, Volume 41, Issue 2, pp 202-224

Levocabastine

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Synopsis

Levocabastine is a long acting, highly potent and selective histamine H1-receptor antagonist, which has been developed for nasal and ocular administration. In controlled trials performed to date levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Comparative studies have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate (cromolyn sodium) in alleviating symptoms associated with seasonal allergic conditions. Although levocabastine appears to be less effective than the topical corticosteroid beclomethasone with regard to relieving runny and blocked nose, further comparative trials between these 2 agents would be desirable. Similar to other antihistamines, levocabastine provides minimal relief of nasal blockage, but this symptom is believed to be mediated by receptors other than histamine H1. The prompt onset of antiallergic activity after application differentiates levocabastine from the reference topical antiallergic, sodium cromoglycate, which has an onset of efficacy characterised by a lag period, thereby necessitating maintenance treatment. The incidence of adverse effects associated with levocabastine therapy is low and is similar to that observed with placebo and sodium cromoglycate.

Levocabastine provides prophylactic protection as well as acute relief from nasal and ocular symptoms in patients with seasonal allergic disorders. With the ever increasing trend towards topical therapy for the treatment of allergic rhinitis and allergic conjunctivitis, levocabastine is a useful addition to the range of drugs currently available. Possible avenues for additional research should include determining whether the antiallergic efficacy of topical levocabastine is superior to that of oral agents such as astemizole and terfenadine, and whether topical therapy is indeed preferred, considering the relative ease of administration of effective oral antiallergic agents.

Pharmacodynamic Properties

In vitro receptor binding techniques and drug-receptor dissociation assays have shown that levocabastine has highly specific and potent antihistaminic H1-receptor activity but displays little or no affinity for serotoninergic, dopaminergic, adrenergic or μ-opiate receptor sites. Standard pharmacological tests of antihistaminic activity in animals — such as death caused by histamine and compound 48/80, and histamine-induced skin reaction, bronchoconstriction and conjunctivitis — have established the potency of levocabastine after oral and ocular administration. In humans, levocabastine 0.05% eyedrops displayed potent topical antihistaminic activity in conjunctival provocation tests.

Levocabastine had the highest potency among 12 reference compounds tested for antiallergic activity in Ascaris-hypersensitive dogs, and its effects were sustained for 16 to 30 hours. Nasal and conjunctival provocation testing with allergens in humans has clearly demonstrated the antiallergic activity of levocabastine when it is applied as a topical nasal spray or as eyedrops. Protection from allergen-induced symptoms was observed within 5 minutes following drug application.

In a few studies of central nervous system (CNS) activity and psychomotor performance testing in healthy volunteers, topically applied levocabastine did not induce electroencephalographic (EEG) changes, impair psychomotor function or potentiate the central affects of depressant drugs such as diazepam.

Levocabastine nasal spray was shown to have no effect on ciliary beat frequency or mucociliary transit time. In ophthalmological examinations in volunteers and atopic patients, levocabastine eyedrops produced minimal or no ocular irritation.

Pharmacokinetic Properties

Absorption of topical levocabastine occurs within 1 to 2 hours after administration and is incomplete; bioavailability following intranasal or ocular application was found to be between 60 and 80% and 30 and 60%, respectively, in volunteers. Nasal absorption appears to be lower in patients with allergic rhinitis. Following administration of single oral doses of levocabastine, peak plasma concentrations were attained in approximately 2 hours and systemic bioavailability was 100%. Steady-state plasma concentrations were achieved in 7 to 10 days with multiple-dose administration of levocabastine, and measured approximately 10.4 μg/L with nasal spray and 1.6 μg/L with eyedrops.

The hepatic metabolism of levocabastine is of relatively minor significance. In humans, 65 to 70% of absorbed levocabastine is excreted in the urine as unchanged drug, 10 to 20% appears in the faeces unchanged, and the remainder is recovered in the urine as the acylglucuronide metabolite. The elimination half-life of levocabastine was found to be between 35 and 40 hours and is similar after single- or multiple-dose administration, indicating that no accumulation of drug occurs. The plasma protein binding of levocabastine is approximately 55%, with most drug bound to albumin.

