The azole antifungals are predicted to raise levels of ergot derivatives, which may lead to ergotism. Concurrent use is contraindicated. Methysergide is also contraindicated with cimetidine andNNRTIs such as delavirdine. Caution is also advised with other CYP3A4 inhibitors,including grapefruit juice and quinupristin/dalfopristin.
Clinical evidence,mechanism, importance and management
The ergot alkaloids are mainly metabolised by cytochrome P450 isoenzyme CYP3A4. The manufacturers of ergotamine dihydroergotamine and methysergide therefore logically predict that their levels will be raised by CYP3A4 inhibitors and advise against their concurrent use. They specifically contraindicate macrolides,, and protease inhibitors, , which are potent CYP3A4 inhibitors(See reference number 1-3) and which have been shown to interact with these ergot derivatives in a number of cases. They also contraindicate azole antifungals and NNRTIs (delavirdine, efavirenz).(See reference number 1,4) Although there appear to be no studies or case reports, given way other potent CYP3A4 inhibitors interact, this seems prudent. Note that, of azoles, ketoconazole, itraconazole are most potent CYP3A4 inhibitors, and would therefore be expected to interact to greatest extent. The US manufacturers of ergotamine and dihydroergotamine specifically contraindicate these azoles,but advise caution with fluconazole and clotrimazole, which are less potent CYP3A4 inhibitors.(See reference number 2,3)The manufacturers of ergotamine also advise caution with use of less potent CYP3A4 inhibitors including grapefruit juice,(See reference number 2)quinupristin/dalfopristin and cimetidine.(See reference number 1) The manufacturers of dihydroergotamine(See reference number 3) and methysergide(See reference number 4) give a similar list.
Given rarity of cases of an adverse effect with potent CYP3A4 inhibitors any clinically significant interaction with these drugs would be expected to be extremely rare indeed, but concurrent use should be well monitored so any adverse effect can be identified swiftly and appropriate treatment given.
Cafergot Suppositories (Ergotamine tartrate and caffeine). Alliance Pharmaceuticals. UK Summary of product characteristics,January 2007.
Cafergot Suppositories (Ergotamine tartrate and caffeine). Novartis. US Prescribing information,March 2003.
Migranal (Dihydroergotamine mesylate). Valeant Pharmaceuticals International. US Prescribing information,March 2006.
Deseril (Methysergide). Alliance Pharmaceuticals. UK Summary of product characteristics,December 2006.