CLINICAL THERAPEUTICSVVOL 22, NO.

$2000

Loratadine Versus Cetirizine: Assessment of Somnolence

and Motivation During the Workday

Luis M. Salmun, MD,l Davis Gates, PhD,’ Martin Schati, MD,2

Leonardo Greiding MD,3 Fabian Ramon, MD,4 and
Kim Heithoff, ScDl
‘Schermg-Plough Corporation, Kenilworth, New Jersey, 2Center for Research in Sleep
Disorders, Cincinnati, Ohio, 31nstituto Argentina de Alergla e Inmunologia, Buenos
Aires, and 41nstltuto de Alergia e Inmunologla de1 Sur, Bahia Blanca, Argentina

ABSTRACT

Objective: This parallel-group, double-blind study compared the somnolence and mo-
tivation profiles of 2 second-generation antihistamines, loratadine and cetirizine, in pa-
ttents with allergic rhinitis.
Background: Second-generation antihistamines were developed to provide symptom-
atic relief from allergic disorders without the unwanted side effects of first-generation an-
tihistamines, including somnolence. Recent research has indicated that not all second-
generation antihistamines are comparable with respect to somnolence and other cognitive
processes.
Methods: Patients aged ~12 years and actively exhibiting symptoms of allergic rhini-
tis were randomized to 2 treatment groups to receive 10 mg loratadine or 10 mg cetirizine
daily at 8:00 AM for 1 week. After patients took the medication, their somnolence and de-
gree of motivation to perform activities were recorded in an electromc diary using a vi-
sual analog scale 4 times durmg the workday (8:00 AM, 1O:OOAM, noon, and 3:00 PM).
Results: Sixty patients (31 men, 29 women) were randomized to treatment. Somno-
lence scores were similar for both groups at baseline and at the time of dosing (8:00 AM).
However, there was a statistically significant difference in somnolence scores between the
loratadine and cetirizine groups at 10:00 AM (P = 0.008), noon (P = O.OOl), and 3:00 PM
(P < O.OOl), with the cetirizine group showing a greater degree of somnolence. The scores
on motivation to perform activities were similar for both groups at the baseline and 8:00-
AM measurements. In parallel with the somnolence scores, there were statistically sigmf-
icant differences in motivation scores between the loratadine and cetinzine groups at
10:00 AM (P = 0.014), noon (P = O.OOl), and 3:00 PM (P < O.OOl), indicating that patients
takmg loratadine were relatively more motivated during the workday.
Conclusion: The results of this study demonstrate that in patients aged ~12 years who
had allergic rhinitis, cetirizine use promoted somnolence and decreased motivation to per-

