RESPIRATORY MEDICINE (2000) 94, 852±858

doi:10.1053/rmed.2000.0813, available online at http://www.idealibrary.com on

Compliance with an oral asthma medication: a pilot

study using an electronic monitoring device
K. F. CHUNG* AND I. NAYA{
{
National Heart and Lung Institute, Imperial College School of Medicine & Royal Brompton & Harefield
Hospital, London and{ AstraZeneca, Macclesfield, U.K.

Compliance with prescribed asthma medication is commonly estimated from tablet counts for oral medications and
canister weights for inhaled medications. Recently, electronic medication monitoring devices, developed to evaluate
numerical compliance as well as drug use patterns, were used to assess compliance with inhaled steroids and b2-
agonists. This was the ®rst study to electronically assess compliance with an oral asthma medication. Fifty-seven
asthmatic patients, stable on inhaled b2-agonists only with a mean FEV1 of 77% predicted (‹ 13%, SD) began 12
weeks of treatment with za®rlukast 20 mg twice daily. The monitoring device, an electronic TrackCapTM, recorded
the date and time on each occasion that patients removed and replaced their medication bottle caps. Patients were
told that compliance would be assessed as part of the study, but patients were not told about the speci®cs of the
TrackCapTM. Compliance was de®ned: 1. as the number of TrackCapTM events per number of prescribed tablets; and
2. as the di€erence between number of tablets dispensed and number returned per number prescribed. Adherence
was de®ned as the number of days with two TrackCapTM events at least 8 h apart per the total number of days'
dosing. Forty-seven patients completed the study with a median compliance of 89% (mean, 80%) and a median
adherence of 71% (mean, 64%) as measured by TrackCapTM events. Compliance as estimated from return-tablet
count was slightly higher (median, 92%). High rates of compliance were maintained throughout the trial. These
results show that compliance with and adherence to a treatment of an oral, twice-daily, maintenance asthma
medication, such as za®rlukast, is high.

Key words: compliance; asthma; electronic TrackCapTM; za®rlukast; leukotriene-receptor antagonist.

RESPIR. MED. (2000) 94, 852±858 # 2000 HARCOURT PUBLISHERS LTD

Introduction treatment advice. In fact, compliance with asthma medica-

Patient compliance with prescribed treatments for chronic
diseases, such as asthma, is an essential aspect of disease
management. Yet studies have shown that only one third of
all patients and 0 to less than 50% of asthma patients take
their medications as prescribed (1±7). In patients with
asthma, treatment non-compliance is thought to play a
major role in the unacceptably high morbidity and
mortality associated with the disease (8±11). To what
extent non-compliance is associated with a lack of disease
comprehension or with diculty in using medication
dispensing devices is unclear; however, both appear to
a€ect a patient's inclination to either adhere to or disregard
Received 17 January 2000 and accepted in revised from 25
February 2000
Financial support: This trial was supported by a research grant
from AstraZeneca, Maccles®eld, U.K.
Correspondence should be addressed to: Kian Fan Chung MD,
FRCP Address: Imperial College School of Medicine at The
National Heart and Lung Institute Dovehouse Street London SW3
6LY, U.K. Fax: ‡44 171 351 8126.
tions is related to several factors including: patient under-
standing of treatment rationale; simplicity of the treatment
regimen; medication e€ectiveness and ease of use; social
support; and a good physician±patient relationship (1,3,
12). In adolescents, who are particularly non-compliant,
compliance is more likely to be enhanced when treatment
plans additionally address steroid phobias, peer pressure,
smoking, and other lifestyle issues (13).
However de®ned, compliance is dicult to measure.
Doing so, however, is a critical step in evaluating whether
or not strategies aimed at improving asthma medication
compliance are succeeding. Currently, both direct and
indirect methods are used (14). Direct measures include
assay of blood, urine, or saliva to con®rm drug use and
direct observation to con®rm that dispensing devices or
metered-dose inhalers (MDIs) are properly used. The value
of these objective assessments is o€set by several dis-
advantages (14). The assay approach is limited by the small
number of assays available for asthma medications and by
the invasiveness of tissue sampling. Direct observations
generally occur only at clinic visits and, although patients
may demonstrate adequate skills with MDIs while under

