Phenytoin Interactions With Fluconazole and Itraconazole: Risk of Toxicity to Treatment Failure

Timothy H. Self, PharmD
Katherine L. March, PharmD
Volume 56 - Issue 9 - September 2016

Phenytoin has numerous clinically relevant drug-drug interactions that have been well-documented since its introduction as an antiepileptic agent in the late 1930s.1,2 These interactions can create difficult problems for prescribers and patients alike.

Phenytoin is 90% to 95% protein-bound and follows Michaelis-Menten or saturable pharmacokinetics.3,4 The free fraction of phenytoin that is pharmacologically active is primarily metabolized via the cytochrome P450 (CYP450) enzymes 2C9 (major) and 2C19 (minor).5,6 Phenytoin is also an inducer of the CYP450 enzymes 3A4, 2C9, 2C19, and 2B6.7 Thus phenytoin has the ability to induce its own metabolism, as well as the metabolism of other drugs, creating interpatient variability and requiring pharmacokinetic monitoring.

The intricate relationship between phenytoin and the CYP450 system can create challenging therapeutic scenarios when administration of other medications that are also inducers and/or inhibitors of the CYP450 system, or are also substrates (eg, phenytoin) of these enzymes, is required for patient care. A classic example of these interactions is coadministration of phenytoin with the systemic azole antifungal agents fluconazole and itraconazole.

The purpose of this brief review is to focus on the mechanisms behind these interactions in an effort to highlight that, while they both involve the CYP450 enzymes, the consequences of each interaction result in dramatically different medication conundrums.

Fluconazole

The accompanying Table briefly describes select case reports surrounding the interaction between phenytoin and fluconazole that have been reported since the late 1980s.8-11 While the exact mechanism of the interaction was not known at that time, the literature has consistently reported cases of phenytoin toxicity in the setting of concomitant administration with fluconazole. In 1990, Lazar and Wilner12 demonstrated that coadministration of phenytoin and fluconazole resulted in a mean increase of 75% of the area under the plasma concentration-time curve (AUC) of phenytoin. This was further corroborated in 1991 by Blum and colleagues’ randomized, placebo-controlled, parallel study in which phenytoin was given in the presence and absence of fluconazole.13 Results from this study showed that serum concentrations of phenytoin were markedly increased by 128% while the AUC was increased by 75% in the presence of fluconazole. Later, in 2005, Niwa and colleagues14 further shed light on this interaction by demonstrating that fluconazole is a strong inhibitor of CYP2C9, 2C19, and 3A4. Fluconazole inhibits the metabolism of phenytoin by inhibiting CYP enzymes 2C9 and 2C19, resulting in increased serum concentrations of phenytoin.

The ability of fluconazole to inhibit these CYP enzymes and the metabolism of phenytoin is significant due to the narrow therapeutic index of phenytoin. When phenytoin serum concentrations begin to reach supratherapeutic levels, patients can begin to experience mild symptoms such as nystagmus and nausea and vomiting. As serum concentrations continue to rise, patients are at an increased risk of developing ataxia, lethargy, coma, and even death.

Itraconazole

In 1988, Hay and colleagues15 first reported cases of treatment failure for onychomycosis using itraconazole in patients concurrently receiving phenytoin. Similarly, in 1992 Tucker and colleagues16 reported the cases of 4 patients receiving fluconazole, itraconazole, and/or fluconazole and concurrent phenytoin and/or carbamazepine who failed to respond to treatment or had a relapse of their fungal infections. Based on these observations, the authors postulated that phenytoin decreased the serum concentrations of itraconazole.

In 1995, Ducharme and colleagues17 characterized the pharmacokinetics of phenytoin and itraconazole when given simultaneously. Results revealed that the serum concentrations and AUC of itraconazole were decreased by a dramatic 10-fold in the presence of phenytoin. This study explained to a great degree the reason for the treatment failures that had been seen previously.

