, Volume 37, Issue 1, pp 42-57
Date: 23 Oct 2012

Loratadine

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Summary

Synopsis

Loratadine is a long acting antihistamine which has a high selectivity for peripheral histamine H1-receptors and lacks the central nervous system depressant effects often associated with some of the older antihistamines. Results from controlled clinical trials have shown that loratadine (usually 10mg once daily) is a well-tolerated and effective antihistamine which will be beneficial in patients with allergic rhinitis and chronic urticaria. It was found to be significantly superior to placebo, faster acting than astemizole and as effective as usual dosages of terfenadine, clemastine, mequitazine and azatadine in eliciting relief of symptoms. Importantly, loratadine is associated with a lower incidence of sedation than azatadine, clemastine, chlorpheniramine and mequitazine.

Thus, loratadine, with its convenience of once daily administration, will be a useful addition to those drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Indeed, it is likely to find a place as one of the newer ‘agents of choice’ in this setting.

Pharmacodynamic Studies

Loratadine is a potent, long acting antihistamine which has a high selectivity for peripheral histamine H1-receptors and low affinity for H1-receptors in the CNS in vitro or in vivo. The drug displays little activity at acetylcholine or α1adrenergic receptors, and is inactive in animal models of assessing anticholinergic effects. Loratadine penetrates poorly into the CNS.

Standard tests of antihistaminic activity in guinea-pigs have shown a greater potency for loratadine than for comparator drugs such as terfenadine, astemizole, promethazine and diphenhydramine, with longer lasting effects (for 18 to 24 hours with loratadine vs 6 to 8 hours with azatadine or terfenadine). In man, suppression of wheal response to intradermally injected histamine was greater with loratadine than with placebo or chlorpheniramine. The magnitude and duration of the response were dose related.

Antiallergic activity has been demonstrated by loratadine in animal models in vivo. In addition, the drug suppressed histamine release from rat mast cells.

A few psychomotor performance studies in small numbers of subjects have shown that, in keeping with its lack of affinity for CNS receptors, loratadine in doses up to 40mg does not impair psychomotor function or potentiate the central effects of drugs such as ethanol or diazepam.

Pharmacokinetic Studies

Loratadine is rapidly absorbed after single-dose oral administration, with peak plasma concentrations of 5, 11 and 26 μg/L occurring 1 to 1.5 hours after the ingestion of 10, 20 and 40mg capsules, respectively; thus, for these doses loratadine pharmacokinetics are not dose dependent, but dose proportional. Similar results were obtained when 40mg capsules were given once daily for 10 days to 12 healthy volunteers, indicating little accumulation of loratadine with multiple once-daily administration.

The chief metabolite of loratadine, descarboethoxy-loratadine (DCL), is pharmacologically active. Similar to the parent compound, the pharmacokinetics of DCL are not significantly altered by multiple dosing. Although tissue distribution studies of loratadine in humans have not yet been published, single-dose studies have reported elimination half-lives of 8 to 11 and 17 to 24 hours for loratadine and DCL, respectively. Similar values of 14 and 19 hours, respectively, were documented following multiple once daily administration for 10 days. Loratadine is secreted into breast milk but the amount is minimal.

Loratadine undergoes rapid and extensive biotransformation in humans with large oral clearance values of 12 and 9 L/h/kg reported after single-dose oral administration of 20 and 40mg capsules in healthy volunteers, respectively. Renal impairment and haemodialysis, and administration to geriatric volunteers, appear to have no effect on the disposition kinetics of both loratadine and DCL. In patients with alcoholic liver disease the half-lives of loratadine and DCL are longer, but generally within the range observed in a population of normal subjects.

Therapeutic Trials

Loratadine has been evaluated in studies involving patients with allergic rhinitis (seasonal and perennial), acute coryza and chronic idiopathic urticaria. In short term clinical trials in patients with seasonal rhinitis loratadine (usually 10mg once daily) was found to be as effective as histamine H1-receptor antagonists such as terfenadine, clemastine, mequitazine and azatadine, and to be quicker acting than astemizole, as assessed by global evaluation of symptom resolution. A dose of 5 to 10mg once daily was shown to be as effective as chlorpheniramine 2 to 4mg twice daily in 231 children aged from 6 to 12 years. Loratadine 10mg once daily was also as effective as terfenadine 60mg twice daily and clemastine 1mg twice daily in patients with perennial allergic rhinitis treated for up to 6 months; complaints of nasal stuffiness, postnasal drainage and nasal discharge were reduced by approximately 50% in these clinical trials.

A combination tablet containing loratadine 5mg and pseudoephedrine 120mg (administered twice daily) was significantly more effective (p < 0.05 to < 0.01) than its individual components and placebo in relieving symptoms in patients with seasonal allergic rhinitis. Similarly, the combination at the same dosage was significantly (p < 0.05) better than placebo in relieving symptoms such as rhinorrhoea, nasal stuffiness, nasal patency, nasal discharge, sneezing and hyperaemia in a 5-day double-blind clinical trial involving 283 patients with acute head colds (coryza).

Loratadine 10mg once daily produced significantly greater symptomatic improvement (itching, erythema and hives) in patients with chronic idiopathic urticaria than did placebo. Furthermore, it tended to be more effective than terfenadine 60mg twice daily in such patients treated for 28 days.

Adverse Effects

In studies reported thus far loratadine 5, 10 or 40mg once daily has been extremely well tolerated and seemed to cause a lower incidence of sedation/somnolence than azatadine, clemastine, chlorpheniramine and mequitazine, administered at their usual dosages. Indeed, in these studies loratadine did not appear to cause a significant increase in adverse effects compared with placebo, was not associated with an increased frequency of anticholinergic effects and did not induce any clinically significant changes in laboratory test indices.

Dosage and Administration

The recommended adult dosage of loratadine is 10mg once daily while that of the combination tablet (loratadine 5mg plus pseudoephedrine 120mg) is 1 tablet twice daily.

Various sections of the manuscript reviewed by: S.T. Holgate, Faculty of Medicine, University of Southampton, Southampton, England; F. Horak, 1st Ear, Nose and Throat Clinic, University of Vienna, Vienna, Austria; A.N. Nicholson, RAF Institute of Aviation Medicine, Farnborough, England; M.D. Rawlins, Department of Pharmacological Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, England; T. Roth, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan, USA; J.S. Turner, Division of Otolaryngology, Emory University School of Medicine, Atlanta, Georgia, USA.