Treatment of allergic rhinoconjunctivitis: a review of the role of topical levocabastine

Lcocabastine is an extremely potent and highly selective H1-receptor antagonist which has been specifically developed as eye drops and nasal spray for the treatment of allergic rhinoconjunctivitis. Clinical experience to date suggests that this topical antihistamine is at least as effective as other current first-line therapeutic approaches for the treatment of this condition, including oral H1-receptor antagonists and sodium cromoglycate. Onset of action is rapid, with clinical effects apparent within minutes of instillation. Moreover, duration of action is sufficiently long to permit a convenient twice-daily dosing regimen. Topical levocabastine is well tolerated with an adverse-effect profile comparable with that of placebo and sodium cromoglycate. As might be expected from the route of drug administration, application site reactions are the most frequent adverse effect associated with levocabastine eye drops and nasal spray with an incidence comparable with that seen in placebotreated controls. The availability of effective and well-tolerated topical antihistamines, such as levocabastine, is an important advance which broadens the range of therapeutic approaches available for the clinical management of allergic rhinoconjunctivitis. Levocabastine appears to be an attractive alternative to oral antihistamines as a first-line therapeutic option for the treatment of this atopic condition.

LCOCABASTINE is an extremely potent and highly selective HI-receptor antagonist which has been specifically developed as eye drops and nasal spray for the treatment of allergic rhinoconjunctivitis. Clinical experience to date suggests that this topical antihistamine is at least as effective as other cm-nt first-line therapeutic approaches for the treatment of this condition, including oral Hi-receptor antagonists and sodium cromoglycate. Onset of action is rapid, with clinical effects apparent within minutes of instillation. Moreover, duration of action is sufficiently long to permit a convenient twice-daily dosing regimen. Topical levocabastine is well tolerated with an adverse-effect profile comparable with that of placebo and sodium cromoglycate. As might be expected from the route of drug administration, application site reactions are the most frequent adverse effect associated with levocabastine eye drops and nasal spray with an incidence comparable with that seen in placebotreated controls. The availability of effective and well-tolerated topical antihistamines, such as levocabastine, is an important advance which broadens the range of therapeutic approaches available for the clinical management of allergic rhinoconjunctivitis. Levocabastine appears to be an attractive alternative to oral antihistamines as a first-line therapeutic option for the treatment of this atopic condition. Epidemiology and Aim of Therapy Mlergic rhinoconjunctivitis is a common atopic condition which is frequently encountered in clinical practice, with current estimates suggesting that as many as 22% of the general population may be affected. Available epidemiological data suggest that the incidence of this atopic disorder 12 is increasing,' particularly in urban areas, possi- [2][3][4] bly as a result of environmental pollution. The relationship between air pollution and the prevalence of allergic disease is, however, complex. Analysis of the prevalence of respiratory diseases and atopic disorders in German children has revealed that the prevalence of allergic disorders was lower in the former East Germany than in West Germany in spite of higher pollution levels. 5 Characteristic clinical manifestations include nasal itching, sneezing, rhinorrhoea and congestion, often accompanied by ocular symptoms of lacrimation, redness and itching. Causative allergens are diverse and include grass, tree and weed pollens, fungal spores, house dust mite and animal dander.
