Pharmacoepidemiologic study of potential drug

interactions in outpatients of a university hospital in

Thailand
B. Janchawee* PhD, W. Wongpoowarak MSc, T. Owatranporn BSc and
V. Chongsuvivatwong MD PhD
*Department of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand,
Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla
University, Hat Yai, Thailand, Pharmaceutical Department, Songklanagarind Hospital, Prince of Songkla
University, Hat Yai, Thailand and Epidemiology Unit, Faculty of Medicine, Prince of Songkla University,
Hat Yai, Thailand
SUMMARY
Background: Drugdrug interaction is a potential
cause of adverse drug reactions. The incidence of
such drug interactions in university hospitals in
Thailand is unknown.
Purpose: To estimate the rate of potential drug
drug interactions in outpatients of a typical Thai
university hospital, and to identify risk factors for
such interactions in Thai patients.
Methods: One-year outpatients prescription data
were retrieved from the hospital computer
records. Potential drug interactions were identi-
ed using the existing drug-interaction database
system. Potential interactions within a specic
prescription and involving drugs prescribed
1-, 3- and 7-day earlier were searched for. Possible
associations between occurrence of an interaction
and a patients age and gender and the number of
items on the prescription were explored.
Results: The overall rate of potential drug inter-
actions was 279%with a maximal value of 578%
at the Department of Psychiatry. The rate of the
most potentially signicant interactions was
26%, being the highest in the Department of
Medicine (60%), with isoniazid vs. rifampin as
the most common interacting combination. The
rate increased with the patients age and pre-
scription size (P = 0000). The odds ratio of hav-
ing at least one potential drug interaction was 18
(642%) when age increased by 20 years
(P = 0000) and 28 (1657%) when another drug
was added (P = 0000). The rate of potential drug
interactions was the same for both genders. The
rate of potential drug interactions detected across
prescriptions was higher than within prescrip-
tions and was dependent on the time interval
between prescriptions.
Conclusions: Potential drug interactions were
common in our sample of patients. The rate of
such interactions increased with the number of
drugs prescribed and the patients age.
Keywords: drug interactions, hospital, outpa-
tients, prescriptions, rate
INTRODUCTION
Drug interactions in patients receiving multi-drug
therapy are of wide concern. Such interactions are
an important cause of adverse drug reactions and
may lead to an increased risk of hospitalization and
higher health care costs (16). Studies conducted in
various, mainly western, countries report rates of
potential drugdrug interactions ranging from
approximately 1 to 52% (720). The incidence of
actual occurrence of drug interactions has been
reported to be much smaller ranging from 0 to 13%
(10, 20). Differences in methods used, including
criteria for data collection, study periods and target
population, contribute to these discrepancies.
In Thailand, a number of short-term studies
report on potential interactions among selected
groups of drugs or patients (2124), or on those
with the most potential clinical signicance (25, 26).
Received 6 November 2003, Accepted 7 July 2004
Correspondence: Benjamas Janchawee PhD, Department of
Pharmacology, Faculty of Science, Prince of Songkla University,
Hat Yai 90112, Thailand. Tel./fax: +66 74 446678; e-mail:
[email protected]
Journal of Clinical Pharmacy and Therapeutics (2005) 30, 1320
2005 Blackwell Publishing Ltd 13
These reports suggest rates of up to 53%. One of
these studies, covering all drugs, reported a 16%
rate of potential interactions (27). The incidence of
clinical drug interactions has not been reported.
One problem in the study of rates of drug
interactions in prescriptions in Thailand is the lack
of appropriate drug databases and drug interaction
software, so that all interactions have to be identi-
ed by hand and objectivity and exhaustive cov-
erage cannot be readily validated. Additionally,
only interactions within single prescriptions have
been searched for in published studies. In a pre-
vious study (28), we described the development of
a computerized drug-interaction database that can
be used by both the public and within Thai hos-
pitals. This computerized system enables the rapid
and accurate detections of potential drug interac-
tions from prescription data.
The aim of this study was to estimate the rate of
potential drug interactions in outpatients attending
a university hospital in Thailand and to identify
risk factors for such interactions.
METHODS
Study design
A retrospective large-scale study was undertaken,
using computerized data held at the Prince of
Songkla University hospital. All drug groups,
patient age ranges and morbidity types were
included.
Study population
Prescription data of outpatients visiting the hospi-
tal over a 12-month period (1 January31 December
2000) were included. The data consisted of drug
names, dispensing dates, departments of the pre-
scribing doctors and patients birth date, gender
and hospital number. To maintain condentiality,
the patient hospital number was encrypted by a
hospital programmer prior to handing the data to
the investigators.
Study protocol
