Ifosfamide‐induced encephalopathy: Brand‐name (HOLOXAN®) vs generic formulation (IFOSFAMIDE EG®)

Abstract

Summary What is known and Objective Two forms of ifosfamide are commercially available in France: HOLOXAN® (brand‐name drug) and IFOSFAMIDE EG® (generic drug). Following the marketing launch of the generic drug, there has been a significant increase in cases of ifosfamide‐induced encephalopathy reported in France. Our objective is to compare the incidence of ifosfamide‐induced encephalopathy in adult patients treated with HOLOXAN® or IFOSFAMIDE EG®. Methods This is a retrospective study of adult patients treated with ifosfamide in two medical centers from 2013 to 2017, with data analysed from medical records. Comparisons of patients were made, according to the formulation used and according to the occurrence of ifosfamide‐induced encephalopathy. The groups of patients were compared using a chi‐square or Fisher's exact test for qualitative parameters and a Wilcoxon test for quantitative parameters. To include confounding factors in the analysis of the impact of drug formulation on the occurrence of ifosfamide‐induced encephalopathy, a generalized linear model was performed with the occurrence of ifosfamide‐induced encephalopathy as the dependent parameter, and the formulation and the confounding factors as explanatory parameters. Results and Discussion A total of 191 patients were included: 103 patients received HOLOXAN® (53.9%) and 88 patients received IFOSFAMIDE EG® (46.1%). In the HOLOXAN® group, the median infusion time was higher (12 hours vs 3h, P < 0.001) and aprepitant was administered more frequently (78.6% vs 69.7%, P < 0.001) than for the IFOSFAMIDE EG® group. Ifosfamide‐induced encephalopathy occurred in 11 patients (5.8%, CI 95% [2.9%, 10.0%]). In the ifosfamide‐induced encephalopathy group, median infusion time was higher (12 hours [12; 24] vs 3 hours [2; 12] P < 0.001) and a poor performance status was more frequent (54.5% vs 13.9%, P = 0.002) than in the group without ifosfamide‐induced encephalopathy. The frequency of ifosfamide‐induced encephalopathy in the HOLOXAN® group was 1.9% (2/103) against 10.2% (9/88) in the IFOSFAMIDE EG® group (P = 0.014). Multivariate analysis revealed that treatment with IFOSFAMIDE EG® resulted in significantly more ifosfamide‐induced encephalopathies compared to HOLOXAN® (OR and CI 95%:7.4 [1.4; 39.5], P = 0.018). We identified two other risk factors for ifosfamide‐induced encephalopathy: long‐term infusion and a performance status of two or higher. What is New and Conclusion The formation of chloroethylamine in solution could be the cause of more frequent ifosfamide‐induced encephalopathies with IFOSFAMIDE EG® compared to HOLOXAN®. Application of these data could help in the choice of ifosfamide formulation in adult patients to decrease the risk of ifosfamide‐induced encephalopathy, and more specifically for patients with risk factors.

VALIDASI KUESIONER EFEK SAMPING PENGGUNAAN IFOSFAMID PADA PASIEN KANKER DI RSUP Dr KARIADI SEMARANG

“…Penelitian Chambord et al menyatakan bahwa gejala ensefalopati yang diinduksi ifosfamid termasuk kebingungan, disorientasi, gelisah, halusinasi, mengantuk, afasia (gangguan komunikasi), letargi (kelelahan), dan kejang. Gejala biasanya bermanifestasi selama pemberian obat atau dalam 48 jam, dan biasanya menghilang secara spontan 48-72 jam setelah penghentian infus (Chambord et al, 2019). Efek samping yang tidak dirasakan oleh pasien kanker RSUP dr. Kariadi Semarang adalah diare, buang air kecil berwarna merah dan rasa nyeri, penurunan kesadaran, dan kejang.…”

Generic substitution of amlodipine is not associated with increased risk of mortality or adverse cardiovascular events: An observational cohort study

“… 1 Many health systems mandatorily require evidence of bioequivalence of a generic medicine to its originator in entry approval, which, however, only justify the equivalent rate and extent of absorption instead of therapeutic efficacy. 2 , 3 , 4 , 5 , 6 Debates have been persisting on the clinical efficacy and safety of generic substitution, 7 , 8 , 9 with emerging real‐world evidence on the comparative effectiveness in the field of oncology, 10 , 11 , 12 , 13 endocrine and metabolic diseases, 14 , 15 , 16 and mental disorders. 17 , 18 , 19 However, data are lacking for medicines that manage hypertension, the most common condition and a strong silent killer undermining population health.…”

Incidence of ifosfamide induced encephalopathy in patients receiving concomitant fosaprepitant

“…Generally accepted risk factors for IIE include: poor performance status, pelvic disease, hypoalbuminemia, and elevated serum creatinine. [6][7][8][9][10][11][12][13][14] Other potential risk factors, in which the literature is mixed, include: higher ifosfamide doses, shorter duration of ifosfamide infusion, obesity, hyperbilirubinemia, prior cisplatin exposure, and drug-drug interactions, namely with CYP2B6 and CYP3A4 inhibitors. 3,[7][8][9][10][12][13][14] Howell and colleagues first characterized a relationship between aprepitant and the development of IIE.…”