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Levocetirizine for the Treatment of Seasonal and Perennial Allergic Rhinitis
a report by
O l i v e r P f a a r and L u d g e r K l i m e k
Centre for Rhinology and Allergology, Department of Otorhinolaryngology, University Hospital Mannheim
Approximately 1040% of the worldwide population is affected by
allergic rhinitis (AR). It has become increasingly common over the last few
decades 1,2 and is now the most prevalent chronic disorder requiring
treatment. Rhinorrhoea, sneezing, nasal congestion, an itchy nose and/or
conjunctivitis are symptoms of the disease. Furthermore, co-morbid
diseases such as allergic asthma, otitis media, chronic sinusitis and lower
respiratory tract infections are common.3 AR influences cognitive
function, resulting in impaired function at work or school and disrupted
sleep patterns.2 These effects mean the disease has an impact on health-
related quality of life (HRQL).4,5 Based on the time of allergic exposure, AR
has traditionally been split into seasonal (SAR) and perennial (PAR)
manifestations.2 This definition does not entirely reflect patterns of AR
symptoms in patients. For example, many patients with PAR do not show
symptoms throughout the year. In light of this, the Allergic Rhinitis and
its Impact on Asthma (ARIA) workshop group has developed a new
classification of AR based on the duration of symptoms.6 Intermittent
allergic rhinitis (IAR) is defined by the occurrence of AR symptoms for less
than four days or less than four weeks a year, whereas persistent allergic
rhinitis (PER) is defined by the occurrence of AR symptoms for more than
four days or at least four consecutive weeks a year.
Management of the disease involves allergen avoidance, specific
immunotherapy and controlling symptoms with pharmacotherapy. The
first-line treatment for symptom-reduction is administration of H1
receptor antagonists. 7 Levocetirizine is a selective, potent, oral
antihistamine H1 receptor antagonist of the latest generation that is
licensed for the symptomatic treatment of both SAR and PAR.8 The
therapeutic efficacy of oral levocetirizine has been calculated in several
clinical studies in patients with SAR, PAR and PER.9 This article reviews
current literature on levocetirizine, although some data are available
only as abstracts and/or poster presentations.
Levocetirizine in the Treatment of Seasonal
Allergic Rhinitis
Both levocetirizine and cetirizine significantly attenuated the
histamine-induced increase in nasal airway resistance by nearly 50%10
and caused a marked inhibition of histamine-induced wheal and flare,
while levocetirizine 2.5mg had comparable antihistaminic activity to
cetirizine 5mg.11 Several studies on both adult and child SAR patients
with oral levocetirizine in two- to six-week trials suggested that
levocetirizine is an effective agent.1215
In a large German study in a primary care setting, oral levocetirizine 5mg
once daily for 32 days was reported effective in treating patients with SAR
and PAR with or without concurrent asthma (n=14,319) (see Table 1).14
Alleviation or improvement of symptoms (e.g. rhinorrhoea, sneezing,
conjunctivitis and asthmatic symptoms) was observed in over 80% of
TOUCH BRIEFINGS 2007
Allergic Disorders
patients after treatment. Global assessments also indicated good or very
good efficacy in over 80%. Adverse effects were minimal.14 In a four-week
non-comparative study of primary care centres in Belgium, these data
were confirmed.15 In addition, the same authors analysed a subgroup of
levocetirizine-treated patients and observed that the degree of pollen load
did not have any influence on the efficacy. In one study of 470 patients,
symptom severity scores for sneezing, rhinorrhoea, itchy nose and eyes were
significantly decreased for all doses of levocetirizine, with 5mg once daily
showing an optimal risk/benefit ratio in the treatment of SAR.16
In large, double-blind, multicentre trials in both adults and children,
levocetirizine revealed significant therapeutic efficacy compared with
placebo in terms of adjusted mean Total 4-Symptoms Scores (T4SS) as the
primary end-point over a two-week interval.13,17 In adults, levocetirizine
2.510mg once daily exposed a linear doseresponse effect relative to
placebo (p=0.0001), with all dosages more effective than placebo.17
Levocetirizine 5mg once daily showed improvement of T4SS from
baseline by <50% relative to placebo under all weather conditions.
However, an improvement of at least 50% (co-primary efficacy end-
point) could not be revealed. Interestingly, this end-point was met under
dry weather conditions. The authors discussed the possibility that rainfall
itself may decrease allergic symptoms in AR patients and consequently
reduce the need for medication.17 In contrast, a T4SS reduction >50%
could be shown in a study on paediatric patients after two weeks of
therapy.13 In addition, in this study levocetirizine was seen to cause
significant improvements of other secondary end-points such as
sneezing, rhinorrhoea and pruritus. HRQL was also increased in the
treatment of children. Individual domain scores such as nasal symptoms,
ocular symptoms and practical problems showed significant
improvements after a two-week therapy interval; however, the overall
Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ)
scores increased from baseline by 34% in the levocetirizine-treated
group. In addition, the clinical efficacy of levocetirizine was evaluated for
symptoms of SAR in vivo in the environmental exposure unit (EEU).18
Oliver Pfaar is an academic staff member at the Centre for
Rhinology and Allergology in the Department of
Otorhinolaryngology at the University Hospital Mannheim.
His main areas of research are clinical allergology and
rhinology, such as prevention and treatment of allergic
rhinitis, including specific immunotherapy and
pharmacological treatment. Dr Pfaar is a member of various
national and international learned societies, such as the
European Academy of Allergology and Clinical Immunology
(EAACI), and is the author of over 30 review or research papers. Dr Pfaar qualified as an ear,
nose and throat (ENT) specialist in 2004 after working at the ENT-University Hospital Dresden.
He performed his medical studies at the Georg-August University of Gttingen in Germany,
obtaining his MD in 2000.
E: oliver.pfaar@hno-wiesbaden.de
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Allergic Disorders