0954-6111/00/090852+07 $35?00/0 # 2000 HARCOURT PUBLISHERS LTD

 COMPLIANCE WITH AN ORAL ASTHMA MEDICATION 853

observation, they may not consistently apply such skills in
all environments. Neither approach provides information
regarding the pattern of drug use (14).
Indirect measures include clinical judgement, self-re-
ported asthma diaries and medication measurements (tablet
counts, canister weights, etc). These methods tend to
overestimate compliance and only infer drug use with
varying degrees of reliability depending on the individuals
involved. The introduction of electronic monitors that
objectively record dates and times of bottle openings or
MDI actuationsÐknown as medication-use eventsÐpro-
vides an advantage over other indirect methods because
researchers now can study patterns of drug use (14).
Noteworthy among the compliance literature is the
®nding that patients with asthma tend to be more
compliant with their oral asthma medication (e.g., theo-
phylline) than with their inhaled asthma medication (e.g.,
corticosteroids and cromolyn sodium) (12). Oral leuko-
triene-receptor antagonists, such as za®rlukast, may pro-
vide a signi®cant alternative for dealing with poor
compliance and may ultimately improve asthma outcomes
(13,15). Orally administered za®rlukast has been shown to
reduce asthma symptoms and rescue use of bronchodila-
tors, improve lung function, improve quality of life
measurements, and decrease exacerbations when adminis-
tered twice a day (16±18). Furthermore, early evaluation of
patient compliance with za®rlukast therapy is promising. In
a study evaluating the long-term ecacy and safety of
za®rlukast, the compliance rate based on tablet counts was
94?5% at 52 weeks of treatment (19). Because tablet count
methods tend to overestimate compliance and do not
provide insight into drug use patterns, a pilot compliance
study, as reported here, was conducted with za®rlukast to
measure long-term compliance electronically and to com-
pare results with compliance calculated from tablet counts
for individual patients.
Methods and materials
PATIENTS
Male and female patients, 18±55 years of age, with a history
of asthma were sought for enrollment. Asthma history was
de®ned as previous patient response to standard asthma
treatment, episodic wheezing, or changes in lung function
over short periods of time. Patients who were using any
asthma medication, other than as-needed, short-acting b2-
agonists, were excluded from screening. Patients eligible to
receive trial treatment were those who, during the screening
period, had a 1-sec forced expiratory volume (FEV1) of
60% predicted; a15% improvement in peak expiratory
¯ow (PEF) or FEV1 after a 400-mg inhaled dose of
salbutamol; and symptomatic reversible airways obstruc-
tion that required additional controller asthma therapy, as
determined from screening diary cards.
Major reasons for exclusion included other signi®cant
respiratory disease; recent hospitalization for asthma;
recent history of respiratory tract infection; seasonal
asthma; use of corticosteroids, cromones, or long-acting
