Original Article Section Pharmacology

Comparison of safety, effectiveness and cost- 1Intern;2Assistant Professor; 3Professor and Head, effectiveness of Combination of Levocetirizine Department of Otorhinolaryngology, Government Medical College and Fexofenadine with Montelukast in Allergic and Rajindra Hospital, Patiala, Punjab Rhinitis and its effect on Quality of Life 4Professor and Head, Department of Pharmacology, Teerthankar Mahaveer Medical 1 2 1 1 College and Research Centre, Suchita , Dinesh Kumar Sharma , Gurjot Kaur , Arshdeep Singh , Teerthankar Mahavir University, Sanjeev Bhagat3, Prithpal Singh Matreja4* Delhi Road, Moradabad, Uttar Pradesh, India-244001

ABSTRACT

Background: Allergic Rhinitis (AR) manifest with rhinorrhea, nasal congestion, obstruction, and th Available Online: 30 June 2020 pruritus. The management of allergic rhinitis consists of: environmental control measures and allergen avoidance, pharmacological management, and immunotherapy. Combination of levocetirizine and fexofenadine with montelukast have shown a significant improvement in patients with allergic rhinitis, so we designed this study to assess the comparison of effectiveness and safety of montelukast- levocetirizine and montelukast-fexofenadine in allergic rhinitis. Received : 15.05.20 Accepted : 10.06.20 Methods: This open-label, randomized, prospective, and parallel group study was conducted at a

tertiary care hospital in a period of two months. All patient clinically diagnosed with allergic rhinitis in *Corresponding Author the age group of 18 to 60 years were included in the study. The patients were divided into two groups by random number table and patients in Group A received a combination of levocetirizine and Montelukast whereas patients n Group B received a combination of fexofenadine with Montelukast Dr. Prithpal S Matreja,

once daily for 20 days. The patients were called for two follow-ups first after 10 days of onset of Professor, Department of Pharmacology, Teerthankar Mahavir therapy and second visit after 20 days of treatment and the patients were assessed clinically. Medical College and Research Centre, Results: The baseline characteristic of patients in both groups were comparable at baseline. There Teerthankar Mahavir University, Delhi was a statistically significant decrease in total nasal symptom scores and total ophthalmic symptom Road, Moradabad, Uttar Pradesh, India- score in both groups at 10 day and 20 days, though there was no statistically significant difference in 244001 both groups. There was a statistically significant decrease in quality of life scores in both groups at Email: [email protected]

10 days and 20 days, though at 20 days patients on levocetirizine had better response. There was a Copyright: © the author(s. IABCR is an official statistically significant higher cost of therapy in Group B. publication of Ibn Sina Academy of Medieval Medicine & Sciences, registered in 2001 under

Conclusions: Both Levocetirizine and Fexofenadine in combination with Montelukast showed Indian Trusts Act, 1882. significant improvement as compared to baseline in terms of TNSS and TOSS. Patients in Levocetirizine group had a comparatively better quality of life, lesser side effects and low cost of This is an open access article distributed in accordance with the therapy. Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original Keywords: allergic rhinitis, fexofenadine, levocetirizine, safety, effectiveness. work is properly cited and the use is non- commercial

INTRODUCTION______Allergic Rhinitis (AR) is over reactivity of the immune system (SAR) are fairly easy to identify as they have a rapid and to airborne allergens namely pollens, animal dander, dust reproducible onset and offset in association with pollen mites, cockroaches, and moulds.1 AR is estimated to affect exposure. SAR can also result due to hyper- responsiveness 20 to 40 million people in the United States alone with an to allergens like cigarette smoke, once pollen season is over. increase in incidence with approximately 20% of cases are While perennial AR is more difficult to detect due to overlap of Seasonal Allergic Rhinitis (SAR); 40% of cases are with sinusitis, respiratory infections, and vasomotor rhinitis. perennial rhinitis; and 40% of cases are mixed type.2 About Perennial AR is defined as occurring during approximately 9 20-30% of population of India suffers from at least one months of the year.2 allergic disease.3 The patients may have a pale nasal mucosa with swollen, AR manifest with rhinorrhea, nasal congestion, obstruction, oedematous turbinate’s and clear nasal secretions 4 and pruritus. The symptoms of Seasonal allergic rhinitis How to cite this article: Suchita, Sharma DK, Kaur G, Singh A, Bhagat S, Matreja Access this article online PS. Comparison of safety, effectiveness and cost-effectiveness of Combination of Website: Quick Response code Levocetirizine and Fexofenadine with Montelukast in Allergic Rhinitis and its effect www.iabcr.org on Quality of Life. Int Arch BioMed Clin Res. 2020;6(2):PH5–PH8.

