Adverse event profiles of ifosfamide-induced encephalopathy analyzed using the Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases.

Abstract

Ifosfamide is extensively used to treat several malignant conditions. Administration of ifosfamide can cause encephalopathy and other neurotoxic effects. The aim of this study was to obtain novel information on the onset profiles of ifosfamide-induced encephalopathy (IIE) considering other associated clinical factors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) databases. We analyzed the reports of encephalopathy between 2004 and 2018 from the FAERS and JADER databases. To define IIE, we used the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and standardized queries. The reporting odds ratios (ROR) at 95% confidence interval (CI) was used to detect the signal for IIE and adjusted for covariates using a multivariate logistic regression technique. We evaluated the time-to-onset profile of IIE and used the association rule mining technique to discover undetected associations, such as potential risk factors. In the FAERS database, the ROR (CI) for encephalopathy (preferred term, PT) and encephalopathy (standardized MedDRA queries, SMQ) was 56.58 (51.69-61.93) and 1.57 (1.48-1.67), respectively. In the JADER database, the ROR (95% CI) for encephalopathy (PT) and encephalopathy (SMQ) was 13.54 (9.91-18.50) and 1.24 (1.01-1.53), respectively. The multivariate logistic regression analysis showed a significant contribution in IIE signal in the ≥ 60year group (p = 0.00094; vs. < 60year group) and ≥ 2000mg/m2 dosage group (p = 0.00045; vs. < 2000mg/m2 dosage group). The association rules of {ifosfamide, aprepitant} → {encephalopathy (SMQ)} demonstrated high lift values. The average dose of ifosfamide in patients with encephalopathy (PT) and without encephalopathy (PT) was 2022.8 ± 592.8 (mean ± standard deviation) and 1568.5 ± 703.2mg/m2, respectively (p < 0.05). Encephalopathy within the first 7days of ifosfamide administration was 94.1% for encephalopathy (PT) and 87.7% for encephalopathy (SMQ), respectively. The present analysis demonstrated that the incidence of encephalopathy with ifosfamide should be closely monitored for a short onset (within 7days). The patients who are administered a high dose of ifosfamide or co-administrated aprepitant should be carefully monitored for the development of encephalopathy.