A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management

Levocabastine is a highly potent and selective H1-receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.


Introduction
Histamine Hi-receptor antagonists are widely considered to be a primary treatment option for the clinical management of allergic rhinoconjunctivitis. However, although the clinical efficacy of second generation non-sedating oral antihistamines is well documented, topical therapy may be preferable due to the reduced potential for systemic adverse effects.
Topical therapy available for the treatment of allergic conjunctivitis includes corticosteroids, sodium cromoglycate and vasoconstrictors, either administered alone or in combination with an Hi-receptor antagonist. Intranasal corticosteroids provide effective relief from nasal symptoms and are generally well tolerated. However, ocular steroid administration should generally be avoided due to an associated risk of 81aucoma, cataracts and opportunistic infections. Sodium cromoglycate is a well tolerated agent for the prophylaxis of allergic rhinoconjunctivitis and is suitable for both intranasal and ocular administration. The therapeutic efficacy of this drug is highly variable and maintenance therapy throughout the period of allergen exposure is essential. Topical vasoconstrictors provide effective relief only for nasal obstructive symptoms and are only suitable for short-term therapy due to the potential for rebound vasodilatation during prolonged use. 3,4 Until recently, topical antihistamines have not been sufficiently potent to enable single agent therapy, necessitating co-administration of a vasoconstrictor. While reports suggest that such combinations may be more effective than Vasoconstrictor monotherapy, 5 they are not suitable for long-term use due to the adverse reactions associated with topical vasoconstrictors.

Levocabastine
Levocabastine is an extremely potent and highly selective Hi-receptor antagonist which has been specifically developed for topical ocular and nasal administration. Levocabastine is the most potent antihistamine available to date expressing antihistaminic activity at doses lower than 0.002 mg/kg, making it some 15 000 times more potent than chlorpheniramine. 7 In addition, animal studies have shown that this agent has a very ,high specificity for HI-receptors being devoid of anticholinergic, antiserotoninergic or antidopaminergic activity at concentrations S26 Mediators of Inflammation Vol 4 (Supplement) 1995 (C) 1995 Rapid Communications of Oxford Ltd considerably greater than effective antihistaminic doses. This suggests that adverse reactions resulting from a lack of receptor specificity are unlikely. Levocabastine is a potent inhibitor of experimentally induced rhinocon-junctivitis providing effective relief from symptoms within minutes of instillation,  with comparative clinical trials demonstrating that this agent is at least as effective as oral antihistamines in patients with clinical disease. [14][15][16][17] Pharmacokinetic analysis suggests that the potential for systemic adverse effects is very low. Levocabastine is incompletely absorbed after intranasal and ocular administration with systemic availability typically ranging from 30-60% for the eye drops and 60-80% for the nasal spray. s Moreover, as the amount of drug applied topically is small, the plasma concentration of levocabastine attained via these routes of administration is extremely low with Cmax values in the range of 0.2-0.29 mg/1 for levocabastine eye drops and 1.4-2.2 mg/1 for the nasal spray. Detailed pharmacokinetic-pharmacodynamic modelling confirms those findings, indicating that the clinical benefits seen with this agent are predominantly due to local antihistaminic effects at the site of application. 9 Coupled with the fact that levoca-bastine is subject to minimal hepatic metabolism, this suggests that the potential for systemic adverse reactions is minimal.
The present review aims to summarize the data available to date concerning the tolerability and safety of levocabastine eye drops and nasal spray with particular reference to implications for the clinical management of patients with allergic rhinoconjunctivitis.

