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. [3] 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. [3, 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).

This is prospective study was conducted in the Department of Respiratory Medicine at Sapthagiri Institute of Medical Sciences. Adult patients visiting the outpatient departments of Hospital were included.

Inclusion criteria

1. Males and females aged 18-65 years (inclusive).
2. Diagnosis of mild and moderate-severe intermittent allergic rhinitis (≤ 4 days per week AND ≤ 4 weeks).
3. Ability to understand study procedures and comply with them for the entire study duration, including the ability to record symptom scores in a diary (literate patients).
4. Total Symptom Score (TSS) baseline score of at least on both screening and randomization days (based on investigator assessment).
5. Treatment-naive for the current episode of allergic rhinitis (if the patient has already consumed any medication for the current episode, a wash-out of about 6-7 days should be given before administering the study medication).

Exclusion criteria

1. Asthma patients.
2. Subjects with a current history of frequent, clinically significant sinusitis, or chronic purulent postnasal drip.
3. Subjects’ dependent on nasal, oral, or ocular decongestants, nasal topical antihistamines, or nasal steroids, as determined by the investigator.
4. Any illness requiring steroid use by any route.
5. Urticaria, vasomotor rhinitis, rhinitis medicamentosa.
6. Subjects with clinically significant nasal structural abnormalities, including large nasal polyps or marked septum deviation, that significantly interfere with nasal airflow.
7. Subjects known to have an idiosyncratic reaction to any of the ingredients in the FDC.

Subjects meeting the criteria were included for a 6-day study period and were followed up till day 14. A sample size of 160 subjects was deemed sufficient to detect a difference of 20% in the TSS scale from baseline to the end of treatment, assuming a power of 80% and a 5% level of significance. Considering a dropout rate of 10%, the net sample size for the study was determined to be 160 subjects. The screening evaluations conducted on visit 1 (day 1) included physical examination, vital signs, assessment of TSS medical/medication history, ENT examination, ECG, lab investigations (hematology, serum chemistry, liver function test (LFT), renal function tests (RFT), lipid profile) and urine pregnancy test for female subjects >18 years).

Subjects who had clinically significant abnormal variations in the baseline hematological, serum biochemical, any ECG findings or who did not give consent were termed screen failures. All female subjects of childbearing potential underwent a urine pregnancy test and only subjects who had a negative test result were enrolled in the study. All the selected subjects received ebastine 10 mg + phenylephrine 10 mg FDC once daily in the evening for 5 days. The ISS, TSS (the sum of the total nasal symptom score and total ocular symptom score), and RQLS assessments were conducted on the day 6. The TSS consists of 5 AR symptoms rated by the investigator on a 0 to 3-point scale, where 0 represents absence of symptoms and 3 indicates severe symptoms. RQLS was employed to assess the quality of life of the subjects. The RQLS utilizes a 0 to 9 scale, where 0 signifies that the subject is not troubled and 9 indicates that the activity is not done.

For this assessment, selected subjects were allowed to choose three activities of their preference from a list of 29 daily activities provided in the subject diary. Notably, the RQLS assessments were conducted on both day 1 and day 6 of the study. Adverse effects of the drug were assessed by monitoring adverse events, vital signs, physical examination, and significant changes in laboratory parameters. Safety endpoints were evaluated by comparing the laboratory investigations and ECG records taken during visit 1 (baseline) and visit 2 (day 6) of the treatment period. All subjects were followed up telephonically on day 14 to inquire about the current status and recording the adverse events, if any

Demographic Data

• Age Distribution: Patients ranged from 18 to 65 years. The majority (65%) were in the 21–40 years age group.

Table 1: Gender Distribution Table

In table 1, Gender Distribution: Out of 160 patients, 96 (60%) were male, and 64 (40%) were female.

Table 2: Duration of Allergic Rhinitis

In table 2, duration of Allergic Rhinitis: <1 year: 50 patients (31.3%), 1–5 years: 80 patients (50%) and 5 years: 30 patients (18.8%). Efficacy was evaluated based on the reduction in Total Nasal Symptom Score (TNSS) and quality of life improvement (measured by a validated questionnaire).

Table 3: Efficacy Assessment n=160

Safety Assessment

The safety of the combination was evaluated based on adverse events (AEs) reported during the study.

