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

Dominique Hillaire-Buys 1 Mégane Mousset 1 Marion Allouchery 2, 3 Brahim Azzouz 4 Marina Babin 5 Florelle Bellet 6 Johana Béné 7 Anne Default 8 Genevieve Durrieu 9, 10 Hélène Géniaux 11 Aurélie Grandvuillemin 12 Valérie Gras-Champel 13 Hélène Jantzem 14 Aude Lambert 15 Marion Lepelley 2 Nathalie Massy 16 Nadine Petitpain 17, 18 Fanny Rocher 19 Paola Sanchez-Pena 20 Marion Sassier 21 Corinne Simon 22 Louise Triquet 23 Marie-Blanche Valnet-Rabier 24 Gwenaëlle Veyrac 25 Jean-Luc Faillie 26 Marie-Christine Zenut 27, 28
17 CRPV Lorraine - Centre Régional de PharmacoVigilance de Lorraine
CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
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.
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https://hal.umontpellier.fr/hal-02542625
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : mardi 14 avril 2020 - 17:55:10
Dernière modification le : vendredi 15 mai 2020 - 12:22:05

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Dominique Hillaire-Buys, Mégane Mousset, Marion Allouchery, Brahim Azzouz, Marina Babin, et al.. Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population. Alternative and Complementary Therapies, Mary Ann Liebert, 2019, ⟨10.1016/j.therap.2019.08.001⟩. ⟨hal-02542625⟩

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