Loratadine

Abstract

Loratadine is a long-acting antihistamine agent, exhibiting partial selectivity for peripheral histamine H₁-receptors. To date, loratadine has been evaluated in allergic rhinitis, urticaria and, to a limited extent, in asthma. In several large controlled comparative clinical studies, loratadine was superior to placebo, faster acting than astemizole and as effective as azatadine, cetiri-zine, chlorpheniramine (chlorphenamine), clemastine, hydroxyzine, mequitazine and terfenadine in patients with allergic rhinitis and chronic urticaria. The clinical effectiveness of loratadine in asthma is at present unclear. Loratadine is well tolerated. At dosages of 10mg daily, commonly reported adverse events were somnolence, fatigue and headache. Sedation occurred less frequently with loratadine than with azatadine, cetirizine, chlorpheniramine, clemastine and mequitazine. Serious ventricular arrhythmias, as reported with some other second generation histamine H₁ -receptor antagonists, have not been observed with loratadine to date. Thus, loratadine, with its attributes of once daily administration, fast onset of action and essentially nonsedating properties, would appear to be an appropriate first-line agent for the treatment of allergic rhinitis or urticaria. Loratadine is a long-acting antihistamine agent which exhibits partial selectivity for histamine H₁-receptors in vitro. It displays weak in vitro affinity for cholinergic receptors and α-adrenoceptors, while no anticholinergic effects have been observed in animal models. In studies of its antihistaminic activity in humans, both the magnitude and duration of wheal suppression by loratadine in response to intradermally injected histamine are dose-related. Direct comparison of single doses of various histamine H₁-receptor antagonists in healthy volunteers, using this standard model, revealed the following order of activity: cetirizine 10mg > terfenadine 120mg > terfenadine 60mg > loratadine 10mg > astemizole 10mg > chlorpheniramine (chlorphenamine) 4mg > placebo. Onset of antihistaminic action with loratadine, as measured by wheal and flare suppression, was apparent within the first hour of administration, and was sustained for up to 24 hours. Loratadine 10 to 20mg exhibits a protective effect on airways in response to inhaled histamine challenge in patients with asthma. The antiallergic activity of loratadine has been demonstrated in humans, using cutaneous, nasal challenge and conjunctival provocation tests. Loratadine, however, does not attenuate early or late airways responses to inhaled allergens. Significant ECG effects were not observed in guinea-pigs given single intravenous doses of loratadine up to 100mg/kg, or in healthy human volunteers given oral dosages of loratadine 40 mg/day for a period of 3 months. At dosages of up to 40 mg/day, loratadine does not appear to impair psychomotor function or potentiate the depressant effects of alcohol in healthy volunteers. Following oral administration, loratadine is well absorbed, with peak plasma concentrations of 24.3 to 30.5 μg/L occurring between 1 and 1.5 hours after ingestion of a 40mg capsule. Both loratadine and its major active metabolite, descarboethoxyloratadine (DCL) exhibit dose proportional pharmacokinetics after single- and multiple-dose administration. Loratadine is 97 to 99% plasma protein bound and has a large volume of distribution (119 L/kg). Distribution half-lives (t1/2α) in both single- (20 and 40mg) and multiple-dose loratadine studies (40mg once daily) range from 0.9 to 1.0 hours. While loratadine is excreted into breastmilk, the amount of an administered dose appearing in the milk is minimal. Loratadine is extensively metabolised by hydroxylation. Plasma elimination half-lives (t1/2β) of loratadine in single-dose studies (20 to 40mg) ranged from 7.8 to 11 hours. At steady-state, a t1/2β value of 14.4 hours was documented following administration of loratadine 40 mg/day for 10 days. Haemodialysis appears to have a negligible effect on loratadine clearance. Although ketoconazole, erythromycin and cimetidine inhibit the metabolism of loratadine, these pharmacokinetic interactions appear to be of little or no clinical significance. Where ECG parameters were measured, adverse cardiovascular effects were not observed as a result of elevated plasma concentrations of loratadine or DCL. In large comparative trials of patients with seasonal allergic rhinitis, short term therapy (2 to 3 weeks) with loratadine at therapeutic doses was significantly superior to placebo, and as effective as azatadine, cetirizine, clemastine, mequitazine or terfenadine. Loratadine was faster acting than astemizole, and was effective in relieving nasal, conjunctival and other non-nasal symptoms. Combination therapy with loratadine 10mg and pseudoephedrine 240mg (as a single daily dose or in 2 divided doses) may further improve nasal symptoms associated with allergic rhinitis. In children and/or adolescents with seasonal allergic rhinitis, loratadine was as effective as astemizole, chlorpheniramine, dexchlorpheniramine and terfenadine in alleviating symptoms, but less effective than intranasal fluticasone in relieving symptoms of nasal blockage. Similarly, at therapeutic doses loratadine was as efficacious as clemastine or terfenadine over treatment periods of up to 6 months in perennial rhinitis: nasal stuffiness, post-nasal drainage and nasal discharge were reduced by approximately 50% with loratadine. Comparable symptomatic improvement was noted with therapeutic doses of loratadine, clemastine, hydroxyzine and terfenadine over treatment periods of up to 12 weeks in patients with chronic urticaria. Preliminary data also suggest that adjuvant treatment with loratadine may relieve pruritic symptoms in patients with atopic dermatitis. In acute coryza, combined therapy with loratadine 5mg and pseudoephedrine 120mg as 1 tablet taken twice daily may provide some symptomatic relief. Whether this combination provides additional relief of cold symptoms over pseudoephedrine monotherapy remains to be confirmed. The clinical effectiveness of loratadine in the treatment of asthma remains unclear. Conflicting results and small patient numbers in studies conducted to date provide inconclusive results and thus do not support its use in asthma at present. Loratadine is generally well tolerated at therapeutic doses in adults, elderly patients and children. In a review of 15 noncomparative studies in which some 55 000 patients received loratadine 10 mg/day, commonly reported adverse events were somnolence, fatigue and headaches (≈ 1%), while dry mouth and gastrointestinal upset occurred less frequently. Loratadine was less sedating than azatadine, cetirizine, clemastine, chlorpheniramine and mequitazine. Serious ventricular arrhythmias, reported with some second generation histamine H₁-receptor antagonists (e.g. terfenadine and astemizole), have not been observed with loratadine to date, although rare cases of supraventricular tachycardia have been reported. The tolerability of a combination preparation of loratadine 5mg with pseudo-ephedrine 120mg, taken twice daily, was comparable with pseudoephedrine monotherapy, but produced a significantly greater incidence of dry mouth and insomnia in comparison with placebo and loratadine alone. In reported cases of overdosage with loratadine, recovery was uneventful. Accidental overdosage in 5 young children at loratadine dosages 10 to 20 times greater than those recommended produced no adverse cardiac events. At present, loratadine is indicated for the relief of symptoms associated with allergic rhinitis, urticaria and other allergic dermatological disorders. The recommended dose of loratadine is 10mg once daily for adults and for children weighing more than 30kg. Children aged 2 to 12 years and weighing less than 30kg should receive 5mg once daily. In adults, 1 combination tablet (loratadine 5mg and pseudoephedrine 120mg) is recommended twice daily for symptomatic relief of the common cold. Although dosage adjustments may be necessary in patients with hepatic impairment, this is unlikely to be required in either elderly patients or those with renal impairment.