2 -agonists in the weeks that preceded the trial; recent
participation in another clinical trial; and any clinically
signi®cant medical condition that would interfere with trial
assessments or increase the patient's risk.
The study was conducted in accordance with the
Declaration of Helsinki and was approved by the desig-
nated ethics committee at each centre. Written informed
consent was obtained after patients received a description
of the trial's purpose and procedures. The informed consent
form mentioned that compliance, pulmonary function and
safety would be measured. Patients, however, were not
informed that compliance was under electronic surveillance
so as not to introduce an unacceptable bias in favour of
compliance (5). Standards of ethics were considered
maintained because patients were not subjected to addi-
tional risk, and patients' rights and welfare were neither
violated nor a€ected.
STUDY DESIGN
This study was a 15-week, open-label, non-comparative
trial and the ®rst to de®ne compliance for za®rlukast
according to a dosing schedule. An initial screening period
of 2±3 weeks was followed by a 12-week treatment period
during which patients took za®rlukast 20 mg twice a day.
The purpose of the screening period was to ®nd out if
patients had reversible airway obstruction that made them
suitable candidates for a stepwise increase in asthma
therapy. At the start of the treatment period, each patient
received 56 tablets of za®rlukast, enough for 3 weeks, with
one week's supply to spare. Tablets were dispensed in
screw-top bottles ®tted with a TrackCapTM medication
event monitoring system (MEMS) device (APREX Cor-
poration, Fremont, California, U.S.A.), that recorded the
date and time on each occasion when the cap was removed
and replaced. Patients were scheduled to return to the clinic
every 3 weeks for four more visits. At three of those visits,
patients exchanged bottles with unused tablets for newly
stocked bottles of 56 tablets; at the fourth visit, no new
supplies were issued.
The following dosing instructions were on the bottle and
outer cartons: `Take one tablet in the morning and one
tablet in the evening approximately 12 h apart. Do not take
the tablets at mealtimes.' Patients were also instructed to
remove one tablet at a time and immediately replace the cap
because the tablets were sensitive to moisture. A desiccant
capsule, found in each bottle, visually reinforced the need to
replace the cap as directed. Patients were not required to
keep asthma diaries during the treatment period, and tablet
counts were neither assessed nor discussed in the patient's
presence.
Each removal of the TrackCapTM was presumed to
indicate a single medication-use event. The device, however,
was programmed to recognize, but not accumulate, multi-
ple openings that occurred within 1 min of each other. If
the cap was left o€ for 15 min or more, the device recorded
one additional event. To prevent extraneous results, study
personnel were asked not to open the bottles before, during,
or after the study period.
854 K. F. CHUNG AND I. NAYA

