The Laryngoscope

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V

Rhinological and Otological Society, Inc.

Does Desloratadine Alter the Serum Levels of Montelukast When

Administered in a Fixed-Dose Combination?
Cemal Cingi, MD; Sema Zer Toros, MD; Iskender Ince, MD; Cigdem Kalaycik Ertugay, MD;
M. Kezban Gurbuz, MD; Hamdi Cakli, MD; Nagehan Erdogmus, MD; Ercument Karasulu, MD;
Ercan Kaya, MD
Objectives/Hypothesis: The aim of this study was to investigate the serum levels of montelukast when administered
alone or in combination with desloratadine.
Study Design: A prospective crossover study.
Methods: Twenty-three healthy volunteers were investigated in two sessions. Volunteers were given 10 mg of montelukast orally with 250 mL water in the first session. The same subjects were given 10 mg of montelukast in fixed combination
with 5 mg desloratadine 10 days after first session. Blood samples were collected 2, 3, and 4 hours after drug administration,
and kept at 280 C after both applications. Plasma samples were analyzed for montelukast concentration.
Results: Mean concentration values of both groups were not statistically different (P >.05), but the differences were
statistically significant according to time (P <.05). Statistically significant difference was not found between the groups
according to the area under curve on the basis of both marginal and cumulative values for all different time intervals
(P >.05).
Conclusions: The absorption rate of montelukast was not altered when administered with desloratadine. This study
suggested that desloratadine does not influence the bioavailability of montelukast, and their combination therapy can be used
safely.
Key Words: Desloratadine, montelukast, fix molecules, drug interaction, bioavailability, allergy.
Level of Evidence: 2b
Laryngoscope, 00:000000, 2013

INTRODUCTION

DOI: 10.1002/lary.24134

Montelukast is a leukotriene receptor antagonist

with proven efficacy in asthma and allergic rhinitis.1
Montelukast blocks cysteinyl-leukotriene receptors and
inhibits endogenous mediators of inflammation in allergic airway diseases. Initially developed as a treatment
for asthma, montelukast has been increasingly accepted
in many indications, such as in allergic rhinitis, and is
reported to have beneficial effects on chronic urticaria.3,4
Desloratadine is a potent, nonsedating H1-receptor
antagonist.5,6 Desloratadine is classified as a modern
second-generation H1-antihistamine, as it is chemically
derived from the second-generation drug, loratadine.5 It
has wider therapeutic margins and negligible central
nervous system effects as it exerts anti-inflammatory
and immunomodulatory activity.7,8 It is used for the
treatment of allergic rhinitis, chronic urticaria, and
recent reports have revealed the efficacy of desloratadine
in mild-to-moderate asthma patients with concomitant
allergic rhinitis or urticaria.5
The chronic nature of the disease requires life-long
treatment for the affected patients. The possibility of
dose-limiting adverse effects, such as sedation and drug
interactions, particularly on long-term use, needs to be
considered.
Based on the pharmacological literature, when any
two active ingredients are combined, the interaction can
potentially cause alterations in the molecular structure
and pharmacokinetic properties of the interacting

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Cingi et al.: Effect of Desloratadine on Montelukast Levels

Allergic rhinitis is a chronic inflammatory disease

of the airways with important comorbidities including
asthma.1 The World Health Organization recommends
that allergic rhinitis and asthma be viewed as endorganrelated expressions of a continuous systemic allergic inflammatory disease.2 Many studies have shown
that allergic rhinitis is associated with significant physical, psychological, and social impairment due to its
symptoms. Recently, there has been renewed interest in
evaluating the clinical efficacy of combinations of antihistamines and antileukotrienes due to an increased
understanding of the different roles played by histamine
and leukotrienes in allergic airway diseases.

