Physician's choice of antihistaminic-leukotriene antagonist combination: An evidence-based comparison of montelukast-fexofenadine versus montelukast- levocetirizine

New Delhi: The pandemic restrictions are unlocking amid the looming fear of a 3rd COVID wave at this year's end. Physicians need to be aware and well-informed about the best drug therapy available to tackle allergic conditions like rhinitis, etc. as the so-called "allergy season" approaches.

An evidence-based choice of anti-allergic drugs is essential for two reasons- firstly there is a strong overlap between the manifestations of seasonal rhinitis and early presentation of COVID-19. (1) Secondly, recurrent bouts of allergic respiratory diseases can increase an individual's predisposition to catching COVID-19 infection and such infections tend to be more severe in these patients. (2) This calls for better awareness and preparation by the health sector about the best choice of drugs available to manage allergic conditions at this stage.

Today, there are multiple antihistaminic and leukotriene drugs available in various combinations. In this review, we discuss the latest comparative evidence for Montelukast-fexofenadine and Montelukast-Levocetirizine combinations and provide a scientific rationale as to which combination confers better response for patients.

1. Fexofenadine-Montelukast- vs levocetrizine-montelukast: Which one to chose for patients?

Direct comparison:

Almost 10%–25% of the population worldwide is affected by allergic rhinitis (AR). (3) Oral/intranasal H1-antihistamine, decongestants, leukotriene receptor antagonists, and intranasal corticosteroids are the pillars in the management of AR. The combination therapy of montelukast with antihistamine provides enhancing and complementary effects, thereby reducing the symptoms effectively. (4)

Mahatme et al have compared the efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine combination in patients of AR. In their prospective, randomized, double-blind, parallel, active-controlled, comparative 4-week trial they recruited patients with total nasal symptom score (TNSS) of 5 or higher and found that the mean change of TNSS, i.e., 9.46 was significant (P < 0.05) in the montelukast-fexofenadine group. The cost-effectiveness ratio was also favorable for the montelukast-fexofenadine combination. (5)

Similar superiority in improving TNSS by montelukast- fexofenadine combination has also been reported by Kumari et al (6) in school going children and by Nayak et al.(7)

It is also noteworthy that bioequivalence data is only available for montelukast-fexofenadine combination and not for montelukast-levocetirizine. This suggests that the former fixed-dose combination is bioequivalent to the individual components of the same strength administered concurrently. (8)

Indirect comparison:

Evidence is also available regarding the comparison of individual antihistaminic components of these combinations. Through a meta-analysis of 51 studies Huang et al concluded that when compared to contemporary first and second-generation antihistaminics (eg. levocetirizine), fexofenadine produced significantly lower adverse events frequency, significantly lower sedative effects frequency, and significantly less chance of all cognitive/psychomotor function. (9) A recent meta-analysis showed that levocetirizine had mild sedative effects although it is a new generation antihistamine. (10)

2. Understanding the safety profile of Fexofenadine-Montelukas

This combination provides a broad-spectrum safety profile and is approved for use by young and geriatric patients alike. It can also be safely used in children above 6 months of age and pregnant women. No association was noted between fexofenadine use during pregnancy and risk of major birth defects, spontaneous abortion, preterm birth, small size for gestational age, or stillbirth. (12)

While comparing the antihistaminic profile of various drugs by Wheal suppression test, Dhanya et al found that fexofenadine has the earliest onset of action and shows a statistically significant suppression of wheal size compared to levocetirizine and desloratadine. (13)

While evaluating the Comparative efficacy of fexofenadine and levocetirizine in chronic idiopathic urticaria, Godse et al have shown that a decrease in urticaria activity scores was 80.5% in the fexofenadine treatment group and 61.8% in the levocetirizine treatment group. (14)

3. What about the sedation profile?

Mahatme et al also highlighted that sedation is also less likely with the fexofenadine-containing combination (9.6% vs 23.2 in levocetirizine-containing combination). (5) In fact, fexofenadine has been safely recommended for use in individuals involved in skilled activities, such as pilots, without the concern of sedation above recommended therapeutic doses. (15)

Interaction with COVID-19:

Virulence of the novel coronavirus is due to the presence of the main protease (Mpro) which is responsible for virus replication. (16) Through molecular docking technique, Singh et al have found fexofenadine acetate is one of the best therapeutic drugs with an inhibitory effect on COVID-19 by its binding to Mpro. (17) Farag et al while screening around 2000 FDA-approved drugs against COVID-19 virus Mpro terminal site found montelukast and fexofenadine to be the top hits among antihistaminics and antiasthma drugs. (16) Hence, the use of this combination can potentially promote rapid recovery from COVID besides effective symptom control

Take home message for the physician

Physicians face the dilemma of prescribing the best drug combination for allergic rhinitis and other allergic disorders since there are so many options available. Evidence-based decision-making is thus warranted. Additionally, in this pandemic era, all clinical decisions are influenced by how well these drug combinations interact with the COVID-19 virus. Summarising the evidence available above, it can be inferred that the fexofenadine-montelukast combination offers good safety and efficacy profile along with a better action against coronavirus that makes it one of the most effective drugs in a physician's toolkit.