Table 1: Efficacy of Oral Levocetirizine 5mg Once Daily in Levocetirizine in the Treatment of Perennial
Patients with Allergic Disorders in the Primary Care Setting Allergic Rhinitis
Several short-term, randomised, double-blind trials have been
Indication No. of Patients performed with levocetirizine at a dose of 5mg daily for the treatment
All allergic disorders 17,638 of PAR in child, adolescent and adult outpatients in the primary care
All allergic airway diseases 14,319
setting.1921 In a randomised, double-blind, eight-week study, 294 PAR
Seasonal allergic rhinitis 12,490
patients were treated with either levocetirizine 5mg or placebo once
Perennial allergic rhinitis 2,507
Other allergic airway diseases 1,438 daily.20 An improvement of the T4SS 50% compared with baseline
In allergic airway diseases Incidence post-treatment (%) [baseline] with significant difference from placebo could be demonstrated after
Nasal pruritus 4.6 [64.9] only one week of therapy with levocetirizine. Furthermore, the
Rhinorrhoea 5.3 [69.2] reduction of the adjusted mean symptoms score of rhinorrhoea,
Sneezing 4.6 [65.2] sneezing, nasal and ocular pruritus and nasal congestion compared
Nasal obstruction 5.9 [53.8]
with baseline was revealed to be significantly higher than placebo after
Asthma symptoms 1.9 [11.7]
one week of therapy (p0.008). The relative improvement for nasal
Eye complaints 3.4 [48.9]
congestion versus placebo reached 154% in favour of levocetirizine
Results from a non-comparative multicentre trial with an average treatment period of 32 days.14
(p=0.002) after only one week of treatment. This was the best relative
improvement among all the individual symptoms. Interestingly, the
Figure 1: Improvement of Quality of Life Under Treatment
with Levocetirizine 5mg Once Daily in Persistent Allergic
Rhinitis Patients
An improvement of the Total
2.0
* *
* Levocetirizine 4-Symptoms Score 50% compared
(n=278 adults)
RQLQ score improvement from baseline

* with baseline with significant

1.5 Placebo
* (n=273 adults)
difference from placebo could be
demonstrated after only one week
1.0

of therapy with levocetirizine.

0.5

beneficial effect on nasal congestion was maintained throughout the

entire study period, with a difference versus placebo reaching even
0 higher statistical significance (p<0.001) over the four-week and six-
BL Week 1 Week 4 Week 3 Month 4.5 Month 6 * p<0.001
week periods. In a similar methodical setting an even higher
RQLQ = Rhinoconjunctivitus Quality of Life Questionnaire.
improvement in symptoms (p0.0001) was seen after a 30-day course
Source: Horak et al., 2004.24 of treatment.21

