Mini Course on Pharmacovigilance

Mini Course on
Pharmacovigilance
Kenneth Hartigan-Go MD, MD (UK),
FPCP, FPSECP, FPSCOT
2006
Course Outline
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
Developing an ADR system in the Philippines
ADR detection and reporting
WHO Program on International Drug
Monitoring
From Signals to Policy
Tips for Consumer Protection
Pharmacovigilance and Rational Drug Use,
regulatory authorities and public health
Medication Errors
Expressing Risks
Course Outline
9. Clinical importance of drug interaction
10. Vaccine safety (AEFI)
11. Drug advertising in the Philippines
12. Ethical relationship between doctor and drug industry
13.  Video: “the Practice”
14.  The management of adverse drug reactions:
practical workups for the patient
15.  Hospital rounds: practicum
16.  Action Planning: organizing national workshops for
ADR monitoring and reporting and social marketing of
drug safety.
Developing an ADR system in
the Philippines
1
Pharmacovigilance
Why bother ?
Salus populi
suprema lex
esto
To undergo treatment you have to be very
healthy, because apart from your sickness
you have to withstand the medicine.
---- Moliere
Definition of PV (WHO)
'The science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects, or any other
possible drug related problems'
Is it working as it should be ?
n 
n 
n 
n 
Most common method
is voluntary
spontaneous reporting.
The pros
The cons.
In evaluation, no one
really is sure !
ADR reporting deals with people
n 
n 
4 types of physicians
& where we failed
Public health vs
clinical patients’
confidentiality.
Why the need for change ?
n  New
paradigms (evolution)
n  Drug reaction information and decisions
taken affect various groups. Lives and
money are involved.
n  Quality assurance
n  Cost-containment
n  We must make the basic science-clinical
connection to be relevant
How should we improve ?
n 
n 
n 
n 
n 
n 
More awareness
More social responsibility
Rational approach in causality
assessment and decisions undertaken
Feedback
Confidence in the management
breeds confidence in notification
Recognition in malpractice issues
Drugs↔ Drug use
Why we do it ?
n  Pharmacovigilance
teaches physicians
to become better in
communicating
matters of drug use
with their patients.
Why ?
n 
n 
n 
n 
n 
An understanding of
PV helps the work of
regulatory authority:
product itself
claims
marketing
advertising
Organisation
BFAD
NADRAC
ADRMP
PGH
UST
MMC
Other centres
Philippine P-vigilance activities
n 
n 
n 
n 
n 
n 
1994, AusAID
assistance
1995, Uppsala
Monitoring Centre
member
Philippines – 75 M
people
1,600+ ADR reports
Training & advocacy
activities (videos)
1997, BFAD
Lessons learned
ADR (AE)- practical applications: turning
cases into useful warning signals or health
advisories
Done to address problem drugs and problem
drug use
Some examples:
Adulteration detected in Chinese herbal
products
Lessons learned
n  Detection
of drug-drug incompatibility in
the ICU
n  Misuse of misoprostol as abortifacient
n  Defective devices and improvement in gov’t
procurements
n  Hazardous weight reduction drugs
n  Issues of irrational self-medication
Philosophy behind use of
traditional medicines
n 
n 
n 
n 
n 
Natural & organic
Popularity with folks:
word of mouth
Expense of
consultation
Traditional concepts:
years of use
Unlikely to report AEs
Regulatory gaps
n 
n 
n 
Regulation by absence
of toxicity but not by
true efficacy
About claims and uses
If traditional chinese
medicines – allowed
for ethnic use, no
regulation (except for
ephedrine)
Clinical gaps
n 
n 
n 
Problem lies in
transforming into
pharmaceutical dosage
forms what is natural
Western trained
doctors lack of
knowledge
Patients who are
chronically or
terminally ill are users
Some examples
n  Mahogany
seeds for diabetes mellitus
n  Morinda citrifolia (noni juice)
n  Chinese drug: Snake bone rheumatism pills
n  Chinese drug: de Witt’s Kidney & Bladder
Pills
n  Health supplements from developed
countries
Traditional Complementary med.
n  Examples
like St. John’s Wort interaction
with other drugs
n  Heavy metal contamination
n  Hence toxicity from herbal products
n  There may be a need to re-examine the
evaluation and registration procedure for
herbal products
ADR detection and reporting
2
Evolution I
n 
n 
n 
n 
n 
n 
Augmented
Bizarre
Continuous
Delayed
Ending of Use
Failure of Treatment
Augmented
n  Dose
dependent
n  Pharmacological explanation
Augmented
n  Augmented
Extension effect:
–  Bradycardia due to metoprolol for hypertension
n  Augmented
Side effect:
–  Constipation due to morphine
–  Mouth dryness due to thorazine
–  Bronchospasm due to propranolol for
hyperthyroidism
Bizarre
n  Idiosyncratic
reaction
n  Dose independent
n  Hypersensitivity reaction
n  Immune response
n  Often no pharmacological explanation
n  Cannot be tested in general
Bizarre
n  Penicillin
hypersensitivity
n  Phenytoin, carbamazepine, barbiturate and
sulfa drug – SJS
n  Thorazine and extra-pyramidal syndrome
n  Neurolept malignan syndrome due to
phenothiazines
Continuous/chronic
n  NSAIDs
gastric ulcer
n  Phenacetin nephropathy
n  INH jaundice
n  Steroid moon facies and virilism
Delayed
n  Affecting
the next generation
n  Thalidomide
n  Hormonals
n  Diethylstilbestrol
Ending of Drug use
n  Diazepam
withdrawal (seizure drugs)
n  Narcotic withdrawal
n  Clonidine withdrawal
n  Steroid withdrawal
Failure of Treatment
n  Counterfeit
n  Substandard
n  Wrong
diagnosis and wrong drugs
n  Drug antagonism
n  Increased elimination
n  Antimicrobial resistance
Evolution II
n 
n 
n 
n 
The need to tie up the
following to work
together:
ADR Centres
Poison Centres
Drug Information
Centres
Evolution III
n 
n 
n 
Adverse Events
following
Immunization
Vaccines are unique
medicines
How drugs are used ?
