Reactions to the infusion of natalizumab (Tysabri) for the treatment of multiple sclerosis (MS) are very uncommon, are usually mild, and nearly always occur during, not after, the infusion, new studies show.
Collectively, the results suggest the need to rethink the drug's mandatory 1-hour postinfusion observation period ― particularly when unnecessarily spending time in medical settings is discouraged because of concerns regarding COVID-19, the researchers conclude.
Their findings "highlight a potential opportunity to improve and streamline the infusion and post-infusion monitoring process," report the authors of one of the studies, presented at the virtual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2021.
"In this systematic review of almost 10,000 natalizumab infusions, all infusion-related adverse events were mild, and no clinically relevant safety concerns were associated with natalizumab infusions," they say.
The 1-hour postinfusion observation period for natalizumab, approved for the treatment of relapsing-remitting MS (RRMS), is mandated by the US Food and Drug Administration as well as the European Medicines Agency and applies to each dose, regardless of treatment duration, owing to concerns of infusion reactions. However, previous evidence has indicated that reactions are rare and are usually mild.
In addition to adding burden to the treatment regimen for patients and providers alike, any extended time in an environment where there is concern of heightened risk for SARS-CoV-2 exposure is a concern.
To evaluate the frequency, severity, and timing of infusion reactions, Yujie Wang, MD, of the Department of Neurology at the University of Washington, Seattle, and colleagues reviewed medical records of all patients who received natalizumab at the University of Washington MS Center's infusion suite between July 2012 and September 2020.
Among 333 patients with RRMS, 9682 infusions of natalizumab were provided over the study period, with a mean of 27 infusions per patient (range, 1 to 174). The mean age of the patients was 41 years, and 87 (26%) were male.
Overall, 33 infusion-related adverse events were reported in 26 patients, representing 0.34% of total infusions and 7.8% of patients.
In 77% of cases, the adverse event occurred during the infusion. In 92% of cases, the adverse event occurred within the first 6 months of treatment.
All of the events were described as mild. The most common were itching, gastrointestinal problems, headache, and flushing.
None of the reactions required emergency care or hospitalization. Symptoms were either self-managed or were managed easily with standard care. The treatment was continued in all cases.
"For physicians and providers who care for patients with MS and are comfortable with infusible therapies, it is no surprise that rates of clinically significant infusion reactions were low," Wang told Medscape Medical News.
"It is indeed consistent with prior studies that reactions generally occur during rather than post infusion," she said.
The authors underscore the array of potential benefits in making changes to the requirement.
"Anticipated benefits may include reducing SARS-CoV2 exposure risks for patients and staff, reducing patients' treatment burden, increasing efficiency, as well as improving access to care without neglecting patient safety," they note.
Additional Studies Show Consistent Findings
Several other recent studies have shown similar results.
In a study published in Multiple Sclerosis in October 2020, researchers with the Amsterdam University Medical Center in the Netherlands found that among 14,174 natalizumab infusions provided to 225 patients with RRMS between 2006 and 2018, 276 infusion-related adverse events occurred (1.95%) among 60 patients.
There were 11 severe infusion-related adverse events in nine patients (4.0%). All documented severe reactions occurred during the infusion. Among 19 moderate adverse events, 17 occurred during the infusion.
The researchers note that the majority of patients who experienced severe infusion reactions had detectable antibodies against natalizumab. Such antibodies are associated with a higher risk for infusion-related adverse events.
Patients who did not have any symptoms of a reaction during the infusion had no clinically relevant moderate or severe reactions.
First author Floor C. Loonstra, MD, PhD, of the Department of Neurology, Amsterdam University Medical Center, the Netherlands, said the authors had already previously observed that all infusion-related adverse events had occurred during or near the end of the natalizumab infusion.
"Thus, based on our own experience and observations, we were not surprised by the results," he told Medscape Medical News.
Loonstra said the center has subsequently adjusted its protocol.
"Before the COVID-19 pandemic we were in the process of implementing this; however, due to COVID-19 we have adjusted our natalizumab infusion protocol," he said.
"The one-hour postinfusion monitoring is now omitted; after a 15-minute rinse of the infusion, patients are allowed to leave the unit."
Loonstra noted that the findings should prompt more research to allow such changes to become mainstream.
"To implement this globally, a few extra studies like these are necessary, and of course adjustment of the label by the FDA and EMA," he said.
In another recent study published in Multiple Sclerosis and Related Disorders in January, researchers in Australia reported on the use of a rapid infusion protocol of natalizumab and ocrelizumb. The protocol was implemented to reduce the amount of time patients are required to spend in clinical settings during the COVID-19 pandemic.
In their analysis of 269 rapid infusions of natalizumab and 100 rapid infusions of ocrelizumab, there were two infusion-related reactions in the natalizumab group and eight in the ocrelizumab group.
All the reactions were mild to moderate, and no discontinuations were required. None of the reactions occurred during the postinfusion observation period.
"In the setting of COVID-19 pandemic, rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis," the authors write.
Under the rapid infusion protocol, patients receive three standard doses for 1 hour followed by 30 minutes of observation. In addition, infusions are reduced to 30 minutes, explained first author Louise Rath, of Clinical Neurosciences, Alfred Health, in Melbourne, Australia.
"For our cohort of patients, the side effects were minimal," she told Medscape Medical News.
"Rapid infusions allowed patients to have option of hospital in-home or office, ensuring work was not at risk by infusion," she added. "Our governance has been very supportive, and we will be keeping rapid infusion post-COVID."
The authors have disclosed no relevant financial relationships.
Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2021: Poster P072. Presented February 25, 2021.
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Cite this: Natalizumab Postinfusion Reactions Rare; Is Monitoring Necessary? - Medscape - Mar 04, 2021.