Drugs 2007; 67 (6): 887-901

REVIEW ARTICLE 0012-6667/07/0006-0887/$49.95/0

© 2007 Adis Data Information BV. All rights reserved.

Montelukast in the Treatment of

Allergic Rhinitis
An Evidence-Based Review
Anjuli Nayak1 and Ronald B. Langdon2
1 Sneeze, Wheeze & Itch Associates, Normal, Illinois, USA
2 Merck Research Laboratories, Rahway, New Jersey, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 887
1. Montelukast Efficacy in Patients with Allergic Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
1.1 Patient Characteristics and Study Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
1.2 Montelukast Monotherapy versus Placebo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
1.3 Montelukast Monotherapy versus Other Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
1.4 Montelukast in Combination with Other Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 892
2. Montelukast in Patients with Concomitant Allergic Rhinitis and Asthma . . . . . . . . . . . . . . . . . . . . . . . . 895
2.1 Evidence for Montelukast Efficacy in Allergic Rhinitis with Asthma . . . . . . . . . . . . . . . . . . . . . . . . . 895
2.2 Satisfaction with Treatment in Patients with Allergic Rhinitis and Asthma . . . . . . . . . . . . . . . . . . . 896
3. Safety and Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896
4. Technical Issues and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
4.1 Placebo Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
4.2 Allergic Rhinitis in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
4.3 Treatment Duration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
5. Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898

Abstract Cysteinyl-leukotrienes (CysLTs) are endogenous mediators of inflammation

and play an important role in allergic airway disease by stimulating bronchocon-
striction, mucus production, mucosal oedema and inflammation, airway infiltra-
tion by eosinophils, and dendritic cell maturation that prepares for future allergic
response. Montelukast inhibits these actions by blocking type 1 CysLT receptors
found on immunocytes, smooth muscle and endothelium in the respiratory muco-
sa. Initially developed as a treatment for asthma, montelukast has more recently
found use in the treatment of allergic rhinitis (AR).
We conducted a systematic review of studies that have evaluated montelukast
in the treatment of seasonal AR (SAR) and perennial AR (PAR), with and without
concomitant asthma. Primary consideration was given to large, randomised,
placebo-controlled, double-blind clinical trials in which AR endpoints were
assessed and the use of concurrent treatments for AR was excluded. Eight such
studies were found in the literature. The primary endpoint in these was daytime
nasal symptom severity represented by a composite score derived from individual
self-ratings of nasal congestion, rhinorrhoea, nasal pruritus and sneezing. Secon-
888 Nayak & Langdon

dary endpoints have included these individual nasal symptom scores, additional
scores for eye, ear and throat symptoms, the impact of rhinitis on quality of sleep,
global evaluations of outcome by patients and physicians, and measures of the
severity of concomitant asthma.
A general outcome was that patients treated with montelukast had significantly
greater improvements in their symptoms of SAR and PAR than did patients who
were given a placebo. As monotherapy, montelukast exhibited efficacy similar to
that of loratadine, but less than that of the intranasally administered corticosteroid
fluticasone propionate. The use of montelukast in combination with antihista-
mines such as loratadine or cetirizine has generally resulted in greater efficacy
than when these agents were used alone, and in some studies has produced results
comparable with intranasally applied corticosteroids. In patients with AR
comorbid with asthma, montelukast treatment has resulted in significant improve-
ments in both, compared with placebo. Montelukast is well tolerated and has a
favourable safety profile; adverse events have occurred at similar frequencies in
patients taking either montelukast or placebo.
Montelukast provides an effective and well tolerated oral treatment for allergic
airway inflammation in patients with SAR or PAR without asthma, and in patients
in whom AR is comorbid with asthma.

Montelukast is an anti-inflammatory agent that
was initially developed as a therapy for asthma and
is now increasingly being applied to the treatment of
seasonal and perennial allergic rhinitis (SAR and
PAR, respectively). It is an antagonist of type 1
cysteinyl-leukotriene receptors (CysLT1Rs) first
synthesised in the early 1990s in response to basic
research that had identified cysteinyl leukotrienes
(CysLTs) as important intermediaries in anaphylax-
is and other forms of allergic airway disease.[1]
CysLTs are arachidonic acid derivatives that are
synthesised and released by immunocytes (mast
cells, primarily) in the respiratory mucosa in re-
sponse to the presence of allergen.[2,3] These inflam-
matory mediators then diffuse to target cells in the
upper and lower airways where they interact with
CysLT1Rs to trigger several untoward actions (fig-
ure 1), including contraction of bronchiolar smooth
muscle, chemoattraction of eosinophils and stimula-
tion of the release of other mediators of inflamma-
tion, increased mucus production, and mucosal
swelling brought about through increased vascular
permeability and blood flow to the mucosa.[4-7]
CysLTs also play a role in dendritic cell maturation
and migration, and are thereby involved in the prep-
aration of the immune system for future allergic
response.[8-10] There is thus a strong scientific ratio-
nale for targeting CysLT1R in the treatment of in-
flammatory airway disease.
Montelukast currently stands as the most thor-
oughly tested and prescribed drug that acts through
antagonism of CysLT1Rs. Its efficacy against asth-
ma was established in the late 1990s in several large,
randomised, controlled clinical trials (RCTs)[11,12]
and it has been widely approved for this indication
since 1998. Beginning in 1997, other RCTs were
initiated to evaluate montelukast efficacy and safety
in the treatment of allergic rhinitis (AR), and based
on the data from these studies, montelukast is now
widely approved for this indication also. The find-
ings from these earlier studies have been sum-
marised in several review articles.[13-18] Since these
were published, however, several large new studies
have been completed, and these have extended our
knowledge significantly, especially with respect to
the use of montelukast in the treatment of AR con-
comitant with asthma. This specific use is of particu-
lar interest because both of these manifestations of
airway inflammation have strong underlying in-
volvement of CysLTs,[7,19] and montelukast current-

