Download Medical Errors: Definition, Causes, and Prevention

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
 Breast cancer
 Highway accidents
16,516
42,297
43,458
 ADR
100,000
percentage of hospital admissions
due to adverse drug reactions:
USA
UK
France
Norway
28%
15.6%
12.6%
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
US
Germany
UK
Australia
Sweden
Serious ADRs
700,000
206,000
148,000
48,000
22,000
Lost Activity Days
1,218,000
358,440
257,520
83,520
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 postgraduate 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.
‫وزارت بهداشت درمان و آموزش پزشكي‬،‫معاونت غذا و دارو‬-‫ دفتر تحقيق و توسعه‬،‫مركز ثبت و بررس ي عوارض ناخواسته داروها‬
Incidence of ADRs to be
detected
1 in100
1 in 1000
1 in 5000
Spontaneous
background incidence
Minimum number of
patients to be exposed
0
360
1 in 10000
520
1 in 1000
730
1 in 100
2000
0
3600
1 in 10000
7300
1 in 1000
20300
1 in 100
136400
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
• 9600 patients
• 13000 patients
for 1 case
for 2 cases
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







Pulmonary embolism
Myocardial infarction
Death fro asthma
Jaundice
Colitis
Colitis
Aplastic anemia
Drug
Time lag(yr)
Oral contraceptive
Oral contraceptive
Sympathomimetic
Halothane
Lincomycin
Clindamycin
Phenylbutazone
3
5
4
7
6
5
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
Cheap
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
solubilize sulphanilamides); the law was
used to
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
Frequency
Antibiotics
Antitumor agents
Anticoagulants
Cardiovascular agents
Anticonvulsant agents
Antihypertensives
Analgesics
Antiasthmatics
Sedative/hypnotics
Antidepressants
Antipsychotics
Peptic ulcer therapy
Most frequent
Least frequent
Ref: J. Russell May. Adverse Drug Reactions and Interactions, In: Pharmacotherapy, A pathophysiologic Approach. 1997,
Types of Drug-Related Effects by Frequency
Type of adverse event
Frequency
Marrow suppression
Bleeding
Central nervous system
Allergic/cutaneous
Metabolic
Cardiac
Gastrointestinal
Renal
Respiratory
Most frequent
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
Essential factors causing ADRs:
Factors related to patient:
 Sex
 Age (weight)
 Genetic (PHARMACOGENOMICS)
 Drug allergy
 Lack of knowledge in patients
Concomitant drugs
Factors related to patient:
•
•
•
•
•
Non-compliance - underestimated
Route of Administration - bioavailability
Food - protein malnutrition
Pollutants - smoking/herbicide residues
Timing - chronopharmacology
Essential factors causing
ADRs:
Factors related to drug:




Route of administration
Dosage
Duration of treatment
Problems with drug:
1-Formulation
2-Problems with preparing of drug
1936
• USA : 107
lethal cases diethylenglycol
was used to solubilize sulphanilamides
Drugs cause hospitalization
Digoxin
Aspirin
Prednisone
Warfarin n
Guanethidine
41
24
15
9
5
Aspirin
Digoxin
Warfarin
HCTZ
Prednisone
25
24
12
11
8
Type of Alerting Order
•
One time stat dose
•
•
PRN orders
Short course therapy
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
Abrupt decrease in dose
Followed by a stat
• Serum level
State laboratory tests
‫فوايد وجود برنامه ‪ ADR‬در بيمارستان‬
‫‪ -1‬افزايش كيفيت درمان‬
‫‪ -2‬جلوگيري از شكايات حقوقي‬
‫‪ -3‬ارزيابي مشكالت دارويي‬
‫‪ -4‬ارزيابي مشاهدات پزشكان و ديگر حرف پزشكي‬
‫‪ -5‬ارتقاء دانش دارويي دست اندركاران درمان‬
‫داليلي كه باعث كاهش گزارشات‪ ADR‬ميگردد‪:‬‬
‫‪ -1‬عدم اطالع از مكانيزم موجود براي ارسال گزارش‬
‫‪ -2‬عدم دسترس ي به فرم مربوطه‬
‫‪ -3‬عدم اهميت عارضه ازنظرگزارشگر‬
‫‪ -4‬نداشتن وقت‬
‫‪ -5‬دررابطه با فرم مربوطه‬
‫‪ -6‬اجتناب ازدرگيري دركارهاي اداري‬
‫‪ -7‬ترس ازشكايات حقوقي‪ ,‬كيفري‬
‫‪ -8‬عدم اطمينان ازبوجود آمدن ‪ ADR‬توسط دارو‬
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
•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.