Potential drugdrug interactions were detected
using our previously developed computerized
drug-interaction database system (28). It contains
information of drugs available locally and list of
over 1700 drugdrug interactions cited in three
sources (2931). The detection algorithm was based
on a structured query language, described else-
where (32).
Searches were performed both within prescrip-
tions and across successive prescriptions for each
patient during periods of 1-, 3- and 7-day. For
within prescription searches, a single prescription
is dened as: for one patient, from one doctor, in
1 day. For 1-, 3- and 7-day across prescription
detection, a single prescription is dened as: for
one patient, within 1, 3 and 7 day(s), respectively.
Potential drugdrug interactions were expressed
as the number of interacting drug pairs, number of
prescriptions with interactions or rate. The rate was
calculated as: (the number of prescriptions with
potential drug interactions)/(number of prescrip-
tions with two or more drugs 100). The whole
population was used to investigate any relation-
ship between rate of potential drug interactions
and patients age and gender, and number of drug
items on the prescription. A sample of 1020, ran-
domly selected prescriptions, was used to estimate
the rates, expressed as odds ratios.
Statistical analysis
Demographic data of patients and prescriptions
were presented as mean, standard deviation and
percentage. Logistic regression analysis was used
to determine the odds ratio. Probability (P) values
of 005 or less were considered statistically signi-
cant. All statistical analyses were performed by
using the statistical package SPSS SPSS version 100 for
Windows.
RESULTS
During a 1-year period, 124 528 patients received
prescriptions. Their average age was
390 224 years (range: 0100 years). Most
patients were adults (20399 years; 308%) and
middle-aged (40599 years; 274%). The ratio of
male to female was 405 : 595%.
Nearly half of all patients (449%) visited the
hospital only once during the whole year and
received only one prescription. The others visited
more frequently and had from two to 53 prescrip-
tions/person/year. Some of these patients had
2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 1320
14 B. Janchawee et al.
more than one prescription dispensed by more
than one department on the same day. Average
visit intervals ranged approximately from 7 to
68 days.
There were in total 360 418 prescriptions, of
which 718% or 258 951 prescriptions were mul-
tiple, containing two or more drugs, and these are
considered to carry a risk of drug interactions.
Most of these (308% or 79 837 prescriptions) were
dispensed from the Department of Medicine. Pre-
scription size ranged from 1 to 15 with an average
of 25 14 items per prescription. The number of
large prescriptions (ve items or more) increased
with increasing age (Fig. 1).
Potential drug interactions detected within a
single prescription expressed as either the number
of interacting drug pairs or the number of pre-
scriptions with interactions at each signicance
level are shown in Table 1. There were in total 612
interacting drug pairs in 72 296 prescriptions with
potential interactions. Forty-eight interacting drug
pairs (out of 6859 prescriptions) were labelled as
signicance-l interactions. The overall rate of
potential drug interactions was 279% (72 296/
258 951). Those of signicance-1 level accounted
for 26%. The most common signicance-1 inter-
acting drug pair was isoniazidrifampin (2507
prescriptions), while the second most common was
digitalis glycosidesloop diuretics, involving 1330
prescriptions (Table 2). Signicance-1 interactions
were highest in the Department of Medicine (4787
prescriptions or 60%). The most common inter-
acting combination prescribed in this department
was again isoniazidrifampin (INH 100 mgrif-
ampicin 300 mg). The second most common was
digitalis glycosidesloop diuretics (lanoxin
025 mgfurosemide 40 mg).
The rates of potential drug interactions in the
different departments within the same prescrip-
tions are shown in Table 3. The overall rate of
potential interactions was highest in the Depart-
ment of Psychiatry, viz. 578%, whilst the number
of prescriptions with interactions was highest in
the Department of Medicine (33 823 prescriptions)
with the rate of 424%. Compared with the within
prescription data, the across prescriptions rate
increased with time interval between prescriptions
(Table 3).
The number of prescriptions with interactions
and the rate of potential drug interactions in rela-
tion to age range of patients are shown in Fig. 2.
The number of prescriptions containing two or
more drugs and those with interactions were
highest among patients aged 40599 years (viz.
74 900 and 23 862 prescriptions, respectively). The
rate increased with age and was highest (425%) in
the 80 years or older age group. Logistic regression
showed that the odds ratio was 1029 [95% CI:
10211037, P = 0000, P = 1/(1 + e
267)003 Age
)]
when the patients age increased by 1 year. The
rate of potential interactions increased with size of
prescription, reaching almost 100% with prescrip-
tions containing eight or more drug items (Fig. 3).
With inclusion of all prescriptions, the relationship
between the rate of potential interactions and
01
1
10
100
019 2039 4059 6079 80 or more
Patient age groups (years)
N
u
m
b
e
r