(iatrogenic issues)
Sources of information/
Monitoring tools
n  Spontaneous
voluntary reporting
n  Post marketing surveillance
n  Intensive medicines monitoring program
n  Clinical trials at various phases
Voluntary Spontaneous Reporting
n  user-friendly
n  non-threatening
n  confidential
n  submission
is not
admission of
causality
Evaluation of risk/harm
n  Which
side effects or adverse events may
occur ?
n  How to recognize them ?
n  How long will they continue ?
n  How to know if this is serious ?
n  What actions may be taken ?
Evaluation may also take the
form
n  Depending
on the patient’s condition
–  High risk profile
–  Contraindications
–  Drug interactions
n  Depending
on patient’s compliance
n  Depending on the prescription
n  Depending on some self-medication
practices
High risk profile means
n 
n 
n 
n 
n 
n 
n 
n 
n 
Pregnancy
Lactation
Child
Elderly
Renal failure
Hepatic failure
History of reactions
Other diseases
Other medications
Safety definitions
n  Contraindications
– determined by the
mechanism of the drug action and the
patient’s profile.
n  Seriousness of drug effects – dependent on
the person or patient sometimes
n  Interactions – effects of one drug altered by
other substances. Consider which are
clinically relevant.
Contraindications, interactions,
high risk groups
n  Is
the active substance suitable for the
patient’s condition ?
n  Is the schedule or dosing correct ?
n  Is the duration of use correct ?
n  Is the patient taking any other substances ?
(OTC meds, herbal supplements etc.)
examples: gingko biloba, St. John’s wort,
alcohol
GRAPH 1. NUMBER OF REPORTS BY YEAR
NUMBER
300
200
100
0
No. of reports
1994
1995
1996
1997
1998
1999
41
137
215
244
186
247
YEAR
Table 1. Most Common Drugs Listed in the ADR Reports
DRUGS
Trovan
Ampicillin
Angiografin
Rifampicin
Paracetamol
Augmentin
Infree
Tegretol
Rocephin
Zantac
Others
TOTAL
FREQUENCY
110
53
47
36
35
33
30
29
27
26
2436
2859
PERCENTAGE
3.8
1.8
1.6
1.3
1.2
1.1
1.0
1.0
0.9
0.9
85.2
100.0
Table 2. Most Common Drugs Listed in the ADR Reports
by Therapeutic Category
DRUGS
Anti-infectives
Nervous system drugs
Musculoskeletal system
and joints drugs
Cardiovascular drugs
Gastrointestinal drugs
Respiratory drugs
Diagnostic agents
Drugs affecting the blood
Vitamins and minerals
Hormones and hormone
antagonists
Others
TOTAL
FREQUENCY
1113
441
239
PERCENTAGE
38.9
15.4
8.4
202
170
111
96
91
91
71
7.1
5.9
3.9
3.4
3.2
3.2
2.5
234
2859
8.2
100.0
Table 3. Common ADR Listed in the ADR Reports
REACTION
Rash, maculopapular or
erythematous
Pruritus
Vomiting
Fever
Urticaria
Rigors
Dyspnoea
Dizziness
Nausea
Abdominal pain
Others
TOTAL
FREQUENCY
744
PERCENTAGE
25.9
228
124
110
98
94
86
74
57
52
1203
2871
7.9
4.3
3.8
3.4
3.3
3.0
2.6
2.0
1.8
41.9
100.0
Table 4. Common ADR Listed in the ADR Reports
by Body Systems
REACTION
FREQUENCY
Dermatologic
1244
Gastrointestinal
397
Multisystem
359
Neurologic
218
Cardiovascular
188
Psychiatric
91
Respiratory
79
Metabolic
53
Hematologic
50
Ocular
49
Others
141
TOTAL
2871
PERCENTAGE
43.3
13.8
12.5
7.6
6.5
3.2
2.8
1.8
1.7
1.7
4.9
100.0
GRAPH 2. ADR BY TYPE OF REPORTER
PERCENTAGE
80
60
40
20
0
Percentage
Physician
Nurse
Pharmacist
Patient
Others
58.7
10.5
16.7
1.6
2.5
TYPE OF REPORTER
PERCENTAGE
GRAPH 2. DISTRIBUTION OF ADR REPORTS BY REPORTING INSTITUTION
100
80
60
40
20
0
Percentage
Hospitals
Industry-Based
Community-Based
79.5
7.7
12.8
TYPE OF REPORTING INSITUTION
PERCENTAGE
GRAPH 3. CAUSALITY ASSESSMENT OF ADR
40
30
20
10
0
Percentage`
Certain
Probable
Possible
Unlikely
Unclassifiable
25
33.7
29.3
3.3
8.7
ASSESSMENT CATEGORY
Of the 1,070 reports, only 92 or 9% had been assessed by the National
Adverse Drug Reaction Committee (NADRAC) for the likelihood of their
relationship to drugs: these were the reports from 1997-98. Of the 92
assessed ADRs, 59% were assessed to be certain or probably caused by
drugs.
