, Volume 59, Issue 2, pp 301-321
Date: 10 Oct 2012

Fexofenadine

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Summary

Abstract

Fexofenadine, the active metabolite of terfenadine, is a selective histamine Hi receptor antagonist that does not cross the blood brain barrier and appears to display some anti-inflammatory properties. Fexofenadine is rapidly absorbed (onset of relief ≈2 hours) and has a long duration of action, making it suitable for once daily administration.

Clinical trials (≤2 weeks’ duration) have shown fexofenadine 60mg twice daily and 120mg once daily to be as effective as loratadine 10mg once daily, and fexofenadine 120mg once daily to be as effective as cetirizine 10mg once daily in the overall reduction of symptoms of seasonal allergic rhinitis. When given in combination, fexofenadine and extended release pseudoephedrine had complementary activity. Fexofenadine was effective in relieving the symptoms of sneezing, rhinorrhoea, itchy nose, palate or throat, and itchy, watery, red eyes in patients with seasonal allergic rhinitis. There were often small improvements in nasal congestion that were further improved by pseudoephedrine. Fexofenadine produced greater improvements in quality of life than loratadine to an extent considered to be clinically meaningful, and enhanced patients’ qualty of life when added to pseudoephedrine treatment. Although no comparative data with other H1 antagonists exist, fexofenadine 180mg once daily was effective in reducing the symptoms of chronic idiopathic urticaria for up to 6 weeks.

Fexofenadine was well tolerated in clinical trials in adults and adolescents and the adverse event profile was similar to placebo in all studies. The most frequently reported adverse event during fexofenadine treatment was headache, which occurred with a similar incidence to that seen in placebo recipients. Fexofenadine does not inhibit cardiac K+ channels and is not associated with prolongation of the corrected QT interval. When given alone or in combination with erythromycin or ketoconazole, it was not associated with any adverse cardiac events in clinical trials. As it does not cross the blood brain barrier, fexofenadine is free of the sedative effects associated with first generation antihistamines, even at dosages of up to 240 mg/day.

Conclusions: fexofenadine is clinically effective in the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria for which it is a suitable option for first-line therapy. Comparative data suggest that fexofenadine is as effective as loratadine or cetirizine in the treatment of seasonal allergic rhinitis. In those with excessive nasal congestion the combination of fexofenadine plus pseudoephedrine may be useful. In clinical trials fexofenadine is not associated with adverse cardiac or cognitive/psychomotor effects.

Pharmacodynamic Properties

Fexofenadine is a selective histamine H1 receptor antagonist. Single doses <180mg suppressed histamine-induced wheal and flare reactions to a similar extent to loratadine 10mg and terfenadine ≤180mg; higher doses of fexofenadine and terfenadine were more effective than lower doses. However, the onset of action of fexofenadine (≤2 hours) was faster than that of loratadine.

In vitro, concentrations of the drug close to those achieved at clinical dosages have been shown to attenuate the release of many inflammatory mediators, in-cluding cytokines, leukotrienes and adhesion molecules, from a variety of cell types.

Dosages ≤120mg rapidly (after a median of 60 min) relieved allergen-induced symptoms in ragweed sensitive volunteers in a randomised, double-blind study. In addition, the drug was as effective as terfenadine at relieving nasal pruritus and congestion, and better at controlling rhinorrhoea and sneezing after nasal provocation tests with allergen in patients with grass pollen-induced rhinitis. A higher allergen concentration was required to provoke a response after fexofenadine than terfenadine.

In animal models of corrected QT interval (QTC) prolongation, fexofenadine did not prolong QTcor decrease heart rate, unlike terfenadine, astemizole and ebastine. Indeed, fexofenadine has a relatively weak affinity for cloned human cardiac potassium channels compared with other antihistamines.

During development, fexofenadine was shown to have no significant effects on heart rate, PR interval, QRS width, QT interval or QTc and to cause no adverse cardiovascular events at single doses up to 800mg and multiple dosages up to 690 mg/day.

Pharmacokinetic Properties

Fexofenadine is rapidly absorbed, reaching peak plasma concentrations approximately 1.0 to 1.5 hours after single doses of oral solution (20 to 240mg) and has a long duration of action (t½ ≈14 hours). It does not appear to cross the blood brain barrier. There is minimal systemic metabolism (≤5%) or accumulation. The drug is predominately excreted in the faeces as unchanged drug. The pharmacokinetic properties of fexofenadine are similar after single and multiple doses and are dose proportional over a range of 10 to 800mg.

Elimination of fexofenadine is decreased in patients with renal impairment. However, mild to severe hepatic impairment did not appreciably affect its pharmacokinetic properties.

Coadministration of erythromycin or ketoconazole resulted in increases in steady state fexofenadine plasma concentrations, but these remained within the range achieved in clinical trials of the drug and QTc intervals were unchanged.