The medical and socioeconomic impact of allergic rhinoconjunctivitis is often underestimated. Although rarely associated with longterm clinical complications, symptoms may be sufficiently severe to impact on the patient's quality of life, with almost all patients experiencing a degree of sleep impairment, limitation of normal daily activities and emotional distress. 6 These findings are supported by data from the US Department of Health which reveal that allergic rhinoconjunctivitis accounts for more than 2 million lost school days and 3.5 million lost work days every year in the USA alone. 7 Treatment of allergic rhinoconjunctivitis should not only be aimed at direct amelioration of symptoms. The subsequent inflammation after allergen exposure may induce non-specific hyperreactivity and nasal priming. '9 Reduction of this inflammation may therefore be expected to interrupt the vicious circle of early and late sequelae of allergen exposure, including nasal hyperreactivity. Indeed, it has been demonstrated that treatment of the nose may have a beneficial effect on lung function and bronchial hyper- R. G. van Wijk responsiveness in patients with concurrent a number of advantages over an orally adminisasthma. 1'11 tered drug, including a faster onset of action, The fundamental approach to the treatment of since it is applied directly to the affected site, and allergic rhinoconjunctivitis is environmental a reduced potential for systemic adverse effects. control, combined with appropriate antiallergic Until recently, however, topical administration of drug therapy and, in selected cases, specific Hi-receptor antagonists has not been feasible as immunotherapy. Levocabastine is a novel H1-the available agents have not been sufficiently receptor antagonist which has been specifically potent to permit single agent therapy. Topical developed for the topical treatment of allergic treatment for allergic rhinoconjunctivitis was rhinoconjunctivitis. The aim of this paper is to therefore limited to sodium cromoglycate, vasoreview the clinical experience of this topical anticonstrictors and corticosteroids. histamine available to date, with particular refer- The mast cell stabilizer, sodium cromoglycate, ence to the implications for patient management, is both effective and well tolerated for the prophylaxis of allergic rhinoconjunctivitis. However, it has a slow onset of action and may take several Pathophysiology: the Role of Histamine days to achieve full therapeutic effects. As a Our understanding of the pathophysiology of result, treatment should preferably be initiated allergic rhinoconjunctivitis has increased conprior to allergen exposure and maintenance siderably in recent years revealing a number of therapy is essential in patients with frequent potential targets for pharmacological intervention, symptoms. As sodium cromoglycate requires fre-Therapeutic approaches available for the clinical quent instillation, sometimes as often as six times management of this atopic condition include H1-daily, patient compliance with a long-term mainreceptor antagonists, vasoconstrictors, cortico-tenance regimen is likely to be problematic. steroids, and mast cell stabilizers, such as sodium Like sodium cromoglycate, topical vasoconcromoglycate. Although multiple inflammatory strictor and antihistamine/vasoconstrictor combimediators have been implicated in the pathogennations are also limited by the need for frequent esis of allergic rhinoconjunctivitis, histamine instillation. Furthermore, although these topical appears to play a prominent role. 12 Experimental preparations provide rapid wmptomatic relief, allergen challenge studies have revealed that his-they are only suitable for short-term use. Longtamine is the only mediator which produces the term administration is associated with rebound full spectrum of clinical manifestations of the vasodilatation which may result in rhinitis and acute allergic reaction when applied to the nasal conjunctivitis medicamentosa. 17 '18 These agents and ocular mucosa. The available pathophysio-should, therefore, generally not be used for more logical evidence therefore supports the current than 5 to 7 days consecutively. clinical practice for use of Hi-receptor antago-Topical corticosteroids are highly effective antinists as a primary treatment option. 1 inflammatory agents, however they also have a The efficacy and tolerability of oral anti-slow onset of action, typically taking several days histamines in the treatment of allergic rhinoto achieve full therapeutic effects.
Conseconjunctivitis is well documented..14 However, quently, these agents are most effective when although the reported incidence of adverse reacadministered prophylactically and treatment tions such as sedation is minimal with newer should preferably be initiated prior to the onset drugs of this class, the potential for unwanted of symptoms for maximum clinical benefit. Fursystemic effects, as exemplified by the arrhythmic thermore, while intranasal corticosteroids are effects seen with certain oral antihistamines, generally well tolerated and the risk of suppresclearly exists. 5 In addition, as might be expected sion of the hypothalamic-pituitary-adrenal axis from the route of drug administration, onset of is low following topical application of these action with oral antihistamines is relatively slow.
drugs, long-term ocular administration should Peak antihistaminic activity ils4 typically not generally be avoided due to the potential for observed for several hours, necessitating serious adverse effects including glaucoma, cataradministration prior to allergen exposure for acts and severe corneal infections. 9 maximum clinical benefit.
Two topical antihistamine preparations are now available for the treatment of allergic rhino-Rationale for Topical Therapy conjunctivitis, levocabastine and azelastine. Levocabastine is an extremely potent and highly Treatment for allergic rhinoconjunctivitis need selective H-receptor antagonist which has been not necessarily be systemic. Topical therapy is specifically developed as eye drops and nasal possible due to the accessibility of the affected spray for the topical treatment of allergic rhino- 20 21 tissues. A topical agent may be expected to have conjunctivitis.