o
f

p
r
e
s
c
r
i
p
t
i
o
n
s

(
%
)
1
24
57
8 or more
Fig. 1. Percentage of prescriptions with various sizes in
different age groups.
Table 1. Number and rate of potential interactions and
their signicance
Signicance
Number of
interacting
drug pairs
Number of
prescriptions
with interactions Rate (%)
1 48 6859 26
2 167 23 793 92
3 88 12 538 48
4 183 23 848 92
5 126 44 476 172
Total 612 111 514
a
279
Total (any signicance) 72 296
Signicance rating is dened by the drug interactions informa-
tion source used for the database system (1 = major severity,
established documentation; 2 = moderate severity, established
documentation; 3 = minor severity, established documentation;
4 = major to moderate severity, possible documentation;
5 = minor or any severity, possible or unlikely documentation).
a
Some prescriptions had more than one potential interaction.
2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 1320
Potential drug interactions in Thai outpatients 15
logarithm of prescription size is shown in Fig. 4.
Logistic regression analysis of rate and size of
prescriptions showed that the odds ratio was
2831 [95% CI: 24273301, P = 0000, P = 1/(1 +
e
436)104 Prescription size
)] when the prescription size
increased by one.
Table 2. The ve most common potential drug interactions with signicance-1
Interacting drug pairs Prescribing drug pairs Number of prescriptions
IsoniazidRifampin INH 100 mgRifampicin 300 mg 2507
Digitalis glycosidesLoop diuretics Lanoxin 025 mgFurosemide 40 mg 1330
MethotrexateNSAIDs MTX 25 mgIbuprofen 400 mg 728
Digitalis glycosidesThiazide diuretics Lanoxin 025 mgAmiloride/HCTZ 627
MethotrexateSulfonamides MTX 25 mgSalazopyrin EN 500 mg 405
Prescribing drugs pairs shown here are only the most common combinations.
Table 3. Rate % (number of pre-
scriptions with interactions) of
potential interactions found either
within or across prescriptions
Department
Within
prescriptions
Across prescriptions
1-Day 3-Day 7-Day
Anaesthesiology 226 (924) 242 (1094) 249 (1178) 257 (1309)
Community
Medicine
334 (3762) 343 (4069) 345 (4182) 353 (4410)
Dentistry 50 (39) 68 (86) 66 (91) 74 (114)
Medicine 424 (33 823) 437 (37 267) 441 (38 398) 449 (40 328)
Obstetrics and
Gynaecology
150 (2770) 156 (3275) 160 (3479) 167 (3827)
Ophthalmology 210 (2074) 202 (2750) 212 (3038) 220 (3386)
Orthopaedic
Surgery
318 (6012) 339 (7043) 343 (7334) 352 (7831)
Otolaryngology 121 (4072) 135 (4974) 140 (5268) 150 (5845)
Pediatrics 131 (4556) 137 (4938) 142 (5218) 150 (5721)
Psychiatry 578 (6049) 599 (6748) 600 (6892) 603 (7139)
Radiology 202 (2393) 209 (2715) 218 (2986) 234 (3482)
Surgery 233 (5822) 242 (6701) 249 (7127) 260 (7870)
Totals 279 (72 296) 288 (81 660) 293 (85 191) 301 (91 262)
0
20000
40 000
60 000
80 000
100 000
120 000
0199 20399 40599 60799 80 or more
Age ranges (years)
N
u
m
b
e
r

