Twenty-five years: The fexofenadine clinical experience

Allergic rhinitis (AR) and urticaria affect a sizable portion of the population worldwide, resulting in reduced quality-of-life and productivity and increased healthcare costs. Fexofenadine (FEX) is a non-sedating second-generation H1 antihistamine with pronounced efficacy and a very good safety profile, used for the treatment of allergic diseases. In addition to its antihistaminic properties, FEX also has anti-inflammatory effects. FEX has a wide therapeutic window and is not associated with any sedative effects, even at higher than recommended doses. There is a need for an integrated management system for AR and urticaria which includes safe and effective treatment options. An ideal anti-allergic formulation should provide fast relief of symptoms and long-lasting effect without drowsiness. Data from randomized clinical trials show that FEX meets these criteria and is an effective treatment option with a favourable safety profile, improving the quality of life of patients suffering from AR and urticaria.

>10 days, 1.3%). 4In adolescents (12-18 years) with AR, absenteeism of 1-3 days was seen in 6.6% of children, 4-6 days in 0.8% and !7 days in 0.9%. 5In adolescents (12-17 years) with seasonal allergic rhinitis (SAR), worse impairment of productivity was seen with greater symptom severity.Meltzer et al  (2017) reported a mean productivity loss of 10.2 days in adolescents with seasonal allergic rhinoconjunctivitis (SARC) in a typical seasonal allergy month.Among high school children (!16 years), the examination scores decreased with increasing pollen counts.In school children aged 15 years with asthma or rhinitis or eczema, educational grades were decreased with increased symptoms.Also, grades were pronouncedly decreased with use of sedating antiallergic medication.6][7][8][9][10][11][12] AR significantly impacts exam performance.A case-control study of students in the United Kingdom sitting national exams in 3 subjects (May-June 2004) found that 36% (662/1834) dropped at least 1 grade in at least 1 subject in summer (pollen season) compared with winter exam.The risk of unexpectedly dropping a grade (cases vs controls) in summer examinations increased after taking first-generation antihistamines (7.7% vs 4.9%; adjusted odds ratio: 1.71, 95% CI: 1.06-2.72)which have a sedating effect and are no longer preferred by physicians. 13

Management of AR
Once a diagnosis of AR has been established, the standard of care includes a treatment plan that considers the severity of the disease, the presence of concomitant allergic diseases, and most importantly, a shared decision-making process that focuses on the patient's preferences.
An international, multicenter, cross-sectional epidemiological study conducted in adults and children with AR involving 2778 patients in 11 countries showed that patients prefer to take oral antihistamines (75.9%) and intranasal corticosteroids (49.2%) predominantly, followed by topical decongestants (33.4%), oral decongestants (29.3%) and others. 14cond-generation oral antihistamines are fast, long lasting, and well tolerated, ensuring better compliance, whereas intranasal antihistamines have a more rapid onset of action.Addition of antihistamine AE leukotriene receptor antagonist to nasal corticosteroid may be considered as per requirement.
Step-up therapy is recommended in case of poor control and step-down therapy if wellcontrolled.In addition, it is important to avoid triggers.Saline douching and specific immunotherapy may be considered if required. 15 case of subliminal allergen exposure, patients may have subclinical inflammation with no symptoms of AR (minimal persistent inflammation).It is important to treat this inflammation. 16

Antihistamines
Histamine is an allergic mediator with 3 defined receptors, but the H 1 receptor is responsible for most of its allergic reactions.Many physicians prefer non-sedating H 1 antagonists as the initial choice of treatment for AR and urticaria.Firstgeneration antihistamines are associated with multiple side effects due to nonspecific binding to many receptors and penetration of the blood-brain barrier.Unlike first-generation antihistamines, second-generation antihistamines have a better safety and efficacy profile, based on greater potency, receptor specificity, and lower central nervous system penetration. 17eatment with sedating antihistamines in children leads to decreased cognitive and psychomotor abilities, impaired school and/or sport performance/ learning, and difficulty concentrating. 18Sedating antihistamines are no longer recommended in AR due to lack of good evidence of efficacy and to adverse events (eg, psychomotor retardation and behaviour disturbance).
An ideal antihistamine should be well-tolerated, easy to use, and provide quick relief. 19exofenadine (FEX) is a non-sedating, secondgeneration H 1 antihistamine with great specificity and favourable safety profile. 20There is good evidence for the use of FEX in AR, without any psychomotor or behaviour disturbance.
The H 1 receptor exists in equilibrium with an active and inactive form.Stabilisation of this inactive form shifts the equilibrium towards the inactive state, thereby reducing the number of active receptors to which endogenous histamine may bind. 21FEX is an inverse agonist that exhibits an antihistaminic effect by binding the inactive form. 20,21It has been observed that FEX occupies more than 90% of the histamine H 1 receptors in less than 1 h with a residence time for binding the human H 1 receptor >100-fold higher than diphenhydramine with a very rapid binding kinetics. 22

