Efficacy and safety of ebastine 10 mg and phenylephrine 10 mg fixed-dose combination in Indian patients with allergic rhinitis: A phase 4 multicentre study

Introduction

The prevalence of allergic diseases is rising globally, affecting about 10-25% of the population and ranking among the top ten reasons for visits to primary care. ^[1] Allergic rhinitis (AR), a widespread condition, impacts 400 million individuals across the globe. ^[2] The burden of AR, characterized by nasal congestion, rhinorrhea, sneezing, postnasal drip, and nasal pruritis, is substantial, both in terms of individual suffering and societal impact. AR affects a significant percentage of adults worldwide, ranging from 18 to 40%. In India, the condition is more prevalent, affecting 20 to 30% of its population.^[1] The direct medical cost associated with AR is a staggering 3.4 billion dollars, with almost 50% of the cost attributed to prescription medication.^[3]

Histamine, which acts mainly through the H1 receptor, is a critical mediator of allergy symptoms in the treatment of AR. During the early stage of the immune response, it is released as a preformed mediator from activated mast cells.^[4] H1-antihistamines, which stabilize the receptor in its inactive form, are the preferred treatment for allergic conditions and are included in international AR management guidelines. However, as a standalone therapy, antihistamines may not comprehensively alleviate all AR symptoms. Therefore, they are often combined with other decongestants like ebastine and phenylephrine.^[5]

Ebastine, a second-generation H1-antihistamine, has been available worldwide for almost three decades. It is non-sedating and increases the threshold quantity of allergens involved in the allergic response. This can result in an anti-allergic effect that lasts for more than 48 hours.^[4], ^[6] On the other hand, phenylephrine is a decongestant and a selective α1 agonist. It induces vasoconstriction by stimulating the post-synaptic α receptors. When combined with ebastine, it is more effective in treating AR and decongestant symptoms without causing sedation compared to other antihistamine drugs.^[7] Studies have reported that the bioavailability of phenylephrine monotherapy is poor due to extensive first-pass metabolism in the gut and liver, and it can be enhanced when used in combination therapy.^[8]

The primary objective of the study was to evaluate the safety and efficacy of the fixed-dose combination (FDC) of ebastine 10 mg and phenylephrine 10 mg by comparing the Individual Symptoms Score (ISS), Total Symptom Score (TSS), and analyzing adverse event profiles reported by patients with AR, assessed by the investigator, from baseline to 6 days. The secondary objective was to assess the impact of this condition on patients' quality of life using the rhino-conjunctivitis quality of life scale (RQLS).

Materials and Methods

We conducted an open-label, non-randomized, single-group, multicentric, phase 4 clinical study and included adult patients visiting the outpatient departments of four sites across India. Ethical approval was obtained prior to the study, and it was registered with the Clinical Trial Registry of India (CTRI/2018/08/015262).

Results

Efficacy results and tabulations of individual patient data

Statistically significant and clinically meaningful improvements in ISS were noted upon comparison of the baseline symptoms with day 6 ([Table 2], [Figure 1]). The change in the mean difference in the TSS from baseline to day 6 was 3.52 ± 1.54 (95% CI: 3.27-3.78; P <0.001), signifying a statistically significant improvement (Figure 2). RQLS also exhibited a significant improvement from day 1 to day 6 (t = 24.44, P <0.001, [Figure 3]). All the adverse events were fully resolved with the administration of over-the-counter medications such as antipyretics, analgesics and/or antacids. The most frequently reported adverse event was fever, noted by 5 subjects (3.2%). Body ache was reported by three subjects (1.95%), and hyperacidity was reported by an equal number of subjects. Furthermore, one subject each reported experiencing headache, nausea, and vomiting (0.65%).

