Topical levocabastine—a review of therapeutic efficacy compared with topical sodium cromoglycate and oral terfenadine on days with high pollen counts

Levocabastine is a new H1-receptor antagonist specifically developed for the topical treatment of seasonal allergic rhinoconjunctivitis. Clinical experience to date clearly demonstrates that levocabastine eye drops and nasal spray are effective and well tolerated for the treatment of this allergic disorder. Analysis of data from a number of comparative trials reveals that topical levocabastine is at least as effective as sodium cromoglycate and the oral antihistamine terfenadine, even on days with high pollen counts (≥ 50 pollen particles/m3 ) when symptoms are severe. Coupled with a rapid onset of action and twice daily dosing, these findings make topical levocabastine an attractive alternative to other therapeutic approaches as a first-line therapy for the treatment, of this common condition.


Introduction
Given the wide array of therapeutic agents available for the treatment of seasonal allergic rhinoconjunctivitis, including H-receptor antagonists, vasoconstrictors, topical corticosteroids and sodium cromoglycate, assessment of comparative efficacy is obviously of considerable importance for optimal patient management. Comparison of the true therapeutic efficacy of these different agents may be somewhat problematic. There are a number of reasons for this, most notably the placebo response or spontaneous improvement in symptoms observed following administration of any anti-allergic medication and particularly a topical drug. Response rates greater than 40% have been reported for placebo eyedrops and nasal sprays. As the pollen count during the trial period may not always be sufficient for symptoms to develop fully, this placebo response may mask differences in therapeutic efficacy. A more realistic assessment of the comparative efficacy of different therapeutic approaches can be obtained by comparing efficacy on days with high pollen counts. This review will focus on levocabastine, a new H-receptor antagonist, specifically developed for the topical treatment of seasonal allergic rhinoconjunctivitis and a comparison of the therapeutic efficacy of this agent with that of two other widely used and anti-allergic agents, the oral Hi-receptor antagonist terfenadine and the topical mast cell stabilizer sodium cromoglycate. In particular, emphasis will be placed on the comparative efficacy of these different therapeutic approaches for the treatment of seasonal allergic rhinoconjunctivitis on days with high pollen counts (defined as greater than or equal to 50 pollen particles/m3). Levocabastine versus sodium cromoglycate: A number of clinical trials have demonstrated that topical levocabastine is significantly more effective than sodium cromoglycate for the treatment of seasonal allergic rhinoconjunctivitis, [2][3][4][5] However, in only two of these trials were periods of high pollen counts sufficiently long to permit separate analysis of therapeutic efficacy as a function of the pollen count. 2'5 Although these were independent trials, the study protocols were similar. Both were doubleblind, parallel-group trials in patients with seasonal allergic conjunctivitis, with or without concurrent nasal symptoms. Patients were randomized to receive either levocabastine (0.5 mg/ ml), sodium cromoglycate (20 mg/ml) or matching placebo eye drops at a dose of one drop in each eye four times daily for a period of 4 weeks. Both the patients and the investigators were required to provide global evaluations of therapeutic efficacy at the end of the trial. In addition, the investigators assessed a range of typical symptoms including ocular irritation, itching, redness, lacrimation and eyelid oedema, at the start of the trial, after 2 weeks of treatment and at the end of the study. Symptom severity (C)  0.008). For ocular irritation, the percentage of symptom-free high-pollen days was 57% in the levocabastine group compared with 28% in the was graded on a set scale where 0 absent, sodium cromoglycate group (p < 0.02)and 25% 1 mild, 2 moderate, 3 severe. The same in the placebo treatment group (p < 0.03). In symptoms were assessed by the patients on a addition, lacrimation was absent on 88% of highdaily basis and recorded on a visual analogue pollen days in the levocabastine group compared scale (VAS; 0 absent, 100 severe), with 64% (p 0.05) and 58% (p 0.01) of A total of 60 patients participated in the first days in the other two treatment groups, respecstudy. 2 In all, 18 patients were randomized to tively. receive levocabastine, 21 to receive sodium cro-The incidence of adverse events was similar in moglycate and 21 to receive placebo. After 4 all three treatment groups. Ocular irritation folweeks of treatment, the investigator rated global lowing application of the eye drops was the most therapeutic efficacy to be excellent or good in frequently reported adverse reaction. This was 89% of levocabastine-treated patients compared reported by 13 patients in both the levocabastine with 67% of those who received sodium cro-and sodium cromoglycate treatment groups and moglycate (p 0.03) and 48% of those in the eight of those treated with placebo. placebo group (p 0.007). These findings are suplorted by the results of Analysis of the patients' VAS ratings of another published study2 Twenty-eight patients symptom severity revealed a consistent trend in received levocabastine eye drops, while 32 were favour of levocabastine (Fig. 1). Statistically sig-treated with sodium cromoglycate and 29 nificant differences in favour of levocabastine received placebo. At the end of the 4-week treatwere observed for the predominant symptom of ment period, 87% of levocabastine-treated ocular irritation and the most severe ocular patients rated therapeutic efficacy as excellent or Poor ocular administration. Drainage of the levocabastine eye drops through the lacrimal ducts into the nasal passages is the most likely explanation for this effect.
