Itraconazole can increase toxicity of vincristine and vinblastine; posaconazole and voriconazole may interact similarly. Thereis a theoretical possibility that itraconazole and ketoconazole mayincrease toxicity of vinorelbine
Clinical evidence,mechanism, importance and management
Four out of 14 patients with ALL given induction chemotherapy with weekly injections of vincristine (with prednisone, daunorubicin and asparaginase) and antifungal prophylaxis with itraconazole 400mg daily, developed severe and early vincristine-induced neurotoxicity (paraesthesia and muscle weakness of hands and feet, paralytic ileus, mild laryngeal nerve paralysis). The degree and early onset of these neurotoxic reactions were unusual,and were all reversible except for mild paraesthesia in one patient. The complications were more serious than in a previous series of 460 patients given vincristine without itraconazole (29% compared to 6%).(See reference number 1) Five children with ALL developed severe vincristine toxicity attributed to concurrent use of itraconazole. They were also receiving nifedipine, , which is known to reduce clearance of vincristine, and which may have made things worse.(See reference number 2) Severe vincristine neurotoxicity developed in four other children(See reference number 3-5) and two adults(See reference number 6) with ALL when they were given itraconazole. Another study similarly indicates that greater vincristine toxicity may occur in patients given itraconazole.
The reasons for this interaction are not understood, but among suggestions are that itraconazole inhibits metabolism of vincristine by cytochrome P450 enzyme system, so that it is cleared from body less quickly (See reference number 1). Another possible explanation is that itraconazole inhibits P-glycoprotein,(See reference number 1) and increased vincristine neurotoxicity may be result of inhibition of this pump in endothelial cells of blood-brain barrier (See reference number 7).
The authors of one report(See reference number 1) suggest that itraconazole should be avoided in patients taking vincristine, and manufacturers of vincristine also issue a warning about increased risks of concurrent use (See reference number 8).
Acute neurotoxicity and myelotoxicity occurred in a boy with Hodgkin’s lymphoma treated with vinblastine,doxorubicin and methotrexate when he was also given itraconazole. The toxicity did not occur when he was given same chemotherapy without itraconazole (See reference number 9).
Some UK(See reference number 10) and US(See reference number 11) manufacturers advise caution if vinorelbine, which is metabolised by CYP3A4, is given with inhibitors of this isoenzyme such as itraconazole and ketoconazole because of theoretical risk of increased neurotoxicity. The manufacturers of vindesine note that concurrent administration with CYP3A inhibitors may result in early onset or increased severity of vindesine side-effects (See reference number 12).
The manufacturers of posaconazole advise avoidance of concurrent use with vinca alkaloids (vincristine and vinblastine are named), but if they are given, then dose adjustments of vinca alkaloids should be considered (See reference number 13).
The manufacturers of voriconazole advise caution if it is given to patients treated with vinca alkaloids (vincristine and vinblastine are named) because of risk of neurotoxicity (See reference number 14,15). The US manufacturer recommends that dose adjustments of vinca alkaloids should be considered (See reference number 15)
Böhme A,Ganser A, Hoelzer D. Aggravation of vincristine-induced neurotoxicity by itraconazole in the treatment of adult ALL. Ann Hematol (1995) 71, 311–12.
Murphy JA,Ross LM, Gibson BES. Vincristine toxicity in five children with acute lymphoblastic leukaemia. Lancet (1995) 346, 443.
Ariffin H,Omar KZ, Ang EL, Shekhar K. Severe vincristine neurotoxicity with concomitantuse of itraconazole. J Paediatr Child Health (2003) 39, 638–9.
Jeng MR,Feusner J. Itraconazole-enhanced vincristine neurotoxicity in a child with acutelymphoblastic leukemia. Pediatr Hematol Oncol (2001) 18, 137–42.
Sathiapalan RK,Al-Nasser A, El-Sohl H, Al-Mohsen I, Al-Jumaah S. Vincristine-itraconazole interaction: cause for increasing concern. J Pediatr Hematol Oncol (2002) 24, 591.
Gillies J,Hung KA, Fitzsimons E, Soutar R. Severe vincristine toxicity in combination withitraconazole. Clin Lab Haematol (1998) 20, 123–4.
Muenchow N,Janka G, Erttmann R, Looft G, Bielack S, Winkler K. Increased vincristine neurotoxicity during treatment with itraconazole in 3 pediatric patients with acute myelogenous leukaemia. Blood (1999) 94 (Suppl 1, part 2) 234b.
Vincristine sulphate. Mayne Pharma plc. UK Summary of product characteristics,April2004.
Bashir H,Motl S, Metzger ML, Howard SC, Kaste S, Krasin MP, Hudson MM. Itraconazoleenhanced chemotherapy toxicity in a patient with Hodgkin lymphoma. J Pediatr Hematol Oncol (2006) 28, 33–5.
Vinorelbine. Mayne Pharma plc. UK Summary of product characteristics,June 2006.
Navelbine (Vinorelbine tartrate). Pierre Fabre Pharmaceuticals Inc. US Prescribing information,August 2005.
Eldisine (Vindesine). Eli Lilly and Company Ltd. UK Summary of product characteristics,September 1998.
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.