As with fluconazole, it was hypothesized that this significant drug-drug interaction with itraconazole was attributable to some imbalance within the CYP450 enzyme system.17 Itraconazole is primarily metabolized via CYP3A4 but is simultaneously a CYP3A4 inhibitor.18 As noted, phenytoin is not only a CYP450 substrate but also induces CYP3A4, 2C9, 2C19, and 2B6.7 Itraconazole has diminished clinical efficacy in the setting of coadministration with phenytoin due to the strong induction of phenytoin on CYP3A4. This interaction has been seen to be so highly significant that it is currently not recommended for itraconazole to be administered with potent inducers of CYP3A4 such as phenytoin.18

Key Points

It is imperative for health care professionals to be aware of these azole antifungal interactions with phenytoin, since they can lead to possibly toxic phenytoin levels in the setting of concomitant fluconazole administration or treatment failures with itraconazole. If fluconazole administration cannot be avoided, it is essential to frequently monitor phenytoin levels and patient clinical status. Itraconazole should be avoided in patients who are currently receiving phenytoin for seizure prophylaxis or treatment.

Katherine L. March, PharmD, is a postgraduate year 2 internal medicine pharmacy resident at Methodist University Hospital and the University of Tennessee Health Science Center in Memphis.

Timothy H. Self, PharmD, is a professor of clinical pharmacy at the University of Tennessee Health Science Center and the program director of the Postgraduate Year 2 Internal Medicine Pharmacy Residency at Methodist University Hospital in Memphis, Tennessee.

References:

  1. Friedlander WJ. Putnam, Merritt, and the discovery of Dilantin. Epilepsia. 1986;27(suppl 3):S1-S20.
  2. Schumacher GE. Antiepileptics. In: Schumacher GE. Therapeutic Drug Monitoring. Norwalk, CT: Appleton & Lange; 1995:367-374.
  3. Allen JP, Ludden TM, Burrow SR, Clementi WA, Stavchansky SA. Phenytoin cumulation kinetics. Clin Pharmacol Ther. 1979;26(4):445-448.
  4. Grasela TH, Sheiner LB, Rambeck B, et al. Steady-state pharmacokinetics of phenytoin from routinely collected patient data. Clin Pharmacokinet. 1983;8(4):355-364.
  5. van der Weide J, Steijns LSW, van Weelden MJM, de Haan K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics. 2001;11(4):287-291.
  6. Desta Z, Zhao X, Shin J-G, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet. 2002;​41(12):913-958.
  7. Cuttle L, Munns AJ, Hogg NA, et al. Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation. Drug Metab Dispos. 2000;28(8):945-950.
  8. Howitt KM, Oziemski MA. Phenytoin toxicity induced by fluconazole. Med J Aust. 1989;​151(10):​603-604.
  9. Mitchell AS, Holland JT. Fluconazole and phenytoin: a predictable interaction. BMJ. 1989;​298(6683):1315.
  10. Cadle RM, Zenon GJ III, Rodriguez-Barradas MC, Hamill RJ. Fluconazole-induced symptomatic phenytoin toxicity. Ann Pharmacother. 1994;​28(2):191-195.
  11. Helldén A, Bergman U, Engström Hellgren K, et al. Fluconazole-induced intoxication with phenytoin in a patient with ultra-high activity of CYP2C9. Eur J Clin Pharmacol. 2010;66(8):791-795.
  12. Lazar JD, Wilner KD. Drug interactions with fluconazole. Rev Infect Dis. 1990;12(suppl 3):​S327-S333.
  13. Blum RA, Wilton JH, Hilligoss DM, et al. Effect of fluconazole on the disposition of phenytoin. Clin Pharmacol Ther. 1991;49(4):420-425.
  14. Niwa T, Shiraga T, Takagi A. Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005;28(9):1805-1808.
  15. Hay RJ, Clayton YM, Moore MK, Midgely G. An evaluation of itraconazole in the management of onychomycosis. Br J Dermatol. 1988;119(3):​359-366.
  16. Tucker RM, Denning DW, Hanson LH, et al. Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations. Clin Infect Dis. 1992;14(1):165-174.
  17. Ducharme MP, Slaughter RL, Warbasse LH, et al. Itraconazole and hydroxyitraconazole serum concentrations are reduced more than tenfold by phenytoin. Clin Pharmacol Ther. 1995;​58(6):​617-624.
  18. Sporanox [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals; 2014.