Effects of FEX on the early response to nasal allergen challenge
The effects of FEX on the early response to nasal allergen challenge have been shown using different models.
In a randomized, double-blind, placebocontrolled, two-way crossover study, 20 SAR subjects outside their allergy season received FEX 180 mg once daily (QD) for a week followed by nasal challenge with allergen.FEX inhibited allergen-induced symptoms including nasal congestion and increased vascular permeability but not the release of histamine and tryptase.Pre-treatment with FEX suppressed sneezing, runny nose, stuffy nose, itchy nose/throat, itchy/watery eyes, and postnasal drainage (Fig. 2).This study is a prime example of how pre-treatment works, supporting this concept 23,24 These observations are consistent with the hypothesis that the partial reduction of nasal congestion seen with FEX is the result of both its H 1 blockade and its additional anti-inflammatory effects. 24histamine-induced inflammatory tissue model 25 was used to assess the effect of histamine and its antagonist FEX on fully differentiated primary human nasal epithelia cultured at the airliquid interface using MucilAirÔ material that contains primary nasal cells isolated from 14 different healthy donors.Pre-treatment of nasal tissue with FEX reduced biomarkers of the histamine-induced response (H 1 R, IL-6 and IL-8) versus the condition without pre-treatment confirming that FEX has a dual mode of action, as it inhibited the basal activity of the H 1 R and was more effective reducing biomarkers associated with histamine response when used before and during histamine challenge than when used just during histamine challenge.The effect was dosedependent regarding H 1 receptor expression level correlating with inverse agonist activity of FEX. 26 In addition to antagonizing the H 1 receptors, FEX decreases the production of LTC 4 , LTD 4 , LTE 4 , PGE 2 , and PGF 2a ; inhibits cyclo-oxygenase 2, the generation of thromboxane (perhaps through cyclo-oxygenase 2); and limits the iNOS generation of NO, as well as the generation of ICAM-1, ELAM-1, VCAM-1, RANTES, I-TAC, MDC, TARC, MMP-2, MMP-9, and tryptase (Fig. 3). 26Immuno-histochemical study of non-lesioned skin in patients with active chronic idiopathic urticaria treated with FEX 180 mg QD for 4 weeks showed a prompt and persistent relief of symptoms compared to placebo.In most cases, FEX significantly decreased the expression of Intercellular Adhesion Molecule-1 (ICAM-1) and Endothelial Leukocyte Adhesion Molecule-1 (ELAM-1) on endothelial cells (p < 0.05), decreased the expression of tryptase and some adhesion molecules in urticaria sufferers.27 AR is a chronic disease requiring an integrated care for optimal management.Fexofenadine has been shown effective and well tolerated in a number of randomized, controlled trials (RCTs, see Table 1).20,[28][29][30] FEX improves SAR symptoms in children 30 Children aged 6-11 years (n ¼ 935) received FEX 30 mg BID or placebo for 14 days in a multicentre, placebo-controlled, parallel-group, double-blind study.Symptom scores were significantly improved with FEX.All 12-h-reflective individual symptom scores, including nasal congestion, were significantly reduced compared with placebo (sneezing, p 0.0001; rhinorrhea, p ¼ 0.0005; itchy nose, palate, throat, and/or ears, p 0.0001; itchy, watery, red eyes, P 0.0001; nasal congestion p ¼ 0.0079).