Patients were assessed at each clinic visit for lung
function [peak expiratory ¯ow rate (PEF) and forced
expiratory volume in 1 sec (FEV1)] and adverse events.
Patients who withdrew underwent a complete physical
examination and a standard battery of laboratory and
pulmonary function tests at the time of withdrawal.
ANALYSIS
Percent TrackCapTM compliance was de®ned as follows:
32 men and 25 women, had a mean age of 29 years, and
they had a mixed socioeconomic background. At entry,
mean % predicted FEV1 was 77%, and duration of asthma
ranged from 10 months to 42 years. Additional patient
characteristics are summarized in Table 1.
Of the 57 patients who received za®rlukast, 47 completed
the prescribed 12 weeks of treatment. Among patients
withdrawn were three who did not comply with the

Number of TrackCapTM events

% Compliance ˆ 100 
Number of prescribed tablets
Compliance also was estimated from returned tablet counts, with percent compliance de®ned as:

Number of dispensed tablets minus number of returned tablets

% Compliance ˆ 100
Number of prescribed tablets
TrackCapTM adherence was the degree to which patients followed dosing instructions precisely on a daily basis and was
de®ned as follows:

Number of days with 2 TrackCapTM events at least 8 h apart

% Adherence ˆ 100
Total number of days0 dosing

In addition, days were classi®ed as days with two events protocol, two who did not return for follow-up visits, two
58 h apart (insucient interval adherence), days with only who withdrew consent, one who had an adverse event (mild
one event (undercompliance), days with no event (no headache), and one who was erroneously enrolled.
compliance), and days with more than two events (over-
compliance). A day was de®ned as the 24-h period from
03?00 h on one day to 02?59 h on the next day. For each TRACKCAPTM ADHERENCE AND
category, the total number of days that a patient was COMPLIANCE
classi®ed as such was calculated and expressed as a
percentage of the total number of days the patient was on As calculated from TrackCapTM events, median adherence
trial treatment. was 71% (mean, 64%) of the days of dosing (lower quartile,
Summaries of compliance and adherence were based on 51%; upper quartile, 81%), and median compliance was
data from patients who completed the entire 12 weeks of 89% (mean, 80%) (Tables 2 and 3). The distribution of
treatment. In the evaluation of TrackCapTM data, only percent adherence and compliance values are shown in
events that were recorded during the treatment period were Figs 1 and 2. Sixty-six percent of the patients had good
considered, i.e., events that occurred before tablets were compliance according to TrackCapTM measurements (took
dispensed or after containers were returned were dis-  80% of the prescribed doses). On days when patients
counted. Initial plans to calculate 95% con®dence intervals took exactly two tablets, the mean time between doses was
for mean compliance and adherence were not applicable 12 h 34 min (range, 17 min to 21 h 1 min), with tablets
after a test for normality (Shapiro±Wilk test) showed that
compliance and adherence data were not normally dis- TABLE 1. Demographic and clinical characteristics at entry
tributed. Therefore, both means and medians are reported.
To evaluate consistency of compliance over time, as well Characteristic (n=57)
as pattern of drug use relative to clinic visits, mean
compliance was calculated weekly for all patients for whom Men/Women, n (%) 32 (56)/25 (44)
data were available during that week. Patients who with- Age (years)
drew were included in this analysis because they were more Mean (SD) 29 (9)
likely to represent a non-compliant population. Range 18 to 55
Race, n
Caucasian/Asian 56/1
Mean % predicted FEV1 (SD) 77% (13)
Results Mean % FEV1 reversibility (SD) 26% (10)
DEMOGRAPHY Mean % PEF reversibility (SD) 20% (7)
Mean years with asthma (SD) 14 (10)
A total of 75 patients from ®ve sites underwent screening
for possible study entry; of those, 57 met entry criteria and SD: standard deviation; FEV1: forced expiratory volume in
began treatment with za®rlukast. The study population, 1 sec; PEF: peak expiratory ¯ow.
 COMPLIANCE WITH AN ORAL ASTHMA MEDICATION 855

TABLE 2. Summary data for compliance, n=47

Mean (SD) Lower quartile Median Upper quartile
% % % %

TrackCapTM compliance* 80 (24) 74 89 96

Tablet count compliance{ 89 (11) 84 92 96

*Number of events divided by number of prescribed tablets6100.{ Number of dispensed tablets minus returned tablets
divided by the number of prescribed tablets6100.

TABLE 3. Summary data for adherence, n=47

Mean (SD) Lower quartile Median Upper quartile

% of days % of days % of days % of days

Full adherence (2 events  8 h apart) 64 (26) 51 71 81

Insucient interval adherence (2 events 58 h apart) 3 (4) 1 2 4
Undercompliance (1 event/day) 20 (14) 10 19 25
No compliance (0 events/day) 10 (21) 0 1 8
Overcompliance (>2 events/day) 2 (2) 0 2 4

FIG. 2. Distribution of percentages of prescribed doses of

FIG. 1. Distribution of percentages of days with full za®rlukast taken (compliance) as determined by
adherence to za®rlukast therapy as determined by TrackCapTM.
TrackCapTM.