© 2007 Adis Data Information BV. All rights reserved. Drugs 2007; 67 (6)
Montelukast in the Treatment of Allergic Rhinitis
IgE
Antigen
Cysteinyl-leukotrienes
Increased
mucus
production
Chemoattraction
of eosinophils
Fig. 1. Principal actions of cysteinyl-leukotrienes in mediating allergically triggered inflammation in the respiratory mucosa and submucosa.
Each of the indicated actions is mediated by the type 1 cysteinyl-leukotriene receptor, the function of which is inhibited by montelukast.
ly stands apart as a single formulation that is demon-
strably beneficial against both.[20] A recent study has
also focused on montelukast in the treatment of
PAR, for which it is now specifically indicated in
many countries. Although PAR is less prevalent
than SAR in many locales, it is nonetheless an
important public health problem worldwide because
of its association with substantially higher rates of
per-patient healthcare costs and comorbidity.[21]
This article provides a systematic consideration
of all of the published data presently available re-
garding the efficacy, safety and tolerability of
montelukast in the treatment of SAR, PAR and
asthma that is concomitant with either.
Searches were conducted on MEDLINE, Em-
base, SciSearch, Derwent Drug File and Biosis in-
© 2007 Adis Data Information BV. All rights reserved.
889
Sensitised
mast cell
Increased
vascular
permeability
Smooth
muscle
contraction
clusive of all indexed dates prior to 19 March 2007,
using the search terms ‘rhinitis’, ‘montelukast’ and
‘MK-0476’. This retrieved 201 potentially relevant
articles out of which 29 were found to satisfy our
preliminary acceptance criteria of being full reports
published in English presenting the findings from
clinical trials with specific AR-related endpoints.
These 29 research articles were then examined fur-
ther to identify those that presented trials that
had been conducted double-blind and placebo-con-
trolled, with patient randomisation, an absence of
concurrent AR therapies such as nasal corticoste-
roids or sodium cromoglicate, and adequate statisti-
cal power. Concerning the latter, we required that
there be at least 80 patients per treatment group. In
studies in which symptoms were scored from 0 to 3
Drugs 2007; 67 (6)
890
(as was most commonly the case), this group size
would be expected to provide 80% power to detect
significant differences as small as 0.25, assuming
that individual scores had a standard deviation of
≤0.56.[22]
1. Montelukast Efficacy in Patients with
Allergic Rhinitis
We found eight RCTs that satisfied the above
criteria and we refer to these hereafter as the core
group of trials (table I). A total of 3950 patients were
represented within these, with a mean of 247 pa-
tients per treatment arm. All of these were industry-
sponsored, either by Merck & Co., the manufacturer
of montelukast, or GlaxoSmithKline, the manufac-
turer of fluticasone propionate aqueous nasal spray
(FPANS).
1.1 Patient Characteristics and
Study Endpoints
A universal inclusion criterion in these studies
was a history of AR of at least 2 years’ duration.
Patients were also required to be positive on one or
more skin tests for relevant allergens and generally
free of significant comorbidity other than asthma.
Concurrent asthma was required in two of the eight
core RCTs.[27,28] In the remaining six, the asthma
prevalence varied from 22% to 28%, and was thus
comparable to that seen more generally among pa-
tients with AR.[30,31]
Seven out of these eight RCTs were specifically
focused on SAR and were 2–4 weeks in duration.
There was also one study of PAR and this was 6
weeks in duration.[29] Montelukast was universally
given at the dose of 10 mg/day, except in one study
in which one treatment arm received 10 mg/day
while another received 20 mg/day.[22] This doubling
of dose was found to provide no greater efficacy
than did the standard 10 mg/day.
All of these studies had the same primary
endpoint, namely daytime nasal symptom (DNS)
severity, a metric calculated from patients’ daily
ratings of four individual symptoms: nasal conges-
tion, rhinorrhoea, nasal itch and sneezing. Seconda-
ry endpoints included individual scores for these
© 2007 Adis Data Information BV. All rights reserved.
Nayak & Langdon
same daytime symptoms, patients’ ratings of night-
time nasal symptoms, daytime eye symptoms, glob-
al assessments made by patients and their physicians
regarding whether or not overall condition had
worsened or improved during the course of the
study, peripheral blood eosinophil count, and scores
that were based on responses to a standardised Rhi-
noconjunctivitis Quality of Life questionnaire
(RQLQ) that evaluated patient well-being in seven
domains: nasal, eye, ear and throat symptoms, sleep,
practical problems, emotions and activity.[32] In ad-
dition, there were asthma endpoints included in the
two studies that specifically focused on patients with
both AR and asthma.[27,28] Some of the studies also
had exploratory endpoints,[23,25,26] but these are not
considered in this review.
1.2 Montelukast Monotherapy
versus Placebo
It was generally observed that montelukast treat-
ment resulted in significant improvements over pla-
cebo in the endpoints listed in section 1.1. The
spring SAR trial by van Adelsberg et al.[25] provides
a representative example. In this study, montelukast
efficacy and safety were evaluated in the spring of
2001 in 522 patients at 32 outpatient clinics located
throughout the US and Canada. The treatment dura-
tion was 2 weeks. The study included a montelukast
arm (n = 522), a placebo arm (n = 521) and a
loratadine arm (10 mg/day; n = 171) as a positive
control. The patients entering the study tended to
have rhinitis of moderate severity, with a mean DNS
score at baseline of 2.12 (where 0 = no symptoms, 1
= mild, 2 = moderate and 3 = severe), and a mean
RQLQ score of 3.25 (where 0 = no impairment and
6 = severe impairment). Twenty-four percent of
patients entered the study with a history of asthma
and one-third of these had experienced asthma
symptoms within the previous 2 weeks. Use of
short-acting β-adrenoceptor agonists for asthma was
permitted during the study but use of inhaled corti-
costeroids (ICSs) was not. Pregnant women and
patients who smoked were excluded, as were those
or who required the use of any AR medications other
than montelukast or loratadine.
Drugs 2007; 67 (6)
© 2007 Adis Data Information BV. All rights reserved.

