FAERS analysis maps early, diverse ifosfamide neurological adverse events

A large-scale pharmacovigilance analysis found that central nervous system adverse events reported with ifosfamide were diverse, often began within days of treatment and included a disproportionate number of reports of encephalopathy. Investigators identified 786 ifosfamide-related central nervous system event reports in the US Food and Drug Administration’s Adverse Event Reporting System, or FAERS, covering the first quarter of 2004 through the fourth quarter of 2024. Encephalopathy produced the strongest disproportionality signal, with 252 reports and a reporting odds ratio of 101.19, followed by neurotoxicity and toxic encephalopathy. The findings characterize reporting associations rather than establishing how often these events occur or proving that ifosfamide caused them.

The study combined four statistical signal-detection methods—reporting odds ratio, proportional reporting ratio, the multi-item gamma Poisson shrinker and the Bayesian information component. A preferred term was counted as a signal only if it met the criteria for all four algorithms. All 42 central nervous system preferred terms identified in the analysis met those criteria. Their reporting odds ratios ranged from 3.19 for lethargy to 101.19 for encephalopathy, while neurotoxicity, reported 117 times, had a reporting odds ratio of 67.42. Toxic encephalopathy, with 33 reports, had a similar value of 66.17. Commoner symptoms such as confusional state, disorientation, agitation, mental-status change, coma, delirium and status epilepticus also generated signals. These results indicate that ifosfamide was reported more often in connection with these terms than expected from the database’s broader reporting pattern, a finding that requires clinical and epidemiological validation.

The analysis also flagged six events that the study said were not listed in the ifosfamide prescribing information: brain oedema, hydrocephalus, spinal cord compression, cerebral ischemia, gaze palsy and Guillain–Barré syndrome. Their report counts ranged from three to six, and all met the study’s four-way signal threshold. These findings do not demonstrate that ifosfamide caused the conditions, which may instead reflect underlying disease, other medicines, metabolic disturbances or combinations of factors. Some events can also resemble tumor progression or complications of other chemotherapy agents, making attribution difficult without complete clinical information. The signals broaden the reported neurological spectrum associated with ifosfamide and identify areas requiring prospective pharmacoepidemiological investigation, rather than establishing new label indications or causal effects.

Timing data were available for 233 of the 786 central nervous system reports. Among these cases, the median time to onset was two days after treatment initiation, with an interquartile range of one to eight days and an observed range of one to 200 days. A total of 204 cases, or 87.55% of those with usable timing data, reported onset within 30 days. Smaller numbers were reported from days 31 to 60, days 61 to 90 and between 91 days and one year. A Weibull model estimated a shape parameter of 0.62, with a 95% confidence interval of 0.57 to 0.68, indicating an early-failure pattern in which documented events tended to occur earlier rather than later. Because the analysis covered only 29.64% of all included reports, the timing distribution should be interpreted as a feature of the available subset rather than the complete reporting population.

Central nervous system reports differed from the broader group of adverse drug events associated with ifosfamide. Sex was available for 669 of the 786 central nervous system reports: 372 concerned females and 297 concerned males. These represented 47.33% and 37.79% of all 786 reports, respectively, or approximately 55.61% and 44.39% among records with known sex. Age was available for 600 reports. Adults aged 18 to 64 accounted for 354 reports, or 45.04% of the complete central nervous system group and approximately 59.00% of records with known age; 131 reports involved people younger than 18 and 115 involved those older than 64. Of all central nervous system reports, 93 were associated with death, 62 with a life-threatening outcome and 269 with hospitalization.

Brain oedema had the highest reported fatal-outcome proportion, at 83.33%, although this estimate came from only six cases. Neurological decompensation was followed by coma, with reported fatal-outcome proportions of 57.14% from seven cases and 56.00% from 25 cases, respectively. Spinal cord compression had a reported fatal-outcome proportion of 50.00% from four cases. By contrast, fatal outcomes were reported in 5.83% of 120 confusional-state cases, 8.77% of 57 disorientation cases, 9.40% of 117 neurotoxicity cases and 11.11% of 252 encephalopathy cases. These high percentages describe outcomes among reported cases and are not mortality risks for the wider treated population. The denominators also differed sharply, and spontaneous reports cannot capture the number of patients who received ifosfamide without an event or the full clinical course of those who did.