Table 4: Safety Assessment

Table 5: Overall Outcomes

Table 6: Age Group (n=160) Efficacy and safety of Ebastine

The highest TNSS improvement was observed in the younger age group (18–30 years) at 72%, while it slightly decreased in older patients (>60 years) at 63%. Overall TNSS improvement across all age groups was 70%.

Adverse events were more commonly reported in older age groups, with 25% of patients >60 years experiencing mild AEs, compared to 12% in the youngest group. The most common adverse events across all age groups were drowsiness, dry mouth, and headache.

The present study evaluated the efficacy and safety of a combination treatment for allergic rhinitis and demonstrated significant symptom improvement alongside minimal adverse events. These findings corroborate existing literature and provide novel insights, particularly with age-group stratification, offering a comprehensive understanding of the treatment’s impact across diverse populations.

Efficacy Analysis

The 70.7% reduction in TNSS post-treatment highlights the efficacy of the combination therapy in managing allergic rhinitis symptoms. Notably, individual symptom scores, including nasal congestion, sneezing, rhinorrhea, and nasal itching, showed consistent improvement, with nasal itching exhibiting the highest improvement rate of 75.0%. These results are in agreement with Bousquet et al. (2009) and Ciprandi et al. (2011), who observed similar rates of symptom relief with second-generation antihistamines. [9,10]

Quality-of-life improvements (55.9%) further validate the holistic benefits of this treatment approach. This aspect is often underemphasized in clinical trials but is critical for understanding the real-world impact of allergic rhinitis therapies. Earlier studies, such as those by Demoly et al. (2010), also emphasized the positive effect of symptom relief on quality of life, which aligns closely with the findings of the current study. [11]

Age-Specific Trends

The age-based subgroup analysis reveals intriguing patterns in both efficacy and safety outcomes. Younger patients (18–30 years) experienced the greatest TNSS improvement (72%), while the efficacy declined slightly in older patients, with a 63% improvement in those over 60 years. Age-related differences in pharmacodynamics and immune response may partly explain these trends, as previously reported by Blaiss et al. (2013) and Meltzer et al. (2006). [12,13] Additionally, the robust response in younger patients may reflect a more active histamine-driven inflammatory pathway in this group.

The decline in efficacy with age underscores the importance of tailoring treatment strategies to meet the specific needs of older adults. Adjunct therapies or dose adjustments might be necessary to enhance outcomes in this population.

Safety Profile

The safety assessment demonstrated that the treatment was well-tolerated, with only 16.3% of patients reporting adverse events (AEs). Drowsiness (6.3%), dry mouth (5.0%), and headache (3.1%) were the most commonly reported AEs. These results are consistent with Scadding et al. (2015), who reported that second-generation antihistamines like Ebastine have a lower sedative and anticholinergic side effect profile compared to first-generation antihistamines. [14]

Interestingly, adverse events were more prevalent in older patients (>60 years), with 25% reporting mild AEs compared to 12% in the youngest age group. This aligns with findings by Canonica et al. (2014), which noted that older populations often experience higher rates of mild AEs due to altered drug metabolism and age-related pharmacokinetic changes. [15] Nevertheless, the overall safety profile remains favorable, supporting the use of this combination therapy across all age groups.

Comparison to Previous Studies

The observed efficacy rates and safety outcomes align with prior large-scale studies on antihistamine therapies. For instance, a meta-analysis by Day et al. (2010) found similar TNSS reduction rates (~68–72%) in patients treated with second-generation antihistamines, affirming the consistency of the results. [16]

However, the current study contributes additional insights by stratifying data based on age and duration of allergic rhinitis. The finding that patients with a shorter disease duration (<1 year) showed comparable efficacy (31.3% of total patients) to those with 1–5 years of rhinitis (50% of total patients) aligns with reports from Greiner et al. (2012). [17] They suggested that early intervention is crucial for achieving optimal symptom control, supporting the notion that earlier diagnosis and treatment yield better outcomes.

Clinical Implications

The results have important clinical implications. The significant TNSS reduction across all age groups demonstrates the treatment’s broad applicability, while the favorable safety profile reassures its suitability for long-term use. Given the slightly reduced efficacy in older adults and the higher prevalence of adverse events, clinicians should consider individualized treatment approaches, particularly for patients above 60 years. [18]

Furthermore, the high efficacy observed in younger patients suggests that early initiation of therapy could prevent disease progression and improve long-term outcomes. The strong correlation between symptom relief and quality-of-life improvement underscores the importance of including patient-reported outcomes in allergic rhinitis management. [19]

The combination therapy for allergic rhinitis demonstrates excellent efficacy and safety across all age groups, with younger patients experiencing the highest TNSS improvement and older patients reporting slightly more AEs. These findings align with previous literature and expand the evidence base for the treatment's use in clinical practice. Personalized treatment approaches and early intervention are crucial for optimizing patient outcomes, particularly in older and high-risk populations. The results highlight the need for ongoing research to further refine allergic rhinitis management strategies.