Efficacy in AR
A metanalysis of 8 double-blind, placebocontrolled randomized-controlled studies found a significant beneficial effect on total nasal symptoms scores and nasal individual symptoms with FEX versus placebo.In patients with SAR, there was a significant beneficial effect with FEX vs placebo on sneezing, nasal itching, nasal congestion, and rhinorrhea (overall effect: À0.27 [p ¼ 0.0006]).No significant differences were found in reports of adverse events between FEX and placebo. 34X improves QoL in AR sufferers as demonstrated in a randomized, placebo-controlled study (n ¼ 688), FEX 120 mg QD was significantly superior to loratadine (LOR) 10 mg QD (p 0.03) and placebo (p 0.005) in improving QoL (Fig. 4).FEX and LOR significantly reduce the mean 24-h reflective and instantaneous total symptom score (TSS, both p 0.0001) and LOR (p 0.001 and p 0.005, respectively) vs placebo.FEX was significantly better than LOR in improving 24-h reflective itchy, watery, red eyes, as well as relieving nasal congestion (p 0.05 for both).29 In addition, FEX reduces work and activity impairment as shown in a double-blind, placebocontrolled study (n ¼ 845), both FEX 120 mg and 180 mg were found to significantly reduce work and activity impairment vs placebo.35 A randomized, double-blind, placebo-controlled, parallel-group, phase III study in 756 Japanese patients with perennial allergic rhinitis showed no significant difference between bilastine 20 mg QD and fexofenadine 60 mg BID in the primary endpoint (Total Nasal Symptom Score from baseline to Week 2).33 A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of FEX (120 and 180 mg administered QD) and cetirizine (10 mg QD) in 722 patients with SAR.There were no differences in efficacy between the 2 doses of FEX or between either dose of FEX and cetirizine.9 Patients with AR exposed to pollution and climate change have significant negative impact on health.Epidemiological studies and clinical evidence show the immunological effects after aeroallergen and pollutant co-exposure.Clinical human studies involving specific pollutant exposure and allergen challenge suggest pollution can exacerbate allergic airway disease and increase organ responsiveness.

FEX reduces SAR symptoms aggravated by air pollutants 36
A phase 3, single-centre, sequential, parallelgroup, double-blind, randomised study was conducted in an environmental exposure unit (EEU) to assess the efficacy of FEX 180 mg in improving AR symptoms aggravated by air pollutants.Period 1 (ragweed pollen alone), Period 2 [ragweed pollen þ diesel exhaust particles (DEP)], and Period 3 (ragweed pollen þ DEP þ single-dose FEX 180 mg or placebo).Results showed that air pollutant significantly exacerbates SAR symptoms, FEX 180 mg significantly alleviated the pollutantaggravated symptoms (Total Nasal Symptom  Score), and all individual symptoms were improved (Fig. 5).

AN OPTIMAL ANTI-ALLERGIC TREATMENT Time to onset of symptom relief
In a randomized, placebo-controlled, doubleblind, parallel-group study conducted to characterize the time to onset of clinically important relief of AR symptoms in 146 ragweed-sensitive subjects upon treatment with either FEX or placebo, FEX showed the symptom relief in 60 min in 82-85% of patients compared to placebo (p ¼ 0.018). 28

Duration of response
In a multicentred, double-blind, parallel-group, placebo-controlled trial in patients with SAR (ITT population ¼ 821; study completed ¼ 722), FEX 120 mg and 180 mg were superior to placebo in reducing the total symptom score.Efficacy was maintained for the entire dosing interval of 24 h. 9imilar results have been observed in other RCTs.