Accepted for pub/fcatron March 8, 2000

Pnnted m the USA Reproduction In whole or part IS not permltted

0149.2918/00/$19 00 573

form activtties during the workday com-
pared with loratadine.
Key words: antihistamine, H,-receptor
antagonist, loratadine, cetirizine, somno-
lence, allergic rhimtis. (Clin Thu. 2000;
22573-582)
INTRODUCTION
Histamine release plays a central role in
allergic responses by binding and activat-
mg histamine-l (Hi) receptors to cause
increased vascular permeability and se-
cretion by nasal glands.’ The symptoms
of seasonal and perennial rhinitis and ur-
ticaria affect an estimated 30% to 40% of
the adult population in the United States.*
Individuals with these conditions incur
considerable medical costs.“-” The first-
generation Hi-receptor antagonists (anti-
histamines), such as diphenhydramine,
were developed to provide symptomatic
relief from allergic disorders. Although
effective in alleviating symptoms, these
antihistamines have unwanted side ef-
fects, including sedatton6-9 and loss of
work productivity. lo The depressant effect
of these antihistamines on the central ner-
vous system (CNS) is due to their ability
to cross the blood-brain barrier and block
histamine neurotransmission through cen-
tral H, receptors. These receptors have a
high density in the hypothalamus, and
they control wakefulness m addition to
other homeostatic functions.“,‘*
The second-generation antihistamines
are generally large hpophobic molecules
that cross the blood-brain barrier poorly
and thus have sigmficantly fewer CNS ef-
fects.13-15Loratadine is a long-actmg com-
pound in this category that has been shown
to successfully relieve the symptoms of
allergic rhimtis and urttcana.16*17 It has an
average ehmination half-life of 7 to 14
574
CLINICAL THERAPEUTICS”
hours, allowmg once-dally dosing at 10
mg.is,i9 It does not readily cross the blood-
brain barrier and, in addition, has a greater
affinity for peripheral versus CNS H, re-
ceptors.20,21This may account for clinical
trial results showmg that loratadme is
nonsedating at its therapeutic dosage of 10
mgid and does not impair psychomotor
processing9,22,23or driving ability.24
In contrast, cetirizme-another antthis-
tamme that relieves the symptoms of al-
lergic rhmitis and urticana-has been re-
ported to have sedative side effects.24-28
Cetirtzme is a carboxylated metabolite of
hydroxyzine. It has an average elimina-
tion half-life of -7 to 10 hours and a rec-
ommended daily dose of 10 mg.29 How-
ever, in many clinical tnals, cetirizme use
has been associated with somnolence25,26
and impairment in simulated assembly
line tasks,27 driving,24 and aviation.28
The present study was designed to com-
pare the somnolence and motivation pro-
files of loratadine and cetirizme in pa-
tients with allergic rhimtis to gain insight
into their personal safety and productivity
during the workday. This study did not
measure the efficacy of either drug in
treating allergic rhmitis but did require
that patients exhibit symptoms of disease
at study entry so the effects of the study
drugs could be more accurately measured
in a symptomatic population.
PATIENTS AND METHODS
Study Design
This randomized, double-blind, paral-
lel-group study was conducted in patients
aged 212 years. Patients with qualifying
rhinitis symptom scores were assigned to
treatment groups according to a computer-
generated randomization code. They re-
L.M. SALMUN ET AL
ceived either 10 mg loratadine or 10 mg
cetirizine at 8:00 AM each day for 7 days.
Adverse effects were recorded in elec-
tronic patient diaries using a visual analog
scale (VAS). Efficacy in treating allergic
rhmms was not evaluated. The study de-
sign was approved by an institutional re-
view board.
Patients
No patient could have significant phys-
ical or mental illness that would interfere
with study evaluations. However, eligible
patients were required to have a history
and diagnosis of allergic rhinitis, as con-
firmed by 2 tests before commencement
of the trial: (1) a positive skin test (aller-
gen skin prick resulting in a wheal whose
diameter was 3 mm greater than control
or allergen intradermal administration re-
sulting in a wheal whose diameter was
7 mm greater than control) to an appro-
priate allergen in the past year; and (2)
positive symptoms of moderate to severe
allergic rhmitis at entry, assessed on a
4-point scale ranging from “no detectable
symptoms” to “severe symptoms.”
Patients excluded from the study were
those with clinically significant diseases
that could impair delivery or efficacy of
medication or appropriate evaluation of
patients, such as hematopoietic, cardio-
vascular, hepatic, renal, neurologic, psy-
chiatric, or autoimmune disease. Also ex-
cluded were patients with asthma that
required chronic use of inhaled or sys-
temic cortrcosteroids, clinically significant
sinusitis, acute respiratory tract infection,
or rhinitis medicarnentosa. In addition, pa-
tients who had nasal structural abnormali-
ties or were dependent on nasal, oral, or
ocular decongestants, topical antihtsta-
mines, or steroids were excluded. Patients
were also excluded if they had a history of
allergic reactions to >2 classes of medica-
tion or could not tolerate antihistamines.
Finally, pregnant or breast-feeding women
were ineligible for the study.
Study Procedures
Written informed consent was obtamed
at the screenmg visit, and medical histories
and vital signs were obtained. Any con-
comitant medications taken by the patients
were checked to ensure that the medication
washout requirements were observed for
prohibited agents. These were drugs that
could affect symptoms or safety assess-
ments in patients with allergic rhinitis and
included the followmg: cromolyn or ne-
docromil sodium, corttcosteroids or other
topical anti-inflammatory drugs, short- or
long-acting antihistamines, decongestants,
nasal atropine, systemic antibiotics, nasal
or ocular salme, ocular levocabastine, zafir-
lukast, and montelukast. No attempt was
made to identify and eliminate patients who
had received loratadine or cetirizine previ-
ously as long as the appropriate washout
requirements were met. Pet-nutted chronic
medications were dosed as usual and acet-
aminophen was allowed as needed for ap-
propriate indications. All patients meeting
the inclusion criteria were familiartzed with
the study procedures and instructed in the
use of the patient diaries and the VAS.
The trial started the day after the screen-
ing visit. Before mmal medication expo-
sure at 890 AM of the first day only, pa-
tients registered a baseline measurement of
somnolence and motivation using the VAS.
On this and all subsequent mornings of the
study, 10 mg loratadine or 10 mg cetirizine
was ingested at 8:OOAM. Patients then used
the VAS to record their somnolence and
motivatton at 8:00 AM, 1090 AM, noon, and
575