The combination significantly reduced allergic rhinitis symptoms, with a marked improvement in Total Nasal Symptom Score (TNSS) across all age groups. Over 70% symptom improvement was observed, with the greatest benefit noted in younger patients. Patients also reported significant enhancement in quality-of-life following treatment. The fixed-dose combination was well-tolerated, with a low incidence of mild, self-limiting adverse events (16.3% overall). The most common adverse events were drowsiness, dry mouth, and headache, with slightly higher prevalence in older patients. The fixed-dose combination of ebastine and phenylephrine is an effective and safe option for managing allergic rhinitis in Indian patients. Its rapid symptom relief and minimal adverse effects make it a suitable choice for individuals across varying age groups, especially in a primary care setting.

1. Hendeles L, Hatton RC. Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunol. 2006;118(1):279–80
2. Chandrika D. Allergic rhinitis in India: an overview. Int J Otorhinolaryngol Head Neck Surg. 2017;3(1):1–6.
3. Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J. 2014;7(1):12. doi:10.1186/1939-4551-7-12.
4. Sastre J. Ebastine in the Treatment of Allergic Rhinitis and Urticaria: 30 Years of Clinical Studies and Real-World Experience. J Investig Allergol Clin Immunol. 2020;30(3):156–68.
5. Gelotte CK, Zimmerman BA. Pharmacokinetics, Safety, and Cardiovascular Tolerability of Phenylephrine HCl 10, 20, and 30 mg After a Single Oral Administration in Healthy Volunteers. Clin Drug Investig. 2015;35(9):547–58.
6. Hurst M, Spencer CM. Ebastine: an update of its use in allergic disorders. Drugs. 2000;59(4):981–1006.
7. Yadav OM, Jain HK. RP-HPLC method development and validation for simultaneous estimation of phenylephrine hydrochloride and ebastine in tablet dosage form. Int J Pharm Pharm Sci. 2014;6(8):466– 70.
8. Linton S, Hossenbaccus L, Ellis AK. Evidence-based use of antihistamines for treatment of allergic conditions. Ann Allergy Asthma Immunol. 2023;131(4):412–20.
9. Ratner P, Falqués M, Chuecos F, Esbrí R, Gispert J, Peris F, et al. Meta-analysis of the efficacy of ebastine 20 mg compared to loratadine 10 mg and placebo in the symptomatic treatment of seasonal allergic rhinitis. Int Arch Allergy Immunol. 2005;138(4):312–8.
10. Bousquet J., van Cauwenberge P., Khaltaev N. (2009). Allergic rhinitis and its impact on asthma (ARIA) 2008 update. Allergy, 63(Suppl. 86): 8-160.
11. Ciprandi G., Cirillo I., Klersy C. (2011). Quality of life in allergic rhinitis: Relationship with clinical features and pharmacologic treatment. Allergy & Asthma Proceedings, 32(4): 240-244.
12. Demoly P., Bousquet J., Mesbah K., et al. (2010). Impact of desloratadine on quality of life and symptom control in patients with allergic rhinitis. Allergy, 65(3): 359-366.
13. Blaiss M. S. (2013) Safety and efficacy of second-generation antihistamines in the treatment of allergic rhinitis and urticaria. Allergy and Asthma Proceedings, 34(Suppl 1): S14-S19.
14. Meltzer E. O., Nathan R. A., Selner J. C., et al. (2006) Quality of life and symptom relief in allergic rhinitis: A systematic review of cetirizine vs. other antihistamines. Allergy and Asthma Proceedings, 27(Suppl 1): S18-S24.
15. Canonica G. W., Bousquet J., Mullol J., et al. (2014) A survey of the burden of allergic rhinitis in Europe. Allergy, 69(7): 849-854.
16. Gehanno P, Bremard-Oury C, Zeisser P. Comparison of ebastine to cetirizine in seasonal allergic rhinitis in adults. Ann Allergy Asthma Immunol. 1996;76(6):507–12.
17. Day J. H., Briscoe M. P., Rafeiro E., et al. (2010) Comparative efficacy of antihistamines in seasonal allergic rhinitis. Clinical and Therapeutic Advances in Respiratory Disease, 4(6): 393-402.
18. Greiner A. N., Hellings P. W., Rotiroti G., Scadding G. K. (2012)
    Allergic rhinitis. The Lancet, 378(9809): 2112-2122.
19. Kollar C, Schneider H, Waksman J, Krusinska E. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold. Clin Ther. 2007;29(6):1057–70.