the two methods were marginal (within +15%), suggesting

taken 8±16 h apart on 86% of treatment days (total
treatment days, 2624).
Patients had one TrackCapTM event on a median of 19% of
the days, and had insucient interval adherence on a median
of 2% days (Table 3). The median percent of days when
patients took no tablets was 1%. Patients were over-
compliant (>two tablets day71) on a median of 2% of days.
COMPLIANCE ESTIMATED FROM TABLET
COUNT
On the basis of tablet counts, median compliance was 92%
(mean, 89%), which was slightly higher than compliance
calculated from TrackCapTM events (Table 2). For 39 of 47
patients (83%), the di€erences between values derived from
that patients removed multiple tablets at a time infrequently
(Fig. 3). For eight patients, however, compliance based on
tablet counts was greater by 20% or more, indicating that
these patients did not remove trial medication as instructed.
The pattern of TrackCapTM events suggested that one patient
removed up to a week's supply of tablets at each opening.
Two patients (4%), recorded multiple events (up to 37 bottle
openings within a 2-min period) before clinic visits, which
suggested that these patients suspected compliance monitor-
ing and attempted to conceal poor compliance.
WEEKLY COMPLIANCE
Three patients did not return the TrackCapTM device, but all
other patients provided at least a week of TrackCapTM event
856 K. F. CHUNG AND I. NAYA
FIG. 3. TrackCapTM observed compliance. vs. tablet count
compliance with za®rlukast therapy.
data. The weekly mean data are summarized in Fig. 4. The
mean level of compliance over time remained consistently
high from week 1 through week 12 of treatment. Clinic
visits did not appear to have a great e€ect on compliance.
OTHER ASSESSMENTS
Za®rlukast was well tolerated throughout the trial. The
most frequently reported adverse events were non-treat-
ment-related infections (primarily respiratory infections) in
11 patients (19%) and headache in 10 patients (18%). Mean
FEV1 remained unchanged but mean PEF increased 8%
from the end of screening.
Discussion
This was the ®rst study to evaluate compliance with an oral
asthma medication using a medication event monitoring
system. As assessed by the electronic TrackCapTM device,
compliance with twice-daily oral za®rlukast was high
(median, 89%). These results con®rm the high levels of
compliance reported for za®rlukast in clinical trials, as
estimated from returned-tablet counts (19). Also, 66% of
patients achieved a good level of compliance. Importantly,
through 12 weeks of treatment, levels of compliance
remained consistently high.
Although median adherence in this study was not as high
as median compliance, it was also high at 71%. The
di€erence between these assessments was primarily asso-
ciated with days when one tablet was taken. Days of no
compliance accounted for only a median of 1% of the days.
Overall, then, patients took za®rlukast according to dosing
instructions for most of the 12-week treatment period; on
most other days, patients took at least half the daily dose.
Adherence with za®rlukast was more than ®ve times greater
than adherence measured electronically (14%) for a four-
times-daily regimen of inhaled nedocromil (4).
FIG. 4. Weekly median TrackCapTM compliance with
za®rlukast therapy and weekly percentages of patients
with TrackCapTM compliance  80% (numbers of patients
in parentheses).
Not surprising was the fact that mean compliance
calculated from the returned-tablet counts (89%) was
greater than that calculated from TrackCapTM events
(80%). This phenomenon of overestimation of compliance
by tablet count may be attributed to accidental loss of
medication, removal of multiple tablets at bottle openings,
or deliberate disposal of tablets to disguise underusage. A
similar corollary is documented for inhaled asthma
medication in that residual MDI canister weights and daily
use records also overestimate compliance (2,4,20,21). In this
study, the di€erence in compliance as calculated by the
TrackCapTM and tablet-count methods was minor and
mostly could be attributed to eight patients who clearly did
not follow speci®c dosing instructions. However, just as it
was possible that some patients may have removed tablets
and not taken them, it was possible that some patients,
despite their failure to comply with instructions regarding
tablet removal, still took the medication according to the
prescribed regimen.
The overall conclusions that can be drawn from this
study are limited in that, without a comparator, we could
not assess how well these patients might have complied with
other asthma treatments. We cannot exclude the possibility
that these patients were simply a more compliant group.
However, mean compliance according to tablet counts was
94?5% in a long-term za®rlukast trial in North America
(19), which suggests that the patients studied in this trial did
not represent a highly compliant group. The patients
included in our study were not previously following a
regular regimen of asthma therapy. It is unclear if patients
who were previously on a regular regimen might have had a
higher compliance. A compliance rate of 79%, which was
similar to that measured in our study, was reported for
twice-daily theophylline when medical records from an
health maintenance organization population were retro-
spectively compared with prescription re®ll records (12).
The theophylline study had the disadvantage of not being

