Ketoconazole Desloratadine

The electrocardiographic safety of desloratadine in combination with the CYP3A4 inhibitor ketoconazole has been assessed in a randomized, two-way, crossover, third-party-blind, multiple-dose, placebo-controlled study over 10 days in 24 healthy volunteers (21). Compared with desloratadine alone there were no significant or clinically important changes in QT , QT, PR, or QRS intervals when desloratadine (7.5mg/day, that is 50% higher than the recommended dose) was co-administered with ketoconazole (200 mg bd). There was a 1.3-fold increase in desloratadine when it was co-administered with ketoconazole, but this was judged not to be clinically important. The authors concluded that co-administration of desloratadine with ketoconazole has no clinically relevant electrocardiographic or pharmacodynamic implications. There was no clinically relevant interaction between desloratadine and ketoconazole (21). 

Ketoconazole raises the levels of desloratadine, emedastine, fexofenadine but as no adverse cardiac effects were seen these combinations are considered safe. No interaction occurs between ketoconazole and azelastine, cetirizine, intranasal levocabastine, and none is expected with levocetirizine. 

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. 

Desloratadine 7.5 mg daily Ketoconazole 200 mg twice daily 10 24 healthy subjects 27% 21% No change 4... 

Loratadine 20 mg single dose Ketoconazole 200 mg twice daily Single dose 12 healthy subjects 144% Loratadine 33% Desloratadine 184% Loratadine 54% Desloratadine 9... 

Loratadine 10 mg daily Ketoconazole 400 mg daily 8 62 healthy subjects 248% Loratadine 82% Desloratadine 346% Loratadine 94% Desbratadine Mean increase of 3.16 milliseconds when antihistamine added to ketoconazole. Mean increase of 10.68 milliseconds from baseline. QTc did not exceed 500 milliseconds in any subject. 5... 

Banfield C, Herron JM, Keung A, Pahdi D, Affrime M. Desloratadine has no clinically relevant electrocardiographic or pharmacodynamic interactions with ketoconazole. Clin Pharmacoklnet 2002) 41 (Suppl 1), 37-44. 

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