Tolerability
The tolerability of levocabastine eye drops and nasal spray has been extensively evaluated in clinical trials. The available data suggests that topical levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate or placebo. Analysis of data from a total of 1628 patients treated with levocabastine eye drops reveals that local irritation is the most frequently reported adverse event following ocular administration with an incidence of 14%. Of 1758 patients who have received levocabastine nasal spray, headache (4%), nasal irritation (3%), somnolence (3%) and fatigue (2%) have been reported. The  is 24%. In separate studies the incidence has wide range of objective ophthalmological tests been comparable for levocabastine and placebo including slit lamp evaluation, tonometry, fluor-(27 versus 31%), levocabastine and cromoglycate escein and rose bengal staining, ophthalmoscopy (36 versus 31%) and levocabastine and terfena-and determination of intraocular pressure, visual dine (40 versus 41%). Figure 1 shows the toleracuity and visual fields. These studies have failed ability of levocabastine compared with sodium to reveal any significant or consistent adverse cromoglycate and placebo, effects attributable to the topical antihistamine at In addition, no clinically significant changes in doses of up to 4 times daily and treatment durabiochemical or haematological parameters have tions of up to 8 weeks. 2 been reported during treatment with this topical As many traditional antihistamines have been antihistamine in clinical trials that have perassociated with anticholinergic activity, which formed routine laboratory tests to date. Sig-may be expected to influence accommodative nificandy, the type and frequency of adverse capacity, the effects of ocular administration of experiences appears to be unrelated to the levocabastine on accommodation have been number of daily applications. Moreover, adverse investigated in healthy volunteers and in patients effects do not appear to be increased by con-with glaucoma. 24 Administration of a single dose comitant use of the eye drops and nasal spray of levocabastine (0.5 mg/ml)was found to have compared with use of either formulation alone, no effect on accommodative capacity in healthy Drug tolerability is a key factor determining volunteers. Similarly, accommodative capacity and choice of therapy in children. Importantly, a intraocular pressure were unchanged in patients study involving 53 children aged between 6 and with glaucoma during twice daily treatment with 15 years reported that levocabastine nasal spray ocular levocabastine over a period of 2 weeks. and eye drops are well tolerated in this patient These findings are in keeping with the highly population with type and incidence of adverse selective pharmacological profile of the drug. reactions similar to those occurring in sodiumcromoglycate-treated children. 2 Psychomotor effects of levocabastine: Many traditional H-receptor antagonists cross the blood-Local tolerance.. It is well documented that intra-brain barrier producing unwanted central nasal administration of certain drugs and addinervous system effects. Increased daytime somfives, in particular decongestants, can influence nolence and reduced alertness, are frequent ciliary activity of the upper airways. 2 The influ-adverse reactions particularly encountered with ence of levocabastine on ciliary beat frequency many first-generation oral antihistamines. and mucociliary clearance has been evaluated in Pharmacokinetic studies indicate that sedative vitro using human adenoid tissue and in vivo effects would be extremely unlikely in patients following single and multiple dose administration receiving intranasal or ocular levocabastine due in healthy human volunteers. 22 Levocabastine was to the low plasma concentrations of the drug seen to have only a small, clinically insignificant obtained by these routes of administration. effect on ciliary beat frequency in human Specific studies of psychomotor and cognitive adenoid tissue. No significant effects on ciliary function following topical administration of levofunction were observed following single-and cabastine support these findings. Objective multiple-dose administration in healthy volunassessment of psychomotor performance and teers, subjective assessment of sedation have failed to Ocular tolerance of levocabastine has been reveal any central nervous system effects in evaluated extensively. Animal studies have failed healthy volunteers treated with levocabastine eye to reveal any adverse effects resulting from drops (0.5 mg/ml, two drops in each eye, four topical administration of levocabastine eye drops, times daily) over a period of 1 week. 25 Potential In an eye irritation study in rabbits, application of central nervous system effects of levocabastine levocabastine eye drops four to eight times daily have also been investigated following single-and for 4 weeks did not produce ocular changes, and multiple-dose administration of levocabastine eye in another study, normal intraocular pressure was drops and nasal spray, and compared with those found to be maintained in rabbits following of oral triprolidine. Performance was assessed application of levocabastine. Levocabastine did following medication by a battery of cognitive not induce dermal sensitization when tested in and psychomotor tests considered as reliable guinea-pigs using the Magnusson maximization measures of the sedative effects of psychoactive technique. 18 drugs. In contrast to the significant sedative The local tolerance of levocabastine eye drops effects of triprolidine, topical administration of has also been extensively evaluated in volunteers levocabastine eye drops and nasal spray at doses and atopic patients during clinical trials using a up to 2.0 mg/ml, a dose level four times greater than normal therapeutic dosages, had no demonstrable effect on central nervous system function in healthy volunteers. 2 Potential pharmacokinetic and psychomotor interactions between levocabastine nasal spray and alcohol or diazepam have also been investigated in healthy volunteers. No evidence of significan psychomotor interactions between levocabastine and either ethanol or diazepam are apparent. Cardiovascular effects of levocabastine: Possible cardiovascular effects of levocabastine have been assessed in vitro on isolated Purkinje fibres of dogs and in vivo in animal studies and in human volunteers following oral, ocular and nasal administration. In vitro studies on isolated Purkinje fibres revealed no effect of levocabastine on action potential amplitude and action potential duration at 50% and 90% repolarization at doses of up to 2.5 mg/1. Similarly, oral administration of doses of up to 0.16 mg/kg have revealed no significant effect on key cardiovascular parameters in dogs.
More relevantly, levocabastine does not appear to produce significant ECG effects in man. Several studies in healthy volunteers (Fig. 2) have revealed no significant effects on QTor QTcintervals after treatment with levocabastine in single or repeated doses, even when the eye drops and the nasal spray are used in combination four times daily (1.2 mg/day) or after administration of oral levocabastine 3 mg daily (for 3 days).27 Drug interactions: As levocabastine plasma con-centrations are extremely low following topical administration and hepatic metabolism is negligible, clinically significant drug interactions are unlikely. But since binding studies have revealed that levocabastine binds to plasma proteins, particularly albumin, the potential for drug interactions involving binding site displacement exists. However, in vitro analysis of potential pharmacokinetic drug interactions have identified levocabastine does not alter the plasma protein binding of imipramine, propranolol, diphenylhydantoin, diazepam, cimetidine, indomethacin or ketoconazole although slight increases in the proportion of unbound levocabastine can be identified with drugs which are highly protein-bound such as sulphamethazine (4.5%), tolbutamide (6%) and warfarin (8.19/o). Although such changes are minor they should be recognized. Obviously this interaction is of no clinical relevance for levocabastine as its plasma protein binding is only 55%. 18

Conclusion
Extensive clinical investigations have shown levocabastine eye drops and nasal spray to be highly effective for the treatment of allergic rhinoconjunctivitis. Levocabastine eye drops and nasal spray are well tolerated with an adverseeffect profile comparable with that of sodium cromoglycate and placebo. Local irritation following administration is the most common adverse reaction reported in levocabastine-treated patients to date with an incidence similar to that seen in placeboor cromoglycate-treated controis. Importantly, the potential for systemic adverse effects is negligible. As would be expected from its pharmacological profile, levocabastine is devoid of significant systemic activity having no apparent effects on cardiovascular function, psychomotor performance, cognitive function and minimal interaction potential. Coupled with its well documented therapeutic efficacy, these findings indicate that topical levocabastine is an attractive therapeutic option for the treatment of allergic conjunctivitis.