Iranian Pharmacovigilance Center

Research & Development OfficeUndersecretary for Food & Drug

Ministry of Health & Medical Education

Are drugs safer today ? • During 1960-1999 there were 121 safety related withdrawals

Worldwide

– Market life was known for 87 of those

– Market life less than 2 years 31%

– Market life less than 5 years 50%

Fung et al. Drug Information Journal, 2001; 35:293-317

• During 1972-1994 in 583 new active substances were approved

– Of these 59 were withdrawn later

– During 1990-2001 in UK 24 drugs were withdrawn due to safety reasons

Limitations of Clinical Trials

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

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

Official member countriesAssociate member countries

WHO Drug Monitoring ProgrammeParticipating countries 1999

58 countries have joined the programme

Official member countriesAssociate member countries

WHO Drug Monitoring ProgrammeParticipating countries 1999

58 countries have joined the programme

Iranian Pharmacovigilance Center

Adverse Drug ReactionAdverse Drug Reaction

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.

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

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 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.

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

Some drugs cause serious ADRs at very low frequencies

bromfenac hepatotoxicity (1 in 20,000)

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

Detection, Assessment & Prevention of ADRs in Human.

Ref: World Health Organization.

• Drugs• Vaccines• Blood products• Traditional and complementary medicines• herbals• Food additives• Medical devices• Biologicals• Biotechnology products• cosmetics

Pharmacovigilance concerns have been

widened to include:

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

04/21/23 35

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

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 frequent

Ref: 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

Important factors to decreases ADR

Preventing ADR

Over 75% of all ADR are dose-dependentMany ADR arise from failure to tailor the

dosage of drugs to widely different 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 patients Concomitant drugs

Factors related to patient:

Essential factors causing ADRs:

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

PREGNANCY & LACTATION

Drugs In ElderlyDrugs In Elderly

Spontaneous Reporting

Case I    

آقاي اورژانس 72بيمار توسط كه باشند مي اي با 115ساله ،آورده بيمارستان اورژانس بخش به هوشياري سطح كاهش . فشار سابقه پدرش كه كند مي ذكر بيمار همراه است شده . پزشك نمايد مي استفاده استنشاقي اپيوم و داشته خونسطح كاهش با بيمار با برخورد پروتكل طبق اورژانس كشيك

گلوكز وي براي عرض cc 25، %50هوشياري و 5در دقيقهنالوكسان تزريق . 0.4mgآمپول از پس نمايد مي عدد 5شروع

بيمار ولي شده بهتر كمي هوشياري سطح ، نالوكسان آمپولپرسنل تالش عليرغم كه شده قلبي ايست دچار بالفاصله

. نمايد مي فوت بيمار احيا، جهت اورژانس 

  چيست؟ بيمار فوت علت شما نظر به

 

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

 

Report of Iranian ADR Monitoring Center

www.fdo.ir

دارو و غذا معاونت

ضروری اطالعات

ايران داروهای الفبايی فهرست •(PDF يا Excel فرمت)

غيردولتی آزمايشگاههای برداری بهره و تاسيس •ضوابطآرايشی و بهداشتی غذايی، مواد كنترل

غذا • كل اداره به مربوط ضوابطايران • اسالمی جمهوری دارويی ملی سياست

ماده 226•فهرست مشمول بهداشتی آرايشی اوليه مواد 16قلمدارويی ارتباطی پروتكلهای و اطالعاتی آيتمهای •

آالت ماشين سازنده وشركتهای فنی دانش دهنده انتقال راهنمای •ها داروخانه امور به مربوط هاي بخشنامه •

داروخانه ها • جديد نامه آييننسخه • بدون داروهایدارو • و غذا معاونت خبرنامه

بهداشتی و آرايشی مجوزهای صدور راهنمای •دارويی • ناخواسته عوارض بررسی و ثبت مركز

داروسازی شركتهای تلفن و آدرس •

www.fdo.ir

كاربردی تحقيقات دبيرخانه

دارويی ناخواسته عوارض بررسی و ثبت مركزIranian Adverse Drug Reaction Monitoring

Center

 

• مركز ADRمعرفي • ADR فرم

عضويت• ها • اطالعيهخبرنامه• مركز • ADRگزارشاتمفيد • لينكهای

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

-

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.