Montelukast in the Treatment of Allergic Rhinitis

Table I. Large, randomised, placebo-controlled, double-blind studies of montelukast efficacy against allergic rhinitis (AR) endpoints
Study Length (d) Type of History of Interventionb Group sizec Outcome (versus placebo, p < 0.05)
AR asthma (%)a
primary secondary endpoints
endpoint
Meltzer et al.[22] 14 SAR (spr) 28 MTK 95 (91) ↔DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt
MTK (20 mgight-time 90 ↔DNS ↔NNS, ↔DES, ↔CSS, ↔RQLS, ↓GERS-
Pt
MTK + LOR 90 ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt,
↓GERS-Ph
Nayak et al.[23] 14 SAR (aut) 22 MTK 155 (149) ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↔GERS-Pt,
↔GERS-Ph, ↓EC-PB
MTK + LOR 302 ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt,
↓GERS-Ph, ↓EC-PB
Philip et al.[24] 14 SAR (spr) 27 MTK 348 (352) ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt,
↓GERS-Ph
van Adelsberg et al.[25] 14 SAR (spr) 25 MTK 522 (521) ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt,
↓GERS-Ph
van Adelsberg et al.[26] 28 SAR (aut) 23 MTK 448 (451) ↓DNS ↓NNS, ↓DES, ↓CSS, ↓RQLS, ↓GERS-Pt,
↓GERS-Ph, ↔EC-PB
Philip et al.[27] 14 SAR (spr 100 MTK + as-needed 415 (416) ↓DNS ↓NNS, ↓DES, ↓RQLS, ↓GERS-Pt,
and aut) SABA and ICS ↓GERS-Ph, ↓GEAS-Pt, ↓GEAS-Ph, ↓use
of SABA
Nathan et al.[28] 28 SAR 100 MTK + FP/S, 100/50μg 282 (290) ↓DNS ↔NNS, ↔PEF-E, ↔DWOA, ↔DWOR
twice dailyd ↔PEF-M
Patel et al.[29] 42 PAR 28 MTK 1002 (990) ↓DNS ↓NNS, ↓CSS, ↓EDNS, ↓RQLS, ↓GERS-Pt
a These values represent prevalence within patient groups of a personal (not familial) history of asthma.
b The dose of montelukast or loratadine was 10 mg/d, except as noted. Lower outcome values uniformly represent improvement in symptoms or quality of life.
c Placebo group sizes are presented parentheses.
d Placebo-group patients were also treated concurrently with inhaled FP/S.
aut = autumn; CSS = composite symptoms score, calculated from both daytime and night-time symptom scores recorded daily; DES = daytime eye symptoms (calculated from
separate scores recorded daily for tearing, pruritus, redness, puffiness); DNS = daytime nasal symptoms (calculated from separate scores recorded daily for congestion, itching,
rhinorrhoea, sneezing); DWOA = percentage of days without asthma; DWOR = percentage of days without use of asthma rescue medication; EC-PB = eosinophil count in the
peripheral blood; EDNS = end-of-day nasal symptoms score; FP/S = fluticasone propionate/salmeterol (taken by inhalation); GEAS-Ph = physician’s global evaluation of change in
asthma symptoms (recorded once at the study’s end); GEAS-Pt = patient’s global evaluation of change in asthma symptoms (recorded once at the study’s end); GERS-Ph =
physician’s global evaluation of change in rhinitis symptoms (recorded once at the study’s end); GERS-Pt = patient’s global evaluation of change in rhinitis symptoms (recorded
Drugs 2007; 67 (6)

once at the study’s end); ICS = inhaled corticosteroids; LOR = loratadine; MTK = montelukast; NNS = night-time nasal symptoms score (calculated from separate scores recorded
daily for difficulty going to sleep because of nasal symptoms, frequency of awakenings, and severity of congestion on awakening); PAR = perennial allergic rhinitis; PEF-E =
evening peak expiratory flow; PEF-M = morning peak expiratory flow; RQLS = Rhinoconjunctivitis Quality-of-Life Score (recorded once at the study’s end); SABA = short-acting β-
adrenoceptor agonist; SAR = seasonal allergic rhinitis; spr = spring; ↓ indicates that the montelukast- and placebo-group means differed significantly (p < 0.05) and that the former

