Ketoconazole Ebastine

Cardiac effects were reported from early experimental work using very high doses of ebastine, but they are not believed to be clinically relevant in normal use. In one study serial electrocardiograms showed no changes with doses up to the maximum used (30 mg). Ebastine in doses up to five times the recommended therapeutic dose did not cause clinically relevant changes in QTc interval in healthy subjects (2). Co-administration of ebastine with ketoconazole or erythromycin did not lead to significant changes in the QTc interval (3,4). 

Ketoconazole increases mizolastine levels, which resulted in some QT prolongation in one study, therefore all azoles are contraindicated. The manufacturers of ebastine advise caution with ketoconazole and itraconazole as ketoconazole raises ebastine levels. The manufacturers of acrivastine advise caution with azoles due to a lack of data. 

In one study the cardiac effects of loratadine were found to be similar to those of ebastine (see C. above), which caused a small increase in the QT interval. However, loratadine alone, given at 4 times the recommended dose for 90 days, had no effect on the QTc interval when compared with placebo, and animal studies suggest that the combination of ketoconazole and loratadine does not significantly affect the QTc interval. As at 1993, there had been no cases of torsade de pointes reported during worldwide clinical use of loratadine, but see also Table 15.2 , (p.583). 

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. 

Ebastine 20 mg daily Ketoconazole 400 mg daily 8 55 healthy subjects 16-fold 42-fold Mean increase of 5.25 milliseconds when antihistamine added to ketoconazole. Mean increase of 12.21 milliseconds from baseline. QTc did not exceed 500 milliseconds in any subject. 5... 

Chaikin P, Gillen MS, Malik M, Pentikis H, Rhodes GR, Roberts DJ. Co-administration of ketoconazole with HI antagonists ebastine and loratadine in healthy sulgects pharmacokinetic and pharmacodynamic effects. Br J Clin Pharmacol (2005) 59, 346-54. 

The use of azole antifungals with mizolastine is also contraindicated, and the manufacturer of ebastine advises against the concurrent use of ketoconazole and itraconazole. Because there are no data on acrivastine with ketoconazole, the manufacturer advises caution. ... 

---