Individual Symptom Score	Mean	SD	Std. Error (Mean)	95% CI (Mean)	t - value	P-value
LB	UB
Nasal congestion	Baseline (day 1)	1.49	0.81	0.07	1.353	1.618	14.600	<0.001
Day -6	0.75	0.59	0.05	0.650	0.843
Rhinorrhoea	Baseline (day 1)	1.76	0.73	0.06	1.640	1.881	18.013	<0.001
Day -6	0.96	0.78	0.07	0.837	1.092
Nasal itching	Baseline (day 1)	1.10	0.75	0.06	0.976	1.221	9.583	<0.001
Day -6	0.51	0.58	0.05	0.419	0.610
Sneezing	Baseline (day 1)	1.82	0.69	0.06	1.711	1.937	17.273	<0.001
Day -6	0.87	0.67	0.06	0.763	0.984
Ocular pruritis	Baseline (day 1)	0.71	0.74	0.06	0.590	0.833	7.901	<0.001
Day -6	0.26	0.49	0.04	0.181	0.341

Table 2 Comparison of ISS between baseline and day 6

On physical examination, patients classically had pale nasal mucosa with swollen, oedematous turbinate’s and clear nasal secretions (rhinorrhea). Some subjects reported headache as well as ocular itching. Safety evaluation included assessment of physical examination, periodic monitoring of vital signs (heart rate, respiratory rate, blood pressure and temperature), clinical, laboratory investigations (including haematology, serum chemistry, LFT, urine-analysis) and 12-lead ECG recording. ECG reports in both the visits did not show any abnormality. The safety parameters including findings in vital signs, laboratory parameters, physical examination findings were summarized and compared.

Vital Signs	Mean	SD	Std. Error Means	95% CI Mean
LB	UB
DBP	Baseline (day 1)	78.62	5.37	0.45	77.738	79.510
	Day-6	78.99	4.76	0.40	78.207	9.778
SBP	Baseline (day 1)	119.24	7.99	0.67	117.922	120.605
	Day-6	199.61	6.03	0.51	118.615	120.605
Pulse rate	Baseline (day 1)	77.88	8.25	0.70	76.506	79.249
	Day-6	78.76	5.26	0.45	77.882	79.629
Respiratory	Baseline (day 1)	17.68	1.88	0.16	17.370	17.992
	Day-6	17.68	1.83	0.15	17.378	17.983
Temperature	Baseline (day 1)	98.42	0.27	0.02	98.372	98.463
	Day-6	98.44	0.23	0.02	98.406	98.482

Table 3 Distribution of safety evaluation parameters

There were no adverse events reported in the follow-up visit [Telephonic visit, visit 3, day 14]. In this study, all adverse events were unrelated to the investigational product and were mild in nature. All events resolved with administration of antipyretics/ analgesics/ antacids. All events resolved completely without any sequale. There was no report of new unknown adverse events were reported. No serious adverse events reported in the study. The most common adverse event was fever with 5 subjects (3.2%) reporting it. Body ache was reported in three subjects (1.95%). Three subjects (1.95%) reported hyperacidity and one subject each reported headache, nausea, vomiting (0.65%).

Discussion

Combining a nasal decongestant with an antihistamine is a standard of care to improve allergy symptom control. This combination approach addresses a broader spectrum of symptoms, as antihistamines primarily target histamine-related symptoms such as sneezing and itching, while nasal decongestants specifically alleviate congestion by reducing swelling of nasal tissues.^[9] However, the literature review reveals a paucity of studies exploring the efficacy and safety of the FDC of ebastine (10 mg) and phenylephrine (10 mg). The present study addresses a notable research gap and adds valuable evidence to the existing literature on the combined use of a decongestant with an antihistamine.