891
was lower; ↔ indicates that the outcome difference between groups was not significant (p ≥ 0.05).
892
The overall DNS score improved significantly in
montelukast-treated patients as compared with pla-
cebo (p = 0.003), as did the scores for each individu-
al nasal symptom, except for pruritus. All secondary
endpoints also improved, including night-time
symptoms relating to sleep quality, daytime eye
symptoms, global end-of-study evaluations by both
patients and physicians, and RQLQ scores. In the
group that received montelukast, the mean DNS
score at baseline was 2.10 ± 0.43 (SD), and this
improved with treatment to 1.72 (95% CI 1.67,
1.77). In the placebo group, mean DNS score was
2.14 ± 0.43 initially, and this improved to 1.85 (95%
CI 1.81, 1.90). Placebo-group responses on this or-
der of magnitude were typical throughout the core
group of RCTs (see section 4.1).
In the one core-group RCT that focused specifi-
cally on the treatment of PAR, significant improve-
ments over placebo were observed for every
endpoint examined, including DNS score, night-
time and eye symptoms, RQLQ scores, and global
ratings of outcome by patients and physicians.[29]
Several of the core RCTs also included analyses of
the time-course of onset of montelukast action, and
it was consistently observed that AR symptoms
improved significantly within 1–3 days from the
start of treatment.[22,23,33,34]
1.3 Montelukast Monotherapy versus
Other Treatments
Five of the studies in the core group included a
treatment arm in which patients received loradatine
at 10 mg/day.[22-26] Although there were no direct
statistical comparisons made in these studies,
montelukast and loratadine did appear to produce
similar outcomes.
There was direct comparison made between
montelukast and cetirizine in two small paediatric
studies conducted in Taiwan (table II). In the first of
these, cetirizine produced a superior outcome with
respect to nasal congestion and combined nose, eye,
ear and throat symptoms.[35] In the second, cetirizine
produced significantly lower scores for nasal itch
and total nose, eye and throat symptoms, whereas
montelukast was more effective in improving night
© 2007 Adis Data Information BV. All rights reserved.
Nayak & Langdon
sleep quality.[36] Recently, montelukast was also
compared with pseudoephedrine (240 mg/day) and
the two treatments produced similar levels of im-
provement from baseline in nasal peak inspiratory
flow and all RQLQ component scores except that of
nasal congestion, which improved more in the
pseudoephedrine arm.[37]
Montelukast and FPANS (200μg once daily)
have been compared head-to-head in three large
studies, all of which produced evidence for superior-
ity of FPANS in treating symptoms of AR. Two of
these were studies of winter SAR in south-central
Texas and had the same general design and
endpoints as the eight core RCTs, but without a
placebo control arm.[42,48] It was found that the vari-
ous symptom scores improved 14–40% more in the
FPANS-treated groups than in the montelukast
groups. The third study specifically concerned AR
in patients who had concomitant asthma and who
received twice-daily ICS plus β-adrenoceptor ago-
nist therapy concurrently.[28] The details of its de-
sign and outcome are discussed in section 2.
1.4 Montelukast in Combination with
Other Treatments
Because inflammation proceeds through multiple
pathways, there is the potential for therapeutic ad-
vantage in combining agents that act through inde-
pendent mechanisms. This approach has proven use-
ful in the treatment of asthma comorbid with AR,
where combination of montelukast with budesonide
improved lung function more than did simply doub-
ling the corticosteroid dose.[51] There are also find-
ings that suggest utility in combining montelukast
with other agents in the treatment of AR.
Two studies within the core group included treat-
ment arms in which montelukast and loratadine
were given in combination.[22,23] The outcomes were
not directly compared head-to-head, but significant
symptom improvements over placebo were ob-
served more consistently with this combination ther-
apy (table I) and symptom scores tended to be lower.
The findings thus suggested greater efficacy when
these two drugs were given in combination.
Drugs 2007; 67 (6)
© 2007 Adis Data Information BV. All rights reserved.