Source of Support: Nil, Conflict of Interest: None DOI: 10.21276/iabcr.2020.6.2.07

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(rhinorrhea). A thorough history and physical examination is assess the comparison of effectiveness and safety of often sufficient to make a preliminary diagnosis and initiate montelukast-levocetirizine and montelukast-fexofenadine as treatment. Role of diagnostic nasal endoscopy and treatment for allergic rhinitis in Indian population. radiological investigation is important for assessing ventilation of sinuses, any polyp formation obstructing the METHODS______osteomeatal complex and thus helping in making a decision for appropriate management of the case. Specific This open-label, randomized, prospective, and immunoglobulin E (IgE) antibodies can be demonstrated by parallel group study was either skin testing or in vitro radioallergosorbent (RAST) conducted in Department of Otorhinolaryngology at a tertiary testing to which a person has become sensitized may be care hospital in a period of two months between April to necessary in patients with difficult to treat allergic rhinitis.5 August 2018 after approval of Institutional Ethics Committee. AR often adversely affects the quality of life of patients, in A total of 100 patients suffering from allergic rhinitis were India it is often regarded as trivial disease and patients fail to enrolled in the study after giving written informed consent. attribute the ill health to symptoms of allergic rhinitis.6 Allergic All patient clinically diagnosed with allergic rhinitis in the age rhinitis tends to have a negative impact on quality of life as it group of 18 to 60 years were included in the study. Any can affect the physical, psychological and social aspects and patients previously treated with steroids during the last 30 impact work productivity. A study done on thirty-four Indian days, previously treated with antihistaminics and nasal patients showed that allergic rhinitis adversely affected decongestants for the last 7 days, with nasal structural behavior, work performance and lifestyle of patients. Further abnormality that significantly interferes with nasal airflow, allergic rhinitis also caused hindrance at work due to history of upper respiratory tract infection in the last 14 days repeated blowing of nose and need to rub eyes and nose were excluded from the study. Pregnant and lactating frequently.7 females were also excluded from the study. The management of allergic rhinitis consists of: environmental control measures and allergen avoidance, Procedure: pharmacological management, and immunotherapy. A total of 100 patients fulfilling the inclusion and exclusion Environmental control measures and allergen avoidance criteria were enrolled in the study. All the patients enrolled in involve both the avoidance of known allergens (substances the study underwent a thorough history and clinical to which the patient has IgE-mediated hypersensitivity) and examination. The patients were divided into two groups by avoidance of nonspecific, or irritant, triggers.7 random number table and patients in Group A received a Pharmacologic options for the treatment of allergic rhinitis combination of levocetirizine and Montelukast once daily for include intranasal corticosteroids, oral and topical 20 days, whereas patients in Group B received a antihistamines, decongestants, intranasal cromolyn, combination of fexofenadine with Montelukast once daily for intranasal anticholinergics, and leukotriene receptor 20 days. The patients were called for two follow-ups first after antagonists.4 Montelukast serves a role in helping reduce 10 days of onset of therapy and second visit after 20 days of symptoms of allergic rhinitis that are not controlled with treatment and the patients were assessed clinically. antihistamines alone by competitively and reversibly inhibits cysteinyl leukotrienes (CysLTs), specifically Outcome assessment: Daily Rhinitis Card: The patients leukotrienes D4 (LTD4), theoretically decreasing congestion were given daily diary card for the symptoms of allergic and stuffiness associated with allergic rhinitis. Montelukast, rhinitis and conjunctivitis which were assessed on a 4-point as monotherapy has been effective in improving daytime and scale (0 to 3) for both daytime (diary card completed in the nighttime symptoms in patients with allergic rhinitis and in evening) and nighttime (diary card completed on awakening). comparison, to antihistamines appear to have significantly The daytime nasal (rhinorrhea, sneezing, itching and better improvement in nighttime symptoms.5 congestion), nighttime nasal (nasal congestion upon Levocetirizine is the enantiomer of cetirizine and is a potent awakening, difficulty going to sleep and night time histamine H-1 receptor antagonist. The antagonism of awakening) and eye (tearing, itching, redness and puffing) histamine is responsible for the inhibition of the increase in symptoms and their rating were described to every patient by vascular permeability and vasodilation. Inhibition of edema the same technician. The ratings of the symptom were: 0 = formation and mucus secretion represent the result of not noticeable, 1 = mild symptoms, 2 = moderate symptoms, levocetirizine effects on respiratory mucosa. These 3 = severe symptoms. The rating was performed by the pharmacological actions underlie the therapeutic effect of patients themselves to increase the creditability of the levocetirizine in rhinitis.8 subjective scale. The mean change of the total day time Fexofenadine is another H-1 receptor antagonist with both nasal symptom scores (PDTS), defined as the average score non-sedating and produces no adverse cardiac effects even of four daytime nasal symptoms. The mean changes of the at supratherapeutic doses and has demonstrated various nighttime nasal symptom scores (PNTS), daytime eye antiallergic activities both in vivo and in vitro9. symptom scores (PES), composite symptom scores (PCS) th th 10 Combination of levocetirizine-montelukast and fexofenadine- were recorded at baseline, 10 day and 20 day . montelukast both have shown a significant improvement in To improvement in patients’ quality of life (QOL) was patients with allergic rhinitis, a combination therapy of assessed as mean change in Rhinoconjunctivitis Quality of montelukast with antihistaminics could provide enhancing life questionnaire (RQLQ) scoring, from baseline to day 10 and complementary effects, reducing both the daytime and and day 20 of the study period. RQLQ is a disease specific nighttime symptoms effectively. 5 There are limited studies QOL questionnaire that has been developed for the available for the comparison of combination therapy of measurement of physical, emotional, and social problems in montelukast-levocetirizine and montelukast-fexofenadine on adults with allergic diseases. It consists of 28 questions in 7 the Indian population. Hence, this study was designed to domains. The questionnaire has 3 ‘patient-specific’ questions in the activity domain which allow patients to select 3 International Archives of BioMedical And Clinical Research Vol 6 | Issue 2 | April – June 2020 PH6 www.iabcr.org Suchita, et al. Levocetirizine and Montelukast in allergic rhinitis Section: Pharmacology

