Drug interactions program
for medical doctors,
pharmacists and other health
care proffesionals
PharmDr. Josef Suchopar
MUDr. Michal Prokes
INFOPHARM a.s., Prague
Czech Republic
Drug interactions:
Are they really important?
• Metaanalysis of 39
prospective clinical
trials has proved:
• Adverse Drug
Reactions are 4th
most frequent cause
of death
• Lazarou et al: JAMA
1998
• Analysis of USA
National Drug
Register has proved:
• The cause of 2/3 of
ADRs are drug
interactions
• Phillips et al: JAMA
2001
Different kinds of drug interactions
Drug interactions:
•
•
•
•
PHARMACOKINETIC
PHARMACODYNAMIC
Interaction drug - drug
Interaction drug - alcohol
Interaction drug - foods (and soft drinks)
Interaction drug – food supplements
All these kinds are divided into:
Drug interactions:
– clinically relevant
– not clinically relevant
Pharmacokinetic drug
interactions
Drug
absorption
Transport
of the drug
inside the
body
Drug
displacement
(protein-binding)
Drug
metabolism
(biotransformation)
CYP3A4, CYP2D6,
CYP2C9…
Drug
excretion
St John´s wort
phenytoine
carbamazepine
rifampicine
grapefruit
juice
fluconazole
itraconazole
ketoconazole
clarithromycin
erythromycin
dilthiazem
350%
cimetidin
Example: Changes of biological availability
of midazolam caused by coincident
medication
300%
250%
200%
150%
100%
50%
0%
-50%
-100%
-53%
-96% -94% -93%
Inhibitors of CYP3A4 increase bioavailability of midazolam,
inducers of CYP3A4 lessen it.
Pharmacodynamic drug
interaction
• Opposing or antagonistic interaction:
– Anticoagulants + vitamin K: Anticoagulant effect
opposed
• Serotonin syndrome
• QT prolongation – can lead to life threatening
cardiac arrhytmia torsade de pointes
• Disturbances in fluid and electrolyte balance
– Kalium loosing diuretics + digoxin: Increased
toxicity of digoxin
Probability of drug interaction
risk of drug interaction
60%
50%
40%
30%
20%
10%
0%
2
5
10
15
20
number of drugs used
Probability of drug interaction rises with the
number of drugs patient uses
16 000
1 600
14 000
1 400
12 000
1 200
10 000
1 000
8 000
800
6 000
600
4 000
400
2 000
200
0
0
2001
2002
clinically relevant
2003
forbidden
2004
Indicence of forbidden
and other life
threatening P DDI
Incidence of clinically
relevant P DDI
Indicence of potencial drug-drug
interactions (P DDI) in the population of
120 000 clients of health insurance fund
ZPS
2005
other life threatening
Why doctors cannot keep
drug interactions on mind?
Too many informations:
• 2 700 drug interaction in CR,
where coincident therapy is
forbidden by manufacturer
• 3 100 drug clinical relevant
interactions in CR, where
coincident therapy may cause
serious damage to patient
Solution is to combine
these activities:
• Education of doctors and pharmacits
• Cooperation of doctors and pharmacists to
identify high-risk patiens
• Feedback to doctors from databases of health
insurance funds
• Computer program:
– alerts doctors when potencial drug-drug
interaction occurs
– offers the most detailed evidence-based
information in the actual time the
prescription is written
Questions asked by doctors
and pharmacists
• Two drugs interact: Is this knowledge theoretical
(speculative) or is it proved in humans (not only in
mice or in vitro)? How strong is the proof?
• Clinical relevance: If the interaction occured in
humans, how serious is it?
• Has it been described many times or only once?
• Are all patients affected or only a few?
• Is it best to avoid these two drugs altogether or can
the interaction be accommodated in some way (and
how)? Dosing of drugs, lab tests, watching for
specific signs and symptoms…
Stockley´s Drug Interactions, Sixth edition
INFOPHARM program offers (I)
• Stratification of the clinical importance of drug
interaction (values from 0 to 5, where values 3,4
and 5 are clinically relevant)
• Validation of quality of documentation of drug
interaction:
–
–
–
–
–
poor evidence
no EBM proof avilable, only manufacturer´s statement
case-report
good (more than 3 case-reports or a small study)
excelent (study)
• Aggregate evaluation of clinical importance and
quality of documentation (values from 0 to 5)
INFOPHARM program offers (II)
• Information, what happens to patient when the
two drugs are applied
• Mechanism of drug interaction (if known)
• What measures are to be applied to lessen the
risk: Decrease dosing, lab tests provided,
watching for specific signs and symptoms, or not
to apply the two drugs together at all
• Comments: Abstracts from medical papers
containing all the neccessary information for
doctor to know how to deal with the situation
• References: Each user can find the primary source
of information
The way the information is provided
Stratification of
quality of
documentacion
and clinical
relevance
What happens to
patient?