Safety data
8][39][40][41][42][43] In a randomized double-blind, placebo-controlled, crossover clinical trial, subjective sleepiness and psychomotor performance were measured in 20 healthy volunteers after administration of FEX 120 mg or cetirizine 20 mg. 42Higher H 1-receptor occupancy in the brain was seen with cetirizine compared to FEX and placebo.In psychomotor tests, FEX was not significantly different from placebo, whereas cetirizine showed a trend towards increased sleepiness compared with FEX and placebo.
In a double-blind, 3-way crossover study with 18 healthy volunteers (20-55 years old) receiving either chlorpheniramine (CPM) 6 mg or FEX 120 mg or placebo QD, CPM 6 mg increased the latencies to sleep onset and rapid eye movement (REM) sleep (p 0.05 for both), and reduced the duration of REM sleep (p 0.01). 37,44There were decrements in performance, the next morning (residual effects), with CPM but not with FEX.CPM 6 mg impaired divided attention (p < 0.001), vigilance (p < 0.05), working memory (p < 0.0001) and sensory-motor performance (p < 0.01), and reduced the latency to daytime sleep (p < 0.0001), but not with FEX.Ciprandi  In a randomized, 3-way cross-over, double-blind study of 15 volunteers, evaluating the effect of FEX 360 mg, promethazine 30 mg or placebo in a driving test.No effect on reaction time and critical flicker fusion (CFF) threshold with FEX at 360 mg dose when compared with placebo.If results are extrapolated to real life situation in a motor vehicle being driven at 112 kph, the promethazine would cause the car to travel 3 m extra before the driver engage the brake pedal.Choice reaction time was significantly higher (p < 0.05) with promethazine 30 mg vs FEX 360 mg.At higher doses of 360 mg, FEX does not influence reaction time and CFF threshold when compared to placebo. 41 a double-blind, 3-period crossover study, a total of 74 healthy naval flight personnel received either FEX 180 mg or cetirizine 10 mg or placebo.No significant differences between FEX and placebo for any speed measurements under normobaric hypoxic conditions.The number of errors was significantly higher with cetirizine vs placebo (95%  CI: 0.0467, 0.3846, p ¼ 0.0127) over the 60 min aeromedical vigilance test and at normobaric hypoxic atmospheric condition.FEX compared to placebo and cetirizine does not cause any increase of risk on the cognitive skills important for piloting. 43multicentre, double-blind, placebo-controlled study evaluated the efficacy of FEX 120 mg or 180 mg vs cetirizine 10 mg or placebo QD in symptomatic patients with SAR showing a similar efficacy with FEX and cetirizine.Incidence of drowsiness and fatigue was similar between placebo and FEX 120 mg or 180 mg.FEX has a comparable frequency of drowsiness/fatigue vs placebo (4% each).Higher combined frequency of drowsiness/fatigue was noted with cetirizine (9%).Adverse events related to study treatment were similar across the treatment groups (23-25%).10 Five randomized, multicentre, placebo-controlled studies established the safety and tolerability of FEX in children aged 6 months to 2 y, 2-5 y and 6-11 y old.Minimal difference was observed in the incidence of drowsiness between treatment groups of FEX 15 mg and 30 mg versus placebo among all the age groups evaluated.Similarly, no difference was noted among the study groups when administered as BID dosing.3,39,40 Based on a large clinical database, fexofenadine HCl had no significant effect on QTc, even at doses >10-fold higher than that is efficacious for AR.Long term studies indicated no statistically significant QTc increases compared with placebo.45,46 Efficacy in children with SAR A pooled analysis of 3 double-blind, placebocontrolled studies in pediatric patients (6-11 years) with SAR found that individual nasal and ocular symptoms were significantly improved with FEX vs placebo.Mean change from baseline in the average 12 h-reflective total symptom score was À1.14 for placebo and À1.75 for FEX 30 mg given BID.Safety of FEX was satisfactory and similar to placebo; somnolence was reported in 0.4% of placebo and 0.1% of FEX recipients.11

CHRONIC URTICARIA
Urticaria is predominantly a histamine mediated disease.Incidence of chronic urticaria continues to increase in men and women across the world. 47A survey in patients with chronic urticaria showed that half of them complained about the effect of their disease on daily functioning (such as sleep, work, school, socializing) and emotions (makes the patient feel annoyed, frustrated, embarrassed, angry, ashamed, anxious, depressed).The results confirmed that chronic urticaria has substantial impact on QoL, with median Skindex-29 scores of 68 for symptoms, 50 for functioning and 53 for emotions. 48[51][52] FEX significantly improves symptoms of chronic idiopathic urticaria [55] A double-blind, placebo-controlled,4-week study in 255 patients with chronic idiopathic urticaria (!12 y of age) receiving FEX 180 mg once a day showed a significant improvement in QoL indicated by reduced pruritus and wheals in chronic idiopathic urticaria vs placebo (Figs. 6 and 7).In the placebo arm, 37% of patients reported at least 1 adverse event compared to 31% in FEX arm. 53 a multicenter, double-blind study, the reduction of mean daily total symptom score of pruritus and wheals was found to be dosage-dependent and statistically significant (p ¼ 0.0041) compared with placebo for the recommended dose of FEX (180 mg). 56randomized, placebo-controlled study enrolling 163 patients (>12 years old) evaluated the mean daily number of wheals and the mean daily severity of pruritus during 180 mg FEX treatment.After a 4-week treatment period, FEX showed greater and significant improvements in both endpoints compared with placebo (mean change in daily number wheals: FEX, À0.78; placebo, À0.40; mean change in mean pruritus severity: FEX, À1.04; placebo, À0.57; p < 0.001 both). 53X possesses a very good safety profile, with a wide therapeutic window, a minimally effective plasma concentration of w15 ng/ml (corresponding to 40 mg daily which is one-third of the recommended dose) and established safety at steady-state plasma concentrationsup to 4677 ng/ml (free from CNS adverse events when assessed objectively at 3 times the recommended dose [360 mg daily: off label] and free from subjective reporting of sedation at 690 mg BID [12x recommended dose: off label]). 54,55meta-analysis of 8 randomized, double-blind, clinical trials including a total of 3532 participants assessed the efficacy of fexofenadine in AR using adverse events, TSS, and other individual symptom scores as a clinical end point.The safety analysis did not show a significant difference in reported adverse events between the active and placebo treatment groups (p ¼ 0.75).34 As previously mentioned, in clinical studies using objective and subjective impairment tests (n ¼ 85) assessing both cognitive and psychomotor performance and feelings of sedation, the effects of FEX were not distinguishable from placebo on a number of tests and have not been associated with any sedative effects, even at higher doses, whereas promethazine caused an overall reduction in CFF thresholds and a significantly higher subjective ratings of sedation when compared to placebo (P < 0.05).41 In two randomized, double-blind, parallel-group trials of 2-week duration, mean QTc were similar between FEX and placebo in adults and children over a wide range of FEX doses.39,45