activities in which they are most limited by their AR. Patients responded to each question on a 7-point scale (0=not Total ophthalmic symptom score: The total ophthalmic impaired at all to 6=severely impaired). The overall RQLQ symptom scores decreased at 10 day and 20 day after the score is the mean of all 28 responses and the individual onset of treatment in both groups (Table 3). There was a domain scores are the means of the items in those statistically significant decrease in total ophthalmic symptom domains.11 scores in both groups at 20 days, though there was no statistically significant difference in both groups at 10 day and Statistical Analysis: 20 day. Through Patients on levocetirizine had better The data was tabulated as mean ± standard deviation response, but this was not statistically significant.

(Mean±SD). Results were analyzed using non- parametric tests (ChiSquareTest), parametric tests (two tail Table 3. Total Ophthalmic Symptom Score in both groups ed student t-test) and correlation (Mean±SD). (Pearson correlation coefficients) analysis. A p<0.05 was Total Ophthalmic Symptom Score Group A (n=39) Group B (n=41) considered statistically significant. Day 0 6.03±1.37 6.42±1.79 RESULTS______Day 10 3.12±1.04 3.29±1.21 A total of 100 patients suffering from allergic rhinitis were Day 20 1.19±0.61* 1.52±0.53* enrolled in the study and divided into two groups, Group A and Group B as per random number table. The patients were *p<0.05 as compared to baseline in both groups using student ‘t’ test either given levocetirizine or fexofenadine with Montelukast and were followed up at 10 day and 20 day. Out of 100 Quality of Life scores: The quality of life scores were patients suffering from allergic rhinitis only 80 patients determined using Rhinoconjunctivitis Quality of Life completed the entire study duration and hence were enrolled Questionnaire (RQLQ) which decreased at 10 day and 20 in the study. 39 patients were Group A completed the entire day after the onset of treatment in both groups (Table 4). study duration, where 5 patients did not report after 10 days There was a statistically significant decrease in quality of life and another 6 patients did not report after 20 days, so they scores in both groups at 10 days and 20 days, there was no were excluded from study. Whereas, in Group B 41 patients statistically significant difference in both groups at 20 day completed the study duration with 5 patients not reporting with patients on levocetirizine having better response.

after 10 days and another 4 patients not reporting at 20 days. The baseline characteristic of patients in both groups are Table 4. RQLQ Score in both groups (Mean±SD). shown in Table 1, both groups were comparable at baseline. Total Ophthalmic Symptom Score Group A (n=39) Group B (n=41)

