Annals of Oncology Advance Access originally published online on May 9, 2006
Annals of Oncology 2006 17(10):1601-1602; doi:10.1093/annonc/mdl088
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© 2006 European Society for Medical Oncology
letters to the editor |
Reply to Letter to the Editor: ‘Toxic epidermal necrolysis in patients with malignancies’, by G. Gravante, G. Esposito, M. Marianetti, D. Delogu, G. Sconocchia & A. Montone (doi:10.1093/annonc/mdl089)
Department of Medicine, New Drugs Development and Clinical Pharmacology Unit, European Institute of Oncology, Milan, Italy
*(E-mail: giuseppe.curigliano{at}ieo.it)
We thank Gravante et al. for their eloquent comment on our report related to a case of toxic epidermal necrolysis (TEN) during voriconazole treatment and for their complete support of our conclusion that ‘caution should be exercised when combining voriconazole with other drugs known to cause skin reaction, such as phenythoin’. Gravante et al. point out that in our report it is not clear whether voriconazole had a direct role in the generation of such disease since (i) the patient was also on phenytoin medication (phenytoin has been clearly linked to TEN in a variety of patients) and (ii) voriconazole and phenytoin were simultaneously discontinued at the onset of TEN manifestation. There is still controversy about whether antiepileptic drugs are associated with the severe cutaneous reactions Stevens–Johnson syndrome (SJS) and TEN. An international case control study evaluated the role of antiepileptic drugs in SJS and TEN, taking into account potential cofactors that might confound or modify the risk. Seventy-three (21%) of the 352 SJS/TEN cases and 28 (2%) of the 1579 controls reported intake of antiepileptic drugs. Among the 73 exposed SJS and TEN patients, 36 reported intake of phenobarbital, 14 of phenytoin, 21 of carbamazepine, 13 of valproic acid, and three of lamotrigine. In this study risk was highest in the first 8 weeks after onset of treatment. For individual antiepileptic drugs the univariate relative risk of SJS/TEN for 8 weeks or less of use was 57 (95% CI 16–360; multivariate risk 59 [12–302]) for phenobarbital; 91 (26–infinity) for phenytoin; 120 (34–infinity) for carbamazepine; 25 (5.6–infinity) for lamotrigine, and 24 (5.9–infinity) for valproic acid. On the basis of this study SJS and TEN are associated with short-term therapy with phenytoin, phenobarbital, and carbamazepine [1]. A recent retrospective analysis estimated the risk of SJS and TEN associated with some antiepileptic drugs (AEDs) based on the number of prescriptions or daily doses. In this study, risk in new users was assessed. More than 90% of SJS and TEN cases occurred in the first 63 days of AED use [2]. In our patient treatment with phenytoin was started 14 weeks (98 days) before administration of voriconazole and 103 days before TEN phenomenon. These observations could support the possible correlation between voriconazole and TEN. During voriconazole treatment adverse cutaneous reactions have been reported, namely cheilitis, erythema, discoid lupus erythematosus, SJS, TEN, erythema multiforme, and photosensitivity reactions [3]. Since voriconazole and phenytoin were simultaneously discontinued at the onset of TEN manifestation (as Gramante et al. speculated) another issue is the potential pharmacokinetic interaction between the two drugs. Voriconazole is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. Two placebo-controlled parallel-group studies have been conducted in healthy male volunteers. The results demonstrated that repeated dose administration of 400 mg b.d. voriconazole increased the mean steady-state Cmax and AUCtau of phenytoin by approximately 70% and 80%, respectively. The authors recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is co-administered with voriconazole [4].
Gravante et al. reported from their retrospective data on 32 TEN phenomenon cases of which four occurred in patients with solid and hematological tumors. We noted that all the cases occurred within few days after antibiotic or antidepressant treatment (8 days after sertraline, 15 days after metronidazole and piperacillin, 6 days after ceftazidime treatment). Gravante et al. do not report any information on concomitant treatment (chemotherapeutics or other drugs) that potentially should be associated to TEN described. Sertraline has been described as associated to SJS rather than TEN [5]. TEN as been already reported as associated with ceftazidine or piperacillin treatment [6, 7]. As stated by Gravante et al. cutaneous reactions to chemotherapeutics and supportive drugs as antibiotics are common in cancer patients and may contribute significantly to the morbidity, and rarely to the mortality, of patients undergoing such treatments. Early recognition and management of these reactions is important to provide optimal care, to prevent treatment-related morbidity, and allows continuation of anti-cancer therapy.
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1. Rzany B, Correia O, Kelly JP, et al. (1999) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study. Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 353:2190–2194 (9171).[CrossRef][ISI][Medline]
2. Mockenhaupt M, Messenheimer J, Tennis P, Schlingmann J. (2005) Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics. Neurology 64:71134–1138.
3. Racette AJ, Roenigk HH Jr, Hansen R, et al. (2005) Photoaging and phototoxicity from long-term voriconazole treatment in a 15-year-old girl. J Am Acad Dermatol 52:5Suppl 1, S81–S85.[CrossRef][ISI][Medline]
4. Purkins L, Wood N, Ghahramani P, et al. ( Dec 2003) Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration. Br J Clin Pharmacol 56:Suppl 1, 37–44.
5. Jan V, Toledano C, Machet L, et al. (1999) Stevens-Johnson syndrome after sertraline. Acta Derm Venereol 79:5401.[CrossRef][ISI][Medline]
6. Thestrup-Pedersen K, Hainau B, Al'Eisa A, et al. (2000) Fatal toxic epidermal necrolysis associated with ceftazidine and vancomycin therapy: a report of two cases. Acta Derm Venereol 80:4316–317.[CrossRef][ISI][Medline]
7. Craycraft ME, Arunakul VL, Humeniuk JM. (2005) Probable vancomycin-associated toxic epidermal necrolysis. Pharmacotherapy 25:2308–312.[CrossRef][ISI][Medline]
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