3:00 PM. They noted any adverse effects in
their diaries daily. After completion of the
trtal, patients underwent a review of med-
ication use, a check of their vital signs, and
an evaluatton of adverse events.
Study Assessments
Patient diaries and the VAS were used
to compare the safety profiles of lorata-
dine and cetinzine. Patients recorded in a
separate diary any adverse events they ex-
perienced, including somnolence, dry
mouth, asthenia, fever, abdominal pain,
diarrhea, vomiting, tinmtus, thirst, arthral-
gia, dyspnea, eptstaxis, pharyngttis, rhmi-
tts, sneezing, or pruntus. They also record-
ed whether the study medication was
taken as directed and if any additional
medications were taken during the study
period. A VAS ranging from 1 to 10 was
used to measure somnolence (from 1 =
wide awake to 10 = extremely somnolent)
and mottvatton (from 1 = fully motivated
to 10 = not motivated at all) to perform
activities 4 times during a workday.
Statistical analyses of the somnolence
and motivation data were performed us-
ing PROC GLM in SAS version 6.09
(SAS Instttute, Cary, North Carolina). A
separate analysis was done for the base-
line reading taken on the first day only, as
well as for the 7-day readings of somno-
lence and motivation taken at 8.00 AM,
10.00 AM, noon, and 3:00 PM. Data from
patients missing baseline assessments
were not included in the analysis.
RESULTS
Sixty patients with active allergic rhmttts
were enrolled in the study. The mean (+ SD)
age of the loratadine group was 3 1.2 + 12.6
years and of the cetirtzine group 32.6 & 11.8
576
CLINICAL THERAPEUTICS”
years. The loratadme group consisted of 16
women and 14 men; the cetirizine group
consisted of 13 women and 17 men. Pa-
tients’ diaries of adverse events indicated
that somnolence occurred with 20% greater
frequency in the cetirizme group than in
the loratadine group (Table I). All other ad-
verse events showed similar profiles, with
510% of patients in both groups reporting
specific events (Table I)
The somnolence scores of patients hav-
ing baseline measurements were analyzed
for each time period, and a 7-day mean
score was computed (Table II). Somno-
lence scores were similar between the lor-
atadme and cetirrzine groups at baseline
and at the time of dosing (8:00 AM). How-
ever, there were statistically significant
differences showing greater somnolence
in the cetirizine group compared with the
loratadme group at 10:00 AM (P = O.OOS),
noon (P = O.OOl), and 3:00 PM (P < 0.001).
The differences in somnolence between
the loratadme and cetntzme groups were
consistent each day and did not diminish
over the 7 days of the study (Figure 1).
Motivation scores showed a similar
pattern to the scores for somnolence Mo-
tivation scores of patients who had base-
line measurements were analyzed, and a
7-day mean score was computed (Table
III). There was no statistically signift-
cant difference between the loratadme
and cetirizine groups at baselme or 8:00
AM. Statistically significant differences
in motivation between the loratadine and
cetirizine groups were noted at 10:00 AM
(P = 0.014), noon (P = O.OOl), and 3:00
PM (P < O.OOl), indicating that patients
taking loratadine were relatively more
motivated. Again, as with the somnolence
scores, the daily differences between the
loratadine and cetirizine groups were con-
sistent throughout the study (Figure 2).
L M. SALMUN ET AL