en
tis
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ar
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Pa
tie
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er
C
G
Ph
ar
m
ac
is
t
Reporters
WHO Drug Monitoring Programme
Participating countries 1999
58 countries have joined the programme
Official member countries
Associate member countries
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.
N
S
A
ge
Mordad 83
A
nt
s
nt
ib
C
io
ar
tic
B
di
lo
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va s
od
sc
&
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C
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M
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no
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H
or
m
El
on
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G
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Va
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ly
cc
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&
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e
M
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&
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A
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al
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pr
od
uc
Sk
ts
in
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Sm
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T
m
A
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cl
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s
re
la
xa
nt
Vi
ta
m
in
s
C
Adverse Drug Reaction vs Drug classes
From:
1377
To
Site of Reaction (CNS agents )
From:
CNS
77
GI
Body as a whole
To
Skin & apprndages
Application site
Cardiovascular
Psychiatric
Respiratory
Autonomic
Musculoskeletal
Urinary
Vision
Heart rate & rhythm
Mordad 83
C
B
a
C
r&
S
ep
ro
du
ct
iv
e
Sy
s
Vi
si
on
bi
lia
ry
oa
gu
la
tin
g
R
N
w
ho
le
I
es
pi
ra
to
ry
Li
ve
R
as
G
Ap
pe
nd
ag
es
od
y
&
77
Sk
in
From:
Site of Reaction (Antibiotics)
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
Age groups
(Reaction of Tramadol):
 0-10
 11-20
 21-30
 31-40
 41-50
 51-60
 61-70
 71-80
 >80
 Unknown
3
7
86
61
51
29
18
11
3
20
Rout of administration
(In patients with Tramadol adverse effects)
.
%
.
.
%
IM
PO
IV
ID
Unknown
%
.
%
.
%
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
Adverse effects of Tramadol from 04.81 to 03.83
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
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
FDA alert (2003)
•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
Celecoxib
Labelling 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 Death
following Administration of Vials with Unusual Color
Benzyl benzoate
.
5 Cases of Sever Systemic Side Effects