able to assess daily compliance but had the advantage of
not introducing the potential for bias related to patient
selection and study participation. In our study, compliance
rates may have been in¯uenced because patients knew they
were in a trial and had obligations to return at set intervals.
In several compliance studies that required follow-up visits,
patients demonstrated a variety of behaviours related to
drug administration, e.g., increasing medication use around
clinic visits, taking only half the recommended dose for the
trial duration, or taking medication as directed for self-
determined blocks of time (5,22,23). None of these
behaviours occurred in this trial, which lends credibility
to the rate of compliance and adherence achieved. Patterns
of multiple-grouped TrackCapTM events did suggest that
some patients realized the purpose of the device.
Among the various direct and indirect methods currently
used to assess compliance, none does so perfectly (14).
Direct methods are ultimately inconvenient, and indirect
methods, with inference of drug use, are problematic in
determining the extent of full compliance and accounting
for patient behaviours. The precedence for use of electronic
methods was previously established in studies that evalu-
ated compliance in patients with hypertension (24) and
epilepsy (25). In addition to achieving adherence rates
similar to the rate achieved in this study, those studies also
revealed that adherence (full compliance) was inversely
proportional to frequency of dosing.
E€orts to prevent a bias in favour of compliance in this
studyÐnot apprising patients of the nature of the
TrackCapTM focusing on lung function and safety at clinic
visits; and not requiring use of diary cards during the
treatment periodÐwere considered to be both necessary to
approximate real-world compliance and within the scope of
acceptable clinical practice. The value of this study will be
re¯ected in future double-blind, crossover studies that
compare electronically assessed compliance among di€erent
forms of asthma treatments and that do not emphasize the
compliance objective to patients.
Despite the proven bene®ts of inhaled steroids, patients
continue, for numerous reasons, to use them inappropri-
ately and inconsistently, thus not achieving the true bene®t
(20,26). That patients with asthma prefer oral treatment
like za®rlukast to inhaled treatment like beclomethasone
dipropionate (27) is not surprising given reported compli-
ance rates. Importantly, such preferences are likely to a€ect
how physicians and other healthcare providers ultimately
approach treatment.
In conclusion, data from this study show that it is
possible to assess adherence and compliance with an oral
asthma medication using a medication event monitoring
system like TrackCapTM. These results show that compli-
ance with and adherence to a treatment of an oral, twice-
daily, maintenance asthma medication, such as za®rlukast,
is high.
Acknowledgements
The authors thank Suzanne Bristow-Marcalus, BSPh, ELS
for writing support, Fiona Campbell for statistical
COMPLIANCE WITH AN ORAL ASTHMA MEDICATION 857
assistance, Ruth Smithers, Allan A. Harris and James
Kennelly PhD for technical assistance, and the clinical
investigators for their e€ort and time: Michael B. Doyle
(Belfast, U.K.), Christopher J. Kyle (Belfast, U.K.), J.
Earnest Smyth (County Tyrone, U.K.), Mary K. Noel-
Paton (West Sussex, U.K.), and Constantinos I. Dellapor-
tas (London, U.K.).
REFERENCES
1. Podell RN, Gary LR. Compliance: A problem in
medical management. Am Fam Physician 1976; 13: 74±
80.
2. Rand CS, Wise RA, Nides M, et al. Metered-dose
inhaler adherence in a clinical trial. Am Rev Respir Dis
1992; 146: 1559±1564.
3. Spector SL. Is your asthmatic patient really complying?
Ann Allergy 1985; 55: 552±556.
4. Braunstein GL, Trinquet G, Harper AE, Compliance
Working Group. Compliance with nedocromil sodium