From the Medical Faculty, Department of Otorhinolaryngology

(C.C., M.K.G., H.C., N.E., E.KAYA), Osmangazi University, Eskisehir;
Department of Otorhinolaryngology/Head and Neck Surgery (S.Z.T.),
Haydarpasa Numune Research and Education Hospital, Istanbul; Center
for Drug Research and Development and Pharmacokinetic Applications
(I.I., E.KARASULU), Ege University, Izmir; Department of Otorhinolaryngology/Head and Neck Surgery (C.K.E.), Tokat State Hospital, Tokat, Turkey.
Editors Note: This Manuscript was accepted for publication
March 11, 2013.
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
Send correspondence to Cigdem Kalaycik Ertugay, MD, Tokat
Devlet Hastanesi, Kulak Burun Bogaz Klinigi, Tokat, Turkey.
E-mail: ckalaycik@gmail.com

ingredients. Although a number of studies have shown

that combination of desloratadine and montelukast in
asthma and allergic rhinitis has shown additional efficacy over single treatment,1,3 the data regarding pharmacokinetic interactions with montelukast and
desloratadine are scarce.
The objective of this study was to investigate the serum levels of montelukast when administered alone or
in combination with desloratadine.

MATERIALS AND METHODS

The study was a prospective parallel-group study conducted in the Department of Ear, Nose, Throat, at the University of Osmangazi, Eskisehir, Turkey. Approval for the study
was obtained from the ethics committee, and informed consent
was obtained from each participant upon enrollment.

Study Population
The study group consisted of 23 healthy volunteers
(12 males, 11 females) with an age range of 22 to 25 years.
Patients with concomitant illness (malignancy, hepatic, psychiatric, endocrine, or other major systemic diseases) were
excluded from the study.

Study Design
This was a crossover study that was performed in two sessions (or phases), with a 10-day washout period to allow complete elimination of the drugs.
Phase 1. Volunteers were given 10 mg montelukast orally
with 250 mL of water. Blood samples were collected at 2, 3, and
4 hours after administration of the drug and kept at 280 C
(M phase).
Phase 2. The same volunteers were given 10 mg montelukast together with 5 mg desloratadine 10 days after phase 1.
Blood samples were collected at 2, 3, and 4 hours after treatment and kept at 280 C (MD phase).
The time to reach plasma peak concentration for montelukast is 3 to 4 hours; therefore, blood samples were not taken after 4 hours.

Measurement of Serum Levels of Montelukast

All collected samples were transferred to Ege University
Center for Drug Research and Development and Pharmacokinetic Applications within dry ice. Measurements were performed with high-performance liquid chromatography (API
4000 LC/MS/MS; AB SCIEX, Framingham, MA), using an
HyPURITY C18 Drop-In Guard Cartridge (Thermo Fisher
Scientific Inc., Waltham, MA) 100 3 2.1 mm inner diameter,

3 lm column. Extraction was performed as fluid-fluid. The calibration samples have been prepared by spiking reference standard into zero plasma at six different levels; 4.0, 10.0, 50.0,
100.0, 200.0, 500.0 ng/mL concentrations for montelukast have
been constructed. Additionally, 0.100, 0.200, 0.400, 0.750, 1.500,
4.500 ng/mL concentrations for desloratadine and 0.200, 0.300,
0.400, 0.600, 0.800, 1.500 ng/mL concentrations for 3-hydroxydesloratadine and their calibration curves have been constructed. Limit of detection (LOD) and limit of quantitation
(LOQ) values have been found as 0.017 ng/mL and 0.051 ng/mL
for montelukast, respectively. LOD and LOQ values have been
found as 0.004 ng/mL and 0.012 ng/mL for desloratadine,
respectively. LOD and LOQ values have been found as
0.006 ng/mL and 0.018 ng/mL for 3-hydroxydesloratadine,
respectively.

Statistical Analyses
Repeated measures analysis of variance was applied to
determine if the application-type dependent averages of concentration values at the times (T) of 2 hours, 3 hours, and 4 hours
showed any difference. The model included time and application
type effect (MMD). Paired comparisons among levels of time
effect (2, 3, and 4 hours) were done using Bonferroni correction.
Marginal and cumulative parameters were taken into account
in evaluating the area under curve (AUC). As a marginal parameter, only the AUC within the relevant time period was
taken into account. The total AUC up to the relevant time was
taken into account as a cumulative area parameter. A t test was
used in the comparison of mean values of application types separately for each time point for statistical evaluation of both parameters. Statistical analyses were performed using SAS 9.2
(SAS Institute Inc., Cary, NC), and P <.05 was considered to be
statistically significant.

