, Volume 50, Issue 6, pp 1032-1049

Levocabastine

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Summary

Synopsis

Levocabastine is a potent and selective histamine H1-receptor antagonist which has been evaluated as a topical treatment (nasal spray and/or eyedrops) for allergic rhinitis and/or conjunctivitis. Data available at the time of the previous review in Drugs, together with more recent results, have clearly demonstrated that levocabastine nasal spray and eyedrops are clinically effective, have a rapid onset of action and are well tolerated in patients with nasal and/or ocular allergic conditions.

Previous evidence indicating that topical levocabastine has efficacy similar to or better than that of topical sodium cromoglycate (cromolyn sodium) has been confirmed in more recent studies. Furthermore, results from a number of controlled clinical trials have also shown that topical levocabastine is at least as effective as oral terfenadine for the treatment of allergic rhinoconjunctivitis. Notably, topical levocabastine appears to be more effective than oral terfenadine in improving the severity of selected symptoms. Limited data indicating efficacy equivalent to that of oral loratadine, oral cetirizine or azelastine nasal spray will need to be confirmed.

Data from several studies have shown that topical levocabastine has a tolerability profile similar to that of placebo, topical sodium cromoglycate or oral terfenadine. The main adverse events seen in patients treated with topical levocabastine are ocular irritation after application of eyedrops, and headache, nasal irritation, somnolence and fatigue after administration of the nasal spray. Administered doses of topical levocabastine, and subsequent plasma concentrations, are low, and the risk of systemic adverse events is therefore expected to be minimal.

Thus, topical administration of levocabastine provides rapid and effective symptom relief with no apparent serious adverse events in patients with allergic rhinitis and/or conjunctivitis. Topical levocabastine is a useful alternative to topical sodium cromoglycate or oral terfenadine. Additional data supporting current evidence that topical levocabastine can provide more effective symptom relief than oral terfenadine, together with clarification of the relative efficacies of these agents in relation to varying pollen exposure, would help to further confirm its clinical potential. However, the results available to date suggest that the topical formulations of levocabastine are a valuable treatment option in patients with allergic rhinitis and/or conjunctivitis.

Overview of Pharmacology

Levocabastine is a potent antagonist of histamine H1-receptors, which has shown little or no affinity for dopaminergic, adrenergic, serotonergic or opiate receptors in vitro. Topical administration of levocabastine (nasal spray or eyedrops) provides fast and relatively long-lasting relief (onset of action within 15 minutes, duration of action up to 12 hours) from the allergic symptoms caused by experimental allergen challenge in healthy volunteers and patients with allergic conditions. In comparative allergen challenge studies, levocabastine nasal spray and/or eyedrops were more effective than topical treatment with placebo, sodium cromoglycate (cromolyn sodium; eyedrops or nasal spray) or nedocromil (nasal spray).

Levocabastine eyedrops were generally similar to placebo eyedrops or oral terfenadine in their pharmacodynamic effects on a range of ophthalmological criteria. Administration of topical levocabastine has not resulted in any clinically significant effects on psychomotor or cognitive function, nor does it appear to potentiate the effects of alcohol or diazepam.

Information on the pharmacokinetic properties of topical levocabastine is somewhat limited. It is absorbed quickly (time to maximum plasma concentration approximately 1 to 4 hours) but incompletely (single-dose systemic bioavailability of 60 to 80% for the nasal spray and 30 to 60% for eyedrops) in healthy volunteers. Peak plasma concentrations after single-dose administration of levocabastine nasal spray (0.2mg) or eyedrops (0.04mg), respectively, were 1.4 to 2.2 μg/L and 0.26 to 0.29 μg/L in healthy volunteers. Steady-state plasma concentrations are reached after 7 to 10 days of topical treatment. The extent of drug absorption from levocabastine nasal spray or eyedrops in patients with allergic symptoms has been reported to be either increased or decreased in comparison with healthy individuals.

Levocabastine is eliminated primarily by the kidneys (elimination half-life of ≈35 to 50 hours), with about 70% of an oral dose being excreted unchanged in the urine. Although direct comparisons with healthy volunteers are lacking, it appears that renal impairment may be associated with reduced elimination of levocabastine.