Subgroup analyses suggested differences in reporting patterns by sex and age. The study detected 27 central nervous system preferred terms among females and 23 among males. Encephalopathy was reported 120 times in females, with a reporting odds ratio of 135.64 and a 95% confidence interval of 112.87 to 163.02, compared with 65 reports and a reporting odds ratio of 47.08 in males. Reporting odds ratios for confusional state, neurotoxicity and disorientation were also higher in the female cohort. Among adults aged 18 to 64, encephalopathy had the strongest signal, with a reporting odds ratio of 78.69. In patients older than 64, confusional state was most frequently reported, while psychomotor impairment, clumsiness and encephalopathy had strong disproportionality values. Reported events among minors included tonic-clonic movements, petit mal epilepsy and behavioral disorders. The observational and spontaneous-reporting design prevents these comparisons from establishing biological differences in susceptibility.

The researchers separately reviewed case reports and case series retrieved from PubMed and SpringerLink through September 2025. Two researchers screened the literature, resolving disagreements with a third, and assessed each included publication with an eight-item Joanna Briggs Institute checklist. Of 42 eligible publications, 38, or 90.5%, met all eight criteria, and the mean number of affirmative ratings was 7.9. The review contained 61 patients aged 3 to 77 years treated for sarcoma, lymphoma, ovarian cancer, breast cancer and other solid tumors. Forty-six patients, or 75.41%, developed central neurotoxicity after one to three cycles of ifosfamide-containing chemotherapy. Impaired consciousness, hallucinations, seizures, delirium, disorientation and psychiatric or behavioral abnormalities were among the manifestations described. The literature was synthesized descriptively because the evidence consisted predominantly of case reports and small case series rather than comparative cohorts.

Outcome and treatment details in the literature review showed that 29 of 46 cases with usable recovery information recovered within 48 hours and 38 recovered within 72 hours, with reported recovery times ranging from minutes to three weeks. Overall, 54 of 61 patients, or 88.52%, were reported to have recovered, while seven had a fatal outcome. Methylene blue was the most frequently reported treatment, appearing in 47.54% of cases, followed by benzodiazepines in 26.23%, antipsychotics in 18.03% and thiamine in 13.11%; several patients received more than one treatment. These figures synthesize heterogeneous reports, sometimes involving combination therapy and varying diagnostic workups, and therefore do not isolate the effectiveness of any individual treatment. They also cannot provide a comparative estimate of recovery because the review did not include a control group or standardized treatment assignment.

The results support a picture of ifosfamide-associated central neurotoxicity that is clinically heterogeneous, frequently reported soon after treatment and not confined to encephalopathy. A sensitivity analysis that removed adverse events related to cisplatin, carboplatin, epirubicin, etoposide and mesna reduced the number of events but left signals for encephalopathy, confusional state, neurotoxicity, disorientation, agitation, mental-status changes, toxic encephalopathy and coma stable. This sensitivity check addressed reporting involving those named concomitant medicines, but it did not exclude every report containing concomitant drugs or fully remove confounding from other treatments, disease-related neurological complications and metabolic disturbances. FAERS is also vulnerable to missing information, duplicate or incomplete reports, selective submission and uncertainty about renal function, albumin, electrolytes, disease progression, prior cranial radiotherapy and other drugs. The case literature is susceptible to publication bias and incomplete diagnostic workups. Prospective studies are therefore needed to determine incidence, causal relationships, risk factors and effective prevention strategies.

Subject of Research: Pharmacovigilance analysis of ifosfamide-associated central nervous system adverse events

Article Title: Exploring ifosfamide-related central nervous system adverse events based on the FAERS database and clinical feature analysis of cases

Article References: Shi, P., Mei, Q., zheng, R., & Wang, S. (2026). Exploring ifosfamide-related central nervous system adverse events based on the FAERS database and clinical feature analysis of cases. Frontiers in Oncology, 16, Article 1961478. https://doi.org/10.3389/fonc.2026.1961478

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1961478

Keywords: ifosfamide, neurotoxicity, encephalopathy, FAERS, pharmacovigilance, adverse drug events, disproportionality analysis, case reports, chemotherapy, time to onset, Exploring, ifosfamide-related