Table 5. Drugs Associated with ADR Reports That were Assessed as
Certainly or Probably Caused by Drugs
DRUG
FREQUENCY
PTU
5
Phenobarbital
4
Cloxacillin
4
Amoxicillin
4
Ampicillin
4
Augmentin
4
Pyrazone
4
Vincristine
4
Ceftriaxone
3
Prednisone
3
Penicillin g
3
Others
129
TOTAL
171
PERCENTAGE
2.9
2.3
2.3
2.3
2.3
2.3
2.3
2.3
1.8
1.8
1.8
75.4
100.0
Table 6. Drugs Associated with ADR Reports That were Assessed as Certainly
or Probably Caused by Drugs (Therapeutic Categories)
DRUG
Anti-infectives
Nervous system drugs
Cardiovascular drugs
Respiratory drugs
Gastrointestinal drugs
Hormones and hormone
antagonists
Diuretics
Antineoplastics and immunosuppressants
Musculoskeletal system
and joints drugs
Drugs affecting the blood
Vitamins and minerals
Others
TOTAL
FREQUENCY
63
24
13
12
12
9
PERCENTAGE
36.8
14.0
7.6
7.0
7.0
5.3
7
7
4.1
4.1
6
3.5
4
4
10
167
2.3
2.3
6.0
100.0
PERCENTAGE
GRAPH 12. OUTCOME OF ADR PATIENTS (1999)
80
60
40
20
0
Percentage
Recovered
Not yet recovered
Died
Unknown
70.4
8.5
5.3
15.8
OUTCOME
In 1999, there were 22 patients (9%) whose hospitalization was
prolonged due to the ADR. Four patients (2%) had unspecified sequelae
to the ADR. Thirteen patients (5%) died during the 6-year period.
Table 8. Drug-ADR Combinations Associated with Prolonged Hospitalization
DRUG
Iloperidone
Ultravist
Angiografin
Ativan
Ventolin
Zinacef
Aredia
Celestamine
Ercefuryl
Estazolam
Solucortef
TOTAL
ADR
Condition aggravated,
schizophrenic reaction,
agitation, chest pain,
dizziness, fatigue, nausea, nervousness, pain,
abnormal vision, vomiting
Rash, urticaria, pruritus, hypertension, periorbital edema, maculopapular rash, skin discoloration
Oedema, hypoaesthesia
Aggressive reaction,
anorexia, insomnia,
schizoprenic reaction
Fever, schizophrenic reaction
Fever
Vomiting
Fever
Fever
Delusion
Fever
FREQUENCY
13
PERCENTAGE
30.2
13
30.2
4
4
9.3
9.3
2
4.7
2
1
1
1
1
1
43
4.7
2.3
2.3
2.3
2.3
2.3
100.0
Table 9. Drug-ADR Combinations Associated with Sequelae
DRUG
Iloperidone
ADR
Condition aggravated,
nervousness, schizophrenic reaction
Ampicillin
Fever, rigors
Ambroxol
Hearing decreased
Calcium carbonate Hearing decreased
Catapres
Hearing decreased
Ciprobay
Estazolam
Ferrous sulfate
Rocatrol
Ventolin
TOTAL
1 ateoulbiR
s.fg-r,cdn)pvh:A
w
3701(IT
D
%
Z
F
zm
q
Hearing decreased
Delusion
Hearing decreased
Hearing decreased
Schizophrenic reaction
FREQUENCY PERCENTAGE
4
28.6
2
1
1
1
14.3
7.1
7.1
7.1
1
1
1
1
1
14
7.1
7.1
7.1
7.1
7.1
100.0
Table 10. Drug-ADR Combinations Associated with Death
DRUG
Feldene
Iloperidone
Zoloft
Trovan
Allopuridol
Angiografin
Aredia
Cisapride
ADR
Oedema,
pruritus, rash
Condition
aggravated,
nervousness,
schizophrenic reaction
Death, depression,
changed sensitivity to
temperature
Death
Jaundice
Dyspnoea
Vomiting
Gastroin testinal disorder
FREQUENCY
3
PERCENTAGE
10.0
3
10.0
3
9.9
2
1
1
1
1
6.7
3.3
3.3
3.3
3.3
Table 10. Drug-ADR Combinations Associated with Death (Cont.)
DRUG
Erythromycin
Ethambutol
Folic acid
Fortum
Losec
Metronidazole
Naproxen
Norvasc
Omeprazole
Piracetam
Plasil
Rifinah
Unisom
Viagra
Zantac
TOTAL
ADR
Gastrointestinal disorder
Jaundice
Jaundice
Hepatitis
Hepatitis
Hepatitis
Dyspnoea
Dyspnoea
Jaundice
Jaundice
Extrapyramidal disorder
Bilirubinemea
Death
Death
Hepatitis
FREPERCENTAGE
QUENCY
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
1
3.3
30
100.0
Conclusion
n 
n 
n 
n 
n 
There is no perfect
system !