and a nedocromil/salbutamol combination. Eur Respir
J 1996; 9: 893±898.
5. Bosley CM, Parry DT, Cochrane GM. Patient com-
pliance with inhaled medication: Does combining beta
agonists with corticosteroids improve compliance? Eur
Respir J 1994; 7: 504±509.
6. Mawhinney H, Spector SL, Kinsman RA, et al.
Compliance in clinical trials of two non-bronchodila-
tor, antiasthma medications. Ann Allergy 1991; 66:
294±299.
7. Creer TL. Medication compliance and childhood
asthma. In: Krasneger NA, Epstein L, Johnson SB,
Ya€e SJ, eds. Developmental Aspects of Health
Compliance Behavior. Hillsdale, NJ: Lawrence Erlbaum
Associates Publishers, 1993: 303±333.
8. Horn CR, Clark TJH, Cochrane GM. Compliance with
inhaled therapy and morbidity from asthma. Respir
Med 1990; 84: 67±70.
9. Birkhead G, Attaway NJ, Strunk RC, Townsend MC,
Teutsch S. Investigation of a cluster of deaths of
adolescents from asthma: Evidence implicating inade-
quate treatment and poor patient adherence with
medications. J Allergy Clin Immunol 1989; 84: 484±491.
10. British Thoracic Association. Death from asthma in
two regions of England. Br Med J 1982; 285: 1251±
1255.
11. National Heart, Lung, and Blood Institute. Data Fact
Sheet: Asthma Statistics. Bethesda, MD: National
Institutes of Health, Public Health Service, 1989.
12. Kelloway JS, Wyatt RA, Adlis SA. Comparison of
patients' compliance with prescribed oral and inhaled
asthma medications. Arch Intern Med 1994; 154: 1349±
1352.
13. Khunti K. Issues in adolescent asthma: Compliance.
Matern Child Health 1996; Feb: 36±38.
14. Rand CS, Wise RA. Measuring adherence to asthma
medication regimens. Am J Respir Crit Care Med 1994;
149: 569±576.
858 K. F. CHUNG AND I. NAYA
15. Fabbri LM, Piattella M, Caramori G, Ciaccia A. Oral
vs inhaled asthma therapy. Drugs 1996; 52 (Suppl
6):20±28.
16. Spector SL, Smith LJ, Glass M, AccolateTM Asthma
Trialists Group. E€ects of 6 weeks of therapy with oral
doses of ICI 204,219, a leukotriene D4 receptor
antagonist, in subjects with bronchial asthma. Am J
Respir Crit Care Med 1994; 150: 618±623.
17. Fish JE, Kemp JP, Lockey RF, Glass M, Hanby LA,
Bonuccelli CM, Za®rlukast Trialists Group. Za®rlu-
kast for symptomatic mild-to-moderate asthma: a 13-
week multicenter study. Clin Ther 1997; 19: 675±690.
18. Nathan RA, Bernstein JA, Bielory L, et al. Za®rlukast
improves asthma symptoms and quality of life in
patients with moderate air¯ow obstruction. J Allergy
Clin Immunol 1998;102: 935±942.
19. Grossman J, Smith LJ, Wilson AM, Thyrum PT. Long-
term safety and ecacy of za®rlukast in the treatment
of asthma: Interim results of an open-label extension
trial. Ann Allergy Asthma Immunol 1999; 82: 361±369.
20. Chmelik F, Doughty A. Objective measurements of
compliance in asthma treatment. Ann Allergy 1994; 73:
527±532.
21. Spector SL, Kinsman R, Mawhinney H, et al.
Compliance of patients with asthma with an experi-
mental aerosolized medication: implications for con-
trolled clinical trials. J Allergy Clin Immunol 1986; 77:
65±70.
22. Cramer JA, Scheyer RD, Mattson, RH. Compliance
declines between clinic visits. Arch Intern Med 1990;
150:1509-1510.
23. Simmons MS, Nides MA, Rand CS, Wise RA, Tashkin
DP. Trends in compliance with bronchodilator inhaler
use between follow-up visits in a clinical trial. Chest
1996; 109: 963±968.
24. Eisen SA, Miller DK, Woodward RS, Spitznagel E,
Przybeck TR. The e€ect of prescribed daily dose
frequency on patient medication compliance. Arch
Intern Med 1990; 150: 1881±1884.
25. Cramer JA, Mattson RH, Prevey ML, Scheyer RD,
Ouellette VL. How often is medication taken as
prescribed? A novel assessment technique. JAMA
1989; 261: 3273±3277.
26. Yeung M, O'Connor SA, Parry DT, Cochrane GM.
Compliance with prescribed drug therapy in asthma.
Respir Med 1994; 88: 31±35.
27. Weinberg EG, Naya I. Treatment preferences of
adolescent patients with asthma. Pediatr Allergy
Immunol 2000;11: 49±55.