Azelastine appears to possess S32 Mediators of Inflammation Vol 4 (Supplement)-1995 other anti-allergic properties in addition to its antihistaminic activity which may be of benefit to patients with this atopic condition, but is currently only available as a nasal spray necessitating combination therapy with other anti-allergic agents in patients with concurrent ocular symptoms.

The Efficacy of Levocabastine in Adults
Levocabastine is the most potent antihistamine available to date, expressing antihistaminic activity at doses lower than 0.002 mg/kg, with in vitro data derived from the compound 48/80 lethality test in rats suggesting that it is 15 000 times more potent than chlorpheniramine and 1000 times more potent than azelastine. 22'23 Levocabastine has a highly specific binding affinity for Hreceptors, with no evidence of anticholinergic activity at doses considerably in excess of therapeutic concentrations. Detailed pharmacokinetic analysis demonstrates that levocabastine is well suited to the topical treatment of allergic rhinoconjunctivitis, with the clinical benefits seen with this agent being predominantly mediated by local antihistaminic effects in the ocular and nasal mucosa. 24,25 Histamine and allergen challenge studies have shown that levocabastine is a potent inhibitor of the allergic response in the human eye and nose.  Onset of action is rapid, with significan symptomatic relief _typically seen within 28 3o minutes of administration.
Duration of action is sufficiently long to permit a convenient twice daily dosing schedule. 2 A comprehensive programme of clinical trials has been undertaken to assess the therapeutic efficacy of topical levocabastine for the treatment of allergic rhinoconjunctivitis in adults. Key findings from studies published to date are summarized below.
Levocabastine and oral antihistamines: A number of clinical trials have assessed the comparative efficacy of levocabastine and secondgeneration oral antihistamines. 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) have been shown to be at least as effective as oral terfenadine (60 mg twice daily) for the treatment of seasonal allergic rhinoconjunctivitis in double-blind studies involving more than 350 patients to date. A number of statistically significant differences in favour of the topical antihistamine have also been reported in some trials. 34 good in 80% of levocabastine-treated patients compared with 73% in those who received terfenadine, with the effect of therapy on nasal symptoms being excellent or good in 62% and 61% of patients in the two groups, respectively (Fig. 1). 33 Similarly, twice daily treatment with levocabastine eye drops and nasal spray has been shown to be at least as effective as oral loratadine (10 mg) once daily in a recent double-blind, primary care based trial involving 95 patients with seasonal allergic rhinoconjunctivitis. 6 A non-significan trend in favour of the topical antihistamine was apparent at the end of the 5-week treatment period, with an excellent or good response to therapy observed in 86% of levocabastine-treated patients compared with 77% for those who received loratadine.
As a double-dummy technique was used in these trials to blind study medication, patients treated with oral H-receptor antagonists also received placebo eye drops and nasal spray. Response rates as high as 73% have been associated with the use of topical placebos, 7  As might be expected from the route of drug administration, onset of action was found to be significantly more rapid in patients treated with topical levocabastine than in those who received oral cetirizine (p < 0.001). In all, 36% of levocabastine-treated patients reported relief from nasal symptoms within 15 min of drug administration compared with 10% of those on cetirizine. Corresponding values for ocular symptoms were 32% and 17% in the two groups, respectively, at this time (Fig. 2). Therapeutic efficacy was generally found to be comparable in the two treatment groups, with no statistically significant intergroup differences reported during the course of the trial. In all, 61% of levocabastinetreated patients rated global therapeutic efficacy to be excellent or good compared with 62% on cetirizine.
Levocabastine and azelastine: The comparative efficacy of levocabastine nasal spray (0.5 mg/ml, two puffs per nostril twice daily) and topical azelastine (1 mg/ml, one puff per nostril twice daily) in the treatment of allergic rhinitis has been evaluated in a total of 242 patients in an open-label, randomized trial. 39  week. Onset of action was found to be comparable for the two topical antihistamines, with over 50% of patients in each group reporting significant relief from symptoms within 30 min of study drug administration. In general, therapeutic efficacy was also similar in the two treatment groups with a comparable reduction in the severity of all symptoms, including nasal congestion, seen in both treatment groups. Assessments of global therapeutic efficacy revealed a non-significant trend in favour of levocabastine, with the effect of treatment considered to be excellent or global therapeutic efficacy after week of treatment with levocabastine or azelastine. 39 good in 70% of patients who received levocabastine compared with 63% of those on azelastine (Fig. 3).
