Ketoconazole and fluconazole increase AUC of eletriptan byabout sixfold and twofold, respectively. Almotriptan is less affected,and ketoconazole only raises its AUC by about 60%. Itraconazole is predicted to interact in same way as ketoconazole.
In a randomised,open label, crossover study, 16 healthy subjects were given ketoconazole 400mg daily on days 1 to 3, with a single 12.5mg dose of almotriptan on day 2. Ketoconazole increased AUC and maximum plasma levels of almotriptan by 57 % and 61%, respectively. The renal clearance of almotriptan was also reduced by approximately 16 % (See reference number 1).
A pharmacokinetic study by manufacturers of eletriptan found that ketoconazole 400 mg increased maximum serum levels of eletriptan 2.7-fold, AUC 5.9-fold and prolonged its half-life from 4.8 to
8.3 hours. Fluconazole caused a lesser 1.4-fold increase in maximum serum levels of eletriptan, and a twofold increase in its AUC (See reference number 2).
Ketoconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4, by which eletriptan is metabolised. Fluconazole is a less potent inhibitor of CYP3A4,and therefore has a more modest effect. Almotriptan is also metabolised by CYP3A4, but as this is not only route of metabolism, and therefore inhibition of CYP3A4 by ketoconazole has a less dramatic effect on its levels.
Although studies are limited these interactions are established. In study with almotriptan and ketoconazole adverse events were not significantly altered, and so no almotriptan dosage adjustment is considered necessary when using this combination (See reference number 1). Ketoconazole dramatically raises eletriptan levels, and therefore manufacturers advise that concurrent use should be avoided.
Itraconazole, which is also a potent inhibitor of CYP3A4, has been predicted to interact in same way as ketoconazole (See reference number 2-4). In addition, US manufacturers recommend that eletriptan should not be given within 72 hrs of itraconazole and ketoconazole (See reference number 2). Fluconazole is a less potent inhibitor of CYP3A4 and therefore may be used with caution. Other triptans would be expected to have little or no interaction with azoles as they are not predominantly metabolised by CYP3A4 (see table 1 below,).
Fleishaker JC,Herman BD, Carel BJ, Azie NE. Interaction between ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol (2003) 43, 423–7.
Relpax (Eletriptan hydrobromide). Pfizer Inc. US Prescribing information,April 2007.
Relpax (Eletriptan hydrobromide). Pfizer Ltd. UK Summary of product characteristics,March2006.
Axert (Almotriptan malate). Ortho-McNeil Pharmaceutical Inc. US Prescribing Information,May 2007.
| Table 1 Interactions between drug metabolising enzymes and the triptans†| ||||||
|---|---|---|---|---|---|---|
| MAO-A | CYP1A2 | CYP2C9 | CYP2C19 | CYP2D6 | CYP3A4 | |
| Almotriptan | Substrate | Substrate | Substrate | |||
| Eletriptan | Substrate | |||||
| Frovatriptan | Substrate | Possible substrate | ||||
| Naratriptan | Substrate (minor) | Substrate (minor) | Substrate (minor) | Substrate (minor) | Substrate (minor) | |
| Rizatriptan | Substrate | Substrate (minor) | ||||
| Sumatriptan | Substrate | |||||
| Zolmitriptan | Substrate | Substrate | Substrate | |||