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Terfenadine is chemically distinct from other antihistamines. Histamine skin wheal studies have shown that terfenadine in single and repeated doses of 60 mg in 64 subjects has an antihistaminic effect beginning at 1-2 hours, reaching its maximum at 3-4 hours, and lasting in excess of 12 hours. The correlation between response on skin wheal testing and clinical efficacy is unclear. The four best controlled and largest clinical trials each lasted 7 days and involved about 1,000 total patients in comparisons of terfenadine (60 mg b.i.d. ) with an active drug (chlorpheniramine, 4 mg t.i.d. dexchlorpheniramine, 2 mg t.i.d. or clemastine 1 mg b.i.d.). About 50-70% of terfenadine or other antihistamine recipients had moderate to complete relief of symptoms, compared with 30- 50% of placebo recipients. The frequency of drowsiness with terfenadine was similar to the frequency with placebo and less than with other antihistamines. None of these studies showed a difference between terfenadine and other antihistamines in the frequency of anticholinergic effects. In studies which included 52 subjects in whom EEG assessments were made, no depressant effects have been observed.
Animal studies have demonstrated that terfenadine is a histamine H1-receptor antagonist. In these animal studies, no sedative or anticholinergic effects were observed at effective antihistaminic doses. Radioactive disposition and autoradiographic studies in rats and radioligand binding studies with guinea pig brain H1-receptors indicate that, at effective antihistamine doses, neither terfenadine nor its metabolites penetrate the blood brain barrier well.
On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 70%. Terfenadine itself undergoes extensive (99%) first pass metabolism to two primary metabolites, an active acid metabolite and an inactive dealkylated metabolite. Therefore, systematic availability of terfenadine is low under normal conditions, and parent terfenadine is not normally detectable in plasma at levels > 10 ng/ml. Although in rare cases there was measurable plasma terfenadine in apparently normal individuals without identifiable risk factors, the implications of this finding with respect to the variability of terfenadine metabolism in the normal population cannot be assessed without further study. Further studies of terfenadine metabolism in the general population are pending. From information gained in the 14C study it appears that approximately forty percent of the total dose is eliminated renally (40% as acid metabolite, 30% dealkyl metabolite, and 30% minor unidentified metabolites). Sixty percent of the dose is eliminated in the feces (50% as the acid metabolite, 2% unchanged terfenadine, and the remainder as minor unidentified metabolites). Studies investigating the effect of hepatic and renal insufficiency on the metabolism and excretion of terfenadine are incomplete. Preliminary information indicates that in cases of hepatic impairment, significant concentrations of unchanged terfenadine can be detected with the rate of acid metabolite formation being decreased. A single-dose study in patients with hepatic impairment revealed increased parent terfenadine and impaired metabolism, suggesting that additional drug accumulation may occur after repetitive dosing in such patients. Terfenadine is contraindicated for use in patients with significant hepatic dysfunction. (See CONTRAINDICATIONS and WARNINGS). In subjects with normal hepatic function unchanged terfenadine plasma concentrations have not been detected. Elevated levels of parent terfenadine, whether due to significant hepatic dysfunction, concomitant medications, or overdose, have been associated with QT interval prolongation and serious cardiac adverse events. (See CONTRAINDICATIONS and WARNINGS).In controlled clinical trials in otherwise normal patients with rhinitis, small increases in QTc interval were observed at doses of 60 mg b.i.d. In studies at 300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%) (mean increase of 46 msec) was observed.
Data have been reported demonstrating that compared to young subjects, elderly subjects experience a 25% reduction in clearance of the acid metabolite after single-dose oral administration of 120 mg. Further studies are necessary to fully characterize pharmacokinetics in the elderly.
In vitro studies demonstrate that terfenadine is extensively (97%) bound to human serum protein while the acid metabolite is approximately 70% bound to human serum protein. Based on data gathered from in vitro models of antihistaminic activity, the acid metabolite of terfenadine has approximately 30% of the H1blocking activity of terfenadine. The relative contribution of terfenadine and the acid metabolite to the pharmacodynamic effects have not been clearly defined. Since unchanged terfenadine is usually not detected in plasma and active acid metabolite concentrations are relatively high, the acid metabolite may be the entity responsible for the majority of efficacy after oral administration of terfenadine.
In a study involving the administration of a single 60 mg terfenadine tablet to 24 subjects, mean peak plasma levels of the acid metabolite were 263 ng/ml (range 133-423 ng/ml) and occurred approximately 2.5 hours after dosing. Plasma concentrations of unchanged terfenadine were not detected. The elimination profile of the acid metabolite was biphasic in nature with an initial mean plasma half-life of 3.5 hours followed by a mean plasma half-life of 6 hours. Ninety percent of the plasma level time curve was associated with these half-lives. Although the elimination profile is somewhat complex, the effective pharmacokinetic half-life can be estimated at approximately 8.5 hours. However, receptor binding and pharmacologic effects, both therapeutic and adverse, may persist well beyond that time.
Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.
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