Encephalopathy Risk With Ifosfamide: Higher With Solution?

Roxanne Nelson, RN, BSN

March 16, 2020

The anti-cancer drug ifosfamide is already known to be associated with a risk of encephalopathy, but now a European body is examining whether this risk is greater when it is used as a ready-made solution as compared with when it is used as a powder and made up for solution as needed. 

The question is being examined by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency, which has begun a review of medicines that contain ifosfamide.

Ifosfamide is available as a ready-made solution, a concentrate for solution, and a powder for solution to be used an infusion in Germany and France; throughout most of the European Union countries, it is only available as a powder.

An alkylating agent and synthetic analog of cyclophosphamide, ifosfamide is indicated for use for use in combination with other antineoplastic agents for third-line germ cell testicular cancer. It has received orphan drug status for bone and soft tissue sarcomas, and is used off-label for cancers of lung, breast, ovary, cervix, pancreas, bladder, and stomach, as well as for non-Hodgkin lymphoma.

PRAC noted that the risk of encephalopathy "is already known and reflected in the product information for these medicines."

Neurotoxicity may occur in 10% to 20% of users, and a black box warning cautions that "confusion and coma due to CNS toxicity have been associated with therapy."

However, the question is if the risk of encephalopathy is higher with the ready-made formulation than with the powder.

A French investigation in 2016 suggested that the incidence of encephalopathy was threefold to fourfold higher with the ready-made solution as compared to the powder.

Analyses that were conducted at the time found that the risk could be associated with the degradation of the active substance and impurities that developed in the solution over time. Based on these analyses, a precautionary measure was taken and the shelf life of the ready-made solution was reduced to 7 months in France.

However, two recent studies from France suggested that the risk of encephalopathy was still greater with the ready-made solutions than with the powder, despite the introduction of the shorter half-life for the ready-made solution.

The first study, published in October in the journal Therapies, describes a case-control study conducted in the pediatric oncology departments of 25 university hospitals between July 1, 2016 and July 1, 2018 involving all patients who received the liquid formulation or lyophilized powder formulation during the study period.

There were a total of 52 cases and 495 controls. The results showed that a residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation vs lyophilized powder (adjusted odds ratio, 1.91). The use of methylene blue as a curative therapy for encephalopathy was more frequent among children who received the liquid formulation vs those treated with the powder (93.3% vs. 78.8%, respectively, P = .017).

The second study, published in March 2019 the Journal of Clinical Pharmacy and Therapeutics, describes a retrospective study that included adult patients treated with ifosfamide in two medical centers from 2013 to 2017. A total of 103 patients received Holoxan (lyophilized powder formulation) and 88 patients received Ifosfamide EG (liquid formulation). Ifosfamide‐induced encephalopathy was observed in 11 patients (5.8%), and the frequency of encephalopathy was 1.9% in the Holoxan group (2/103) vs 10.2% (9/88) in the Ifosfamide EG group (P = .014).

Upon multivariate analysis, there were significantly more treatment-related encephalopathies with Ifosfamide EG compared with Holoxan (P = .018). The authors noted that these results "confirm data from spontaneous reports that led to the precautionary measure for the liquid formulation."

With study results suggesting that the risk of encephalopathy is higher with the solution as compared with the powder, the EMA says that it will now assess the available data and then recommend whether the marketing authorizations for these products should be maintained, varied, suspended, or revoked.

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