Therapeutic Efficacy

In patients with seasonal allergic rhinitis, 2 weeks’ treatment with fexofenadine once (120 or 180mg) or twice (40 to 240mg) daily produced significantly (p < 0.01) greater improvements in total symptom score (TSS) than placebo. The effects of the drug persisted for up to 24 hours. Nasal congestion, which was not included in the TSS, was generally reduced by dosages ≥120 mg/day. With respect to improving TSS, fexofenadine 60mg twice daily and 120mg once daily was as effective as loratadine 10mg once daily and fexofenadine 120mg once daily was as effective as cetirizine 10mg once daily after 7 to 14 days’ treatment (p < 0.05 vs placebo for all). Individual symptom scores (including sneezing, rhinorrhoea, itchy nose, palate or throat, and itchy, watery, red eyes) were similarly improved by fexofenadine and loratadine, except itchy, watery, red eyes, which only significantly improved with fexofenadine.

Fexofenadine and pseudoephedrine had complementary activity in patients with ragweed-induced allergic rhinoconjunctivitis. Importantly, nasal congestion scores improved more with the combination than with fexofenadine alone.

In patients with chronic idiopathic urticaria, fexofenadine dosages ≥40 mg/day for 4 or 6 weeks produced improvements in TSS compared with placebo but higher dosages tended to have greater efficacy.

Fexofenadine improved quality of life and decreased work and activity impairment in patients with seasonal allergic rhinitis and chronic idiopathic urticaria. In patients with seasonal allergic rhinitis, the drug produced greater improvements in quality of life than loratadine to an extent considered to be clinically meaningful, and enhanced patients’ quality of life when added to pseudoephedrine treatment.

Tolerability

Fexofenadine (≤240 mg/day for up to 6 weeks and ≤480 mg/day for up to 4 weeks) was well tolerated in clinical trials in adults and adolescents (aged ≥12 years) with seasonal allergic rhinitis or chronic idiopathic urticaria, and in children aged 6 to 11 years with seasonal allergic rhinitis. The drug was also well tolerated in 2 long term trials with dosages of 60mg twice daily for 6 months and 240mg once daily for 12 months. The incidence of treatment-related adverse events associated with fexofenadine was similar to those of placebo, loratadine and cetirizine, and lower than that associated with pseudoephedrine. Headache was the most frequently reported adverse event during treatment, which occurred with a similar incidence to that seen in placebo recipients.

No adverse electrocardiographic events or episodes of torsades de pointes occurred during randomised, placebo-controlled clinical trials with fexofenadine. In short and long term (2-week to 12-month) studies with dosages ≤240mg twice daily, there were no significant increases in QTc compared with placebo. In addition, there was no increase in QTc when the drug was administered in combination with erythromycin or ketoconazole.

In comparison with placebo, fexofenadine did not increase the incidence of sedation or drowsiness and did not impair cognitive or psychomotor function, even at dosages exceeding those recommended (up to 240 mg/day).

Dosage and Administration

In the US, the recommended dosage of fexofenadine for the treatment of seasonal allergic rhinitis is 60mg twice daily, alone or in combination with pseudoephedrine 120mg, for adults and adolescents aged >12 years. In the UK, the recommended dosage of fexofenadine for relief of symptoms of seasonal allergic rhinitis is 120mg once daily and the recommended dosage for the treatment of chronic idiopathic urticaria is 180mg once daily. For patients with decreased renal function or those on haemodialysis a lower starting dosage of 60mg once daily is recommended in the US, but not in the UK. Dosage adjustment is not necessary in elderly patients or those with hepatic impairment.

Various sections of the manuscript reviewed by: M. Bagnasco, Clinica Allergologica e Immunologica, DIMI Universitá di Genova, Genoa, Italy; D.I. Bernstein, Division of Immunology, University of Cincinnati, Cincinnati, Ohio, USA; J. Berth-Jones, Department of Dermatology, Walsgrave Hospital, Coventry, England; M.S. Kennedy, Northwest Asthma & Allergy Center, Seattle, Washington, USA; D.C. Salmaso, Clinica Allergologica e Immunologica, DIMI Universitá di Genova, Genoa, Italy; Z. Shamsi, Human Psychopharmacology Research Unit, University of Surrey, Guilford, Surrey, England; F.E.R. Simons, Health Sciences Centre, Children’s Hospital of Winnipeg, Winnipeg, Manitoba, Canada; F. Spertini, Division d’Immunologie et d’Allergie, Département de Médecine Interne, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; B.M. Stone, Protection and Performance Department, Centre for Human Sciences, DERA Farnborough, Hampshire, England; G.L. Sussman, The Wellesley Central Hospital, Division of Immunology, Toronto, Ontario, Canada.

Data Selection

Sources: Medical literature published in any language since 1966 on fexofenadine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand),Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were ‘fexofenadine’ or ‘MDL-16455’ or ‘MDL-16455A’. Medline search terms were ‘fexofenadine’ or ‘MDL 16455’ or ‘MDL 16455A’. EMBASE search terms were ‘fexofenadine’ or ‘MDL 16455’ or ‘MDL 16455A’. Searches were last updated 12 January, 2000.
Selection: Studies in patients with seasonal allergic rhinitis or chronic idiopathic urticaria who received fexofenadine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: fexofenadine, seasonal allergic rhinitis, chronic idiopathic urticaria, pharmacodynamics, pharmacokinetics, therapeutic use.