Day 0 126±18.8 128.4±18.2 Table 1: Baseline Characteristic of patients in both groups Day 10 79.12±11.04* 83.29±12.21* Demographic parameters Group A (n=39) Group B (n=41) p value Day 20 31.19±10.61*# 61.52±10.53* Age (in years) (Mean±SD) 35.49±11.03 36.49±12.49 >0.05* *p<0.05 as compared to baseline in both groups using student ‘t’ test #p<0.05 as compared to the other group using student ‘t’ test Sex (M:F) 21:18 24:17 >0.05#

Total Nasal Symptom 9.46±1.30 9.51±1.29 >0.05* Cost of therapy: the cost therapy of both groups was also Score (Mean±SD) Total Ophthalmic Symptom calculated in INR, the cost of therapy for Group A was Rs. 6.03±1.37 6.42±179 >0.05* Score (Mean±SD) 192.80±123.33 vs. Rs. 240.50±162.80 for Group B. There Quality of Life (RQLQ) 126±18.8 128.4±18.2 >0.05* was a statistically significant higher cost of therapy in Group (Mean±SD) B. * Using Student ‘t’ Test Safety Analysis: The safety analysis was done for the # Using Chi-Square Test patients using spontaneously reported adverse events. Both groups tolerated the therapy well and there was no withdrawal from therapy due to associated adverse events. Total nasal symptom score: The total nasal symptom The number of adverse events reported in Group A were 5 scores decreased at 10 day and 20 day after the onset of as compared to Group B where 7 adverse events were treatment in both groups (Table 2). There was a statistically reported. The patients reported of dizziness and lethargy with significant decrease in total nasal symptom scores in both one patient in group B also reporting of drowsiness. groups at 10 day and 20 days, though there was no statistically significant difference in both groups at 10 day and DISCUSSION______20 day. Through Patients on levocetirizine had better Allergic rhinitis (AR) is induced by an allergen associated response, but this was not statistically significant. with an inflammatory disease of the nasal mucosa. AR with a prevalence between 9-42% among general population is a Table 2: Total Nasal Symptom Score in both groups (Mean±SD). global health problem and is the commonest form of allergy Total Nasal Symptom Score Group A (n=39) Group B (n=41) which has more than 50% of all allergies in clinical problems Day 0 9.46±1.30 9.51±1.29 in India.12-15 The most common therapeutic intervention for Day 10 5.43±1.34* 5.63±1.46* allergic rhinitis is medicines which form significant proportion Day 20 2.12±0.67* 2.52±0.88* of total health care cost.12,16 The aim of our study was to *p<0.05 as compared to baseline in both groups using student ‘t’ test compare the safety and effectiveness of levocetirizine and fexofenadine along with Montelukast in patients suffering