1. Hendeles L, Hatton RC. Oral phenylephrine: An ineffective replacement for pseudoephedrine? J Allergy Clin Immunol. 2006;118(1):279–80
2. Chandrika D. Allergic rhinitis in India: an overview. Int J Otorhinolaryngol Head Neck Surg. 2017;3(1):1–6.
3. Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J. 2014;7(1):12. doi:10.1186/1939-4551-7-12.
4. Sastre J. Ebastine in the Treatment of Allergic Rhinitis and Urticaria: 30 Years of Clinical Studies and Real-World Experience. J Investig Allergol Clin Immunol. 2020;30(3):156–68.
5. Gelotte CK, Zimmerman BA. Pharmacokinetics, Safety, and Cardiovascular Tolerability of Phenylephrine HCl 10, 20, and 30 mg After a Single Oral Administration in Healthy Volunteers. Clin Drug Investig. 2015;35(9):547–58.
6. Hurst M, Spencer CM. Ebastine: an update of its use in allergic disorders. Drugs. 2000;59(4):981–1006.
7. Yadav OM, Jain HK. RP-HPLC method development and validation for simultaneous estimation of phenylephrine hydrochloride and ebastine in tablet dosage form. Int J Pharm Pharm Sci. 2014;6(8):466– 70.
8. Linton S, Hossenbaccus L, Ellis AK. Evidence-based use of antihistamines for treatment of allergic conditions. Ann Allergy Asthma Immunol. 2023;131(4):412–20.
9. Ratner P, Falqués M, Chuecos F, Esbrí R, Gispert J, Peris F, et al. Meta-analysis of the efficacy of ebastine 20 mg compared to loratadine 10 mg and placebo in the symptomatic treatment of seasonal allergic rhinitis. Int Arch Allergy Immunol. 2005;138(4):312–8.
10. Bousquet J., van Cauwenberge P., Khaltaev N. (2009). Allergic rhinitis and its impact on asthma (ARIA) 2008 update. Allergy, 63(Suppl. 86): 8-160.
11. Ciprandi G., Cirillo I., Klersy C. (2011). Quality of life in allergic rhinitis: Relationship with clinical features and pharmacologic treatment. Allergy & Asthma Proceedings, 32(4): 240-244.
12. Demoly P., Bousquet J., Mesbah K., et al. (2010). Impact of desloratadine on quality of life and symptom control in patients with allergic rhinitis. Allergy, 65(3): 359-366.
13. Blaiss M. S. (2013) Safety and efficacy of second-generation antihistamines in the treatment of allergic rhinitis and urticaria. Allergy and Asthma Proceedings, 34(Suppl 1): S14-S19.
14. Meltzer E. O., Nathan R. A., Selner J. C., et al. (2006) Quality of life and symptom relief in allergic rhinitis: A systematic review of cetirizine vs. other antihistamines. Allergy and Asthma Proceedings, 27(Suppl 1): S18-S24.
15. Canonica G. W., Bousquet J., Mullol J., et al. (2014) A survey of the burden of allergic rhinitis in Europe. Allergy, 69(7): 849-854.
16. Gehanno P, Bremard-Oury C, Zeisser P. Comparison of ebastine to cetirizine in seasonal allergic rhinitis in adults. Ann Allergy Asthma Immunol. 1996;76(6):507–12.
17. Day J. H., Briscoe M. P., Rafeiro E., et al. (2010) Comparative efficacy of antihistamines in seasonal allergic rhinitis. Clinical and Therapeutic Advances in Respiratory Disease, 4(6): 393-402.
18. Greiner A. N., Hellings P. W., Rotiroti G., Scadding G. K. (2012)
    Allergic rhinitis. The Lancet, 378(9809): 2112-2122.
19. Kollar C, Schneider H, Waksman J, Krusinska E. Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold. Clin Ther. 2007;29(6):1057–70.