RESULTS
Although 23 healthy volunteers were included in
the first phase of the study, 22 participated in the second
phase in which montelukast was administered with
desloratadine.

Concentration Measurements
Mean concentration values were not statistically
different according to groups (M, MD; F 5 2.99;
P 5.0869, P >.05), but the differences were statistically
significant according to time (2 hours, 3 hours, 4 hours;
F 5 11.49; P .0001, P >.05) (Table I). This demonstrated
that elimination rate of montelukast were not altered
with desloratadine administration.
When we looked at the comparisons of the concentrations, which were gathered during 2 hours (T2),

TABLE I.
Comparisons Between the Test Groups According to Time.
Time
2 Hours

3 Hours

4 Hours

Total

Treatment

Mean

StdDev

Mean

StdDev

Mean

StdDev

Mean

StdDev

MD
M

22
23

488.89
365.62

279.39
194.49

22
22

410.14
355.79

165.65
132.86

23
23

255.19
292.34

80.79
105.50

Total

45

425.88

245.06

44

382.96

150.92

46

273.77

94.79

ANOVA Test Results

67
68

382.80
337.65

213.12
150.63

F 5 2.99, P 5.0869, >.05

135

360.06

185.01

F 5 11.49, P 5.0001, <.05

ANOVA 5 analysis of variance; M 5 10 mg montelukast only; MD 5 10 mg montelukast together with 5 mg desloratadine; StdDev 5 standard deviation.

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Cingi et al.: Effect of Desloratadine on Montelukast Levels

TABLE II.
Dual Comparisons According to Application Time.
Time (Hours)

T2

T3

T4

T2
T3

P  0.05

T4

P < 0.05

P < 0.05

3 hours (T3), and 4 hours (T4), the concentration during

T4 was found to be different from T2 and T3 (P <.05),
whereas there was no statistically significant difference
between T2 and T3 (P >.05) (Table II).

Comparison of Groups According to Area Under

the Curve
Evaluation of marginal values. As shown in
Table III, for the 0 to 2-hour time interval, the difference
between the groups was not statistically significant
(t 5 1.72; P 5.0919, P >.05). For the 2 to 3-hour time
interval, the difference between the groups was not statistically significant (t 5 1.76; P 5.0855, P >.05). Additionally, for the 3 to 4-hour time interval, the difference
between the groups was not statistically significant
(t 5 0.17; P 5.8644, P >.05).
Evaluation of cumulative values. As shown in
Table IV, for the 0 to 2-hour time interval, the difference
between the groups was not statistically significant
(t 5 1.72; P 5.0919, P >.05). There were also no statistically significant differences for the 0 to 3-hour time
interval (t 5 1.73; P 5.0912, P >.05) or the 0 to 4-hour
time interval (t 5 1.49; P 5.1450, P >.05).

DISCUSSION
The optimal treatment of allergic diseases should
control all of the symptoms of patients and also improve
their quality of life. Treatment should be provided in a
stepwise manner according to the severity of symptoms.
When the recommended first-line treatment is inadequate, second-line therapies should be added. Desloratadine, a new generation antihistamine with proven
efficacy in treating most of the symptoms of allergic rhinitis, including nasal congestion, is recommended as a
first-line treatment.9,10 In some situations, montelukast,
with its anti-inflammatory activity, should be added as a
second-line complementary therapy to antihistamines.

