Loading ...

Although clinicians and advocates applauded the US Food and Drug Administration (FDA)’s recent decision to discontinue a risk management and evaluation program for the antipsychotic clozapine, some say that hurdles to access to the medication remain.

The agency announced on February 24 that it no longer expected prescribers, pharmacies, and patients to participate in the risk evaluation and mitigation strategies (REMS) program or to report results of absolute neutrophil count (ANC) blood tests before pharmacies dispense clozapine. The ANC testing is part of labeling, as the drug poses a risk for neutropenia.

The REMS required that physicians and pharmacists be certified to prescribe and dispense the drug, which was originally approved in 1989. Patient status forms also had to be submitted monthly, showing ANC levels and appropriateness of continuing treatment.

Among the biggest problems with the REMS: Test results would fall through the cracks and, without them, pharmacies would refuse to refill prescriptions.

Clinicians, patients, family members, and professional organizations such as the American Psychiatric Association (APA) had long sought an end to the program, which was established in 2015 and had undergone multiple revisions.

The agency’s decision followed a November 2024 joint meeting of two FDA advisory panels. As reported by Medscape Medical News, panelists urged the agency to end the REMS requirements.

“The FDA’s decision to end the clozapine REMS is a crucial step toward improving access to this life-saving medication, made possible by the collective efforts of patients, families, clinicians, researchers, and advocates,” Robert Cotes, MD, professor of psychiatry and behavioral sciences at Emory University School of Medicine, Atlanta, told Medscape Medical News. It will “remove a long-standing regulatory obstacle,” he said.

Ending the REMS should result in fewer refusals at the pharmacy “because the labs weren’t sent to the pharmacy or because someone didn’t update the REMS system,” said Cotes, who is co-director of the Clinical and Research Program for Psychosis at Grady Health System in Atlanta.

Prescribing Challenges Persist

Pharmacies and insurers may be slow to understand that the FDA has ended the REMS, Cotes said. It was several days after the agency’s decision before the REMS program website was updated. During that time, Cotes said he “was informing many pharmacies about this change and directing them to the FDA website.”

Although advocates initially celebrated the FDA decision, reports of problems with prescription refills surfaced quickly.

“Within hours, our celebrations turned into chaos,” wrote the patient advocacy group The Angry Moms on a blog post.

“Some larger chain pharmacies have implemented requirements beyond the FDA’s REMS program requiring their staff to enter patients’ recent ANC values in their own internal system prior to dispensing clozapine,” the group wrote. “Some insurance plans which pay for prescription medications still require a REMS Dispense Authorization (RDA) code to pay for a clozapine pharmacy claim.”

The confusion has continued, the group claimed. Even after the FDA updated the REMS website, “one of our members was refused clozapine by a CVS pharmacist who told them the ‘REMS system is down,’” the group wrote.

ANC Testing Still Required

At the FDA advisory committee meeting, many members said that clozapine was no more dangerous than many antipsychotics and that the REMS was preventing clinicians from prescribing.

As reported by Medscape Medical News, research presented at the 2024 APA annual meeting showed that the risk for moderate and severe neutropenia is low to minimal in people taking clozapine for treatment-resistant schizophrenia.

The FDA noted in its announcement, however, that the agency still recommends that prescribers monitor patients’ ANC according to the labeling and that prescribing information would continue to warn about the potential for severe neutropenia.

The Angry Moms group urged patients to adhere to current testing requirements — weekly for the first 6 months, followed by biweekly, and then monthly after 1 year.

Cotes said the risk for neutropenia seems to decrease “significantly” after a year, and that he expected there would be more advocacy efforts to change labeling to reduce testing frequency.

Will Ending REMS Increase Use?

At the FDA panel meeting, agency officials said that 148,000 outpatient clozapine prescriptions were written in 2023. An estimated 814,000 to 1.2 million Americans have treatment-resistant schizophrenia, the main indication for clozapine.

Cotes estimated that only 4% of people with schizophrenia in the United States are prescribed clozapine, but that 25%-30% of individuals with the disorder could benefit from use.

“Clozapine is highly underutilized,” Cotes said.

FDA panel member Walter Dunn, MD, PhD, said at the meeting that modifying or eliminating the REMS might not increase the number of clinicians willing to prescribe. If monitoring ANC levels is still recommended in labeling, clinicians will regard it as the standard of care, said Dunn, staff psychiatrist at the Veterans Administration Greater Los Angeles Healthcare System.

“There are a whole host of other issues associated with clozapine,” that are “more concerning,” added Dunn, at the meeting.

Cotes agreed that the REMS “is just one of many barriers to clozapine’s wider use.”

Many prescribers don’t feel comfortable using the drug because of side effects such as myocarditis and gastrointestinal hypermotility, he said. And patients may not have the resources and support necessary to get weekly blood testing for the first 6 months, said Cotes.

The concerns about clozapine were likely not settled by a recent meta-analysis in The Lancet Psychiatry. The authors found that clozapine was not superior to other antipsychotics. Its side effects profile “warrants prudent use,” investigators wrote.

However, authors of an accompanying editorial said that the findings were potentially riddled with bias and needed to be contextualized.

“We believe clozapine remains the most effective medication for treatment-resistant schizophrenia,” wrote Dan Siskind and colleagues from the University of Queensland, Brisbane, Australia, and the University of Oxford, Oxford, England.

It’s not clear whether ending the REMS will reassure providers, said Cotes. But he added that he is “optimistic that it will ultimately ease the burden on patients to make sure their clozapine is continued without interruption.”

Cotes reported that his institution has received research funding from Otsuka, Bristol Myers Squibb, Roche, and Alkermes. He is a consultant to IQVIA, Boehringer Ingelheim, and Syneos Health on behalf of the Clozapine Product Manufacturers Group. He is a speaker and consultant to Saladax Biomedical.

Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.