Ketoconazole causes a small to moderate rise in serum carbamazepine levels. A marked rise in carbamazepine levels hasbeen seen in two patients taking fluconazole,with toxicity in one.Adverse effects were seen in another patient when carbamazepinewas given with miconazole. Carbamazepine may markedly reduce levels of itraconazole and possibly voriconazole, and ispredicted to lower levels of posaconazole.
24.5 micrograms/mL. Symptoms resolved when both drugs were stopped,and carbamazepine was later re-introduced without problem (See reference number 1). Another well-documented case report describes a threefold increase in carbamazepine levels (without any signs of toxicity) 10 days after fluconazole 400mg daily was started (See reference number 2).
About 14 days after starting carbamazepine 400mg daily,a patient taking itraconazole 200mg daily was noted to have low itraconazole levels
(0.15 mg/L),and about 2 months later they were undetectable. About 3 weeks after stopping carbamazepine, itraconazole levels had reached therapeutic range (0.36 mg/L) (See reference number 3). For mention of 2 patients taking carbamazepine with phenytoin,who had undetectable or very low itraconazole levels, and who relapsed or did not respond to itraconazole therapy, see Phenytoin + Azoles interaction.
When ketoconazole was stopped serum carbamazepine levels returned to their former levels (See reference number 4)
A patient receiving long-term treatment with carbamazepine 400mg daily developed malaise,myoclonia and tremor within 3 days of being given oral miconazole 1.125 g. The same reaction occurred on each subsequent occasion that miconazole was given. These toxic effects disappeared when miconazole was withdrawn (See reference number 5).
Carbamazepine levels are thought to rise because azole antifungals inhibit cytochrome P450 isoenzyme CYP3A4, which is concerned with metabolism of carbamazepine. Different azoles affect CYP3A4 to varying degrees,see azole antifungals, . Carbamazepine is an enzyme inducer, and appears to decrease levels of azole antifungals by increasing their metabolism.
Evidence for these interactions is limited and in some cases effects are only modest. Nevertheless, it would seem prudent to monitor outcome of adding azole antifungals to established carbamazepine treatment, being alert for any evidence of increased carbamazepine adverse effects.
Note also that carbamazepine may reduce levels of azole antifungals: a marked reduction in itraconazole levels has been reported, and some manufacturers of itraconazole consequently say that concurrent use of potent enzyme inducers such as carbamazepine is not recommended (See reference number 6,7). Based on interaction with phenytoin, , which results in reduced posaconazole levels, manufacturer of posaconazole suggests that concurrent use of posaconazole and carbamazepine should be avoided, unless benefits outweigh risks (See reference number 8). If both drugs are given it would seem sensible to consider increasing posaconazole dose, and increase monitoring of carbamazepine levels. Based on interaction with phenytoin, , manufacturers of voriconazole also contraindicate concurrent use of carbamazepine and voriconazole (See reference number 9,10).
Nair DR,Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother (1999) 33, 790–2.
Finch CK,Green CA, Self TH. Fluconazole-carbamazepine interaction. South Med J (2002) 95, 1099–1100.
Bonay M,Jonville-Bera AP, Diot P, Lemarie E, Lavandier M, Autret E. Possible interactionbetween phenobarbital, carbamazepine and itraconazole. Drug Safety (1993) 9, 309–11.
Spina E,Arena D, Scordo MG, Fazio A, Pisani F, Perucca E. Elevation of plasma carbamazepine concentrations by ketoconazole in patients with epilepsy. Ther Drug Monit (1997) 19, 535–8.
Loupi E,Descotes J, Lery N, Evreux JC. Interactions médicamenteuses et miconazole. A propos de 10 observations. Therapie (1982) 37, 437–41.
Sporanox Capsules (Itraconazole). Janssen-Cilag Ltd. UK Summary of product characteristics,March 2004.
Sporanox Capsules (Itraconazole). Janssen. US Prescribing information,June 2006.
Noxafil (Posaconazole). Schering-Plough Ltd. UK Summary of product characteristics,October 2006.
VFEND (Voriconazole). Pfizer Ltd. UK Summary of product characteristics,July 2007.
VFEND (Voriconazole). Pfizer Inc. US Prescribing information,November 2006.