Infusion reactions following administration of intravenous rolapitant at an academic medical center

Abstract

In 2017, due to a fluid shortage secondary to Hurricane Maria's devastation of Puerto Rico, hospitals and health-systems began to substitute rolapitant for fosaprepitant as part of chemotherapy-induced nausea and vomiting prevention and treatment strategies. However, despite advantageous pharmacologic and formulation (e.g. long half-life, quicker time to onset, and lack of first-pass hepatic metabolism) profiles, there seems to be significant risk of infusion-related hypersensitivity reactions associated with the administration of intravenous rolapitant. In January 2018, the U.S. FDA issued a Health Care Provider Letter stating that anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions have been reported in the postmarketing setting. Importantly, these reactions were observed at a higher rate than initially reported in the phase 1 bioequivalence study that led to FDA approval of intravenous rolapitant (2.8%), with many resulting in hospitalizations. At our institution, rolapitant-induced infusion-related reactions also occurred in more patients than expected (8.7%). Described herein are six cases of infusion-related hypersensitivity reactions with intravenous rolapitant at the North Carolina Cancer Hospital. Due to the quick onset of the infusion-related hypersensitivity reactions with intravenous rolapitant, interpatient differences in pharmacokinetics or pharmacodynamics are unlikely to be the cause. An objective assessment utilizing the Naranjo Causality Scale rates these infusion-related hypersensitivity reactions as definite adverse drug reactions.

Identification of an Intravenous Injectable NK1 Receptor Antagonist for Use in Traumatic Brain Injury

“…Whilst EUC-001 has greater aqueous solubility than many NK1 antagonists, it was found to still possess good CNS penetration, with a brain/plasma ratio of 3/7. [51,52].…”

“…The development of a phosphoryl prodrug has been subsequently utilized for other NK1 antagonists, most notably fosnetupitant [ 50 ]. In contrast, an iv formulation of rolapitant was developed that involved generating an emulsion using polyoxyl 15 hydroxystearate [ 51 ]. Unfortunately, a significant risk of anaphylaxis and severe hypersensitivity reactions was observed with this formulation, leading to its production and use being suspended [ 51 , 52 ].…”

2023 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting

“…An injectable emulsion of rolapitant was approved by the Food and Drug Administration in 2017, but due to serious hypersensitivity reactions, 28 the rolapitant emulsion approval was withdrawn in January 2021.…”

Challenges in the Development of Intravenous Neurokinin‐1 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose‐Finding, Phase 1 Study of Intravenous Fosnetupitant

“…The novel approach to increase solubility with a tolerable formulation was used in the development of IV rolapitant, the early IV netupitant and aprepitant preparations, and HTX‐019 (aprepitant IV emulsion). The rolapitant IV emulsion, which contained polyoxyl 15 hydroxystearate, was found to cause anaphylaxis, anaphylactic shock, and other serious hypersensitivity reactions 20 and was subsequently withdrawn from the market in the European Union, and a safety warning was issued in the United States. 9 Both the first IV netupitant and aprepitant formulations were also discontinued in early development due to tolerability issues, predominantly thrombophlebitis.…”