Poor reporting
Technical skills in
processing &
evaluation
Policy implementation
Communicating drug
safety warnings
WHO Program
3
WHO Uppsala monitoring centre
WHO Programme for
International drug monitoring
n  Global
forum, collaboration in monitoring
n  individual cases suspected and ADR cases
collected
n  operational issues are addressed here
n  currently 58 members, 6 associate member
centres
n  Over 2 million reports
n  Bayesian neural network & communications
Systems
n  Vigibase
on line
n  Vigimed communications
n  www.umc-who.int
WHO Drug Monitoring Programme
Participating countries 1999
58 countries have joined the programme
Official member countries
Associate member countries
Official member countries & year of entry
n 
n 
n 
n 
n 
n 
n 
Japan 1972
Thailand 1984
Indonesia 1990
Malaysia 1990
Korea 1992
Singapore 1993
Philippines 1995
n 
n 
n 
n 
n 
n 
China 1998
India 1998
Russia 1998
Vietnam 1999
Sri Lanka 2001
Pakistan (associate
member country)
Differences among Asian
countries
n 
n 
n 
n 
n 
n 
n 
Population
number of doctors
number of patient population
number of drugs in the
market
legislation
center policies in assessing
cases
Taking actions
Conclusions
n 
By adopting a global
perspective one can
learn, harmonize cases
and perhaps strengthen
this soft science with
signals.
n 
By taking local actions
to some degree
encourages safer drug
and drug use.
From Signals to Policies:
The Philippines
4
SIGNALS
n 
n 
n 
a suspicion of a
relationship between a
reaction and a drug and
that no regulatory action
has taken place yet
how to assess
how to implement action
(including
communication)
Proposed methods (1)
n 
n 
is the signal true ?
establish the strength
of evidence
–  drug indication
–  event outcome
–  frequency of events
–  patient risk factors
–  seek more
information
sources of information
n  local ADR
database
n  WHO Database
n  consult medical
professionals
n  manufacturers/
company
n  researches
Proposed methods (2)
n  biological
plausibility
n  pharmacological
plausibility
n  temporal causation
n  calculate a rough
estimate of risk
Proposed methods (3)
n 
n 
n 
will release of
information lead to
more harm ?
is there an alternative ?
actions to be taken
–  issue warnings
–  revise the information
–  withdraw the drug
Consumer Protection Tips
5
The issue of access & perception/
claims
n  Internet
access
n  Unregulated advertisements
n  Smuggled products
n  Unregistered and unevaluated products
n  Legitimate products but misused as diet
control pills
n  Sold by health professionals
Examples of legitimate drugs
n  Fenfluramine/dexfenfluramine
& heart
valve damage
n  Phenylpropanolamine and hemorrhagic
strokes
n  Take home message: product registration
does not mean it is completely safe; learn
from the value of delisting from market
when public health requires it
The issue of irrational drug use
n  Thyroid
hormones
n  Anabolic steroids
n  Stimulants
n  Furosemide
Example of illegitimate drugs
n  Bangkok
pills & its harm
–  Ephedrine
–  Pseudoephrine
–  Fen/dexflenfluramine
–  Furosemide
–  Bisacodyl
–  diazepam
Overall adverse effects
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Anorexia
Hypertension
Diarrhea
Fluid and electrolyte imbalance
Metabolic acidosis
Insomnia
Mood swings
Strokes
Increased metabolism
Bone cannibalism
Malnutrition
Other consequence of losing
weight too rapidly.
The healthy way
n 
n 
n 
n 
n 
Eat properly
Exercise regularly
Get enough rest and
recreation
Avoid cigarettes
Drink alcohol
moderately
Consumer protection: spotting
false claims
n 
n 
n 
n 
n 
If advertised as a quick and effective cure-all
Key words like scientific breakthrough, miracle
cure, all natural without side-effects or ancient
remedy
Claims of scientific suppression and conspiracy
Undocumented anecdotal cases, no science
Claims that these products are used in developed
countries and registered by their FDA
Cont.
n  Selling
false hopes
n  Selling short cuts to health
n  No emphasis to value of healthy lifestyle
n  Advertised as available from only one
source
n  A label of Natural is not guarantee of
efficacy
n  Money-back guarantee
Cont.
n 
n 
n 
n 
Claims that you can eat all
you want and lose weight
effortlessly just by taking
their products
Body building pills to tone
up muscles effortlessly
without exercise
Products claiming to slow
aging process
Some dietary supplements
are harmful under some
conditions of use
Teaching Consumers
n  Read
label
n  Look for BFAD registration numbers
n  Look for expiry dates
n  Ask for a product information insert
n  Don’t buy piecemeal drugs
n  Develop a mechanisms for consumer
reporting to their doctors.
Take home messages:
n 
n 
n 
n 
n 
n 
Diet pills act by:
Decreasing intake or absorption
of food
Increased metabolism
Increased urine elimination
Increased bowel movements
they work but someone has to
pay the price !