The significant decrease (P <0.001) noted in the current study in terms of ISS, including nasal congestion, rhinorrhea, nasal itching, sneezing, and ocular pruritus, as well as the TSS, as assessed by the investigator, validates the efficacy of the combination therapy with ebastine (10 mg) and phenylephrine (10 mg). In a meta-analysis, Ratner et al. demonstrated that ebastine exhibited good efficacy and induced a significant decrease from baseline in the mean AR symptom score compared to loratadine. ^[10] A double-blind multicentre study conducted by Murris-Espin et al. concluded that the individual and total baseline symptom scores of ebastine 10 mg are comparable to that of cetirizine in reducing perennial AR symptoms. ^[10], ^[11] Sastre evaluated 30 years of real-world data and clinical experience of ebastine in the management of AR. The study has concluded that ebastine, at recommended doses, is generally well-tolerated and ranks among the antihistamines with the lowest risk of adverse cognitive/psychomotor effects. Sastre has also highlighted the modulating effects of ebastine on the allergic inflammatory process apart from its antihistamine effects. ^[6] A meta-analyses of 7 crossover studies and the reanalysis of a parallel-group study corroborated the effectiveness of phenylephrine 10 mg as a decongestant in adults with acute nasal congestion related to the common cold. ^[12]

The significant improvement observed in the RQLS from day 1 to day 6 in the present study suggests a positive impact of the treatment on the subjects' overall quality of life. In addition, the manageable nature of the reported adverse events adds to the overall favourable safety and tolerability profile of the FDC. Although there are no sufficient data validating the safety of the FDC combination ebastine (10 mg) and phenylephrine (10 mg), there are studies reporting their safety as individual therapies. Gelotte and Zimmerman found that single oral doses of phenylephrine HCl at 10, 20, and 30 mg were well-tolerated with no serious adverse events. The researchers also noted that the treatment was not associated with clinically significant occurrences of pulse or blood pressure beyond the reference limits. ^[13] Hurst and Spencer reported that the efficacy of ebastine was comparable to other second-generation antihistamines and the treatment was not associated with any serious adverse cardiac effects. ^[14]

The synergistic effects of antihistamine and decongestant FDC offer a targeted approach to symptom management, addressing both histamine-mediated symptoms and congestion simultaneously. In addition, the FDC enhances patient compliance by simplifying the medication regimen. Stroms et al. revealed that combination therapy of antihistamine and decongestant was more effective that of monotherapy in relieving the symptoms of AR. The combination was better than its components in reducing nasal stuffiness and nasal discharge at day 4 evaluations. ^[9]

Overall, there was a significant decrease (p<0.001) for all the individual symptom scores viz. nasal congestion, rhinorrhea, nasal itching, sneezing, ocular pruritis as well as the total symptom scores as assessed by the investigator proving the efficacy of Ebastine (10 mg) and Phenylephrine (10 mg). There was significant improvement in quality of life (RQLS) from baseline to day 6 after administration of Ebastine (10 mg) and Phenylephrine (10 mg). No statistical difference between baseline and visit 2 (day 6) for safety parameters viz., adverse events, ECG, lab investigations after administration of Ebastine (10 mg) and Phenylephrine (10 mg). There were no adverse events reported in the follow-up visit. In this study, all adverse events were unrelated to the investigational product and were mild in nature. All events resolved with administration of antipyretics/ analgesics/ antacids. All events resolved completely without any sequale. There was no report of new unknown adverse events were reported. No serious adverse events reported in the study.

The present study holds significant relevance as there are no literature studies evaluating the FDC of ebastine and phenylephrine in the Indian population. One of the major strengths of the study is the robust enrolment of a diverse and clinically defined study population. Additionally, the study has gathered comprehensive baseline characteristics, including demographic information and baseline symptom scores. However, limitations include a relatively small sample size, potential bias from subjects lost to follow-up, a short study duration, potential reporting bias in adverse events, absence of a placebo control, and limited diversity in reported adverse events.

Conclusion

The FDC combination of ebastine (10 mg) and phenylephrine (10 mg) was safe and effective with favourable clinical outcomes and good safety profile in the management of AR.

Source of Funding

This study was sponsored by Micro Labs Limited, Bangalore.

Conflict of Interest

Dr Manjula S and Dr Krishna Kumar M are employees of Micro Labs Limited, Bangalore.

Acknowledgement

None.