After 4 weeks of treatment, lacrimation (p < 0.01), ocular redness (p < 0.05) and the most severe ocular .symptom (p < 0.05) were significantl less severe in levocabastine-treated patients than in those who received sodium cromoglycate. Analysis of the patients' diaries revealed that 37% of patients in the levocabastine group were virtually symptom-free (VAS ratings < 10) for at least 75% of the treatment period compared with only 6% of cromoglycate-treated patients (p < 0.01) and 4% of the placebo group (p < 0.01).
This trend was maintained on days with high pollen counts (approximately 54% of the study period) (Fig. 3). A total of 33% of levocabastinetreated patients were virtually symptom-free on Both levocabastine and sodium cromoglycate were well tolerated. As expected, ocular irritation good compared with 689/o of those treated with following administration of eye drops was the sodium cromoglycate (p 0.006) and 63% of most frequently reported adverse effect with an the placebo treatment group (p 0.05) (Fig. 2). incidence of 17.9% for levocabastine, 15.6% for Symptom severity was generally lower in the sodium cromoglycate and 27.6% in the placebo levocabastine treatment group. Investigator treatment group. assessments revealed that levocabastine provided significantly greater relief of nasal symptoms after Levocabastine versus oral terfenadine 2 weeks of treatment than either sodium cromoglycate (p < 0.01) or placebo (p < 0.01).
To date, three independent, randomized, This is of interest, as levocabastine was only double-blind, double-dummy, parallel-group trials administered ocularly and systemic absorption of have been published which assess the comparalevocabastine is reported to be minimal following tive efficacy of topical levocabastine and oral ter- to receive either levocabastine eye drops (0.5 mg/ml, one drop in each eye twice daily) and nasal spray (0.5 mg/ml, two puffs in each nostril twice daily) plus a twice daily oral placebo or to receive oral terfenadine (60 mg twice daily) in combination with placebo eye drops and nasal spray for a total of 8 weeks.
Both the patients and the investigators performed a global evaluation of therapeutic efficacy at the end of the study period. In addition, the investigators rated the severity of ocular symp- basis using a VAS (0 absent, 100 severe).
The results of these studies show that levocaperiod, levocabastine was consistently more bastine eye drops and nasal spray are at least as effective than oral terfenadine at controlling effective as oral terfenadine for the treatment of symptoms of seasonal allergic rhinoconjunctivitis. this allergic condition and statistically significant The incidence of severe lacrimation and ocular differences in favour of topical levocabastine itching was significantly lower in the levocabaswere reported even though patients in the terfetine group on days with high pollen counts (p < nadine group also benefited from the use of 0.05), while the percentage of days free from placebo eye drops and nasal spray. In particular, ocular and nasal itching (p < 0.05) and lacrimathe available data suggest that topical levocabastion (p < 0.01) was significantly higher (Fig. 4).
