!

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

طبقه بندي عوارض (A-E) جانبي

انواع فرعي:

(Continuos) Cنوع •

( Delayed) D نوع •( Ending of use) E نوع•

انواع اصلي:

(Augmentedنوع •

A)

(Bizarre) Bنوع •

AB

-+قابل پيش بيني •-+وابستگي به دوز•كمزيادميزان شيوع•زيادكممرگ و مير•قطع تنظيم دوزدرمان•

مصرف

Aمقايسه عوارض جانبي نوع Bو

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

چگونه يك عارضه

جانبي به

دارو نسبت داده ميشود؟

شرايط ارزيابي ارتباط عارضه

جانبي با داروارتباط منطقي بروز عارضه با - 1

زمان مصرف دارو

- ارتباط عارضه با خصوصيات 2 شناخته شده دارو

- رفع عارضه با قطع مصرف دارو 3

- عود عارضه با شروع مصرف 4 مجدد دارو

- توجيه منطقي ارتباط عارضه با 5 يا ...بيماري مريض

بجانبيعارضهارتباطبررسي داروا

5 4 3 2 1 ارزيابي ارتباط0 + + + + Definit قطعي

_ 0 + + + احتمالي

Probable + 0 0 + + Possible ممكن

_ 0 0 _ + مشروط

Conditional0 0 0 0 0 غير قابل بررسي

Unassessable + 0 0 0 _

Unlikely غیر محتمل

Detection, Assessment,

Prevention of ADRs in Human.

Ref: World Health Organization.

اهداف اصلي فارماكوويژيالنس

شناسائي زودهنگام واكنشهاي ناشناخته •داروئي

تعيين ميزان افزايش در بروز عوارض•شناسائي فاكتورهاي خطر•ارزيابي كيفي مخاطرات•پيشگيري از بروز مخاطره غير ضروري در •

بيمارمصرف منطقي و سالم داروها•

The ultimate goal of pharmacovigilance is

improving pharmacotherapy

Ref:World Health Organization

تاريخچه فارماکوويژيالنس

:1968 سال • توسط سازمان مللDrug Monitoringشروع برنامه

(: 1848 سال قبل )160 حدود • کلروفرم ساله در بيهوشي با 15 فوت جوان

)جراحي ناخن پا( بعلت فيبريالسيون بطني

عاري از هر گونه و خالص ”فراورده هاي داروئي بايد بيانيه:

باشند“ آلودگي :1936 سال•بعنوان دي اتيلن گليکول مورد مرگ ناشي از 107

:1961 سال •حالل سولفوناميدتاليدوميد مورد نقص عضو ناشي از 4000گزارش

:1964 سال •از استرالياشروع استفاده از سيستم کارت زرد در انگليس

Drug Classes Responsible for ADRsDrug 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.

• Patient’s specification

• Patient’s drug history

• Pharmacology of prescribed drugs

• Prescription of minimum effective

dosage

Preventing ADR

Over 75% of all ADR are dose-dependent

Dosage of many drugs widely different

to individual needs.

Ref:World Health Organization

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:

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 (Cont):

فوايد وجود ADR در بيمارستان برنامه

افزايش كيفيت درمان -1جلوگيري از شكايات حقوقي -2

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

حرف پزشكيارتقاء دانش دارويي دست -5

اندركاران درمان

داليلي كه باعث كاهش ميگردد:ADRگزارشات

عدم اطالع از مكانيزم موجود براي -1ارسال گزارش

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

نداشتن وقت -4فرم مربوطهتكميل در رابطه با -5

اجتناب از درگيري در كارهاي اداري -6ترس از شكايات حقوقي, كيفري -7

ADR- عدم اطمينان از بوجود آمدن8 توسط دارو

Drugs cause hospitalization

Digoxin 41 Aspirin 25

Aspirin 24 Digoxin 24

Prednisone 15 Warfarin 12

Warfarin 9 Prednisone 8

Guanethidine 5

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

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

Diclofenac Na Above 100 Cases of Foot drop

Withdrawal from Iranian Pharmacopoeia

Streptokinase

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

Adverse Reaction of Tramadol from 04.81 to 03.83

6 Major Adverse Effects of Tramadol:

•Nausea 125•Vomiting 116•Vertigo 109•Asthenia 57•Dyspnea 42

•Hypotension 41

84.78%

9.34%5.19%

0.35%

0.35%

IM PO IV ID Unknown

Rout of administration(In patients with Tramadol adverse effects)

Bupivacaine

4 Cases of Para-plegia following IT injection

2 of them led to Death

Sildenafil

•Sildenafil has cardiac related side effect.

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

drug.

www.fdo.ir

دارو و غذا معاونت

كاربردی تحقيقات دبيرخانه

دارويی ناخواسته عوارض بررسی و ثبت مركزIranian Adverse Drug Reaction Monitoring

Center

 

ADRمركزمعرفي • ADR فرم• عضويت• ها • اطالعيهخبرنامه• مركز • ADRگزارشاتمفيد • 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

Report of Iranian ADR monitoring center

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

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(:

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

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

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/