References:

1. CDC COVID-19 Response Team Coronavirus disease 2019 in children - United States, february 12-april 2, 2020. MMWR Morb Mortal Wkly Rep. 2020 Apr 10;69(14):422–426.

2. Yang JM, Koh HY, Moon SY, et al. Allergic disorders and susceptibility to and severity of COVID-19: A nationwide cohort study. J Allergy Clin Immunol. 2020;146(4):790-798. doi:10.1016/j.jaci.2020.08.008

3. Fang SY, Perng DW, Lee JY, Lin DY, Huangs CY. An open-label, multicentre study of levocetirizine for the treatment of allergic rhinitis and urticaria in Taiwanese patients. Chin J Physiol. 2010;53:199–207.

4. Gupta V, Matreja PS. Efficacy of montelukast and levocetirizine as treatment for allergic rhinitis. J Allergy Ther. 2010;1:103

5. Mahatme, M. S., Dakhale, G. N., Tadke, K., Hiware, S. K., Dudhgaonkar, S. D., & Wankhede, S. (2016). Comparison of efficacy, safety, and cost-effectiveness of montelukast-levocetirizine and montelukast-fexofenadine in patients of allergic rhinitis: A randomized, double-blind clinical trial. Indian journal of pharmacology, 48(6), 649–653. https://doi.org/10.4103/0253-7613.194854

6. Abha Kumari, Sandeep Kumar. A Study of Levocetirizine and Monteleukast versus Fexofenidine and Monteleukast in School Going Children with Allergic Rhinitis. Int J Med Res Prof. 2018 Jan; 4(1):268-71

7. Prateek Nayak et al. Randomised, open label, prospective, comparative, Multicentric study to evaluate the efficacy and safety of Montelukast and fexofenadinefixed dose combination vs Montelukast and levocetrizine fixed dose combination in Allergic rhinitis. Indian Journal of Clinical Practice, August 2013.

8. Walekar A, Chodankar D, Naqvi M et al, Assessment of Bioequivalence of Fexofenadine and Montelukast Fixed Dose Combination Tablet Versus Separate Formulations of the Individual Components at the Same Dose Levels. Indian J Pharm Sci 2016; 78(5): 651-656

9. Huang, Cz., Jiang, Zh., Wang, J. et al. Antihistamine effects and safety of fexofenadine: a systematic review and Meta-analysis of randomized controlled trials. BMC PharmacolToxicol 20, 72 (2019)

10. Snidvongs K, Seresirikachorn K, Khattiyawittayakun L, Chitsuthipakorn W. Sedative effects of Levocetirizine: a systematic review and Meta-analysis of randomized controlled studies. Drugs. 2017;77(2):175–86.

11. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2000 May;84(5):517-22.

12. Andersson NW, Torp-Pedersen C, Andersen JT. Association Between Fexofenadine Use During Pregnancy and Fetal Outcomes. JAMA Pediatr. 2020;174(8):e201316.

13. Dhanya NB, Thasleem Z, Rai R, Srinivas CR. Comparative efficacy of levocetirizine, desloratidine and fexofenadine by histamine wheal suppression test. Indian J Dermatol VenereolLeprol. 2008 Jul-Aug;74(4):361-3.

14. Godse K V, Jain A, Pharande P. Comparative efficacy of fexofenadine and levocetirizine in chronic idiopathic urticaria. Indian J Dermatol 2007;52:212-3

15. Mohler SR, Nicholson A, Harvey P, Miura Y, Meeves SG. The use of antihistamines in safety-critical jobs: a meeting report. Curr Med Res Opin. 2002;18(6):332-7.

16. Farag A, Wang P, Ahmed M, Sadek H. Identification of FDA Approved Drugs Targeting COVID-19 Virus by Structure-Based Drug Repositioning. ChemRxiv. Cambridge: Cambridge Open Engage; 2020

17. Singh, Sweta, and Hector Florez. "Coronavirus disease 2019 drug discovery through molecular docking." F1000Research vol. 9 502. 3 Jun. 2020, doi:10.12688/f1000research.24218.1