Terfenadine

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Abstract
Terfenadine is a selective histamine H1-receptor antagonist which, in pharmacodynamic studies, is devoid of central nervous system depressant activity. In clinical studies terfenadine is well tolerated and at a dose of 60mg administered twice daily the drug provides effective relief of symptoms in patients with allergic rhinitis (seasonal and perennial), allergic dermatological conditions (particularly chronic urticaria), and other histamine-mediated disorders. Terfenadine is superior to placebo, has a more rapid onset of action than astemizole and is as effective as most other histamine H1-receptor antagonists, in relieving rhinitis symptoms. In allergic rhinitis, terfenadine relieves ocular symptoms to a greater extent (but nasal symptoms to a lesser extent) than inhaled corticosteroids. Administration of oral terfenadine with inhaled sodium cromoglycate (cromolyn sodium) or an inhaled corticosteroid appears more effective than terfenadine alone. Despite the absence of CNS depressant activity in pharmacodynamic studies, sedation is the adverse effect most frequently associated with terfenadine treatment. However, it is important to realise that the incidence of this adverse effect is similar in terfenadine and placebo recipients, and is less frequent than with traditional histamine H1-receptor antagonists. In conclusion, terfenadine is a clinically effective antihistamine which has an improved adverse effect profile compared with classic histamine H1-receptor antagonists. Like other nonsedating antihistamines, it can be considered as a first-line agent in the treatment of allergic rhinitis and chronic urticaria. With additional clinical experience, the drug could find a similar role in other disorders in which a histamine H1-receptor antagonist is indicated. Terfenadine is a histamine H1-receptor antagonist which is selective for peripheral receptors in vivo and is active in several animal tests of antihistaminic activity. It has no significant affinity for histamine H2-receptors, or α - or β-adrenergic receptors, and has little or no antiserotoninergic, anticholinergic, and α - or β-adrenergic activity. In healthy volunteers, and in patients with allergic rhinitis or atopic asthma, a single dose of terfenadine 60mg suppressed the weal and flare response to intradermally injected histamine for at least 12 hours, with a peak effect seen after about 3 hours. Terfenadine inhibited histamine-induced bronchoconstriction in asthmatic patients and increased FEV1 by about 10% over a dose range of 60 to 180mg. Antiallergic activity demonstrated in animal models has been confirmed in atopic asthmatic patients. Terfenadine inhibited bronchoconstriction induced by inhaled allergen, nebulised distilled water or exercise, reduced the response to nasal allergen provocation, and inhibited the weal response to skin prick tests with allergen. Terfenadine does not impair psychomotor performance or reactivity and in doses up to 600 mg/day causes no more sedation than placebo. Like loratadine and acrivastine, terfenadine does not potentiate the central depressant effects of alcohol or diazepam. Terfenadine is rapidly absorbed after single-dose administration, with a mean peak plasma concentration of 1.5 μg/L occurring about 1 hour after a 60mg oral dose. The drug is extensively metabolised following oral administration. After single and multiple doses of up to 240 mg/day, peak plasma concentrations of intact terfenadine are generally less than 10 μg/L. However, the major metabolite (metabolite I) which retains antihistaminic activity reaches peak levels 2 to 3 hours after a single terfenadine dose in healthy adult volunteers and in children with allergic rhinitis and is detectable within 30 minutes of initial administration. Metabolite I peak plasma levels and AUC values increase linearly with doses up to 180mg. The terminal elimination half-life of metabolite I is approximately 17 hours. Plasma concentrations of metabolite I are not significantly affected by food or increasing age. Peak plasma concentrations of metabolite I appear to precede maximum antihistaminic activity by 1 to 3 hours. Animal studies have shown that after administration of 14C-terfenadine, radioactivity levels are highest in lung and liver tissue and lowest in brain tissue. Elimination of 14C-terfenadine is via urine (40% of an oral dose) and faeces (60%). The efficacy of terfenadine has been evaluated in patients with allergic rhinitis (mainly seasonal), allergic dermatological