Country Profile

Countries Population Physicians Pharmacists Dentists N.Drugs

Iran 60,000,000 53,927 7,327 10,076 1,300

India 900,000,000 450,000 300,000 200,000 >5,000

Thailand 59,000,000 21,105 11,058 5,590 25,511

S.Africa 38,700,000 28,381 9,450 4,235 7,308

Australia 7,720,000 18,737 3,745 3,002 7,490

France 58,000,000 190,000 59,800 42,000 30,986

Germany 81,800,000 274,000 43,700 60,600 50,500

Italy 57,000,000 308,440 56,700 33,805 5,285

UK 57,700,000 36,049 40,117 28,000 15,974

WHO. National Pharmacovigilance System. Second Edition 1999

Country ProfileCountries Year of

establishment Physicians Pharmacist/

ScientistAdministrative/Secretariat

Average Number of ADR Reports/year

Iran 1997 - 6 1 1,600

India 1997 2 2 1 -

Thailand 1983 - 2 2 3,500

S.Africa 1987 1 2 1 250

Australia 1987 - 4 3 500

France 1975 7 6 2 15,000

Germany 1978 13 9 29 19,000

Italy 1980 6 1 2 3,000

UK 1964 7 30 22 18,000

WHO. National Pharmacovigilance System. Second Edition 1999

1837 1793

734671

446

17 7

276

730

200

400

600

800

1000

1200

1400

1600

1800

2000

Pharmac

ist

Gen

eral p

ractit

ioner

Special

ist

Nurse

Patie

nts

Dentis

t

Clinic

al p

harm

acist

Oth

ers

Unknown

Reporters

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 &

Appen

dages G

I

Body as

a w

holeCNS

Respira

tory

Liver

& b

iliar

y

Visio

n

Coagula

ting S

ys

Repro

ductiv

e

From:

77

To

Mordad 83

87

140 137

109

145

127

162171

83

136

121 120

0

20

40

60

80

100

120

140

160

180

ردينفرو

شتيبه

ارددادخر تير داد

مر

ورهريش هر

مانآب ذر

آدي

منبه

سفندا

Reports of 1382 year

189

150 149

79

143

100

118

159

133

155

98

41

0

20

40

60

80

100

120

140

160

180

200

ردينفرو

شتيبه

ارددادخر تير داد

مر

ورهريش هر

مانآب ذر

آدي

منبه

سفندا

Reports of 1381 year

Diclofenac Na Above 160 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

Tehean 70 Khorasan 29 Yazd 27 Esfahan 24 Markazi 16 Mazandaran 13 Kerman 12 Fars 9 Cha va bakh 9 Lorestan 8 Azar e gharbi 7 Hamedan 7 Kermanshah 7 Ardebil 7

Ilam 7 Khoozestan 5 Azar e sharghi 5 Gilan 5 Koh va boyer 5 Semnan 4 Ghom 3 Sistan va baloo 3 Booshahr 2 Ghazvin 2 Zanjan 1 Golestan 1 Unknown 1

States

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 use Second line of treatment Labeling Contraindication Precaution

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.

Risperidone

Extrapyramidal Reactions:

Rabbit Syndrome

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

.

IV IG

3 Cases of Death3 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

Drugs of current Interest

• Strptokinase• Tramadol• Risperidone• Celecoxib • Sildenafil• Clozapin• Cisapride

• Diclofenac Na• Anti -TB Agents • Hypiran• Co-trimoxazol

All New AgentsAll New Agents

The FDA Safety Information and Adverse Event Reporting Program:

Safety alerts Recalls Withdrawals Important labeling changes Biologicals, Drugs, Dietary supplements

MedWatch

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

Journals of special interest

Reference books

WHO Publications

04/21/23 105