DISCUSSION
FEX is classified as a non-brain-penetrating antihistamines based on the brain H 1 receptor occupancy (H 1 RO) which is an index of sedative properties. 57A review focussed on non-sedative Fig. 6 Reduction of itching and wheals symptoms with fexofenadine treatment QD, once daily Fig. 7 Improvement in quality of life with fexofenadine treatment in patients with chronic idiopathic urticaria QD, once daily; QoL, quality of life properties of antihistamines for allergic rhinitis treatment summarized that non-brain-penetrating antihistamines like FEX should be considered for the first-line therapy of allergic rhinitis. 57[41][42][43] Results of a double-blind, randomized, parallel group, placebo-controlled study shows FEX improves AR symptoms aggravated by air pollutant and may be used for management of AR symptoms aggravated by air pollution. 39,58Second-generation non-sedating antihistamines are the first-line pharmacological approach to resolve urticaria symptoms.FEX is one of the second-generation antihistamines available over the counter and a valid option for the treatment of urticaria in adult and pediatric populations. 49A review of the cardiac safety of second-generation H 1 -antihistamines like bilastine, cetirizine, levocetirizine, ebastine, FEX, loratadine, desloratadine, mizolastine and rupatadine found that all these drugs had no evidence of cardiotoxicity even when dosed up to 4 times their standard licensed dose in chronic spontaneous urticaria (off label). 59FEX has been found to be free of sedative effects even at higher than therapeutic doses. 60,61FEX improves nasal congestion symptoms more effectively than loratadine.Effect on nasal congestion might be related to its antiallergic effects.A review including nasal challenge studies and clinical trials reported the effects on nasal congestion of the newer secondgeneration antihistamines desloratadine, fexofenadine, and levocetirizine, showed that in 4 trials reporting objective and/or subjective measures, FEX showed significantly lower nasal congestion scores compared with placebo (P < -0.05). 62ability to cross the blood-brain barrier and high selectivity for peripheral H 1 -receptors might explain the fact that, at even very high doses (360 mg), FEX does not cause sedation and does not impair driving performance.Fexofenadine is not associated with serious cardiac adverse events, and changes in electrocardiogram parameters are not significantly different from those observed with placebo.The high selectivity of FEX for peripheral H 1 -receptors and the lack of interaction with muscarinic receptors might offer a potential advan-tage compared with other second-generation antihistamines. 63An evidence based review of secondgeneration H 1 -antihistamines in patients with chronic urticaria found that patients who received FEX experienced less work productivity impairment, overall work impairment, and activity impairment than those who received placebo as assessed by the Work Productivity and Activity Impairment (WPAI) questionnaire.In all doses studied, there were no differences in adverse effects between FEX and placebo.Overall, the evidence is high for FEX being well tolerated and effective in chronic urticaria, leading to a strong recommendation for its use in this indication. 64

CONCLUSION
FEX is a non-sedating H 1 antihistamine with pronounced efficacy and a very good safety profile in the AR and urticaria control improving the patient's QOL.Its efficacy is not just confined to its high affinity towards the H 1 receptor but may also apply to its anti-inflammatory properties.Secondgeneration non-sedating antihistamines are firstline therapies for AR and urticaria.Data from RCT showed fexofenadine meets all criteria considered for an optimal allergic disease treatment.

Funding
Not applicable.

Fig. 4
Fig. 4 Mean change from baseline to visit 4 for individual and overall QoL scores a a Data presented as changes in observed means for fexofenadine 120 mg QD, loratadine 10 mg QD and placebo (n ¼ 509).Adapted from van Cauwenberge, P et al. 2008 29 Volume 17, No. 9, Month 2024