Desloratadine, which is a metabolite of loratadine,

relieves the seasonal and perennial allergic rhinitis signs
and symptoms, reduces nasal congestion, and also reduces
bronchial symptoms during the pollen season in patients
with seasonal allergic rhinitis and asthma.9,11,12 Moreover,
desloratadine ameliorates pruritus, sleep disturbances,
and improves daily living activities in chronic urticaria.13
Montelukast, which is a leukotriene receptor antagonist, has entered the market in the last 10 years. Montelukast blocks cysteinyl-leukotriene receptors and
inhibits endogenous mediators of inflammation in allergic airway diseases. Initially developed as a treatment
for asthma, montelukast has been increasingly accepted
for many indications, such as allergic rhinitis, and is
reported to have beneficial effects on chronic urticaria.3,4
There are many clinical studies about the combination
of montelukast and desloratadine including their additional efficacy on nasal congestion, asthma, chronic urticaria, and quality of life.1,3,9
Nasal congestion is a crucial symptom that leads to
sleep fragmentation and subsequent daytime fatigue and
alone can have a considerable impact on quality of life. A
number of studies have shown the considerable effect of
the combination of montelukast and desloratadine on
nasal congestion.1,14 Ciebiada et al. compared the efficacy
of montelukast, desloratadine, and levocetirizine in monotherapy and the combination of montelukast with desloratadine or levocetirizine, and they supported that
combination therapy with montelukast and an antihistamine may have a positive impact on persistent allergic
rhinitis and improve quality of life and nighttime symptoms. They emphasized that this benefit is probably due to
the effect of the combination of montelukast plus either of
the newer generation antihistamines on nasal congestion.1
Davis et al. suggested that the administration of
montelucast, desloratadine, and fixed-dose combination
regimen of these two drugs had reduced the amplitude
of late asthmatic response when compared with placebo.
They concluded that the maximum effect (complete
blocking) had been achieved by the combination therapy.
Although not as much as late asthmatic response, early
asthmatic response was also diminished.15,16 Nettis
et al. demonstrated that desloratadine plus montelukast
improved the symptoms and quality of life significantly
more than desloratadine alone in chronic urticaria.3
Consequently, the previous studies have supported the
synergistic effect of the combination of montelukast and
desloratadine on allergic diseases.

TABLE III.
Comparisons of Marginal Area Under the Curve Values of the Test Groups According to Time Intervals.
Time
02 Hours
Treatment

Mean

MD (marginal)
M (marginal)

22
23

488.89
365.62

t Test results

23 Hours
StdDev

279.39
194.49

t 5 1.72, P 5.0919, >.05

Mean

22
22

449.51
362.48

34 Hours
StdDev

198.72
119.32

23
23

t 5 1.76, P 5.0855, >.05

Mean

329.54
334.72

StdDev

109.88
93.90

t 5 20.17, P 5.8644, >.05

M 5 10 mg montelukast; MD 5 10 mg montelukast together with 5 mg desloratadine; StdDev 5 standard deviation.

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Cingi et al.: Effect of Desloratadine on Montelukast Levels

TABLE IV.
Comparisons of Cumulative Area Under the Curve Values of the Test Groups According to Time Intervals.
Time
02 Hours
Treatment

MD (cumulative)

22

M (cumulative)
t Test results

23

Mean

03 Hours
N

Mean

279.39

22

938.40

365.62
194.49
t 5 1.72, P 5.0919, >0.05

22

488.89

StdDev

04 Hours
StdDev

Mean

470.99

22

1270.81

731.64
304.75
t 5 1.73, P 5.0912, >.05

22

StdDev

554.97

1068.13
319.03
t 5 1.49, P 5.1450, >.05

M 5 10 mg montelukast; MD 5 10 mg montelukast together with 5 mg desloratadine; StdDev 5 standard deviation.