o
f

p
r
e
s
c
r
i
p
t
i
o
n
s
0
5
10
15
20
25
30
35
40
45
R
a
t
e

(
%
)

Total prescriptions Prescriptions with > 1 drug
Prescriptions with interactions Rate
Fig. 2. Number of prescriptions with interactions and
rate of potential drug interactions among different age
ranges.
1
10
100
1000
10 000
100 000
1 000 000
24 57 8 or more
Prescription size
N
u
m
b
e
r

o
f

p
r
e
s
c
r
i
p
t
i
o
n
s
0
10
20
30
40
50
60
70
80
90
100
R
a
t
e

(
%
)

Prescriptions with > 1 drug Prescriptions with interactions Rate
Fig. 3. Number of prescriptions with interactions and
rate of potential drug interactions among different sizes
of prescriptions.
2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 1320
16 B. Janchawee et al.
The rates of potential drug interactions in pre-
scriptions for male and female patients were equal
(viz. 279%).
DISCUSSION
This study revealed that the rate of potential drug
interactions in outpatients was 279% overall and
26% for the most potentially signicant combina-
tions. These values cannot be directly compared
with those reported previously because of the dif-
ferences in the study design. However, a retro-
spective study of drugdrug interactions in
outpatients of a provincial hospital in Thailand
reported the rate of potential interactions during
2 weeks among all drug groups involving 3119
prescriptions as being 159% (27). Two studies
involving a 3-month period of data collection and
investigating 40 pairs of potentially important or
major signicant drug interactions reported the
rate of less than 05% (25, 26).
Our nding clearly shows that the rate of
potential drug interactions is directly proportional
to the patients age. A higher rate was seen among
older patients. This corresponds to other studies
reporting that potential drug interactions were
common in elderly people who were on multi-
drug regimen (9, 10, 12, 14, 19). Our study shows
that the odds ratio of having potential drug
interaction was 1029 at every 1-year period or
1786 at every 20-year increment of age, and that
the probability of having at least one drug inter-
action increased by 15 or 642%. None of previous
studies has directly demonstrated such a
relationship nor resulted in a numerical prediction
gure.
The rate of potential drug interactions was also
directly related to prescription size. This result is
similar to that established by Weerutamasen (27),
who studied potential drug interactions in pre-
scriptions of patients in all age ranges during
2-week period and revealed that the rate increased
by the number of drug items. Results from other
studies indirectly support this nding. Reviewing
medical record, Mitchell et al. (8) showed that the
percentage of patients with potential drug interac-
tions increased with number of drug prescribed per
patient. A result from Nolan and OMalley (33)
indicated that the percentage of elderly patients
being prescribed potentially interacting combina-
tions increased greatly with the number of medi-
cations given. Our study showed that the odds
ratio of having potential drug interactions was
2831, and that the probability increased by 1657%,
as the number of prescribed drug increased by one.
Another study (12) reported a smaller probability
that, while the number of concurrent medications
per patients increased by one, the probability of
having at least one drugdrug interaction increased
by 224%.
In this study, regression analysis showed that
there is a slight correlation between patient age and
prescription size. In addition, the proportion of
large size prescriptions tended to increase with
increasing age. On the other hand, most of the large
size prescriptions were given to older patients.
These data correspond to the works reported by
Muranaka et al. (13) that the number of drugs in
any one prescription increased with the age of the
patient, and by Stewart and Cooper (34) that
elderly patients used more medications than
younger patients and that the trend of increasing
drug use continued to 80 years of age. Thus the
higher rate of potential drug interactions in old age
seen in this study is probably because of the higher
number of prescribed medications. Our data sug-
gests that prescription size is a clear predictor of
potential drug interactions.
Our study shows that the highest overall rate of
potential drug interactions was that of the
Department of Psychiatry (578%), followed by that
of the Department of Medicine (424%). Generally,
the highest rate is expected to be of the Department
of Medicine because of wider range of drugs used
0
20
40
60
80
100
120
0 02 04 06 08 1 12 14
Log (prescription size)
R
a
t
e