disorders, bronchial asthma and the common cold. Terfenadine 60mg administered twice daily provides significantly superior relief of seasonal allergic rhinitis symptoms compared with placebo. Symptom relief and onset of improvement are similar in patients treated with terfenadine 60mg twice daily or 120mg once daily. In double-blind studies, terfenadine 60mg twice daily was comparable to chlorpheniramine (chlorphenamine) 12 mg/day, loratadine 10 or 40 mg/day, and mequitazine 10 mg/day, and superior to clemastine 2 mg/day in improving rhinitis symptoms. Terfenadine is, however, less efficacious than dexchlorpheniramine 12 mg/day but is comparable to a dosage of 6 mg/day. Terfenadine provides more rapid relief of symptoms compared with astemizole but in most studies both drugs appeared comparable after 8 weeks of treatment. In a study of children with seasonal allergic rhinitis, terfenadine 60 mg/day and astemizole 2 mg/day provided similar relief of nasal and ocular symptoms; however, astemizole appeared superior based on patients’ and investigators’ global assessment after 4 or 8 weeks. Ocular symptoms of allergic rhinitis were reduced to a greater extent by oral terfenadine than by inhaled beclomethasone dipropionate or flunisolide, but inhaled corticosteroids tended to be more effective in relieving nasal symptoms. Coadministration of terfenadine and inhaled flunisolide enhanced the effect on nasal symptoms of either drug given alone, and similarly a combination of terfenadine and inhaled sodium cromoglycate (cromolyn sodium) appears more effective than terfenadine alone. In patients with perennial allergic rhinitis, terfenadine 60mg twice daily is comparable to ketotifen 1mg twice daily, cetirizine 10 mg/day, loratadine 10 mg/day, and chlorpheniramine 8mg twice daily but was less effective than astemizole 10 mg/day in reducing the severity of most symptoms. Terfenadine 60mg twice daily produced marked or complete relief of pruritus, size and number of weals after 1 week in patients with chronic urticaria and was equally effective when administered as a single daily 120mg dose. Based on global assessment of efficacy, the drug was at least as effective as brompheniramine 24 mg/day, hydroxyzine 100 mg/day, cetirizine 10 mg/day, chlorpheniramine 12 mg/day or clemastine 2 mg/day, but appeared less effective than azatadine 2 mg/day and had a less rapid and persistent effect than astemizole 10 mg/day. Combined treatment with terfenadine and ranitidine, a histamine H2-receptor antagonist, produced greater relief of pruritus than terfenadine or ranitidine alone in patients with chronic idiopathic urticaria. Compared with placebo, terfenadine 240 or 540 mg/day had a slight but significantly superior effect on asthmatic symptoms and pulmonary function. Studies conducted in Japan show that terfenadine 120 or 240 mg/day is superior to ketotifen 2 mg/day in asthmatic patients, with no difference seen between the dosages of terfenadine after 4 weeks. The role of terfenadine in the treatment of the common cold is not well defined and further studies are needed to clarify the results reported to date. Sedation is the most frequently reported adverse effect associated with terfenadine therapy. The incidence of sedation and related effects (12.6% in 965 patients treated with terfenadine) is, like the incidence associated with other new antihistamines such as astemizole, azatadine, and loratadine, comparable with the incidence in placebo recipients and almost half that seen in patients treated with older antihistamines (e.g. chlorpheniramine, clemastine or dexchlorpheniramine). Dry mouth, nose or throat have been reported in 2.6% of terfenadine-treated patients (vs 2.2% of placebo recipients and up to 4.6% of patients receiving other classical antihistamines) and the incidence of headache (up to 18%) was similar in terfenadine and placebo groups. Other adverse effects associated with terfenadine treatment are gastrointestinal complaints (6.5%), allergy symptoms (9.1%), skin disorders (1.2%), musculoskeletal disorders (1.3%), cardiovascular effects (1.3%) and genitourinary disorders (1.1%), all of which tended to occur in a similar percentage of patients administered placebo. The recommended terfenadine dosage in adults is 60mg administered twice daily. Children aged 3 to 5 years should receive terfenadine 15mg twice daily as an oral suspension, and in those aged 6 to 12 years a dosage of 30 to 60mg twice daily, depending on bodyweight, is recommended. A daily dosage of up to 540mg has been used in asthmatic patients.