Clinical Efficacy

Since the previous review in Drugs, data from several clinical trials have confirmed earlier results which showed that topical levocabastine is at least as effective as topical sodium cromoglycate in providing symptom relief in patients with allergic rhinitis and/or allergic conjunctivitis. In addition, global evaluations of clinical efficacy were similar for topical levocabastine and oral terfenadine in a number of more recent clinical trials involving patients with allergic rhinoconjunctivitis. Good or excellent ratings for nasal symptoms were reported for 63 to 75% of topical levocabastine recipients compared with 61 to 75% of oral terfenadine recipients; for ocular symptoms, the ranges were 76 to 88% and 75 to 81%, respectively. Although investigators’ assessments of symptom severity were generally similar for both treatments, data from patients’ self assessments of individual symptoms indicated some statistically significant differences in favour of topical levocabastine in 2 studies. In addition, topical levocabastine produced more symptom-free days than oral terfenadine in 115 patients with allergic rhinoconjunctivitis. In contrast, no significant differences in efficacy were observed between topical levocabastine and oral terfenadine in 128 patients with allergic rhinoconjunctivitis.

Definitive data are still required to confirm the relative efficacy of topical levocabastine and oral terfenadine on days when the pollen count is high. However, studies to date have shown that topical levocabastine is at least as effective as oral terfenadine under such conditions.

Levocabastine nasal spray (plus eyedrops as required) produced a faster onset of therapeutic action than oral cetirizine in a study of patients with perennial allergic rhinoconjunctivitis. Global efficacy evaluations were similar for both treatments in this investigation and in a comparative study of topical levocabastine and oral loratadine in patients with seasonal allergic rhinoconjunctivitis. Levocabastine nasal spray was as effective as azelastine nasal spray in a single study in patients with allergic rhinitis.

Tolerability

Headache, nasal irritation, somnolence and fatigue are the most commonly reported adverse events in patients receiving levocabastine nasal spray. Ocular irritation after application is the most frequent adverse event in patients treated with levocabastine eyedrops. Severe adverse events were not reported in patients treated with either formulation of topical levocabastine. Indeed, the incidence of adverse events in patients receiving topical levocabastine is similar to that seen in placebo recipients. Recent data have also confirmed previous reports that topical levocabastine has a tolerability profile similar to that of topical sodium cromoglycate.

Results from a number of well-controlled clinical trials have shown that the incidence, type and severity of adverse events experienced by patients receiving levocabastine nasal spray plus eyedrops are similar to those observed in patients receiving oral terfenadine. Levocabastine nasal spray plus eyedrops did not differ significantly from oral cetirizine or oral loratadine with regard to tolerability profile in patients with allergic rhinoconjunctivitis, although data are available only from a single study for each comparison. Levocabastine nasal spray was at least as well tolerated as azelastine nasal spray in a single clinical trial in patients with allergic rhinitis.

Dosage and Administration

Levocabastine is available as a 0.5 mg/ml nasal spray and 0.5 mg/ml eyedrops; the recommended treatment regimen in adults and children is 2 sprays/nostril and 1 drop/eye twice daily. Treatment frequency may be increased to 3 or 4 times daily. Levocabastine nasal spray should be used with caution in patients with renal impairment, although formal dosage recommendations have not been made. Patients receiving levocabastine eyedrops should not wear soft contact lenses.

Various sections of the manuscript reviewed by: M.B. Abelson, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; A. Knight, Sunnybrook Health Science Centre, Toronto, Canada; A.G. Palma-Carlos, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; S. Shuster, The Dental School, The University of Newcastle upon Tyne, Newcastle, England; T.C. Stokes, Brook General Hospital, London, England; K. Tasaka, Department of Pharmacology, Okayama University, Okayama, Japan; N.W. Todd, Section of Otolaryngology, The Emory Clinic, Atlanta, Georgia, USA; J. Zazgornik, Department of Medicine and Nephrology, General Hospital Linz, Linz, Austria.