Montelukast in the Treatment of Allergic Rhinitis

Table II. Studies in which montelukast was directly compared with other treatments in patients with allergic rhinitis
Study Interventions compareda Group size Endpoints Outcomes (p < 0.05)b
Wilson et al.[38] MTK + CTZ vs MMF vs PBOc 22c CNG, INT, NES and MTK + CTZ and MMF > PBO
NPIF
Wilson et al.[39] MTK + CTZ vs BUD vs PBOc 21c DNS, DES, INT and MTK + CTZ and BUD > PBO
NPIF
Wilson et al.[40] MTK + LOR vs FEX (120 mgight-time vs PBOc 37c DNS, DES, INT and MTK + LOR and FEX > PBO
(permitted concurrent use of sodium cromoglicate) THR
Pullerits et al.[41] MTK vs 16 DNSd MTK + LOR and FPANS > PBO
MTK + LOR vs 15 NNSd FPANS > MTK
FPANS vs 13 FPANS > MTK, MTK + LOR and PBO
PBO 18
(permitted concurrent use of sodium cromoglicate and
additional LOR)
Ratner et al.[42] MTK vs FPANS 352 DNS, CNG, NIT, RHI, FPANS > MTK
353 NNS and SNZ
Saengpanich et MTK + LOR vs 31 RQLQ-NSD FPANS > MTK + LOR
al.[43] FPANS 29
Di Lorenzo et al.[44] MTK + CTZ vs 20 NES, RHI, SNZ and MTK + CTZ, FPANS, MTK + FPANS and CTZ +
MTK + FPANS vs 20 NIT FPANS > PBO
CTZ + FPANS vs 20 NES, RHI and NIT CTZ + FPANS > MTK + CTZ
FPANS 20 NES and NIT FPANS > CTZ + FPANS
PBO 20 CNG FPANS, MTK + FPANS and CTZ + FPANS > MTK
NIT + CTZ and PBO
CTZ + FPANS > MTK + FPANS
Hsieh et al.[35] MTK (5 mgight-time vs 20 TSS CTZ > MTK > PBO
CTZ (10 gmight-time vs 20 CNG CTZ > MTK > PBO
PBO 20 NPEF MTK and CTZ > PBO
(paediatric patients with PAR, ages 6–12y)
Kurowski et al.[45] MTK vs 11 RHI MTK + CTZ > MTK, CTZ and PBO
CTZ vs 11 CNG MTK + CTZ > PBO
MTK + CTZ vs 19 SNZ MTK + CTZ and CTZ > PBO
PBO 19 NIT MTK > PBO
(prophylactic treatment of SAR begun 6 weeks in EIT MTK + CTZ > CTZ and PBO
advance of the pollen season) MTK + CTZ > CTZ and PBO
Moinuddin et al.[46] MTK + LOR vs 34 NSQ MTK + LOR > FEX + PSE
FEX + PSE 34
Nathan et al.[28] MTK + FP/S vs 282 PEF MTK + FP/S ≈FPANS + FP/S ≈FPS
FPANS + FP/S vs 291 DNS FPANS + FP/S > MTK + FP/S > FPS
Drugs 2007; 67 (6)

FP/S 290 NNS FPANS + FP/S > MTK + FP/S ≈FPS

Continued next page

893
© 2007 Adis Data Information BV. All rights reserved.

894
Table II. Contd
Study Interventions compareda Group size Endpoints Outcomes (p < 0.05)b
Chen et al.[36] MTK (4 mgight-time vs 20 NAR and RQLQ MTK, CTZ > PBO
CTZ (5 mgight-time vs 20 TSS CTZ > MTK > PBO
PBO 20 NSQ MTK > CTZ > PBO
(paediatric patients with PAR, ages 2–6y) NIT CTZ > MTK and PBO

Mucha et al.[37] MTK vs 23 CNG PSE > MTK

PSE (240 mgight-time 19

Ciebiada et al.[47] MTK vs DLR vs MTK + DLR vs PBOe 20e DNS, CNG MTK, DLR and MTK + DLR > PBO
MTK + DLR > MTK and DLR

MTK vs LCZ vs MTK + LCZ vs PBOe (adult PAR) 20e DNS, CNG MTK, LCZ and MTK + LCZ > PBO
MTK + LCZ > MTK

Martin et al.[48] MTK vs 369 DNS, CNG, NIT, RHI, FPANS > MTK
FPANS 367 NNS and SNZ

Razi et al.[49] MTK (5 mgight-time vs PBO (paediatric patients, ages 28 DNS, CNG, NIT, RHI, MTK > PBO
7–14y) 29 SNZ and DES

Barnes et al.[50] MTK + CTZ vs BDP vs PBOf (adult PAR with asthma) 17f DNS MTK + CTZ and BDP > PBO

a Doses (except as noted): beclametasone dipropionate 400 μ/d inhaled extra fine powder (hydrofluoroalkane-134a as propellant) + 200 μ/d intranasal spray; budesonide
400 μg/d inhaled dry powder + 200 μg/d aqueous intranasal drops (100 μg/d in each nostril); cetirizine 10 mg/d; desloratadine 5 mg/d; fexofenadine 60 mg/d; FPANS 200
μg/d (100 μg/d in each nostril); FP/S 100/50μg twice daily; levoceterizine 5 mg/d; loratadine 10 mg/d; mometasone furoate 200 μg/d; montelukast 10 mg/d;
pseudoephedrine 120 mg/d.

b ‘x > y’ indicates that treatment ‘x’ resulted in a significantly better outcome than did treatment ‘y’ (p < 0.05). ‘x ≈ y’ signifies that there was no significant difference in the
outcome (p ≥ 0.05) in a comparison made between treatment groups of at least 80 patients each.

c These studies had a single-blind crossover design in which the interventions followed this temporal sequence: placebo, first study drug, placebo, second study drug.
Treatment duration with the study drugs was 2 weeks; the placebo intervals were for 7–10 days each.

d Endpoints were measured at three timepoints in this study. The results here are from the middle timepoint (‘weeks 3–5’) when pollen exposure was the highest.

e This was an adult PAR study with double-blind, three-way crossover design and two independent arms. Treatments were 6 weeks in duration and separated by 2 weeks
of washout.

f This was a double-blind, double-dummy crossover study in adults with both asthma and PAR. Treatments were given for periods of 8 weeks, each preceded by 2 weeks
of placebo.