tine is more effective than oral terfenadine on These findings are supported by those of a days with high pollen counts. <s A total of 115 smaller trial initiated primarily to assess the tolerpatients with a documented history of grass and/ ability of levocabastine eye drops. In this study, or birch pollen-induced allergic rhinoconjunctivi-13 patients were randomized to receive topical tis participated in the larger of these two trials, 8 levocabastine while 14 were treated with oral ter-58 of whom were randomized to receive topical fenadine. Use of oral medication and eye drops levocabastine. Both treatment regimens were was mandatory, however, patients were requested well-tolerated and the incidence and type of only to use the nasal spray as required. The use adverse reactions were similar in the two treat-of nasal spray was lower in the levocabastine ment groups, group (46%) than in the terfenadine group Global evaluations of therapeutic efficacy (56%), suggesting that topical levocabastine was revealed a consistent, yet non-significant, trend in more effective at relieving nasal symptoms than favour of the topical approach. However, after 4 oral terfenadine. weeks of treatment, investigator assessments In all, 88% of levocabastine-treated patients revealed that the severity of ocular redness and considered the effect of treatment on ocular the most severe ocular symptom were sig-symptoms to be excellent or good compared nificantly lower in the levocabastine group than with 75% of those who received terfenadine, in the terfenadine group (p < 0.01 and p< 0.05, while 75% of patients in each group were satisrespectively). Analysis of the patients' diaries fled with the effect of the study medication on revealed that VAS ratings were significantly lower nasal symptoms. Investigator assessments in the levocabastine group for ocular and nasal revealed that symptom severity was consistently itching (p < 0.05), lacrimation (p 0.001)and lower in the levocabastine treatment group. In the most severe ocular symptom (p < 0.05). In particular, the severity of ocular itching was sigaddition, the percentage of symptom-free days nificantly lower (p 0.02) in levocabastinewas generally higher in the levocabastine group, treated patients than in those who received terfewhile the percentage of days with severe sympnadine after 8 weeks of treatment. toms tended to be lower.
Analysis of the patients' VAS ratings revealed High pollen counts were recorded during a that levocabastine was significantly more effective consecutive period of 2 weeks. During this than terfenadine for sneezing (p 0.03), rhino-]-"] L Levocabastine (n=57) $24 rrhoea (p 0.05) and the most severe nasal symptom (p 0.02). Furthermore, the percentage of days with severe nasal congestion (p 0.01), rhinorrhoea, sneezing, itching, the most severe nasal symptom (p < 0.01) and the most severe of all symptoms (p 0.04) were also significantly lower in the levocabastine group.
Analysis of therapeutic efficacy as a function of the pollen count revealed that this trend was maintained on high pollen days. Levocabastine provided significantly greater relief from all nasal symptoms (p 0.001-0.02) and for the most severe of all symptoms (p 0.04) than oral terfenadine on days when the pollen count was high.
Both treatment regimens were well tolerated. Ocular irritation was the most common adverse reaction with a similar incidence in the two treatment groups.

Implications for patient management
Clinical experience to date clearly demonstrates that levocabastine eye drops and nasal spray are effective and well tolerated for the treatment of seasonal allergic rhinoconjunctivitis 9 with a number of comparative trials revealing that topical levocabastine is at least as effective as sodium cromoglycate and oral terfenadine for the treatment of this common condition, even on days with high pollen counts. Studies have shown that treatment efficacy is maintained for up to 4 months, 1 indicating that topical levocabastine is suitable for long-term therapy throughout the hay fever season.
Topical levocabastine has a number of distinct advantages over other agents used to treat seasonal allergic rhinoconjunctivitis. Firstly, levocabastine has an extremely rapid onset of action providing almost immediate relief from symptoms. 11'12 Moreover, unlike sodium cromoglycate, levocabastine is also effective when administered after allergen challenge.
In addition, the duration of action of levocabastine is sufficient to permit a convenient, twicedaily schedule. Patient compliance with such a regimen is likely to be good. In contrast, other topical agents for the treatment of seasonal allergic rhinoconjunctivitis must be administered as frequently as six times daily.
It is obviously important that any anti-allergic medication is well tolerated during long-term therapy. Although oral Hi-receptor antagonists such as terfenadine are generally well tolerated, topical application of a Hi-receptor antagonist is preferable as a topical drug is associated with a minimal risk of systemic adverse effects. Levocabastine eye drops and nasal spray are both well tolerated. Local irritation following administration is the most frequently reported adverse reaction associated with topical levocabastine, however the incidence is comparable with that observed following administration of placebo or sodium cromoglycate.
In conclusion, topical levocabastine is an attractive alternative to other common therapeutic approaches for the treatment of seasonal allergic rhinoconjunctivitis and the available clinical data clearly support its use as a first-line therapy for the treatment of this common condition.