Icet 13 I 8 P 314

Indian Medical Gazette
314
AUGUST 2013
Clinical Study
Efficacy and Safety of Montelukast Plus Fexofenadine Fixed

Dose Combination in Allergic Rhinitis :
Results of Post-Marketing Study In India
Manoj Naik, Chief Manager,
Prashant Khandeparkar, Chief Manager,
Ashwini Nayak, Medical Advisor,
Qayum Mukaddam, Director
Medical Services Division, Abbott Healthcare Private Limited, Mumbai.
Abstract
Background: Allergic rhinitis is one of the most common
conditions in clinical practice. Motelukast and second
generation antihistamine fexofenadine are routinely used in
the management of allergic rhinitis. Individually both drugs
have been found to be effective in allergic rhinitis. Fixed
dose combination of montelukast 10 mg plus fexofenadine
120 mg is available in India is also used in the treatment of
allergic rhinitis. Objective: To evaluate the efficacy and
safety of montelukast and fexofenadine fixed dose
combination in the management of patients with allergic
rhinitis. Material and methods: Post marketing observational
study was conducted in 809 patients from all over India.
All the patients were treated with montelukast 10 mg plus
fexofenadine 120 mg fixed dose combination once daily
for 14 days. The primary outcome criteria was the change
in total symptom score (Sum of total nasal symptom score
and total ocular symptom score) at the end of study
compared to baseline. The secondary outcome criteria
included change in total nasal symptom score (nasal
congestion, rhinorrhea, nasal itching, and sneezing) and
total ocular symptom score (Itching/burning eyes, tearing/
watering eyes and eye redness) at the end of study compared
to baseline and physicians and patients global assessment
for efficacy and tolerability. The patients were evaluated at
baseline, day 7 and day 14 for efficacy evaluation while the
safety parameters were assessed at screening and day 14.

Results: The fixed dose combination of fexofenadine plus
montelukast was significantly effective in reducing total
symptom score, total nasal symptom score and total ocular
symptom score (p<0.0001 for all parameters). The global
assessment of efficacy evaluation by both patient and
investigators demonstrated excellent to good efficacy in
>95% of patients. Most of the study population reported
good tolerability with the fixed drug combination. No
adverse events were reported in the study. Conclusion: The
fixed dose combination of fexofenadine plus montelukast
was found to be efficacious and well tolerated in allergic
rhinitis in Indian adult patients.
Keywords
allergic rhinitis, montelukast, fexofenadine
Introduction
Rhinitis is defined as inflammation of the nasal mucosa.
Allergic rhinitis is a symptomatic disorder of nose induced
by allergen exposure. It is characterized by symptoms like
sneezing, itching, rhinorrhea and nasal obstruction. Allergic
rhinitis is often associated with ocular symptoms1. Allergic
rhinitis affects 1030% of adults and up to 40% of children2.
It is a global health problem causing major illness and
disability. It has wide adverse impact on the patient in
Address for correspondence: Dr Manoj Naik. Chief Manager, Medical Services Division, Abbott Healthcare Private Limited, Mumbai.
E-mail: [email protected]
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AUGUST 2013
different aspects like affecting social life, school, work and