BDP = combined inhalation and intranasal therapy with beclametasone dipropionate; BUD = budesonide; CNG = nasal congestion; CTZ = cetirizine; DES = daytime eye symptoms;

Nayak & Langdon

DLR = desloratidine; DNS = daytime nasal symptoms; EIT = eye itch; FEX = fexofenadine; FPANS = fluticasone propionate aqueous nasal spray; FP/S = fluticasone propionate/
Drugs 2007; 67 (6)

salmeterol; INT = interference of symptoms with daily activity; LCZ = levoceterizine; LOR = loratadine; MMF = mometasone furoate; MTK = montelukast; NAR = nasal airway
resistance; NES = combined nasal and eye symptoms; NIT = nasal itch; NNS = night-time nasal symptoms; NPEF = nasal peak expiratory flow; NPIF = nasal peak inspiratory flow;
NSQ = night sleep quality; PAR = perennial allergic rhinitis; PBO = placebo; PEF = peak expiratory flow (to assess asthma); PSE = pseudoephedrine; RHI = rhinorrhoea; RQLQ =
Rhinoconjunctivitis Quality-of-Life Questionnaire overall score; RQLQ-NSD = nasal symptoms domain score from the RQLQ questionnaire; SAR = seasonal allergic rhinitis; SNZ =
sneezing; THR = throat itch and irritation; TSS = total symptom score (nasal, eye, ear, palate and throat symptoms).
Montelukast in the Treatment of Allergic Rhinitis
The combination of montelukast and loratadine
has also been evaluated in several small studies
(table II). In two of these, its efficacy was found to
be less than that of FPANS.[41,43] In other studies, its
efficacy was determined to be comparable to that of
fexofenadine plus pseudoephedrine (60/120mg) by
most measures, but superior with respect to quality
of sleep.[40,46]
Other small studies have evaluated the combina-
tion of montelukast with either cetirizine (10 mg/
day), levoceterizine (5 mg/day) or desloratidine (5
mg/day), and findings from these have favoured
combination therapy over monotherapy with respect
to congestion, rhinorrhoea, sneezing, nose and eye
itching.[47] Elsewhere, montelukast with cetirizine
has been found to have efficacy against AR compa-
rable to that of intranasal mometasone,[38] budeso-
nide.[39] and combined treatment with both inhaled
and intranasal beclometasone.[50] When compared
with FPANS, montelukast with cetirizine was found
to have similar efficacy in the improvement of nasal
itch, sneezing and rhinorrhoea, but not nasal conges-
tion.[44]
2. Montelukast in Patients with
Concomitant Allergic Rhinitis
and Asthma
Individuals with AR are at a 3- to 12-fold greater
risk of also having asthma or developing it later in
life.[52-55] Conversely, most asthma patients also
have a history of AR[31,56] and, increasingly, these
two medical conditions have come to be regarded as
interacting manifestations of a common underlying
pathology.[56-62] They are often triggered by the
same environmental challenges[63,64] and they share
common pathophysiological features such as paral-
lel early- and late-response components,[65-67] prom-
inent infiltration of the mucosa by eosinophils[68]
and mediation of key inflammatory events by
CysLTs.[2,3,7,19] Moreover, laboratory studies in hy-
persensitive individuals have shown that the entire
airway tends to respond with inflammation even
when antigen exposure is localised.[69-72] Outcomes
research has shown that adult and paediatric asthma
patients with active AR are more likely to require
© 2007 Adis Data Information BV. All rights reserved.
895
rescue therapy with short-acting β-adrenoceptor ag-
onists, emergency treatment and hospitalisa-
tion.[73-75] Taken together, these facts suggest that
treatment of AR in such patients may not only
reduce their AR but also result in better control of
their asthma.[55,76-79]
2.1 Evidence for Montelukast Efficacy in
Allergic Rhinitis with Asthma
Two of the eight core studies focused specifically
upon patients with AR and asthma of mild-to-mod-
erate severity.[27,28] In the first of these, 41% of
patients were using ICS therapy when enrolled and
they were permitted to continue this therapy during
the study.[27] DNS scores and other AR endpoints
improved significantly for patients in the
montelukast arm in this study, as compared with
placebo (p < 0.001), and three asthma endpoints also
improved significantly, namely the frequency at
which patients resorted to as-needed use of short-
acting β-adrenoceptor agonists, a global evaluation
of asthma severity made by the patients, and a
similar evaluation made by their physicians (p <
0.05). In addition, it was found that those patients
whose AR symptoms benefited the most from
montelukast treatment (based on their global evalua-
tions) also realised the greatest improvements in
their asthma (p < 0.001).
The second of these two studies had a more
complicated design and a somewhat different out-
come.[28] Following randomisation, all of the pa-
tients in this study (including those in the placebo
group) were placed on an aggressive course of asth-
ma treatment consisting of inhaled fluticasone pro-
pionate plus salmeterol (FP/S; 100/50 μg, twice
daily). Prior to randomisation, only 12% of the
patients in this study were receiving daily ICS com-
bined with a long-acting β-adrenoceptor agonist.
Thus, the term ‘placebo group’ must be used with
some reservation; there was no comparison made
between montelukast treatment and no treatment at
all, as all patients received inhaled FP/S. There were
three treatment arms: (i) oral montelukast (10 mg/
day) plus a placebo nasal spray plus inhaled FP/S;
(ii) an oral placebo (in lieu of montelukast) plus
Drugs 2007; 67 (6)
896
intranasal FPANS (200μg once daily) plus inhaled
FP/S; and (iii) placebo montelukast plus placebo
nasal spray plus inhaled FP/S.
It was found that neither montelukast nor FPANS
provided any further benefit over inhaled FP/S in
controlling asthma in these patients, based on mea-
surements of morning and evening peak expiratory
flow. As for symptoms of AR, all patients showed
substantial improvements over baseline, but these
were larger and more consistent in the group
