SSRIs + Azoles - Drug Interactions

Anorexia developed in a patient taking fluoxetine when itraconazole was started, and it disappeared when itraconazole wasstopped. The pharmacokinetics of citalopram in healthy subjectswere not affected by ketoconazole. The clearance of escitalopramwas not affected by ketoconazole in an in vitro study.

Clinical evidence,mechanism, importance and management

In a double-blind, placebo-controlled, crossover study in 18 healthy subjects, a single 200mg dose of ketoconazole did not affect pharmacokinetics of citalopram 40mg (See reference number 1). Ketoconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4,which, in part, metabolises citalopram, but as several other cytochrome P450 isoenzymes are also involved in citalopram metabolism it would seem that inhibition of only one pathway does not result in clinically significant effects. Similarly,escitalopram is metabolised by CYP3A4, CYP2C19, and CYP2D6, and it has been suggested that its clearance is also unlikely to be affected by impaired activity of only one CYP isoform (See reference number 2).

A man taking fluoxetine 20mg daily,diazepam and several anti-asthma drugs (salbutamol (albuterol), salmeterol, budesonide, theophylline) was given itraconazole 200mg daily for allergic bronchopulmonary aspergillosis. Within 1 to 2 days he developed anorexia without nausea. He stopped itraconazole after a week, and anorexia resolved 1 to 2 days later. The author of report suggested that itraconazole, a potent enzyme inhibitor, increased levels of fluoxetine metabolite, norfluoxetine, which resulted in anorexia (See reference number 3). Anorexia is a recognised adverse effect of fluoxetine. However,drug levels were not taken, so this suggestion has not been confirmed.

This report and conclusions reached are uncertain, but they draw attention to possibility of an interaction between fluoxetine and itraconazole. Consider this interaction if fluoxetine adverse effects are troublesome.

Gutierrez M,Abramowitz W. Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy (2001) 21, 163–8.

Von Moltke LL,Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos (2001) 29, 1102–9.

Black PN. Probable interaction between fluoxetine and itraconazole. Ann Pharmacother (1995) 29,1048–9.