Similar results were found in the treatment of children.22 In a placebo-

Figure 2: Improvement of Rhinoconjunctivitus Quality of Life
Questionnaire Domains Under Treatment with Levocetirizine 5mg
Once Daily in Persistent Allergic Rhinitis Patients
2.2
RQLQ score improvement from baseline
controlled study of 306 children with PAR, a significant improvement
of T4SS was shown. As secondary end-points, both the overall PRQLQ
score (p0.05) and the individual domain scores (p<0.001) were
significantly greater after two weeks of therapy with levocetirizine. In
* *
a study with the Vienna challenge chamber, patients sensitised to dust
mites underwent a two-day allergen challenge and revealed an

*
improvement of the complex symptom score (CSS) compared with
*
*
*
baseline after only four hours.23
*
1.1

Levocetirizine in the Treatment of Persistent Allergic

Rhinitis The Xyzal Persistent Allergic Rhinitis Study
The Xyzal Persistent Allergic Rhinitis (XPERT) study group investigated
the efficacy of levocetirizine 5mg once daily in 551 adult outpatients
0
with PER in a six-month, randomised, double-blind, parallel-group,
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multicentre trial.24 In this study the change of HRQL scores and Total 5-
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Symptoms Scores (T5SS) compared with baseline were analysed as

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Placebo (n=273 adults) Levocetirizine (n=278 adults) * p<0.001

primary efficacy end-points. Over the first four weeks of therapy both
total scores were significantly improved in the levocetirizine group
Data at week four; similar improvement maintained over six months.
compared with placebo (see RQLQ score, Figure 1). Four of the five
RQLQ = Rhinoconjunctivitus Quality of Life Questionnaire. individual T5SS (sneezing, rhinorrhoea, nasal pruritus and ocular
Source: Horak et al., 2004.24
pruritus) were improved, while the fifth symptom of the T5SS, nasal

54 EUROPEAN RESPIRATORY DISEASE 2007

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Levocetirizine for the Treatment of Seasonal and Perennial Allergic Rhinitis

congestion, revealed significant improvements in levocetirizine versus Figure 3: Improvement of Health-related Status (SF-36) Under
placebo controls from three months until the end of the study at six Treatment with Levocetirizine 5mg Once Daily in Persistent
Allergic Rhinitis Patients
months. However, all seven individual HRQL domains improved
significantly after four weeks of therapy (see Figure 2). In addition, a
significantly higher amount of rescue medication (p=0.002) was needed *** Placebo (n=273 adults) *** p<0.001
25 Levocetirizine (n=278 adults) ** p<0.01
in the placebo group compared with levocetirizine-treated patients over * p<0.05
***
the first four weeks of XPERT.

SF-36 improvement from baseline

20

Furthermore, the general health status (SF-36) of the patients as another 15 **

secondary efficacy end-point was incorporated into the study at the
design stage. All eight domains of the SF-36 health-status assessment 10 **
* **
revealed significant improvements in both mental and physical ***
*
components (p<0.05, see Figure 3). Interestingly, the physical role or 5

emotional role domains revealed significantly high efficacy (p<0.001).

0
An exploratory analysis of the XPERT data demonstrated that the

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number of patients with allergic asthma experienced significantly fewer

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acute asthma attacks compared with the placebo group during the six-

cia

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ica

month treatment period.25 Taken together, these data suggest that
long-term treatment with levocetirizine causes sustained improvement
in HRQL and reduces disease burden in PER patients. Another piece of
important information that XPERT provides for physicians is a link
between symptoms (including congestion) and quality of life, as
measured by the RQLQ.
Absorption, Pharmacokinetics and Side Effects
Pharmacokinetic trials revealed fast and high gastrointestinal
absorption.26 The metabolic pathways involved in levocetirizines
metabolism are oxidation (hydroxylation, O-dealkylation, N-oxidation and
N-dealkylation), glucuroconjugation, taurine conjugation and glutathione
conjugation with formation of the mercapturic acids. The metabolic
So
ys
Ph
Improvement of individual SF-36 scores over six-month treatment period.
Source: Horak et al., 2004.24
products are mostly excreted in the urine, but the need for dose
adjustment in patients with moderate or severe renal insufficiency is
suggested.27 So far, specific guidelines are not available. However, based
on data for racemic cetirizine, a 50% reduction in the dose of
levocetirizine should be considered in patients with severe renal
dysfunction.28 The side effect profile of levocetirizine is mild. Importantly,
levocetirizine does not produce any deleterious effect on psychometric or
cognitive functions.29 However, headaches, dizziness, fatigue and rashes
have been reported.30

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