Levocabastine and topical corticosteroids: Twice daily treatment with levocabastine eye drops and nasal spray appears to be as effective as twice daily flunisolide nasal spray for the treatment of nasal symptoms of allergic rhinoconjunctivitis, according to the results of a randomized, parallel-group, single-blind study involving a total of 66 patients. 4 At the end of the 1 month treatment period, response to therapy was found to be excellent or good in 53% of levocabastinetreated patients compared with 64% of those who received the topical corticosteroid (N.S.). In this study, corticosteroid-treated patients also received naphazoline/antazoline eye drops four times daily. Levocabastine was found to provide significantly greater relief from concurrent ocular symptoms than this vasoconstrictor/antihistamine combination, with an excellent or good response to therapy reported in 47% and 19% of patients in the two groups, respectively, at the end of the trial (p < 0.05). It is well documented that oral antihistamines are generally less effective than topical corticosteroids for the relief of nasal congestion. 41 '42 This is not surprising as other mediators such as kinins, prostaglandin D2 and leukotrienes C4 and D4 are also known to increase nasal airway resistance. 43 '44 In order to assess whether combination therapy with an intranasal steroid could provide additional clinical benefit to that seen with a topical antihistamine alone, the efficacy of beclomethasone diproprionate nasal spray was evaluated as add-on therapy in a double-blind trial in 44 patients with allergic rhinitis who were already receiving intranasal levocabastine. 45 As might be expected, the severity of nasal congestion was found to be significantly lower in patients receiving both agents (p < 0.001), however, combination therapy was not associated with any additional improvement in the severity of other symptoms of allergic rhinitis compared with that seen with levocabastine alone (Fig. 4). t G. van Wijk significantly more effective for the treatment of those who have received levocabastine eye allergic rhinoconjunctivitis than topical therapy drops. This compares with incidences of 4% and with sodium cromoglycate (Fig. 5). To date, two 15% for topical placebos, and 5% and 16% for double-blind trials, involving a total of 114 sodium cromoglycate nasal spray and eye drops, patients with allergic rhinitis, have been pubrespectively. lished which compare the efficacy of levocabas-Levocabastine appears to be better tolerated tine nasal spray (0.5 mg/ml; two puffs per nostril than azelastine. Results of the only comparative four times daily) with that of intranasal sodium study of levocabastine and azelastine undertaken cromoglycate (20 mg/ml; two puffs per nostril to date reveal significantly higher incidences of four times daily). 46 '47 In both trials, levocabastine application site reactions and taste disturbances was found to be significantly more effective than in azelastine-treated patients than in those who sodium cromoglycate at the end of the 2-week received levocabastine (5% versus 1%; p < 0.05, treatment period, with an excellent or good and 5% versus 0%; p < 0.01, respectively). 9 response to therapy seen in 76% and 46% of Levocabastine also appears to be better tolerated patients in the two groups, respectively (p < than other topical therapeutic approaches, with 0.01). Levocabastine eye drops (0.5 mg/ml; one local irritation following administration reported drop in each eye twice daily) also appear to in up to 36% of patients receiving the vasoconprovide significantly greater relief from symptoms strictor/antihistamine eye drops naphazoline/ of allergic conjunctivitis than ocular sodium cro-antazoline, and 25% of those treated with the moglycate (20 mg/ml; one drop in each eye four intranasal steroid flunisolide. 4 times daily). In two double-blind, placebo-con-Long-term ocular administration of levocabastrolled studies involving a total of 158 patients, tine appears to be well tolerated, with comprean excellent or good response to therapy was hensive ophthalmological examinations in observed in 87% of levocabastine-treated patients patients receiving levocabastine eye drops revealcompared with 78% in those who received ing no serious adverse effects to date. 5 Similarly, sodium cromoglycate (p < 0.05). 48 '49 there has been no evidence of tachyphylaxis or rebound in patients receiving levocabastine eye drops, to date, with treatment durations of up to The Efficacy of Levocabastine in Children 4 months. 54 The therapeutic efficacy of topical levocabas-In addition, it is important that a nasal spray tine for the treatment of allergic rhinoconjunctivi-should not affect ciliary function. The effects of tis in paediatric patients has been assessed in levocabastine nasal spray on ciliary function have studies involving more than 300 children and a been studied in vitro on human adenoid tissue comprehensive review of the role of topical anti-and in vivo in healthy volunteers. Levocabastine histamine therapy in this patient population has was not found to affect either ciliary beat frebeen published. 5 Clinical experience, to date, quency or mucociliary transit time suggesting that suggests that topical levocabastine is at least as ciliotoxicity during long-term intranasal adminiseffective and well tolerated as the current firsttration is extremely unlikely. 55 line therapy for the treatment of allergic rhinoconjunctivitis in children, sodium cromoglycate, The Role of Levocabastine both as monotherapy or in combination with oral antihistamines, with a number of statistically An understanding of the immunological events significant differences in therapeutic efficacy in during and after allergen exposure is necessary favour of the topical antihistamine reported in for the optimal clinical management of allergic the largest of these trials. 5 rhinoconjunctivitis. As in bronchial asthma, a step-wise approach to therapy appears to be Tolerability indicated depending on symptom frequency and severity.