Levocabastine pharmacokinetics are similar in adults and children. Because of limited metabolism, hepatic impairment is unlikely to affect the disposition of this newer agent. In renally impaired patients, however, the absorption of an oral dose of levocabastine 0.5mg was reduced and the elimination half-life was prolonged compared with healthy controls.

Therapeutic Use

Levocabastine has been evaluated in clinical trials involving patients with allergic rhinitis (both seasonal and perennial) and/or seasonal allergic conjunctivitis. Global evaluations of the drug in alleviating the symptoms of allergic rhinitis showed that, in general, a higher percentage of patients had an ‘excellent’ or ‘good’ response to levocabastine than to placebo or sodium cromoglycate. Scores by patients and investigators to rate the severity of individual symptoms of allergic rhinitis were typically lower with levocabastine than with placebo or sodium cromoglycate. However, the symptom of nasal obstruction did not respond well to any of the study medications, suggesting that mediators other than histamine are likely to be involved. A single-blind study incorporating small numbers of patients found levocabastine to be less effective than beclomethasone in relieving runny and blocked nose in patients with allergic rhinitis.

In a few studies investigating the efficacy of levocabastine nasal spray in the treatment of patients with perennial allergic (and nonallergic) rhinitis, levocabastine was significantly superior to placebo and similar in efficacy to sodium cromoglycate or beclomethasone.

In patients with seasonal allergic conjunctivitis, the efficacy of levocabastine eyedrops was superior to that of placebo in spite of a frequently high placebo response rate. Levocabastine was at least as effective as and, in some instances, was slightly more effective than sodium cromoglycate in the prophylaxis and treatment of ocular symptoms associated with allergic conjunctivitis, under both high and low pollen count conditions. A few long term studies demonstrated that the antiallergic activity of levocabastine was maintained during continued use.

Combination therapy with nasal and ocular formulations of levocabastine was evaluated in patients with allergic rhinoconjunctivitis. The differences between levocabastine and sodium cromoglycate did not reach statistical significance. While levocabastine and flunisolide nasal therapy received comparable ratings by patients, a significantly larger proportion of patients preferred ocular levocabastine to antazoline/naphazoline eyedrops.

Tolerability

Levocabastine is well tolerated and has an adverse effect profile comparable to placebo and sodium cromoglycate. In patients treated with topical nasal therapy, nasal irritation has been the most frequently reported adverse effect, with an incidence of 5.4, 5.6 and 6% among those receiving levocabastine, placebo and sodium cromoglycate, respectively. The incidence of somnolence was 3.8, 3.5 and 3.3%, respectively, and dry mouth was 3.3, 2.6 and 2.7%, respectively.

In patients receiving levocabastine eyedrops, ocular irritation was reported by 16.4%. This was similar to that reported by patients receiving placebo (15.8%) and sodium cromoglycate (15.6%). The incidence of headache was 3.5% in patients receiving ocular levocabastine, 4.2% in placebo recipients and 6.5% in patients treated with sodium cromoglycate.

Dosage and Administration

The minimum effective dosage of levocabastine 0.5 mg/ml nasal spray in the treatment of patients with allergic rhinitis is 2 sprays into each nostril twice daily. In the treatment of allergic conjunctivitis, the minimum effective dose of levocabastine 0.5 mg/ml eyedrops is 1 drop into each eye twice daily. The frequency of administration may be increased to 3 or 4 times daily if necessary.

Various sections of the manuscript reviewed by: M.B. Abelson, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA; D.N. Bateman, Northern Regional Clinical Pharmacology Unit Wolfson Unit Newcastle upon Tyne, England; G. Feinberg, Department of Immunology, United Medical and Dental Schools St Thomas Hospital, University of London, London, England; K. Holmberg, ENT Department, Lundby Hospital’ Göteborg, Sweden; F. Horak, Vienna Hospital, Vienna, Austria; A.R. Pecoud, Department of Internal Medicine’ Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; T.C. Stokes, Department of Immunology United Medical and Dental Schools, St Thomas’s Hospital, University of London, London, England; N.W Todd, The Emory Clinic, Atlanta, Georgia, USA; J.S. Turner Jr, The Emory Clinic, Atlanta, Georgia, USA; J.W. Wilson Department of Thoracic Medicine, Royal Melbourne Hospital, Melbourne, Victoria Australia