sleep1.
Histamine is one of the key mediators released
from mast cells and basophils which play a major role in
the pathophysiology of rhinitis. H1 antihistamines are
the first-line medicines for the treatment of allergic rhinoconjunctivitis3. When selecting an oral H1 antihistamine, it
is important to consider the clinical efficacy and balance it
against the risk of adverse effects of an antihistamine2. Firstgeneration H1-antihistamines have detrimental effects on
sleep and learning. Allergic diseases are also known to impair
the functions. The detrimental effects caused by first
generation H1 antihistamines may be exacerbated by the
allergic diseases4. Newer antihistamines provide similar
efficacy as first-generation antihistamines but with less
sedation5. Montelukast, a leukotriene receptor antagonist,
is effective in improving daytime and night-time symptoms
of allergic rhinitis6. A study by Cingi C et al7 demonstrated
both objective and subjective evidence with combination
of montelukast plus fexofenadine combination therapy in
allergic rhinitis. The combination of fexofenadine plus
montelukast was more effective compared to fexofenadine
alone in the control of allergic rhinitis symptoms. However,
there are no published studies with fixed dose combination
of montelukast plus fexofenadine in India.
Objective
The present study was conducted to evaluate the
efficacy and safety of montelukast and fexofenadine fixed
dose combination in the management of patients with allergic
rhinitis in Indian adult patients.
Materials and methods
A post marketing observational study was carried out
in 809 patients from 81 centres across India. Male and
female patients > 18 years of age suffering with allergic
rhinitis willing to sign written informed consent form and
comply with study procedure were enrolled in the study.
Patients having bronchial symptoms along with allergic
rhinitis were also allowed to be part of the study.
Children and adolescent (<18 years of age), pregnant,
lactating women, patients with severe asthma requiring
emergency room treatment within 1 month or hospitalization
within 3 month before the trial, patients with upper
respiratory tract infection or acute/chronic pulmonary
disorder and patients with known hypersensitivity to
montelukast or fexofenadine or other piperazine derivatives
were excluded from the study. Patient requiring other antihistamine, corticosteroids, cromolyn sodium, nedocromil
and inhaled cholinergics, oral or long acting beta-agonist,
theophylline and other leukotriene modifiers were not
enrolled in the study. Decongestants, anti-inflammatory
medicines and other rescue medicines for allergic rhinitis
were not permitted during the study
All the enrolled patients were treated with one tablet of
montelukast 10 mg plus fexofenadine 120 mg fixed dose
combination for 14 days.
Evaluation criteria
The primary outcome criteria was the change in Total
Symptom Score [(TSS: sum of total nasal symptom score
(TNSS) and total ocular symptom score (TOSS)] at the
end of study compared to baseline.
The secondary outcome criteria included change total
nasal symptom score (TNSS) (nasal congestion, rhinorrhea,
nasal itching, and sneezing) and total ocular symptom score
(TOSS) (Itching/burning eyes, tearing/watering eyes and
eye redness) at the end of study compared to baseline,
physicians and patients global assessment for efficacy
and tolerability.
Total nasal symptom score (TNSS) and total ocular
symptom score (TOSS) were graded on 4-point categoric
scale (0 = none/ no symptoms, 1 = mild symptoms, not
affecting any activities during the day/sleep at night; 2 =
moderate symptoms affecting at least one activity or
disturbing sleep; 3 = severe symptoms affecting >2 daily
activities or disturbing sleep all night or most of the night)
Safety of the fixed dose combination was evaluated by
analyzing the type, number, frequency and proportion of
patients with adverse events during the study.
The enrolled patients were followed up for assessing
signs and symptoms at baseline, day 7 and day 14 while
the safety parameters were assessed at screening and day
14. Global assessment for efficacy and tolerability by
investigator and patient was assessed at the end of study
i.e. on day 14.
Statistical analysis
Data describing quantitative measures were expressed
as mean ( SD) or the median with range while qualitative
variables were presented as counts and percentage. For
symptoms score, Friedman test was used for overall
316
comparison of baseline and follow up visits, followed by

post-hoc Wilcoxon sign rank test for individual values at
each follow up visit versus baseline values. All the statistical
tests were interpreted at 5% level of significance and p
value <0.5 was considered as significant.
AUGUST 2013
Fig. 3
Reduction in total ocular symptom score (TOSS)
Results
A total of 809 patients were enrolled from 81 centres
across the country. The mean age of the patients (n=785)
in the study was 35.87 (12.05). Male to female ratio was
6.3: 3.7.
Treatment with fixed dose combination resulted in
significant decrease in total symptom score compared to
baseline (p<0.0001) (Fig. 1).
Fig. 1
Reduction in total symptom score (TSS)
Fig. 4
Global assessment of efficacy (n=809)
Fig. 2
Reduction in total nasal symptom score (TNSS)
significant compared to baseline (p<0.0001) (Fig. 2).

The total ocular symptom score also reduced
significantly compared to baseline (p<0.0001) (Fig. 3).
More than >95% of patients reported excellent-good
efficacy as per the global assessment of efficacy evaluation
by both patient and investigators (Fig. 4).
Treatment with montelukast and fexofenadine fixed dose

combination was effective in reducing total nasal symptom
score. The reduction in total nasal symptom score was
Montelukast plus fexofenadine fixed dose combination

was effective in reducing all the individual nasal symptoms
(nasal congestion, rhinorrhea, nasal itching and sneezing)
(p<0.0001) as well as ocular symptoms. (burning/itching
of eyes, tearing/watering of eyes and redness of eyes)
(p<0.0001) (Tables 1 and 2).
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AUGUST 2013
Fig. 5
Global assessment of safety
Safety analysis
Ninety three percentage patients reported good
tolerability of the fixed dose combination of montelukast
plus fexofenadine. The global assessment done by both
investigators (n=809) and patients (n=808) reported good
to moderate tolerability by >99% of the patients (Fig. 5).
Adverse event was not reported by any patient during
the study.
Discussion
This study evaluated the efficacy and safety of
fexofenadine plus montelukast fixed dose combination in
Indian patients with allergic rhinitis. The results
demonstrated that fixed dose combination is significantly
effective in reducing all the symptoms of allergic rhinitis.
Fexofenadine is a selective, non-sedating H1 receptor
antagonist having an additional impact on the inflammatory
mediators, other than histamine. These anti-inflammatory
effects may provide benefit to some of the responses of an
acute allergic reaction8. Montelukast is a highly selective
cysteinyl leukotriene type-1 receptor antagonist of
leukotreine D4. It is an alternative for the treatment of
seasonal allergic rhinitis. The benefits of montelukast
monotherapy in seasonal allergic rhinitis are equivalent to
antihistamines. The literature review also establishes that
the addition of an antihistamine to montelukast may have
added benefits9.
Second-generation antihistamines have little effect on
congestion6. Cingi C et al7 compared monotherapy of
fexofenadine versus fexofenadine-montelukast combination
and fexofenadine-placebo combination for 21 days in 275
patients. The authors showed effectiveness of combination
treatment in terms of significantly better control of nasal
congestion both subjectively i.e. using patient diary and
318
visual analog scale evaluations, as well as objectively by

using rhinomanometry and physical examination compared
to fexofenadine alone and fexofenadine-placebo
combination. This study used montelukast and fexofenadine
separately.
AUGUST 2013
collaboration with the World Health Organization,