Pharmacovigilance
6
SESSION: LINKING
PHARMACOVIGILANCE WITH
RATIONAL DRUG USE
How to bring experiences from drug
safety monitoring in the Philippines into
drug information services, therapeutic
guidelines, teaching and ADR
prevention
PHARMACOVIGILANCE
DEFINITION:
è  detection, assessment and
prevention of adverse drug reactions
i.e. monitoring and early warnings of
adverse effects with the view for
validating them and turning signals to
useful actions
è Should be linked to toxicovigilance
Benefits
n  Early
recognition, better clinical management,
lesser iatrogenic harm
n  More detection, safer drugs and safer drug use
n  Better understanding, hence better risk-harm
communication to patients
n  Better regulatory control (should be consulting
poison centers’ experience)
n  Better industry performance
ADR Monitoring & Drug use:
Practical considerations
n  Minimize
iatrogenic problems
n  Promote rational and safe drug use
n  Detect quality problems of medicines
n  Promote rational drug procurement
Some estimates
n 
n 
3-5% of
hospitalizations – due
to ADRs
30% hospitalized
patients may risk
having some drug
induced ill-effects
PHARMACOVIGILANCE
è  one of the regulatory functions
of the government
è  one of clinical functions of
health professionals
è  ethical responsibility of
industry
Product Services Division
Making communications with a
regulatory body that could give
relevant information (reported ADR
cases) of registered products
Drug Information
Service
Providing relevant
pharmaceutical
information tailored to
those in need
ADR
Therapeutic Committee
Play a significant role in encouraging
health professionals to report ADR
incidents
Health
Insurance
Essential system for
making decision on
paying (reimbursement)
of drugs
ADR Monitoring
n  Looking
at the reasons why they occur &
preventing them
(e.g. Mefenamic acid brand - revision of
misleading product advertisement and
information)
n  Indicators for local regulatory action
(e.g. delisting drugs, tightening regulations
on use of medicines; defective devices like
needles)
ADR and Drug use
n  Teaches
us to communicate with our
patients:
(e.g. hypoglycemia due to Minidiab and
metformin intake when patient skips meals)
n  Misuse of ADR rumors & compromising a
public health programme
(e.g. abortifacient found in Tetanus vaccine)
EXAMPLES
n 
Unregistered Chinese
Medicines
n 
n 
n 
“snake bone
rheumatism pills”
not registered
contains
phenylbutazone &
unspecified steroid
compound
EXAMPLES (Cont.)
n 
Unregistered
Antimicrobial
Drugs
n 
n 
n 
August 1996, 10 cases of
dermal reaction with
ampicillin sodium in
Sultan Kudarat
7 cases of ADRs were
reported in Aurora
All parenteral ampicillin
preparations were
confiscated
EXAMPLES (Cont.)
n 
The Media and
Humulin Death
n 
n 
Phil. Newspapers
reported deaths from
Humulin use
Investigation revealed
these reports were made
by a disgruntled
employee who was fired
from the company.
EXAMPLES (Cont.)
n 
Slimming
Formulations
n 
n 
19 yr. old woman died
from Powerup
capsules
Package insert
revealed the product
contains ephedra, a
regulated drug in the
Philippines
EXAMPLES (Cont.)
n 
Body Building Pills
n 
n 
Body builder taking
Stanozol developed
severe jaundice
Stanozol was brought
into the Philippines
illegally
EXAMPLES (Cont.)
n 
Mood Altering
Drug
Supplement
(unregistered
locally)
n 
n 
n 
A patient taking
Cybergenic products
attempted suicide.
BFAD analysis revealed
the drug contains steroids
Patient exhibited paranoia
after use of Americanmade nutritional products
containing ephedrine
EXAMPLES (Cont.)
n 
Suspected
Two ineffective drugs were
reported:
Therapeutic
n  chloramphenicol (Biosis)Inefficacy and
TCs placed this drug under
Empowering
Hospital Therapeutic questionable efficacy and
excluded it in the formulary
Committees (TCs)
n 
oxytocin (Scandrug) - clinical
observation revealed that 2
ampules had to be used to
reached the desired effect
Examples
n 
n 
Substandard
Methylergometrine
Maleate. Bohol 2000
16 obstetricians
reported 5 cases of
emergency
hysterectomy with one
death because of
uterine atony
Finding Evidence for comparative
safety: clinical concerns
n  You
want to know what goes through a
clinical decision in making a prescription
n  Share with you a few rules and caveats
n  Some suggested directions to find evidence
Some rules in drug safety
n 
n 
n 
n 
n 
Drugs are double edged
chemical sword
Preclinical data on toxicity
is followed by PMS
Treat the patient, not the
disease nor the lab values
Communicate efficacyharm/benefit-risk
information effectively
Don’t believe everything
you get from the industry
Doc, I prefer the disease
To the side effects of the
Medicines you gave.
rules
n 
n 
n 
n 
Read and validate
information/literature
Consider the high risk
groups as potential victims
Prescribers have moral/
ethical/public health
obligations to share ADR/
toxicological information
Contraindications do not
always mean you must not
use the drug
Pharmacovigilance and
improvement of clinical practice
n  Improvement
in clinical history taking and
documentation of patient’s chart (ie. Taking
of alternative meds and OTC meds)
n  helps you to understand drug behavior
better
n  helps you in developing differential
diagnosis
n  early detection means early intervention and
management of drug induced diseases
Pharmacovigilance and
improvement of clinical practice
n  Limit
irrational drug use, drug interactions
and inappropriate polypharmacy
n  Improves medical practice on patient
follow-ups
n  takes into consideration the role of clinical
toxicology
Contraindications, interactions,
high risk groups
n  Is
the active substance suitable for the
patient’s condition ?
n  Is the schedule or dosing correct ?
n  Is the duration of use correct ?
n  Is the patient taking any other substances ?
(OTC meds, herbal supplements etc.)
examples: gingko biloba, St. John’s wort,
alcohol
Depending on patient compliance
(drug use problem)
•  Considerations
Understanding drug
effects and why needed
Understanding ADR and
what to do
Ability of patient to take
meds regularly
Access to available drugs
Laboratory testing
Follow-up with the doctor
n 
warfarin
n 
Aspirin
An example
n 
Suppose anticholinergic
drug like thorazine:
– 
– 
– 
– 
– 
n 
Dry mouth
Urinary difficulties
Constipation
EPS
NMS
What to do
– 
– 
– 
– 
Dec. dose
D/C
Shift to another class
Give countering agents
A clinician’s dilemna
n 
n 
n 
n 
Complementary,
alternative medicines
What to do ?
What to advise ?
Where to get the
information ?