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from allergic rhinitis. The study also evaluated the cost- CONCLUSION______effectiveness between two therapy as well as any difference To conclude our study showed that both Levocetirizine and in quality of life in these two group of patients. The result of Fexofenadine in combination with Montelukast should our study showed that both the drugs provided statistically significant improvement as compared to baseline in terms of significant improvement in total nasal symptom score, total TNSS and TOSS. Patients in Levocetirizine group had a ophthalmic symptom score as well as quality of life as comparatively better quality of life, lesser side effects and low compared to baseline values. There was significant cost of therapy. So levocetirizine was better as compared to improvement at 10 days and 20 days of therapy. The result fexofenadine. of our study also showed that as compared to fexofenadine, levocetirizine was statistically better at 20 days in terms of quality of life, cost effectiveness and reduced number of side REFERENCES______effects. 1. Immunotherapy for environmental allergies. Available at url: A study done by Snidvongs K, et.al. Comparing the https://web.archive.org/web/20150617190743/http://www.niaid.nih.gov/t opics/environmental-allergies/Pages/immunotherapy.aspx (Last effectiveness of fexofenadine and levocetirizine in Thailand Accessed 22nd April, 2020) 2. Skoner DP. Allergic rhinitis: Definition, epidemiology, pathophysiology, demonstrated that there were no differences in effectiveness detection, and diagnosis. J Allergy Clin Immunol 2001;108:S2-8. between these two drugs in patients with persistent allergic 3. Prasad R, Kumar R. Allergy situation in India: What is being done? Indian J Chest Dis Allied Sci. 2013;55:7-8. rhinitis. The results of our study are different from this study 4. Sur DK, Scandale S. Treatment of Allergic Rhinitis. Am Fam Physician as our study demonstrated that levocetirizine was 2010;81(12):1440-6. 5. Gupta V, Matreja PS. Efficacy of montelukast and levocetirizine as comparatively better as compared to fexofenadine at the end treatment for allergic rhinitis. J Allergy Ther 2010;1:103. of 20 days of therapy.17 6. World allergic association (WAO) white book on allergy. Eds Pawankar R, Canonica GW, Holgate ST, Lockey RF. Available at url: Another study done by Pentewar GS, et.al. in Maharashtra https://www.worldallergy.org/UserFiles/file/WAO-White-Book-on- Allergy_web.pdf (Last Accessed on 22nd April, 2020) where they compared the efficacy and pharmacoeconomic 7. Sheikh J. Allergic rhinitis treatment and management. Available at url: assessment in allergic rhinitis demonstrated that https://emedicine.medscape.com/article/134825-treatment#d9 (Last Accessed 22nd April, 2020) levocetirizine as compared to fexofenadine controlled the 8. Nettis E, Calogiuri GF, Di Leo E, Cardinale F, Macchia L, Ferrannini A, symptoms of allergic rhinitis better and was also a better et.al. Once daily levocetirizine for the treatment of allergic rhinitis and chronic idiopathic urticaria. J Asthma Allergy 2009;2:17-23. choice due to its cost effectiveness. The results of our study 9. Meeves SG, Appajosyula S. Efficacy and safety profile of fexofenadine HCl: A unique therapeutic option in H1-receptor antagonist treatment. J are quite similar to this study as our study as demonstrated Allergy Clin Immunol 2003;112(4):S69-77. that levocetirizine was better as compared to fexofenadine in 10. Draft Guidance for Industry on Allergic Rhinitis: Clinical Development Programs for Drug Products. US Dept. of Health and Human Services, controlling the symptoms and was cost effective. Our study Food and Drug Administration; April 2000. is different from this study as they also compared loratadine 11. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin Exp Allergy1991; along with the other drugs in allergic rhinitis.12 21: 77-83. 12. Pentewar GS, Wagh RJ, Chincholkar AS. Pharmacoeconomic One more study done by Nayak P, et.al. Comparing the assessment and comparing efficacy between cetirizine, levocetirizine, efficacy and safety of combination of levocetirizine and loratadine and fexofenadine in allergic rhinitis patients. Int J Basic Clin Pharmacol 2017;6:2684-9. fexofenadine with Montelukast in allergic rhinitis, the results 13. Shah A, Pawankar R. Allergic rhinitis and co-morbid asthma: perspective of study demonstrated that fexofenadine showed better from India-ARIA Asia-Pacific Workshop report. Asian Pacific journal of allergy and immunology. 2009 Mar 1;27(1):71. improvement in symptoms of AR and a better global 14. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic rhinitis and its impact on asthma (ARIA). Allergy. 2008 Apr impression as compared to levocetirizine. The results of 1;63(s86):8-160. study are quite different from this study as our study 15. Bauchau V, Durham SR. Epidemiological characterization of the intermittent and persistent types of allergic rhinitis. Allergy. 2005 Mar demonstrated that levocetirizine as better as compared to 1;60(3):350-3. fexofenadine.18 16. Scarupa MD, Michael A. Kaliner Inflammatory Nature of Allergic Rhinitis: Pathophysiology. Medscape Allergy & Immunology. 2006;6(1). There are certain limitations to our study, firstly our study was 17. Snidvongs K, Rotjanasiriphong S, Phannaso C, Chusakal S, Auemjaturapat S. Fexofenadine and levocetirizine have equivalent an open label study as this was not a funded study so we effectiveness for persistent allergic rhinitis. Asian Biomedicine could not conduct a double-blind study. Secondly, the 2015;9(3):387-95. 18. Nayak P, Srinivas CV, Jagade MV, Chandrasekharan S. A randomized, sample size of our study was small, India being a country of open label, prospective, comparative, multicentric study to evaluate the varying seasons and allergic rhinitis manifest in a particular efficacy and safety of montelukast and fexofenadine fixed-dose combination vs. montelukast and levocetirizine fixed-dose combination season only and this study was a short-term study, so large in allergic rhinitis. Indian Journal of Clinical Practice 2013;24(3):241-6. number of patients could not be enrolled in the study.

Thirdly, the follow-up was for limited duration, along term

follow-up could give different results but, as most of patients in this part of sub-continent do not tend to take medication

after symptoms regress.

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