Drug interactions program for medical doctors,

pharmacists and other health care proffesionals

PharmDr. Josef SuchoparMUDr. 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

PHARMACOKINETICDrug interactions:

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

Drug absorptio

n

Drug excretion

Drug metabolism

(biotransformation)

CYP3A4, CYP2D6, CYP2C9…

Pharmacokinetic drug interactions

Drug displacemen

t (protein-binding)

Transport of the drug inside the

body

Example: Changes of biological availability of midazolam caused by

coincident medication

-96% -94% -93%

-53%-100%

-50%

0%

50%

100%

150%

200%

250%

300%

350%

cim

etid

in

dilth

iaze

m

eryt

hro

myc

in

clar

ithro

myc

in

keto

conaz

ole

itra

conaz

ole

fluco

naz

ole

gra

pef

ruit

juic

e

rifa

mpic

ine

carb

amaz

epin

e

phen

ytoin

e

St

John´s

wort

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

0%

10%

20%

30%

40%

50%

60%

2 5 10 15 20

number of drugs used

risk

of dru

g inte

ract

ion

Probability of drug interaction rises with the number of drugs patient uses

Indicence of potencial drug-drug interactions (P DDI) in the population of 120 000 clients of health insurance fund

ZPS

0

2 000

4 000

6 000

8 000

10 000

12 000

14 000

16 000

2001 2002 2003 2004 2005

Inci

dence

of cl

inic

ally

rele

vant P D

DI

0

200

400

600

800

1 000

1 200

1 400

1 600

Indic

ence

of fo

rbid

den

and o

ther

life

th

reate

nin

g P

DD

I

clinically relevant forbidden 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 providedStratification 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

Name and number of insurance card of the

patient

Notes (eg. diagnosis, adress 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

Where drug interaction is

identified, line is automatically drawn

Red line: drug interactionBlack line: contraindication!

Number: Clincal relevance of drug

interaction

Program identifies:• Potential drug interactions – red connection-line• Contraindicated drug interactions – black

connection-line• 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

0 no drug interaction1 very small risk A Probably no clinical relevance2 small risk, usually unimportant, in some cases

timing of application of one drug should be changed

B Clinical relevance not completely assessed

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

Risk-clasification by INFOPHARM Clinical relevance by FASS

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

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 2 well documented case-reports

4 good evidence - small human studies (up to 5 probands)

3 based on studies in volunteers or on pilot studies in patients

5 very good evidence - one or more human studies (6 and more probands)

4 based on controlled studies in relevant patients groups

Documented evidence: FASS

1 incomplete case-records, or in vitro studies, or LI is presumend (evidence from similar drugs)

Evicence-documentation: INFOPHARM

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

Lower index: Both drug prescribed by specialistsUpper index: Dr. prescribed both drugs

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