Mechanism of
interaction
What
measures
are to be
made?
Abstracts from medical papers are
detailed
Sources – to
identify the
medical papers
Three ways to use INFOPHARM
drug interaction program
• Isolated use of the program
• Drug interaction program is used like a
module for other program, such as:
– patient notes including medication on PC
– pharmacy programs for warehousing
activities
• Health insurance funds database use the
program to provide drug prescription analysis
and rational drug prescription support to the
doctors
Isolated use of drug
interactions program
INFOPHARM
Notes (eg. diagnosis,
adress of the patient…
Name and number of
insurance card of the
patient
Here user writes the
name of the medicinal
product
Write first 4 letters and
list of drugs pops up.
Scrool down to find the
right drug and then
ENTER
List of drugs is being
made
Number: Clincal
relevance of drug
interaction
Red line: drug interaction
Black line: contraindication!
Where drug interaction
is identified, line is
automatically drawn
Program identifies:
• Potential drug interactions – red connection-line
• Contraindicated drug interactions – black connectionline
• No drug interaction – green connection-line (evidence
from human studies)
• 2 or more drugs with the same active ingredient –
blue connection-line
• 2 or more drugs with similar active ingredient, when
co-prescription is usually erroneous – violet
connection-line
• 2 or more drugs with marked hepatotoxicity,
myelotoxicity or nephrotoxicity, when co-prescription
is to be avoided – yellow connection-line
Stratification of the risk of drug interactions
in ČR and in other countries
Risk-clasification by INFOPHARM
0 no drug interaction
1 very small risk
2 small risk, usually unimportant, in some cases
timing of application of one drug should be
changed
3 medium risk, dosing should be changed
sometimes, and/or lab tests, or clinical
symptoms watched
4 large risk, usually dosing should be
changed, and/or lab tests, or clinical
symptoms watched
5 very large risk, avoid (if possible),
and/or lab tests, clin.symptoms!
6 contraindication
Clinical relevance by FASS
A Probably no clinical relevance
B Clinical relevance not completely assessed
C Clinical relevance. Interaction may
modify the effect of the drug, but
this is susceptible to control by dose
adjustment (includes beneficial and
adverse drug interactions)
D Clinically relevant, may serious
clinsonsequences, ought to be
avoided.
In drug-interaction program filters should be implied
Documented evidence in ČR
and in other countries
Evicence-documentation:
INFOPHARM
1 incomplete case-records, or studies with
different outcomes (never only analogies,
never only in vitro)
2 report from manufacturer, when other
information is not avilable
3 complete case-reports
4 good evidence - small human studies (up to
5 probands)
5 very good evidence - one or more human
studies (6 and more probands)
Documented evidence:
FASS
1 incomplete case-records, or in
vitro studies, or LI is
presumend (evidence from
similar drugs)
2 well documented casereports
3 based on studies in
volunteers or on pilot studies
in patients
4 based on controlled studies in
relevant patients groups
When only clinically
relevant interaction are
to be identified, press
filter button
Buttons for saving the
patient medical record
and opening another
one
Now filter is set
only for clinical
relevant
interactions level 4 and 5
To get detailed
information on the
drug interaction
press this button
Examplex of health insurance
database report on drug
interactions using
INFOPHARM program
Drug
interactions
prescribed to
patients which
are client of
particular
general
practicioner
Upper index: Dr. prescribed both drugs Lower index: Both drug prescribed by specialis
The same GP:
drug
interactions
are sorted by
individual
patients
INFOPHARM a.s.
•
•
•
•
•
•
Adress: Hvozdanska 3
Post code number: 148 00
City: Prague 4
Country: Czech Republic
www.drugagency.cz
tel. +420 226 211 791-3, +420 724 375 439
(Prokes Michal, MD)
• fax: +420 226 211 794