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Observational Study
. 2020 Sep-Oct;75(5):471-480.
doi: 10.1016/j.therap.2019.08.001. Epub 2019 Oct 28.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population

Dominique Hillaire-Buys  1 , Mégane Mousset  2 , Marion Allouchery  3 , Brahim Azzouz  4 , Marina Babin  5 , Florelle Bellet  6 , Johana Béné  7 , Anne Default  8 , Geneviève Durrieu  9 , Hélène Géniaux  10 , Aurélie Grandvuillemin  11 , Valérie Gras-Champel  12 , Hélène Jantzem  13 , Aude Lambert  14 , Marion Lepelley  15 , Nathalie Massy  16 , Nadine Petitpain  17 , Fanny Rocher  18 , Paola Sanchez-Pena  19 , Marion Sassier  20 , Corinne Simon  21 , Louise Triquet  22 , Marie-Blanche Valnet-Rabier  23 , Gwenaëlle Veyrac  24 , Jean-Luc Faillie  2 , Marie-Christine Zenut  25
Affiliations
Observational Study

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population

Dominique Hillaire-Buys et al. Therapie. 2020 Sep-Oct.

Abstract

Background: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal.

Methods: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups.

Results: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53).

Conclusions: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

Keywords: Case-control; Children; Chloroethanamine; Chloroethylamine; Encephalopathy; Ifosfamide; Liquid formulation.

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