Table I. Adverse events (AEs) reported in patients’ diaries.

No (%) of Patients
Reporting AE
Loratadme Cetirizine
(n = 30) (n = 30)

Any adverse event (2 1) 10 (33) 16 (53)

Somnolence 5 (17) 11 (37)
Rhimtis 1 (3) 3 (10)
Dry mouth 2 (7) -
Asthema - 1 (3)
Fever 1 (3)
Abdominal pain 1 (3)
Diarrhea 1 (3)
Vomitmg 1 (3) -
Tinmtus - 1 (3)
Thirst 1 (3) -
Arthralgia - 1 (3)
Dyspnea 1 (3)
Epistaxis - 1 (3)
Pharyngitis 1 (3) -
Sneezing 1 (3) 1 (3)
Pruritus - 1 (3)

Table II. Summary of mean somnolence scores in patients receiving loratadine 10 mg or

cetirizine 10 mg.*

Time Point Loratadme Cetirizme P

Baseline 344 3.89 0.541

800 AM 4 04 4.21 0.808
lo:00 AM 2 67 3 98 0.008
Noon 2.07 3.46 0.001
3:00 PM 1.95 4.13 <O.OOl

*Mean somnolence scores were computed from patterns evaluations over 7 days usmg a vrsual analog scale that
ranged from 1 = wade awake to 10 = extremely somnolent The basehne measure of somnolence was recorded
before the 8 OC-AM dose on the first day of the tnal Analyzed data Included no patrents for whom a baseline
reading was mrssmg. Thus, the analysts mcluded 27 patrents m the loratadme group and 28 pattents m the ce-
tuizme group.

577
 CLINICAL THERAPEUTICS”

0 Loratadme
n Cetwtne

0 ; I I I I I I I
1 2 3 4 5 6 7
Day

Figure 1. The daily somnolence profile of the loratadine and cetirizine groups. Somno-
lence was assessed using a visual analog scale ranging from 1 = wide awake
to 10 = extremely somnolent. Assessments made at 8:00 AM, 10:00 AM, noon,
and 3:00 PM for 7 days were pooled, and a mean (e SEM) score was calculated
for each day. Analyzed data included no patients for whom a baseline reading
was missing. *P < 0.01; +P = 002; SP = 0.04; §P = 0.01.

Table III. Summary of mean motivation scores m patients receiving loratadine 10 mg or

cetirizine 10 mg.”

Time Point Loratadme Cettrtzine P

Baselme 3 78 4 14 0 595
8 00 AM 4 02 443 0551
10’00 AM 2 97 4 24 0 014
Noon 2 45 3 85 0.001
3:00 PM 2.31 4 67 <o 001

*Mean motwatlon scores were computed from patients’ evaluatmns over 7 days usmg a wsual analog scale that
ranged from 1 = fully motwated to 10 = not motivated at all The baselme measure of motwatlon was recorded
before the 8 00-AM dose on the first day of the tnal Analyzed data mcluded no patients for whom a baseline
readmg was mlssmg Thus, the analysis mcluded 27 patlents m the loratadine group and 28 patients m the ce-
tmzme group

