Drug-Drug Interaction

CARBAMAZEPINE/SELECTED AZOLE ANTIFUNGALS

MECHANISM OF ACTION
Fluconazole(1-3) and ketoconazole(4-6) may inhibit the metabolism of carbamazepine by CYP P-450-3A4. Carbamazepine may induce the metabolism of itraconazole.(7-8)

DISCUSSION
There are three case reports of elevated carbamazepine levels (levels ranged from 18 mcg/ml to 24.5 mcg/ml) following the addition of fluconazole (150 mg/day to 400 mg/day).(1-3) In two of the reports, the patients reported symptoms of carbamazepine toxicity such as blurred vision, dizziness, severe diplopia, oscillopsia, nausea, vomiting, gait instability, nystagmus,(1) lethargy, and lack of response to painful stimuli.(2) In the third report, the patient had no signs of carbamazepine toxicity.(3)

CLINICAL EFFECTS
Concurrent use of fluconazole(1-3) or ketoconazole(4-6) may result in elevated levels of and toxicity from carbamazepine.

SEVERITY LEVEL
3-Moderate Interaction: Assess the risk to the patient and take action as needed.

PATIENT MANAGEMENT
Monitor carbamazepine levels in patients if fluconazole or ketoconazole therapy is initiated. The dosage of carbamazepine may need to be adjusted if fluconazole or ketoconazole is initiated or discontinued.

PREDISPOSING FACTORS
None determined.

REFERENCES

  1. Ulivelli M, Rubegni P, Nuti D, Bartalini S, Giannini F, Rossi S. Clinical .Ulivelli M, Rubegni P, Nuti D, Bartalini S, Giannini F, Rossi S. Clinical evidence of fluconazole-induced carbamazepine toxicity. J Neurol 2004 May; 251(5):622-3.
  2. Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. .Nair DR, Morris HH. Potential fluconazole-induced carbamazepine toxicity. Ann Pharmacother 1999 Jul-Aug;33(7-8):790-2.
  3. Finch CK, Green CA, Self TH. Fluconazole-carbamazepine interaction. South .Finch CK, Green CA, Self TH. Fluconazole-carbamazepine interaction. South Med J 2002 Sep;95(9):1099-100.
  4. Spina E, Arena D, Scordo MG, Fazio A, Pisani F, Perucca E. Elevation of .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 Oct;19(5):535-8.
  5. Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An .Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol 1992 Apr 15; 43(8):1675-82.
  6. Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine .Pearce RE, Vakkalagadda GR, Leeder JS. Pathways of carbamazepine bioactivation in vitro I. Characterization of human cytochromes P450 responsible for the formation of 2- and 3-hydroxylated metabolites. Drug Metab Dispos 2002 Nov;30(11):1170-9.
  7. Bonay M, Jonville-Bera AP, Diot P, Lemarie E, Lavandier M, Autret E. .Bonay M, Jonville-Bera AP, Diot P, Lemarie E, Lavandier M, Autret E. Possible interaction between phenobarbital, carbamazepine and itraconazole. Drug Saf 1993 Oct;9(4):309-11.
  8. Tucker RM, Denning DW, Hanson LH, Rinaldi MG, Graybill JR, Sharkey PK, .Tucker RM, Denning DW, Hanson LH, Rinaldi MG, Graybill JR, Sharkey PK, Pappagianis D, Stevens DA. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis 1992 Jan;14(1):165-74.