(
%
)

Fig. 4. Relationship between rate of potential interac-
tions and logarithm of prescription size.
2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 1320
Potential drug interactions in Thai outpatients 17
and, as shown in this study, the highest number of
prescriptions at risk of drug interactions. When the
number of interacting drug pairs are taken into
account, it was found that overall, and those with
the label signicance-1 were the highest in the
Department of Medicine, viz. 80 670 and 5984
pairs, respectively. In the Department of Psychi-
atry, those numbers were 9431 and 157 pairs,
respectively. The number of interacting drug pairs
per prescription with interaction was 24 for the
Department of Medicine and 16 for the Depart-
ment of Psychiatry. As calculation of the rate in this
study was based on the number of prescriptions
with interactions, the rate and the number of
interacting drug pairs should be simultaneously
considered.
No difference in the rate of potential drug
interactions between male and female patients was
observed in this study. This suggests that the pat-
tern of drug use in this population was similar in
both genders.
It was observed that some patients received
more than one prescription during each hospital
visit or received a different one earlier during a
certain period of time. In this study, we detected
any potential interactions both within and across
prescriptions, whilst in previous studies only
interactions within a single prescription were
investigated. In clinical practice, interactions across
prescriptions can occur and the rate may well be
higher compared with that of within prescriptions.
According to prescription data retrieved from the
computer system of the hospital, only drug name
and strength of drug preparation were shown (e.g.
Inderal 40 mg tablets), but not the duration of drug
treatment. Even though the amount of drug pre-
scribed and how the drug was taken, were recor-
ded by the hospital, estimation of the duration of
drug treatment from the data needs further pro-
gramming. However, assuming that a patient had
been taking any drug continuously prior to
receiving another drug in the next period, for
example 1-, 3- or 7-day, we have shown that the
rate of drug interactions was higher and dependent
on the period of time.
This study revealed a relatively high rate of the
potentially most signicant drug interactions.
These included the commonly prescribed combi-
nation regimen, isoniazid and rifampin, for tuber-
culosis treatment. The risk of hepatotoxicity is
increased in patients receiving both drugs (35, 36).
Other interacting drug pairs may also cause serious
adverse events. Loop- or thiazide-diuretic-induced
electrolyte disturbances, may predispose to digita-
lis-induced arrhythmias (37, 38). NSAIDs (3941)
and sulfonamides (4244) may increase methot-
rexate toxicity, especially when given concomit-
antly with a high dose of methotrexate was used.
The clinical signicance of such interactions
depends on many factors such as drug dosage,
period of concurrent drug use and extent of patient
monitoring by physicians.
CONCLUSIONS
Potential drug interactions are frequent among
outpatients prescribed multiple medications. The
rate is directly related to number of drugs pre-
scribed and patient age. Older patients are prone to
drug interactions partly because they receive more
medications. With close management, drug inter-
actions often need not have clinically important
adverse consequences.
ACKNOWLEDGEMENTS
The study was supported nancially by the Health
System Research Institute (HSRI), Thailand and the
World Health Organization. We thank Asst. Prof.
Dr Sorayut Vasiknanonte, Associate Dean for
Medical Informatics, Faculty of Medicine, Prince of
Songkla University and the programmers of the
Computer Unit, Songklanagarind Hospital, for
providing the available prescription data. We also
thank Mrs Naowanit Trisdikhun, Head of Phar-
macy Department, Songklanagarind Hospital and
the Director of Songklanagarind Hospital. The
support of the HSRI Network, Prince of Songkla
University as to the coordination and cooperation
throughout the research has been highly appreci-
ated.
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