GA2LEN and AllerGen). Allergy. 63 (Suppl. 86): 8
160, 2008.
2.
Lehman J.M. and Blaiss M.S. Selecting the optimal

oral antihistamine for patients with allergic rhinitis.
Drugs. 66 (18): 2309-2319, 2006.
3.
Motala C. H1 Antihistamines in allergic disease.

Current Allergy & Clinical Immunology. Vol 22, No.
2: 71-74, June 2009.
4.
Church M.K., Maurer M., Simon F.E.R., BindslevJensen C., van Cauwenberge, Bousqyet J. et al.
Risk of first-generation H1-antihistamines: a GA2LEN
position paper. Allergy. DOI:10.1111/j.13989995.2009.02325.x, 2010.
5.
Banerji A., Long A.A., Camargo C.A.

Diphenhydramine versus nonsedating antihistamines
for acute allergic reactions: A literature review. Allergy
Asthma Proc. 28:418 426, 2007.
6.
Ciebiada M., Ciebiada M.G., Kmiecik T., DuBuske

L.M., Gorski P. Quality of life in patients with
persistent allergic rhinitis treated with montelukast
alone or in combination with levocetirizine or
desloratadine J Investig Allergol Clin Immunol. Vol.
18(5): 343-349, 2008.
Acknowledgement
7.
The authors of study wish to thank all the investigators

for participation in the study, Dr. Deepak Langade for
statistical analysis and Dr. Anant Patil for writing manuscript
of the study.
Cingi C., Gunhan K., Gage-White L., Unlu H.

Efficacy of leukotriene antagonists as concomitant
therapy in allergic rhinitis. The Laryngoscope. 20;9:
1718-1723, Sept 2000.
8.
Axelrod D., Bielory L. Fexofenadine hydrochloride

in the treatment of allergic disease: a review. Journal
of Asthma and Allergy. 1 1929, 2008.
9.
Lagos J.A., Marshall G.D. Montelukast in the

management of allergic rhinitis. Therapeutics and
Clinical Risk Management. 3(2) 327332, 2007.
Our study demonstrated effectiveness of fixed dose

combination of montelukast plus fexofenadine in reducing
nasal congestion. The fixed dose combination has an
advantage of reduced pill burden and in turn may improve
patient compliance.
The second-generation H1 antihistamines cause much
less sedation. They are essentially free of sedation at
recommended therapeutic doses for the treatment of allergic
disorders3.
The results of this study demonstrate that fixed dose
combination of montelukast plus fexofenadine is an
significantly effective and well tolerated option for the
treatment of allergic rhinitis.
Conclusion
The fixed dose combination of fexofenadine plus
montelukast was found to be efficacious in reducing all
nasal symptoms, ocular symptoms as well as total symptom
score of allergic rhinitis. The fixed dose combination was
well tolerated without any adverse event.
References
1.
Bousquet J., Khaltaev N., Cruz A.A., Denburg J.,

Fokkens W.J., Togias A. et al. Allergic rhinitis and
its impact on asthma (ARIA) 2008 Update (in

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Indian Medical Gazette

Efficacy and Safety of Montelukast Plus Fexofenadine Fixed

safety parameters were assessed at screening and day 14.

Indian Medical Gazette

different aspects like affecting social life, school, work and

Indian Medical Gazette

comparison of baseline and follow up visits, followed by

significant compared to baseline (p<0.0001) (Fig. 2).

Treatment with montelukast and fexofenadine fixed dose

Montelukast plus fexofenadine fixed dose combination

Indian Medical Gazette

Indian Medical Gazette

visual analog scale evaluations, as well as objectively by

collaboration with the World Health Organization,

Lehman J.M. and Blaiss M.S. Selecting the optimal

Motala C. H1 Antihistamines in allergic disease.

Banerji A., Long A.A., Camargo C.A.

Ciebiada M., Ciebiada M.G., Kmiecik T., DuBuske

The authors of study wish to thank all the investigators

Cingi C., Gunhan K., Gage-White L., Unlu H.

Axelrod D., Bielory L. Fexofenadine hydrochloride

Lagos J.A., Marshall G.D. Montelukast in the

Our study demonstrated effectiveness of fixed dose

Bousquet J., Khaltaev N., Cruz A.A., Denburg J.,

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