Levocabastine eye drops and nasal spray
The basic approachin the clinicalmanagement appear to be well tolerated with an adverse effect of any allergic disorder is environmental control. profile comparable with that seen with sodium Following identification of the causative allergen, cromoglycate or placebo. 52 As might be expected measures to reduce allergen exposure and from the route of drug administration, applicaappropriate patient education are essential. tion site reactions are the most frequent adverse However, in many patients, complete allergen effect associated with topical levocabastine. In avoidance may be difficult to achieve. Specific large scale clinical trials, local irritation following immunotherapy may also be beneficial if the cauapplication has been reported in 3% of patients sative allergen is well defined, especially in modtreated withlevocabastine nasal sprayand 14% of erate to severe pollen allergy, however the individual response to therapy with other allergens is highly variable. Consequently, almost all patients with allergic rhinoconjunctivitis will also require appropriate anti-allergic medication.
The wide range of pharmacological approaches available for the clinical management of allergic rhinoconjunctivitis enables treatment to be individualized according to patient needs. Oral H-receptor antagonists are generally considered as first-line therapy due to the central role of histamine H-mediated effects in the pathogenesis of this allergic condition. 12 rapid onset of action, such as levocabastine, may be a more appropriate therapeutic choice. Topical levocabastine appears to be at least as effective as oral antihistamines for the treatment of allergic rhinoconjunctivitis, with the advantage of a significantly more rapid onset of action 8 and, in particular, may provide greater relief from symptoms on days with high pollen counts. 56 Furthermore, topical levocabastine is at least as effective as azelastine nasal spray, with the advantage of a more favourable tolerability profile and the availability of eye dro9Ps for the relief of concurrent ocular symptoms.
It is well documented that nasal congestion is generally less responsive to treatment with HIreceptor antagonists than other symptoms of allergic rhinoconjunctivitis. 41'42 Mthough preliminary data suggest that topical levocabastine may provide more effective relief from nasal symptoms than oral antihistamine therapy, 4'5 concurrent treatment with an intranasal steroid, or a topical or oral decongestant, may be indicated in patients with more severe daily symptoms, particularly if nasal congestion is predominant. The available data suggest that addition of an intranasal steroid provides significantl greater relief from nasal congestion than treatment with levocabastine nasal spray alone. 45 Sodium cromoglycate is often considered as a primary treatment option for the treatment of allergic rhinoconjunctivitis in children due to its excellent adverse-effect profile. Results from paediatric trials suggest that levocabastine may be a more appropriate first-line therapy in this patient population being significantly more effective and as well tolerated. 5'5 A proposed algorithm for the treatment of allergic rhinoconjunctivitis is shown in Fig. 6. It is apparent that the availability of an effective and well-tolerated topical antihistamine, such as levocabastine, is an important advance which broadens the range of therapeutic approaches available for the clinical management of allergic rhinoconjunctivitis. Clinical evidence available to date suggests that levocabastine is an attractive alternative to oral antihistamines and that this topical antihistamine should be considered as a first-line therapeutic option for the treatment of this atopic condition.