that had received intranasal FPANS plus FP/S. Pa-
tients who received montelukast plus FP/S showed
significantly greater improvement in their total
DNS scores than did those who received placebo
plus FP/S. However, for the individual nasal symp-
tom scores, differences from placebo were statisti-
cally significant for pruritis and sneezing alone.
Looking beyond the core group of studies, there
have been two other large RCTs that examined
montelukast therapy in concomitant AR and asthma.
However, neither of these was designed to study
treatment of AR; one had no AR endpoints[51] and
the other allowed patients to take nasal corticoste-
roids and other AR medications concurrently while
in the study.[80] Both studies found that montelukast
significantly improved asthma symptoms and re-
duced the use of asthma rescue medications.
2.2 Satisfaction with Treatment in Patients
with Allergic Rhinitis and Asthma
In Europe, a large (n = 5855) observational study
has recently been completed in which patients with
concomitant asthma and AR were asked to rate their
satisfaction after 4–6 weeks of montelukast treat-
ment.[81] Overwhelmingly, patients chose the terms
‘good’ or ‘very good’ to describe the extent to which
their symptoms and quality of life had improved
(81.8% and 83.5% of patients with regards to asth-
ma and AR symptoms, respectively). In addition,
88.1% reported having reduced their concurrent use
of other AR medications, and 92.3% answered that
they planned to continue their montelukast therapy
beyond the end of the study.
In the study by Nathan et al.,[28] patients were
asked to rate their global level of satisfaction with
© 2007 Adis Data Information BV. All rights reserved.
Nayak & Langdon
their treatment, and 69% of patients in the FPANS
plus FP/S arm responded that they were either satis-
fied or very satisfied compared with 55% of patients
in the montelukast plus FP/S arm (difference signifi-
cant at p < 0.001). Caution is warranted in generalis-
ing this outcome to real-world use because all of the
patients in this comparison had been treated daily
with intranasal spray (either FPANS or the placebo),
and the use of an intranasal medication may be
associated with odours, irritation and other sensa-
tions that have a significant impact on patient prefer-
ence, satisfaction and compliance.[82]
3. Safety and Tolerability
Montelukast has exhibited an excellent profile of
safety and tolerability, with the frequency of adverse
events consistently being indistinguishable in com-
parisons made between montelukast- and placebo-
treated patient groups. The most commonly reported
clinical adverse event has been headache, and this
has occurred in ≈5% of patients regardless of treat-
ment arm, including placebo. Other adverse events
have included upper respiratory tract infection, dry
mouth, asthenia/fatigue, pruritus, sinusitis, naso-
pharyngitis, dizziness and rash, and these too were
seen with similar frequency in montelukast-treated
and placebo groups. Laboratory adverse events have
occurred very infrequently (<1%) and have been
minor in nature, with similar distributions observed
between treatment and control groups. There have
been no findings to suggest adverse interaction be-
tween montelukast and any of the other drugs with
which it was combined. Some evidence has suggest-
ed that treatment of childhood AR with intranasal
corticosteroids may result in bone growth suppres-
sion,[83,84] whereas normal growth (as compared
with placebo) was observed in a large RCT in chil-
dren who received daily montelukast for 56 weeks
for treatment of asthma.[85]
There have been isolated reports of Churg-
Strauss syndrome (CSS) developing in asthma pa-
tients treated with montelukast and other drugs, such
as inhaled fluticasone propionate, budesonide, sodi-
um cromoglicate, pranlukast and zileuton.[86-90] CSS
is a rare necrotising vasculitis that occurs with an
Drugs 2007; 67 (6)
Montelukast in the Treatment of Allergic Rhinitis
annual prevalence on the order of 60 per million in
asthma patients and 2–7 per million in the general
population.[91] It did not occur in any of the patients
enrolled in the clinical trials covered in this review.
Its precise aetiology is not known, but its clinical
onset is most often preceded by discontinuation or
tapering of corticosteroid therapy,[88] such as occurs
in patients who are deriving benefit from treatment
with montelukast or another corticosteroid-sparing
agent. Hence, the association of CSS with treatment
by montelukast and other such agents is widely
thought to involve the unmasking or exacerbation of
latent disease, rather than direct causality.[86,90,92]
4. Technical Issues and Limitations
In this review, we have systematically avoided
the consideration of preliminary reports (such as
meeting abstracts) and unpublished data. We chose
this constraint so that our findings and conclusions
would be based entirely on evidence that had met a
well accepted standard of quality (peer-reviewed
publication). Nonetheless, it is recognised that a bias
in favour of positive findings may be inherent in the
literature, in that such findings are likely to progress
through the publication process more readily and
reliably than negative and inconclusive results.[93]
As concerns the clinical trials themselves, there
are certain technical challenges of special impor-
tance in studies that evaluate AR therapies.[94] Prom-
inent among these are the need to time treatments to
coincide with the pollen season, the evaluation of
symptoms in young children, and the tendency to-
wards substantial symptom improvements in place-
bo-treated patients.
4.1 Placebo Response
It was commonly observed that symptom scores
improved by about 60–80% as much in placebo-
treated patients as they did in patients treated with
montelukast or a positive control such as loratadine.
Differences in placebo response were decisive, at
times, in determining which specific symptoms