Nevertheless, when a particular drug is administered with another drug or with food, drug-drug interactions may occur and affect the bioavailability of the
ingredients. Although the scientific literature has some
published reports on the efficacy of combination therapy,
there are no reported data regarding their pharmacokinetic interactions. We designed this study to investigate
the effect of desloratadine on the bioavailability of
montelukast.
Montelukast blocks cysteinyl-leukotriene receptors
that are involved in both early- and late-phase allergic
responses.17 Cysteinyl-leukotrienes mediate several different effects on airway cells and structures. They have
chemoattractive properties for many inflammatory cells
(mainly eosinophils), and effect vascular permeability,
mucous secretions, and sensory nerve activation.
Generally, montelukast is accepted as a safe drug.
In many studies investigating the effectiveness of montelukast in allergic disorders, no clinically significant
changes in vital signs, laboratory parameters, or electrocardiographic (ECG) criteria occurred. The most commonly reported treatment-related adverse event was
headache (3.5% with montelukast).3,9 Montelukast is
one of the drugs that is metabolized by the cytochrome P
450 enzyme system, and CYP3A4 and CYP2C8 are the
major P450 enzymes involved in the turnover of montelukast. Montelukast is metabolized in the liver in great
amounts. In vitro studies have shown that microsomal
enzymes like CYP3A4 and 2C9 play a major role in montelukast metabolism. Montelukast undergoes oxidative
metabolism, with the majority of the metabolites
excreted in bile and <1% eliminated in the urine.18
Antihistamines act as inverse agonists at the H1 receptor to downregulate both basal and histamine-stimulated nuclear factor jB, which in turn promotes the
expression of inflammatory cytokines.19 Desloratadine is
a potent and selective antagonist at the human H1receptor and is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently
glucuronidated. The enzymes responsible for the metabolism have not been identified.6 The absorption of desloratadine in the presence and absence of food was studied
by Gupta et al., who found no clinically relevant interference with the pharmacology of desloratadine by
foods.20 The studies about the interaction between
desloratadine and compounds known to influence
CYP3A4 showed no significant impact on the function of
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3A4 isoenzyme.21,22 Although minor elevations in desloratadine serum concentrations and its metabolite
(3-hydroxydesloratadine) were observed when desloratadine is coadministered with erythromycin, azithromycin,
ketoconazole, cimetidine, and fluoxetine, there was no
impact on ECG parameters, and these interactions were
not considered clinically significant.2124
Generally, desloratadine has minimal side effects.
There are no clinically relevant cardiovascular effects.
Most common side effects are fatigue, dry mouth, headache, and gastrointestinal disturbances.24
The current study was planned to investigate the
potential interaction between montelukast and desloratadine. There are no reports of significant adverse reactions of montelukast in combination with antihistamines
except for a case report. Tedeschi reported a patient
with chronic urticaria whose condition was exacerbated
by H1-antihistamines, montelukast, and controlled by
immunosuppressive drugs including cyclosporine and
azathioprine. It was suggested that the reason for this
side effect may be the shift of the H1 histamine receptor
and the leukotriene receptor to the active formation
instead of inactive state.25
Mcleod et al. evaluated the nasal decongestant
effects of loratadine and montelukast alone and in combination in an animal model of nasal congestion. They
found that the magnitude of decongestant activity with
combination therapy of montelukast with loratadine was
greater than the effects of these drugs given separately.
They also demonstrated that the plasma concentrations
of montelukast, loratadine, and desloratadine were not
different when montelukast or loratadine were administered individually or in combination.17
The studies emphasizing the efficacy of combination
therapy supported that this greater efficacy could be
because although desloratadine interferes with cystenilleukotriene production, montelukast interferes with the
LTD4 receptors that produce additive or potentially synergistic efficacy.
This study showed no altered montelukast metabolism with desloratadine. Our results indicated that both
marginal and cumulative AUC values were not altered
in volunteers taking montelukast with desloratadine as
compared to with water at all different time intervals.
This connotes that desloratadine does not alter montelukast peak concentrations and AUC values. Consequently,
the combination of desloratadine and montelukast is
Cingi et al.: Effect of Desloratadine on Montelukast Levels

proven to be more effective as compared to monotherapy,

and application of fixed molecules seems safe and more
practical in the management of allergic disorders.

CONCLUSION
Desloratadine and montelukast are becoming popular drugs in the treatment of allergic disorders and are
accepted as safe drugs. Although there are many clinical
studies about the efficacy of combination therapy with
montelukast and desloratadine, the data regarding pharmacokinetic interactions with montelukast and desloratadine are scarce. This study showed that desloratadine
does not alter montelukast serum levels. The results of
this study have shown that the combination of desloratadine and montelukast as a fixed combination drug can
be used safely.

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Cingi et al.: Effect of Desloratadine on Montelukast Levels