Another example (Clinician’s
concern)
n 
n 
n 
n 
n 
n 
Jeepney driver
Smoker
Chronic dry cough
Self medication failed
Use of codeine (Rx)
AE: drowsiness and
driving
•  Child of less
than 2 year old
at home also has
cough
•  Father (driver)
then use meds
on this child
•  What happens
next ???
Depending on self-medication
practice
n  The
issue of phenylpropanolamine
n  The issue of stilnox (Zolpidem)
n  The issue of BFAD allowing drug promo
and contest rewards like trips may
encourage irrational stocking and abuse of
medicines.
Where to find comparative
evidence ?
n 
n 
n 
n 
n 
Problem with literature search (only common
ones, and often delayed; issue of publication bias)
Consulting with your national centers for
pharmacovigilance (how to pick up signals and
how to document these ?)
Dear Doctor letters/newsletters/advisory
Product information updates (industry)
Consulting with World Health Organization
Uppsala Monitoring Centre
internet: www.who-umc.org
Pharmacovigilance and regulatory
authorities
Conundrum with Public health programs ?
-  HIV
-  Antimalarial drugs in pregnancy
-  TB resistance
Pharmacovigilance and
regulatory functions
n  Looking
at the product marketing,
advertising and claims (incl. Health suppl)
n  absence of ADR/toxicity make help
regulators consider downregulating a
prescription drug to an OTC (or vice-versa)
n  look into “clinical trials” & regulate
n  Source of QA checks and GMP inspections
or development of DMF
Pharmacovigilance and
regulatory functions
n 
n 
n 
Vaccine safety
International networking- sharing of vital information improves package
information (both of the product and generic
equivalents)
–  why a product was withdrawn and prevent
dumping in some countries
Internet sales of drugs is a public health &
toxicology concern
Pharmacovigilance and
regulatory functions
n  Requirement
of use of generic terms lessen
chances of ADR:
–  eg. Mesulid vs Mellaril;
–  Ceporex vs Leponex;
–  Diatabs vs Dia-tabs;
–  thiamine vs thorazine;
–  terbulin vs theodur;
–  EMB vs EMBR
Pharmacovigilance and
regulatory functions
n  Generic
medicines Product Information ?
n  Important to have some scientific
excellence and credibility to encourage
ADR reporting (perception of bureaucracy)
What DRA should do after
identifying safety problems?
Benefit/risk evaluation
Edit product
information:
n 
n 
n 
n 
n 
n 
n 
n 
Indications/use
Dosing instructions
Contra-indications
Interactions
Pregnancy/lactation
Warnings/precautions
Undesirable effects
Over dosage
Withdraw
marketing
authorisation
In Conclusion
n  doctor
who practice clinical work should
look at pharmacovigilance seriously as part
of day to day work.
n  Healthcare facilities should make their
presence felt in critical drug regulatory
decisions (ADR reporting)
n  In the final analysis, it is about making
drugs and their use safer for patients
I have an earache
2000BC – here eat this root
n  1000AD – that root is heathen, say this prayer
n  1850 AD – this prayer is superstition, here drink this
potion
n  1940 AD – this potion is snake oil, here swallow this
pill
n  1985 AD – this pill is ineffective, here take this
antibiotic
n  2001 AD – this antibiotic is artificial, here eat this
root.
n 
Medication Errors
7
Some estimates
n 
n 
3-5% of
hospitalizations – due
to ADRs
30% hospitalized
patients may risk
having some drug
induced ill-effects
Recent study
n  Archives
of Internal Med
n  > 40 potentially harmful errors/day on the
average in US hospitals (From 1999)
n  Most common were: giving medicine at
wrong time, completely omitting dosage;
sometimes overdosage.
n  Average of 2 errors per patient daily.
n  7% are considered potentially harmful.
references
n  Medication
errors observed in 36 health
care facilities. Barker, KN, et al (2002)
Archives of Internal Medicine. Vol. 162:
1897-1903.
n  Discrepancies in the Use of Medicines. S.
Bedell et al. (2000). Archives of Internal
Medicine, Vol. 160: 2129-2134
Significance
n 
n 
n 
n 
n 
Doctor’s command
responsibility
Possible malpractice
lawsuits
Role national health
insurance
Role of the drug
regulatory authorities
Role of drug industry
Definitions
n 
n 
n 
n 
n 
n 
Adverse drug reactions (WHO)
Adverse drug events (to include medication errors)
Bates et al 1995.
ADR may be due to medication errors (fetal
malformation due to mothers taking retinoids for
acne).
Aspiration pneumonia due to erroneous overdose
of a sedative is not ADR but ADE.
Medication errors are not sometimes harmful (10X
penicillin dose) in some patients but may be so
with liver and kidney impairment.
Errors can be undetected.
Proposed working definition
n 
Medication error is a
failure in the treatment
process that leads to,
or has the potential to
lead to, harm to the
patient.
Treatment process
n  Diagnosis
n  Prescription
written
n  Prescription received and processed
n  Drug dispensed
n  Drug administered
n  Patient receives drug
n  Patient response.
