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Three Reasons for Urging FDA Reanalysis of Boxed Warnings on Antipsychotics

Published December 10, 2024

Variety of pills

On December 10, the Margolis Institute for Health Policy at Duke University hosted a virtual public meeting, “Mortality and Antipsychotic Use in Dementia-related Behavioral Disorders.” The workshop’s objective was to review data regarding risks associated with medications in the antipsychotic class in older adults with behavioral and psychiatric symptoms associated with dementia. Alliance for Aging Research President and CEO Sue Peschin, MHS, delivered the following statement during the panel:

Thank you to the Duke-Margolis Institute for Health Policy and the FDA for convening today’s important workshop and for inviting me to speak.

There are 3 reasons why we advocated with the American Society of Consultant Pharmacists for this workshop—including a reanalysis of the data behind the FDA’s nearly 20-year-old boxed warning on antipsychotics:

The first is to urge the agency to re-examine application of the antipsychotics boxed warning on a drug-by-drug basis, rather than as a blanket application to the class, for current products and future applications.

The FDA’s attempt to thread the needle between mortality data on older antipsychotics and newer medications such as Nuplazid and Rexulti—which the agency deemed safe and effective—has resulted in overly confusing boxed warning language. The impact on patients and caregivers is that they are not left with good information on the actual risks and benefits of the newer treatment options.

The second reason we advocated for this meeting is to urge the agency to recognize that applying boxed warning to the entire antipsychotics class likely contributes to the stigma of neuropsychiatric symptoms, and the prescribing practices of primary care physicians to treat them—including for on-label, FDA-approved uses.

According to the Alzheimer’s Association, about 85% of people with dementia are first diagnosed by a non-dementia specialist, usually primary care physicians. PCPs are also responsible for most of the post-diagnostic care and management of complex needs like neuropsychiatric symptoms.

Alzheimer’s and Parkinson’s are progressive and fatal diseases. Neuropsychiatric symptoms not only worsen disease-related cognitive and function decline, but also accelerate time to institutionalization and eventual death. A large, longitudinal observational study published in the September 2013 issue of the American Journal of Psychiatry showed that it is the symptoms—not the use of antipsychotic medications—that predict nursing home admission and death.

It is not the FDA’s job to tackle stigma, but it is important to understand that application of the boxed warning may exacerbate it.

That leads me to the third, and final reason. While we know it was not FDA’s intent, in practice the impact of the boxed warning for people living with Alzheimer’s and other neurodegenerative diseases has limited access to desperately needed therapies.

Since 2020, the Alliance and the ASCP have co-convened Project PAUSE, which stands for Psychoactive Appropriate Use for Safety and Effectiveness. We, alongside members of PAUSE from across the healthcare community, have urged CMS to fix the agency’s outdated antipsychotic nursing home quality measures. In fact, a May 2021 HHS IG report requested by CMS found the measures have failed to distinguish between appropriate and inappropriate use. Those measures, buttressed by the boxed warning, hamper clinicians from following best practices for clinical care, require changes of medication regimens even for well-managed patients, and harm the ability for patients, families, and their clinicians to appropriately manage care. 

So, we look to you. Thank you for considering these important issues.

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