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

  • Kazuyo Shimada
  • Shiori Hasegawa
  • Satoshi Nakao
  • Ririka Mukai
  • Kiyoka Matsumoto
  • Mizuki Tanaka
  • Hiroaki Uranishi
  • Mayuko Masuta
  • Shohei Nishida
  • Shinya Shimizu
  • Yuichi Hayashi
  • Akio Suzuki
  • Mitsuhiro NakamuraEmail author
Original Article



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 ≥ 60 year group (p = 0.00094; vs. < 60 year group) and ≥ 2000 mg/m2 dosage group (p = 0.00045; vs. < 2000 mg/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 ± 703.2 mg/m2, respectively (p < 0.05). Encephalopathy within the first 7 days 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 7 days). The patients who are administered a high dose of ifosfamide or co-administrated aprepitant should be carefully monitored for the development of encephalopathy.


Ifosfamide Encephalopathy FDA Adverse Event Reporting System Japanese Adverse Drug Event Report FAERS JADER 



This research was partially supported by the Japan Society for the Promotion of Science KAKENHI (Grant no. 17K08452). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

Conflict of interest

There are no conflicts of interest to declare.

Ethical approval

Ethical approval was not sought for this study because the study was a database-related observational study without directly involving any research subjects.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kazuyo Shimada
    • 1
  • Shiori Hasegawa
    • 1
    • 4
  • Satoshi Nakao
    • 1
  • Ririka Mukai
    • 1
  • Kiyoka Matsumoto
    • 1
  • Mizuki Tanaka
    • 1
  • Hiroaki Uranishi
    • 1
    • 5
  • Mayuko Masuta
    • 1
    • 6
  • Shohei Nishida
    • 2
  • Shinya Shimizu
    • 2
  • Yuichi Hayashi
    • 3
  • Akio Suzuki
    • 2
  • Mitsuhiro Nakamura
    • 1
    Email author
  1. 1.Laboratory of Drug InformaticsGifu Pharmaceutical UniversityGifuJapan
  2. 2.Department of PharmacyGifu University HospitalGifuJapan
  3. 3.Department of NeurologyGifu University Graduate School of MedicineGifuJapan
  4. 4.Department of PharmacyKobe City Medical Center General HospitalKobe-cityJapan
  5. 5.Division of PharmacyNara Medical University HospitalNaraJapan
  6. 6.Division of PharmacyKyoto City HospitalKyotoJapan

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