The Pharmaceutical Journal
Vol 280 No 7492 p280
8 March 2008

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Drug interactions that can occur with azole antifungals

A patient who was stable taking carbamazepine for epilepsy, and ranitidine for gastro-oesophageal reflux, required treatment for oesophageal candidiasis following extended treatment with antibacterials. Oral therapy was considered appropriate for this patient.

When considering a suitable antifungal to prescribe several potential areas of concern were considered.

The gastrointestinal absorption of ketoconazole is markedly reduced by ranitidine, and the absorption of itraconazole is reduced (possibly halved) by H₂-receptor antagonists. This is because ketoconazole is a poorly soluble base, which must be transformed by the acid in the stomach into the soluble hydrochloride salt.

Ranitidine will decrease gastric acidity so that the dissolution of the ketoconazole and its absorption are reduced. The absorption of itraconazole is also affected by changes in gastric pH, but to a lesser extent.

The most significant interactions caused by the azoles are usually those resulting from inhibition of cytochrome P450 isoenzymes.

The Panel shows the effect various azole antifungals have on selected isoenzymes. Carbamazepine is metabolised by CYP3A4, which the azoles inhibit to varying extents. Therefore the concurrent use of carbamazepine and an azole may lead to carbamazepine toxicity.

Carbamazepine induces CYP3A4, and can also act as an inhibitor of CYP2C19, thus potentially reducing the levels of azoles that are substrates of CYP3A4 and increasing the levels of azoles that are substrates of CYP2C19.

Itraconazole and ketoconazole were not considered to be suitable antifungals, as their absorption would be reduced by ranitidine, and their metabolism also be increased by carbamazepine. Antifungal treatment failure would therefore be a serious possibility. Carbamazepine toxicity may also occur as itraconazole can inhibit carbamazepine metabolism.

Voriconazole was also considered inappropriate, because it is contraindicated with carbamazepine, due to potential interactions.

Fluconazole was selected at a dose of 50mg daily. No initial monitoring was planned since this low dose would not be expected to affect carbamazepine levels. However, the patient was advised to be alert for symptoms of raised carbamazepine levels (which may present as nausea, vomiting, ataxia or drowsiness).

Note that if enzyme inhibition occurs, it is likely to be apparent within two to three days, and persist for a similar time after stopping the fluconazole. Carbamazepine is not known to affect the pharmacokinetics of fluconazole.

This case demonstrates that drugs from the same therapeutic family can demonstrate quite different interaction profiles due to differences both in the way in which they are metabolised and the effect that they have on drug metabolising enzymes.

Although relatively uncommon, drug interactions can also occur as a result of alterations in gastric pH.