SEVERE VINCRISTINE NEUROTOXICITY WITH CONCOMITANT USE OF ITRACONAZOLE
30 June 2003
Dear Editor,
SEVERE VINCRISTINE NEUROTOXICITY WITH CONCOMITANT USE OF ITRACONAZOLE
We would like to share our experience of severe itraconazole− vincristine interaction which emphasizes the need to use this particular antifungal agent with caution when co-administering vincristine to patients. Itraconazole, with its broad-spectrum of antifungal activity, is often prescribed for childhood cancer patients for both treatment and prophylaxis of fungal infections. However, many of the chemotherapy protocols that these children are treated with, especially for lymphoid malignancies, also include the vinca alkaloid, vincristine.
Our first patient was an 8-year-old boy with T-cell acute lymphoblastic leukemia (ALL) who was receiving induction therapy with oral dexamethasone and weekly intravenous vincristine (1.5 mg/m2). Concomitantly, he received prophylactic itraconazole (5 mg/kg per day) as there had been a recent rise in the incidence of fungal infections in our unit. This was believed to be related to major building and earth works being carried out in the vicinity of the hospital. Four days after the third dose of vincristine, he presented with bilateral ptosis and paralytic ileus. Twenty-four hours after the onset of the initial symptoms, he developed generalized tonic-clonic seizures with progression to status epilepticus. Examination of the cerebrospinal fluid (CSF) and computerized tomography of the brain were normal. Serum sodium at this time was 120 mmol/L and serum osmolarity was 205 mosm/L, suggesting a syndrome of inappropriate antidiuretic hormone secretion (SIADH) as the cause of severe hyponatremia.
He required assisted ventilation for 72 h and the seizures were controlled with phenytoin. The combination of neuro-toxicity and SIADH pointed to vincristine toxicity, which was likely to have been aggravated by co-administration of itraconazole. Following cessation of itraconazole and reduction in the subsequent doses of vincristine, the SIADH resolved after 2 weeks while the bilateral ptosis resolved 3 weeks thereafter.
The second patient was a 2-year-old boy with precursor B-cell ALL who was also started on prophylactic itraconazole with the commencement of induction chemotherapy. After the second weekly dose of vincristine (1.5 mg/m2), he presented with severe abdominal pain associated with abdominal distension and absent bowel sounds. He was diagnosed as having vincristine-induced ileus. This improved after 8 days with conservative measures. He was then deemed well enough to receive the third dose of vincristine. The itraconazole was not stopped. Unfortunately, 2 days after receiving the vincristine, he returned with inability to walk and to pass urine. Clinical examination revealed bilateral lower limb weakness grade 2/5, areflexia, a palpable bladder and reduced anal tone. An urgent magnetic resonance imaging (MRI) scan ruled out a spinal cord lesion.
However, the MRI scan of the brain showed bilateral symmetrical demyelinating changes in the parietal and occipital areas. This was thought to be consistent with vincristine neurotoxicity and this diagnosis was further supported by the electromyography findings, which showed electrophysiological evidence of sensorimotor peripheral neuropathy. Examination of the CSF was normal. Itraconazole was stopped and the remaining two doses of vincristine were omitted. The paraparesis and bladder control improved over the following 4 weeks.
Although vincristine neurotoxicity is not an unknown entity1, such side effects are unusual with the cumulative doses administered to both these patients (5 mg in patient 1 and 2.7 mg in patient 2).
The most likely explanation is the co-administration of itraconazole, which blocks the CYP3A subfamily of hepatic cytochrome P450 enzymes which then leads to the consequent delay in the metabolism of vincristine. In addition, itraconazole inhibits the P-glycoprotein efflux transport pump of the cells, resulting in high intracellular vincristine levels2. Clinicians administering chemotherapy need to be aware of the interaction between vincristine and itraconazole, where even a single dose can lead to severe toxicity3−5. Although previous reports of itraconazole interaction have only involved vincristine, it is reasonable to assume that all vinca alkaloids interact in the same manner because they share similar metabolism pathways. We agree with the recommendation that prophylactic itraconazole be interrupted during the time of vincristine administration to minimize the incidence and/or severity of neurotoxicity which in turn leads to the omission of scheduled vincristine doses and deviation from the treatment protocol.
