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Sous presse. Epreuves corrigées par l'auteur. Disponible en ligne depuis le mercredi 13 novembre 2019
Doi : 10.1016/j.therap.2019.08.001
Received : 18 July 2019 ;  accepted : 20 August 2019
Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population

Dominique Hillaire-Buys a, , Mégane Mousset a, Marion Allouchery b, Brahim Azzouz c, Marina Babin d, Florelle Bellet e, Johana Béné f, Anne Default g, Geneviève Durrieu h, Hélène Géniaux i, Aurélie Grandvuillemin j, Valérie Gras-Champel k, Hélène Jantzem l, Aude Lambert m, Marion Lepelley n, Nathalie Massy o, Nadine Petitpain p, Fanny Rocher q, Paola Sanchez-Pena r, Marion Sassier s, Corinne Simon t, Louise Triquet u, Marie-Blanche Valnet-Rabier v, Gwenaëlle Veyrac w, Jean-Luc Faillie a, Marie-Christine Zenut x
a Department of medical pharmacology and toxicology, CRPV, CHU de Montpellier, 371, avenue Doyen-Giraud, 34295 Montpellier, France 
b Department of clinical pharmacology and vigilances, CPRV, CHU de Poitiers, 86021 Poitiers, France 
c Department of pharmacovigilance and pharmacoepidemiology, CRPV, CHU de Reims, 51092 Reims, France 
d Department of pharmacology and toxicologie, CRPV, CHU d’Angers, 49933 Angers, France 
e Department of pharmacovigilance, CRPV, CHU de Saint-Étienne, 42055 Saint-Étienne, France 
f Department of pharmacovigilance, CRPV, CHU de Lille, 59045 Lille, France 
g Department of clinical pharmacology, CRPV, Sainte-Margueritte hospital, AP–AHM, 13274 Marseille, France 
h Department of clinical pharmacology, CRPV, CHU de Toulouse, 31000 Toulouse, France 
i Department of pharmacology, toxicology and pharmacovigilance, CRPV, CHU de Limoges, 87000 Limoges, France 
j Department of vigilances, CRPV, CHU de Dijon, 21079 Dijon, France 
k Department of human biology, CRPV, CHU d’Amiens-Picardie, 80054 Amiens, France 
l Department of pharmacovigilance, CRPV, CHU de Brest, 29609 Brest, France 
m Department of pharmaocvigilance, CRPV, Civil hospital of Strasbourg, 67091 Strasbourg, France 
n Department of public health, CRPV, CHU Grenoble-Alpes, 38700 Grenoble, France 
o Department of clinical biology, CRPV, CHU de Rouen, 76031 Rouen, France 
p Department of clinical pharmacology and toxicology, CRPV, CHU de Nancy, 54511 Nancy, France 
q Department of pharmacovigilance, CRPV, Cimiez hospital, CHU de Nice, 06003 Nice, France 
r Department of medical pharmacology, CRPV, Pellegrin hospital, CHU de Bordeaux, 33300 Bordeaux, France 
s Department of pharmacology, CRPV, CHU de Caen, 14000 Caen, France 
t Department of pharmacosurveillance, CRPV, CHU de Tours, 37044 Tours, France 
u Department of clinical pharmacology and biology, CRPV, Pontchaillou hospital, CHU de Rennes, 35033 Rennes, France 
v Department of pharmacovigilance, CRPV, CHU de Besançon, 25030 Besançon, France 
w Department of clinical pharmacology, CRPV, CHU de Nantes, 44093 Nantes, France 
x Department of medical pharmacology, CRPV, CHU de Clermont-Ferrand,63003 Clermont-Ferrand, France 

Corresponding author at: Department of medical pharmacology and toxicology, CRPV, CHU de Montpellier, 371, avenue Doyen-Giraud, 34295 Montpellier, France.Department of medical pharmacology and toxicology, CRPV, CHU de Montpellier371, avenue Doyen-GiraudMontpellier34295France

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.


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.


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).


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.

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

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