Causes of Medication Errors (1)
n 
n 
The manufacture of medicines (cardiac catheter,
sulphonamide elixir, change of excipient calcium
sulphate to lactose in phenytoin)
Packaging and storage
–  100 mg vs 100 microgram thyroid hormone
–  fanconi’s syndrome and expired tetracycline
n 
n 
n 
Failure to provide drug information
Failure to do PMS by manufacturers
Misleading health and treatment claims by the
industry
Causes of Medication Errors (2)
n 
Prescribing the wrong drug
–  Writing illegibly
–  Confusing the name of one drug with that of another
(terbulin vs theodur; chlorpropamide vs chlorpromazine)
n 
Prescribing the wrong dose
–  Calculating or Writing wrong dose
–  Wrong route of administration
n 
n 
Prescribing the wrong formulation (slow release
drugs)
Prescribing the duration of treatment incorrectly
Causes of Medication Errors (3)
n  Prescribing
wrongly for a given individual
–  Error in identity
–  Failing to account pre-existing disease
–  Failing to account concurrent therapy
n  Prescribing
with inadequate or incorrect
instructions
n  Prescribing without informed consent of the
patient
n  Off label use of drugs
Causes of Medication Errors (4)
n 
n 
Dispensing errors
The use of generic terms lessen chances of ADR:
–  eg. Mesulid vs Mellaril;
–  Ceporex vs Leponex;
–  Diatabs vs Dia-tabs;
–  thiamine vs thorazine;
–  EMB vs EMBR
–  terbulin vs theodur
n 
Experience with a top drugstore chain in
Philippines:
–  Amoxicillin vs ampicillin
–  Paracetamol 125 mg/5 mL vs 250 mg/5 mL
Causes of Medication errors (5)
n 
Errors in drawing up and giving medicines
–  Wrong drug
–  Correct drug, wrong dose
–  Correct drug, wrong dilution
–  Correct drug, wrong formulation
–  Entraining air, particles or other contaminants with the
drug
n 
Errors in administration
–  giving a drug outside or against currently accepted
practice
–  Wrong route, wrong site, wrong rate, wrong patient
–  Wrong drug by mistake
–  IV drug incompatibility
Good prescribing practice -1
n 
n 
n 
If it is possible to write the dose as a whole
number, then do so:
If it is impossible or more confusing to write the
dose as a whole number, then ensure that a zero
precedes the decimal point
Which is better ? :
–  150 microgram of clonidine vs 0.15 mg
–  0.25 mg of digoxin vs 250 microgram
–  1 mg atropine vs 1.0 mg atropine (read as 10 mg)
–  .5 mg atropine (read 5 mg) vs 0.5 mg atropine
n 
n 
Place the decimal point properly
Avoid dangerous abbreviations.
Dangerous abbreviations
n 
n 
n 
n 
n 
n 
n 
n 
D/C
AU vs OU
DPT vs dPT
HCl vs KCl
MgSO4 vs morphine
OD vs right eye
Per os vs left eye
QD vs QID
n 
n 
n 
n 
n 
n 
n 
QN vs every hour qh
QOD vs daily
Sub q (subcutaneous)
misread as every so hours.
SC vs SL
IU vs IV
X3d vs three doses
Inderal40 vs Inderal 40
mg (mistaken 140 mg)
Dosage label concerns
n  100
mg/kg 6 hourly
Vs
n  100 mg/kg/day divided in 4 equal doses
given every 6 hours.
Interpret this:
n 
n 
n 
Expiry date 12 09 04
Expiry date 09 12 04
Expiry date 25 09 04
GPP -2
n  Use
units properly (Grams vs grain)
n  Communicate clearly (modern technology)
n  Write clearly a prescription and instruct.
n  Elements of a good prescription: drug
name, dosage strength, number, frequency
of administration, route of administration.
n  Be conservative.
GPP -3
n 
n 
n 
n 
n 
n 
n 
n 
Know your patient’s condition.
Pay attention to past history of hypersensitivity.
Take note of patient’s occupation.
Prescribe a drug which is familiar to you.
Prescribing a generic drug, know the company.
(bio-A, substandard issues)
Avoid overprescribing and hence overstocking
(accidents, sharing, reselling)
Avoid polypharmacy.
Spend time to educate patients.
GPP - 4
n  Some
medicines started should be
completed (antibiotic resistance)
n  Some medicines taken for long time should
not be stopped abruptly.
n  Some medicines taken for long time may
lead to abuse, dependence.
n  Be wary of drug paroxysms.
Negligent acts
n 
n 
n 
n 
n 
n 
n 
n 
Failure to obtain consent from a patient to use a
drug in off-label manner
Treatment of a condition with a drug not suitable
for the condition (cough with ethambutol;
depression with sedatives)
Failure to note a drug hypersensitivity history
Failure to test
Improper injection techniques
Failure to stop medicine suspected for ADE
Failure to intervene and counteract ADE
Failure to communicate with patient.
In summary, find ways to prevent
n  Incomplete
patient information
n  Unavailable, not updated drug info
n  Miscommunications on drug orders
n  Lack of correct labeling as drugs are
repacked into smaller units
n  Environmental factors that can distract a
health professional.
Take home messages
n 
n 
n 
Anyone in the
treatment chain should
be responsible to
recheck orders.
If unsure, ask and
validate.
Detect, report, analyze
and feedback.
Doc, I prefer the
disease
To the side
effects of the
Medicines you
gave.
