Paraplegia and Paraparesis From Intrathecal Methotrexate and Cytarabine Contaminated With Trace Amounts of Vincristine in China During 2007

• Published in: Journal of clinical oncology Vol. 29; no. 13; pp. 1765 - 1770
• Main Authors: Zeng, Guang, Ma, Huilai, Wang, Xiangbo, Yan, Huifang, Wan, Xinhua, Jiang, Bin, Fontaine, Robert E, Wu, Zhenglai, Lin, Shaobin, Ruan, Feng, Liu, Huihui
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 01-05-2011
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Child; Child, Preschool; China; Cytarabine - administration & dosage; Cytarabine - chemistry; Drug Compounding - instrumentation; Drug Contamination; Equipment Contamination; Female; Humans; Infant; Male; Methotrexate - administration & dosage; Methotrexate - chemistry; Paraparesis - chemically induced; Paraplegia - chemically induced; Vincristine - administration & dosage; Vincristine - analysis; Vincristine - poisoning; China
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2010.32.7072

The production and administration of drugs used intrathecally requires special care to prevent contamination with neurotoxic agents. In 2007, we investigated a widespread outbreak of paraplegia and paraparesis among Chinese patients who received intrathecal drugs to identify the presumed contaminant and its source to prevent further cases.
We defined a case as onset from January 1 to October 31, 2007, of bilateral flaccid paraparesis or paraplegia or retention and incontinence of stool or urine, in a patient receiving intrathecal drugs. Using a retrospective cohort approach, we selected 12 hospitals from all hospitals that had reported cases. In these hospitals, we identified all 448 patients (including 107 cases) who received intrathecal chemotherapy or chemoprophylaxis in 2007. We calculated attack rates and Mantel-Haenszel adjusted risk ratios for intrathecal drug type and lot.
All 12 hospitals used intrathecal methotrexate or cytarabine produced by one pharmaceutical plant. Only two lots of each drug were associated with cases. Lot-specific attack rates ranged from 42% to 100% (risk ratio, ∞; lower confidence bounds, 1.8 to 7.3). Vincristine production had immediately preceded production of the implicated lots on the same equipment. By using ultra performance liquid chromatography, we detected vincristine (0.28 to 18 μg) in unused vials from implicated lots of methotrexate and cytarabine.
Trace amounts of vincristine that contaminated intrathecal drugs caused a large outbreak of severe neurologic damage. Vincristine and other neurotoxic drugs should not be produced on any equipment that is also used for producing drugs that are to be administered intrathecally.