578
L.M. SALMUN ET AL

0 Loratadme
n Cetwne

6-

0 1 I I I I I I I
1 2 3 4 5 6 7

Day

Figure 2. The daily profile of motivation to perform activities of the loratadine and ce-
tinzme groups. Motivation was assessed using a visual analog scale ranging
from 1 = fully motivated to 10 = not motivated at all. Assessments made at
8:OO AM, 10:00 AM, noon, and 3:00 PM for 7 days were pooled, and a mean
(& SEM) score was calculated for each day. Analyzed data included no patients
for whom a baseline reading was missing. *P < 0.01; +P = 0.01; $P = 0.04.

DISCUSSION 300 PM) there was a statistically significant

Allergic rhinitis is highly prevalent, and al-
though treatment with antihistamines can
alleviate the symptoms of this condition,
sedative side effects may impair work per-
formance and safety.&lo The objective of
the present study was to compare somno-
lence and motivation, as well as adverse
events, in patients with active allergic rhini-
tis while undergoing treatment with lorata-
dine and cetirizine. Patients taking lorata-
dine and cetirizine had similar somnolence
and motivation scores at baseline and 890
AM. This was not unexpected, because peak
absorption and alleviation of allergic symp-
toms occur ~1 hour after dosing with both
loratadine18*19and cetirizine.29 In contrast,
at later time points (lo:00 AM, noon, and
difference: patients in the cetirizine group
appeared more somnolent at these 3 time
points (P = 0.008, P = 0.001, and P < 0.001,
respectively) and less motivated (P =
0.014, P = 0.001, and P < 0.001, respec-
tively) in comparison with loratadine pa-
tients. Moreover, no tolerance of the seda-
tive effects of cetirizine developed, with
patients continuing to report somnolence
and reduced motivation for each day of
the study compared with patients in the
loratadine group.
The majority of studies to date indicate
that loratadme is nonsedating9*22-26whereas
cetirizine has sedative side effects.24-28
Two studies were identified by a search of
the literature that directly compared the
acute effects of loratadine and cetuizine

579

on CNS-controlled activities. The first, by
Pechadre et al,30 was a double-blind,
crossover, randomized trial that compared
the CNS effects of acute doses of lorata-
dine (10 and 40 mg) with those of ceti-
rizine (10 mg) The authors found that nei-
ther drug affected patients’ subjective
evaluation of CNS effects. The lack of se-
dation reported in their study may be due
to its measurement at early time points, as
sedative side effects are more likely to
peak well after maxlmal absorption of the
drug.31 The second study, by Ramaekers
et al,24 was a 6-way, double-blind, cross-
over tnal that compared the performance
of subjects receivmg single doses of lorat-
adine (10 mg), cetirizine (10 mg), and
placebo on a psychometric test battery and
a standard driving test. Loratadme had no
significant effect on any test result. In
contrast, cetn-lzme caused lmpanment m
driving and also induced differences in
subJective feelings and psychometric test
performance compared with placebo.
CONCLUSIONS
The results of our study further support the
findings of Ramaekers et al.24 Results of
our 7-day study indicate that the use of lor-
atadine in patients with allergic rhinitis is
assoctated with greater motivation and less
somnolence durmg the workday than use
of cetirizine. Cetirizine patients were more
somnolent and less motivated for each day
of the study, indicating that tolerance to Its
sedating effects was not achieved.
ACKNOWLEDGMENTS
The authors acknowledge Susan F. Law,
PhD, for help in preparation of the manu-
script and Sobin Chang, MPH, for critical
review of this work.
580
CLINICAL THERAPEUTICS”
Address correspondence to: Luis M.
Sahnun, MD, Schering-Plough Corporation,
2000 Galloping Hill Road, Kenilworth, NJ
07033.
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