were judged to have been improved significantly by
active treatments such as montelukast.[25] Several
factors may have been responsible for this. Disease
© 2007 Adis Data Information BV. All rights reserved.
897
severity varies over time and patients are most likely
to seek treatment when symptoms are especially
troublesome. Subsequently, with or without treat-
ment, symptom severity will tend to regress back
towards more normal levels.[95] In addition, symp-
toms may improve as a result of a true ‘placebo
effect’, meaning a response generated psychologi-
cally by participation in a study and the experience
of pill-taking. This effect tends to be especially
prominent in studies with subjective endpoints,[96]
such as were reviewed here.
It is also likely that spontaneous fluctuations in
allergen exposure played a role and, to the extent
that they did, this would contribute towards underes-
timation of true drug efficacy. Symptoms of SAR
are closely linked in time to pollen exposure,[41,97]
and secondary analysis in one study indicated that
some patients did not complete enrolment and their
run-in period until after pollen exposure was already
on its seasonal decline.[98] This analysis went on to
show that placebo-treated patients recorded their
largest symptom improvements during times of low
pollen exposure and montelukast efficacy (as deter-
mined by comparison with placebo) was highest
during times of highest pollen exposure.
4.2 Allergic Rhinitis in Children
Montelukast is widely approved as a treatment
for paediatric asthma, and its pharmacokinetics and
safety have been evaluated in children as young as 3
months of age.[99-101] In contrast, there has been little
study to date of montelukast in the treatment of
paediatric AR. None of the eight core RCTs includ-
ed children or adolescents aged <15 years. However,
relevant data have come from the two small
Taiwanese studies mentioned in section 1.3[35,36] and
from a study of paediatric PAR in Turkey.[49] In the
Taiwanese studies, montelukast was given to chil-
dren aged 6–12 years and 2–6 years, and significant
improvement was found in individual and compos-
ite nasal, eye and throat symptom scores, nasal peak
expiratory flow, eosinophil counts in nasal smears,
and responses to a version of the RQLQ adapted for
paediatrics.[35,36] In the Turkish study, treatment
with montelukast significantly improved symptoms
Drugs 2007; 67 (6)
898
of spring SAR and peripheral eosinophil counts in
children aged 7–14 years.[49] There were no signifi-
cant differences in the frequencies of adverse events
observed in these montelukast- and placebo-treated
children.
4.3 Treatment Duration
Given that CysLTs are involved in the regulation
of dendritic cell function,[8-10] it is possible that long-
term anti-leukotriene therapy might provide an addi-
tional benefit over time by blunting allergic sen-
sitisation. Studies to date with montelukast have
generally been too brief to explore this possibility.
However, the paediatric study by Chen et al.[36] did
present a pattern of progressively increasing benefit
during 12 weeks of treatment. In addition, a small
study of SAR in Poland has produced data sug-
gesting that it is beneficial to prescribe montelukast
prophylactically, several weeks prior to the start of
the pollen season.[45]
5. Other Considerations
No medication can benefit patients who choose
not to take it and there may be strong preferences
related to whether an AR medication must be taken
intranasally. The comparisons between montelukast
and FPANS reviewed here have not addressed this
issue because they were conducted with double-
blind, double-dummy design in which all patients
were required to use a nasal spray, whether active or
placebo. To our knowledge, this issue has not been
formally examined in any study of montelukast in
AR, but it has been examined in the use of
montelukast to treat asthma. In a sample of pharma-
cy claims made by 48 751 patients who were aged
6–55 years (mean age, 30.4 years), persistence in the
filling of prescriptions was approximately twice as
great in asthma patients prescribed oral montelukast
as in those who were prescribed inhaled long-acting
β-adrenoceptor agonists or corticosteroids.[102]
6. Conclusion
Montelukast has been evaluated as a treatment
for SAR and PAR in large, double-blind, RCTs, and
it has been generally observed that it produces sig-
© 2007 Adis Data Information BV. All rights reserved.
Nayak & Langdon
nificant improvements within 1–3 days in daytime
nasal and eye symptoms, night-time symptoms,
sleep quality and quality of life. As monotherapy,
montelukast (10mg) taken orally once daily appears
to be similar in efficacy to loratadine, but less effec-
tive than intranasally applied fluticasone propionate.
Combinations of montelukast with either cetirizine
or loratadine tend to be more effective than
monotherapy with these same agents, and may in
some cases be comparable in efficacy to intranasally
applied corticosteroids. In patients with comorbid
asthma and AR, montelukast has been found to
improve symptoms and measures of both.
Montelukast is well tolerated and has a favourable
safety profile, in that adverse events have consist-
ently been observed to occur at similar frequencies
in patients treated with either montelukast or place-
bo.
Acknowledgements
Dr Anjuli Nayak has received research grants, educational
support, honoraria and/or consultancy fees from the follow-
ing pharmaceutical companies involved in the manufacture
and sale of drugs that are evaluated in this article: AstraZene-
ca, GlaxoSmithKline, Merck & Co., Pfizer, Schering-Plough,
and Wyeth. Dr Ronald B. Langdon is an employee of Merck
& Co.
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Correspondence: Dr Anjuli Nayak, Sneeze, Wheeze & Itch
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USA.
E-mail: drnayak@asthma2.com
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