following Topical Administration
3 of them led to Death
‫مرگ ناشی از تزریق سرم‬
‫حیوانی به جای سرم انسانی‬
‫درود‪ -‬آبان ‪1381‬‬
Salmeterol
3 cases of Asthma attack
1382 ‫ بهمن ماه‬-‫تهران‬
‫‪ 3‬مورد مرگ ناشی از تزریق اشتباه‬
‫÷تاسیم کلراید به جای مترونیدازول‬
‫تیر ماه ‪1384‬‬
One case of Death
Promethazin + Hyoscin+Dicyclomin
1385 ‫اردیبهشت‬
‫محلولهای دیالیز صفاقی ساخت شرکت‬
‫ثامن‬
‫‪ 250‬مورد ÷ریتونیت شیمیایی‬
‫اردیبهشت ‪1385‬‬
Contribution of Drug Interactions to the
Overall Burden of preventable ADRs
Drug interactions represent 3-5% of preventable inhospital 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
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
‫معاونت غذا و دارو‬
‫‪www.fdo.ir‬‬
‫دبيرخانه تحقيقات كاربردی‬
‫مركز ثبت و بررسی عوارض ناخواسته دارويی‬
‫‪Iranian Adverse Drug Reaction Monitoring Center‬‬
‫مركز ثبت و بررس ي عوارض ناخواسته داروها‬
‫دفتر تحقيق و توسعه‪-‬معاونت غذا و دارو‬
‫وزارت بهداشت درمان و آموزش پزشكي‬
‫تلفن‪6405569:‬‬
‫نمابر‪6417252:‬‬
‫‪E-mail: [email protected]‬‬
‫‪Case II‬‬
‫خانم ‪ 35‬ساله اي با سابقه افسردگي و فشار خون تحت درمان با ترانيل سيپرومين‪،‬‬
‫اناالپريل و هيدروكلرتيازيد مي باشد‪ .‬ايشان به دليل جراحي اورژانس‪ ،‬تحت بيهوشي‬
‫با هالوتان و پتيدين قرارمي گيرد‪ .‬پس از جراحي براي بيمار در اطاق ‪Recovery‬‬
‫فشار خون ‪ 210/120‬و انقباضات ميوكلونيك ثبت مي شود‪ .‬بيمار به دليل عدم‬
‫هوشياري كامل و به دليل فشار خون اورژانس به ‪ ICU‬منتقل و تحت درمان با نيترو‬
‫پروسايد قرار مي گيرد‪.‬پس از اقدام به كاهش ويا قطع نيتروپروسايد‪ ،‬فشار خون‬
‫بيمارمجددا افزايش مي يابد‪ .‬كليه آزمايشات پاراكلينيك بيمار طبيعي مي باشد‪.‬‬
‫سوال ‪ :‬به نظر شما علت افزايش فشار خون بيمار چيست؟‬
‫‪Ccase III‬‬
‫بيمار پسر بچه ‪ 4‬ساله اي است كه با تشخيص اوتيت مدياي حاد تحت درمان با آموكسي سيلين قرار گرفته‬
‫است‪ .‬شكايت اوليه بيمار تب – بي قراري و درد گوش بوده است‪ 2 .‬روز بعد از شروع دارو تب بيمار قطع‬
‫شده و حال عمومي بهتر شده است‪ 4 .‬روز بعد از شروع درمان‪ ،‬كودك دوباره تب كرده است ولي حال عمومي‬
‫خوب بوده و ‪ Toxic‬نمي باشد ‪ .‬مادر بيمار ذكر مي نمايد كه آموكسي سيلين را به موقع داده است و هنوز‬
‫درمان ادامه دارد‪.‬‬
‫پزشك در منطقه اي كه طبابت مي كند تجربه اوتيت مقاوم به آموكسي سيلين را نداشته و بيمار نيز سابقه‬
‫مصرف آنتي بيوتيك در يك ماه اخير و اوتيت مكرر را نمي دهد‪.‬‬
‫در معاينه اخير راشهاي ماكولوپاپوالر بر روي تنه مشاهده مي شود‪ .‬در‪ CBC‬اخير بيمار ‪:‬‬
‫‪WBC = 9000‬‬
‫‪PMN = 57%‬‬
‫‪L= 30%‬‬
‫‪E=10%‬‬
‫‪M=2%‬‬
‫‪B= 1%‬‬
‫پزشك تصمیم به قطع داروي آموكسي سیلین و ادامه درمان با اریترومایسین مي گیرد‪.‬‬
‫‪ 48‬ساعت بعد از قطع آموكسي سیلین تب بیمار قطع شده و راشهاي جلدي محو مي شود‪.‬‬
‫لطفا در مورد این بیمار به سواالت زیر پاسخ دهید‪:‬‬
‫‪ -1‬تشخیص شما در مورد مشكل بیمار چیست؟‬
‫‪ -2‬چه نكات مثبتي به تشخیص شما كمك مي كند؟‬
‫‪ -3‬تشخیص هاي افتراقي در این بیمار كدامند؟‬
‫‪ -4‬درمان مشكل اخیر بیمار چیست؟‬