Terfenadine, toxicity/interactions

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

This particular regimen apparently resulted in a second interaction, since unexpectedly very high concentrations of terfenadine were found (SEDA-18,283). The phenomenon has been described by others, with a marked rise in terfenadine serum concentrations, and increased toxicity of the drug during concurrent ingestion of itraconazole. The mechanism is not known, but it is likely to be related to inhibition of CYP3A4 (62). 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrohdes, especially clarithromycin (87-89,116), typically resnlting in prolongation of the QT interval and cardiac dysrhjdhmias (torsade de pointes) (111). The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine pins placebo (90). However, azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QTc interval. 

Flockhart, D. A. 1996. Drug interactions, cardiac toxicity and terfenadine from bench to clinic Journal of Clinical Psychopharmacology 16 101-02. 

Accumulation of the parent drug and resultant QT prolongation may occur following a overdose, a drug interaction that limits metabolism of terfenadine (e.g., concomitant administration with erythromycin or other macrolide antibiotic or with the azole derivatives ketoconazole or itraconazole), or significant hepatic dysfunction that limits metabolism of terfenadine. Patients with preexisting cardiac disease or those with electrolyte abnormalities are also at increased risk for cardiac toxicity. 

Studies of the concomitant use of azithromycin with carbamazepine, terfenadine, and zidovudine have not reported drug interactions [131-133]. With the potential exception of antacids, no drug interactions have been reported with azithromycin, which does not appear to be metabolized by the cytochrome P-450 system [4, 134], Both azithromycin and clarithromycin have been associated with digoxin toxicity. The postulated mechanism is by eradication of Eubacterium lentum, an anaerobic gram-positive bacteria responsible for the metabolism of digoxin in some patients [43]. 

Carbamazepine toxicity, attributed to the use of terfenadine, has been described in one case report but the interaction is not established. 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

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