FDA Officially Removes REMS Requirement for Clozapine

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The US Food and Drug Administration announced that it “does not expect prescribers, pharmacies, and patients to participate in the risk evaluation and mitigation strategies (REMS) program for clozapine or to report results of absolute neutrophil count (ANC) blood tests before pharmacies dispense clozapine.”¹ This comes after a November 20, 2024, joint meeting of the FDA’s Drug Safety and Risk Management Advisory Committee and Psychopharmacologic Drugs Advisory Committee, in which members decided the clozapine REMS (Risk Evaluation and Mitigation Strategy) protocol was no longer necessary and may even be a barrier to access.¹

In their announcement, the FDA did not completely dismiss the importance of monitoring ANC, adding that the organization “still recommends that prescribers monitor patients’ ANC according to the monitoring frequencies described in the prescribing information.” They also clarified that prescribing information would continue to include warnings about severe neutropenia, including in the existing Boxed Warnings.

“This is a momentous day for everyone impacted by treatment-resistant schizophrenia—for those who rely on clozapine to manage their symptoms and allow them to thrive, and for their families, who have put so much energy into making this happen,” Gordon Lavigne, MEd, chief executive officer of the Schizophrenia & Psychosis Action Alliance, told Psychiatric Times in an exclusive interview.

Psychiatric Times' editor in chief, John J. Miller, MD, echoed the sentiment. "This is great news for both patients and prescribers. The FDA's decision to eliminate the REMS protocol for clozapine will undoubtedly increase the usage in patients with schizophrenia for multiple reasons," he told Psychiatric Times. "One of the largest impediments to a patient agreeing to a trial of clozapine is the patient's unwillingness to participate in the rigorous absolute neutrophil count lab monitoring previously required. However, the importance of informed consent and ANC monitoring remains an active part of treatment with clozapine, and it remains to be seen how this monitoring will evolve."

Peter J. Weiden, MD, a clinical professor of psychiatry at SUNY Stony Brook School of Medicine, Psychiatric Times' Schizophrenia & Psychosis Section Editor, agreed. "Ending the REMS doesn’t mean ending monitoring for clozapine side effects. Hopefully the ending of this REMS can free up time and resources that can be put to better use with facilitating clozapine access and addressing other important side effects," he told Psychiatric Times.

Weiden added that clinicians should always be aware of and monitor adverse events associated with this agent. "Prescribers need to be mindful of other side effects that can be clinically serious such as weight gain, sedation, seizures and central and peripheral anticholinergic effects," he explained. "One example is extreme constipation that can lead to complete bowel obstruction. We hope that clinicians will have continued access to training and support to free up time and resources that would otherwise have gone to REMS."

Moreover, Weiden expects the decision to help clinicians provide appropriate care to all patients, saying the decision should eliminate "clozapine discontinuation disasters due to errors in interpretation of ANC in Black patients." "The problem of unnecessary discontinuation of clozapine among Black populations due to mistaking normal ethnic variations ANC in Black populations as a neutropenia concern is solved and, hopefully, will reduce disparities in clozapine utilization."

The November advisory meeting that led to this decision included testimony from experts like John Kane, MD, The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. At the time, Kane told the committees that “Clozapine is a cornerstone in the treatment of schizophrenia,” noting its ability to improve functioning, reduce mortality, reduce risk of relapse, among other clinical features.² Clozapine also plays a crucial role in treatment-resistant schizophrenia, he said. Kane detailed the delays in obtaining clozapine as a result of the REMS, noting that the US lags behind in its use as compared to other countries. “Long-term risk excess is small compared with advantages of clozapine in outcomes, including life expectancy,” Kane told the committees. “Relaxing long-term monitoring could favor the advantages of clozapine use, without incurring risk of neutropenia.”²

As a result of the testimony, the committees overwhelmingly voted that REMS was no longer appropriate, with only Walter Dunn, MD, PhD, disagreeing. Instead of removing REMS completely, Dunn, Health Sciences Assistant Clinical Professor in the department of psychiatry at UCLA David Geffen School of Medicine, director of the Mood Disorders Clinic at West Los Angeles Veterans Affairs Medical Center, was in favor of monitoring when the risk was the greatest—during the first 18 weeks of treatment.³

Ultimately, the FDA agreed that the benefits of REMS program for clozapine outweighed the risks to appropriate patient care, stating, “Eliminating the REMS is expected to decrease the burden on the health care delivery system and improve access to clozapine.”¹

Next steps according to the FDA press release is to have the clozapine manufacturers “formally submit a modification to eliminate the Clozapine REMS and to update the prescribing information, including removing mandatory reporting of ANC blood tests to the REMS program.” The FDA will be working closely with manufacturers to ensure this happens.¹

Critics of the REMS program have long complained of the hassles and delays in getting the medication to patients, and the impact of these delays on patients and their families. “As well intended as it might once have seemed, the federal REMS program is now one of the primary obstacles standing in the way of patients receiving their medicine on time,” wrote Gilbert Honigfeld, PhD.⁴ “It is a major factor limiting access to clozapine for individuals with serious mental illnesses whose very lives might well depend on it. Solution? Eliminate FDA’s clozapine REMS program and allow psychiatrists to practice medicine just like their peers in all other medical specialties.”⁴

What does this mean for prescribers and patient care and how will the roll out? Psychiatric Times will continue its coverage to ensure readers are kept informed. Be sure to subscribe to e-newsletters and follow us on social media.

References

1. Information on Clozapine. Latest Update. FDA press release. February 24, 2025. Accessed February 25, 2025. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/information-clozapine

2. FDA Advisory Committee Meeting Clozapine Risk Evaluation and Mitigation Strategy. November 19, 2024. Accessed February 25, 2025. https://www.fda.gov/media/183655/download

3. Sutter S. Clozapine REMS A Barrier To Treatment And Unnecessary For Safe Use, US FDA Adcomms Say. The Pink Sheet. February 25, 2025. Accessed November 20, 2024. https://insights.citeline.com/pink-sheet/product-reviews/us-advisory-committees/clozapine-rems-a-barrier-to-treatment-and-unnecessary-for-safe-use-us-fda-adcomms-say-KDK6ICJKNBHPTBGVFFL3C6ME7U/

4. Honigfeld G. Clozapine REMS: Regulatory Discrimination Against Psychiatrists? Psychiatric Times. October 3, 2024. Accessed February 25, 2025. https://www.psychiatrictimes.com/view/clozapine-rems-regulatory-discrimination-against-psychiatrists