Expressing Risks
8
Terms and definition
n 
n 
n 
n 
Absolute Risk –probability of an event affecting
members of a particular population (1 in 1000)
Attributable Risk – the difference in the
probability of an event happening, directly
attributable to a drug or other variable
Relative risk – a comparison of the probability of
an event happening for the exposed and nonexposed population (the reference risk), expressed
as a ratio
Communicating Risk – read Erice Declaration
Attributable risk
n  Background
rate of 13 in 1000 people with
skin disease developing skin rash when not
taking any drug
n  If there are 13 experiencing skin rash in a
study group of 1000 people or patients, then
it is unlikely due to the drug
n  If there are 22 rashes in the study group,
then there is increased attributable risk (9 in
1000)
How Common is common ?
n  Common
or Frequent: between 1 in 100
(1%) and 1 in 10 (10%)
n  Uncommon or infrequent : between 1 in
1,000 (0.1%) and 1 in 100 (1%)
n  Rare : Between 1 in 10,000 (0.01%) and 1
in 1,000 (0.1%)
n 
CIOMS working group, Geneva 1995
More terms
n 
n 
n 
n 
n 
Benefits- proven good of a product but should
include patient’s subjective assessment of the
effects
Risk – probability of harm
Harm – nature and extent of the actual damage
that could be caused (not to be confused with risk)
Effectiveness – probability of the drug working as
expected in the clinical setting (opposite of risk)
Efficacy – capacity of the drug to work as
intended in ideal experimental circumstances
differences
n  Mild
n  Moderate
n  Severe
n  Serious
The Organizations to join :
n 
n 
n 
International Society of Pharmacovigilance
Drug Information Association
Philippines Society of Experimental and Clinical
Pharmacology
Conference to attend :
ISOP Convention in Manila October 16-19, 2005
Clinical Importance of Drug
Interactions
9
Philosophical Considerations
n  Polypharmacy
? Good or bad ?
n  Medical Malpractice Bill issues: failure to
disclose critical drug info
n  Role of drug industry (manufacturing/R&D)
n  Role of Medical Representatives (The
Practice episode Sept 18, 2002) ?
High risk groups
n  Very
young
n  Very old
n  Multiple diseases
n  Taking multiple drugs (particularly, those
with narrow margin of safety)
n  Critically compromised patients: cancer,
HIV-AIDS, psychiatric, septic
Clinical Considerations
n  Is
it life-threatening and harmful ?
n  Adverse reactions may be attributable to the
disease and not the drug combinations.
n  But listen to your patients and what the
nurses and relatives of patients tell you.
Factors that affect our lives
n 
n 
n 
n 
n 
n 
n 
n 
Coffee/caffeine intake
Alcohol intake
Cigarette smoke and second hand smoke
Hormones, pesticides and antibiotics in food
Food intake: grapefruit
Herbal/alternative supplements
OTC drugs self medication by patients
Overconfidence and lack of reading/validation
Effects
n  Enhanced
effects to toxicity
n  Diminished effect to antagonism
n  Alteration to absorption
n  Alteration to metabolism
n  Alteration to clearance
n  Adverse effects may be slow or may be
rapid, hence may not be detected
Diabetes
n  Decreased
effects:
–  Ethanol abuse
–  Rifampicin
–  Nifedipine
–  Thyroid hormones
n  Enhanced
hypoglycemic effects:
–  Alcohol
–  Skipping meals
Heart patients
n  RHD
& arrhythmias
–  penicillin & oral contraceptive (dec effects)
–  estrogen & oral anticoagulants (dec effects)
–  Anticoagulants & phenytoin (inc effects)
n  HTN:
–  Beta-blockers & theophylline – antagonism
–  2 or more anti-HTN: additive/synergism
–  Captopril & spironolactone : dangerous hyperK
Heart
n  CHF:
–  Digitalis & hyperK or hypoK
–  Digitalis & Betablockers – increased effects
Respiratory/endocrine
n  Asthma/COPD
–  Steroids & ASA – GI bleeding
–  Beta-agonists – sympathetic effects
–  Theophylline vs norfloxacin: increased serum
theophylline
n  Goiter
–  Thyroid hormones & sympathomimetics – inc
cardiac toxicity
lifestyle
n  Alcohol:
–  Cephalosphorin - disulfiram
–  Metronidazole - disulfiram
–  INH/Rifampicin - hepatotoxicity
–  Iron - hepatotoxicity
–  NSAIDS – GI bleeding
Lifestyle
n  Shabu
(ampethamines) & general
anesthesia: enchanced cardiotoxicity
n  Appetite suppresants (PPA) & INH or MAO
inhibitors: inc sympathetic actions
n  Enhanced sedation: anticholinergics &
benzodiazepines
Psychiatry/TB
n  Psychiatric
conditions:
–  Phenothiazines & metoclopramide: increased
risk for EPS
n  TB:
–  INH & Rifampicin & PZA: hepatotoxicity
–  Rifampicin & oral contraceptives: decreased
effect
Infection
n  Dec
effect because of dec binding:
–  Milk, antacids & iron vs tetracycline
n  Enhance
effect because of reduced
clearance:
–  Isoniazid vs phenytoin
Infection
n  Increased
neuromuscular blockade:
–  Aminoglycoside vs NMB
n  Increase
nephrotoxicity:
–  Aminoglycoside vs cephalosporin
–  Aminoglycoside vs furosemide
Phenomenon of QT prolongation
n  QT
prolongation:
–  Grapefruit juice/ketoconazole vs astemizole/
terfenadine
–  Quinolone affects liver metabolism of CYP2D3
Vaccine safety
10
Drug advertising in the
Philippines
a safety issue
11
Ethical relationships between
the doctor and
the Pharmaceutical industry
12
“The Practice”
Critical appraisal
13
Issues to be discussed
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Off-label use of medicines
Role of med reps
Role of the doctor
Role of the expert witness
Role of the lawyer: plaintiff vs defendant
Role of the FDA
Role of the drug company
Role of the patient/family
Role of the health insurance
Role of the judge and jury
The management of adverse drug reactions:
practical workups for the patient
14
Thank you !