FDA Reviewing Clozapine REMS to Determine if Monitoring Requirements Can Be Modified

The Food and Drug Administration (FDA) is conducting a review of the Risk Evaluation and Mitigation Strategies (REMS) for the antipsychotic clozapine to determine if the REMS requirements for blood monitoring of neutropenia can be modified “to minimize burden on patients, pharmacies, and prescribers while maintaining safe use of clozapine,” the FDA said in a statement last year.

The clozapine REMS is a safety program required by the FDA to manage the risk of severe neutropenia associated with clozapine treatment; it was originally instituted in September 2015. The REMS applies to all clozapine medicines on the market and requires the use of a centralized system to monitor patients and prevent or manage clozapine-induced neutropenia. In 2021, the FDA approved modifications to the clozapine REMS, and those requirements went into effect on November 15, 2021.

But prescribers, pharmacists, and patients and their families say the REMS has been a source of enormous trouble, sometimes resulting in delays in patients receiving a medication that is regarded as the most effective for treatment-resistant schizophrenia.

Moreover, many believe the risk of neutropenia has been vastly overstated; a November 2023 epidemiologic report on neutropenia among clozapine users in New Zealand and Australia in Lancet Psychiatry found that most serious neutropenia leading to clozapine cessation occurs within 18 weeks of treatment and becomes negligible after two years. “Weekly hematological monitoring after the first 18 weeks could be safely reduced to once every four weeks and ceased after two years unless clinically indicated,” the report concluded.

As part of the reevaluation, the FDA has funded a study by Brigham and Women’s Hospital that includes an analysis of clozapine utilization, adherence to the REMS requirement for monitoring of absolute neutrophil count (ANC), and clinical outcomes. In addition, the FDA is conducting a study in collaboration with the Veterans Health Administration to better understand the incidence and severity of neutropenia in patients taking clozapine; it is also conducting a study using the Sentinel to better understand adherence to monitoring requirements. (The FDA uses Sentinel data to evaluate the safety of medical products and learn more about potential side effects.)

“All three studies are currently ongoing, and we expect the findings from these studies to be complete within the next year,” according to the FDA. “The agency intends to take appropriate regulatory action, as needed, based on its reevaluation of the clozapine REMS.”

APA Advocacy Was Crucial

Prescribers who spoke with Psychiatric News said that the reevaluation is the result of advocacy by APA and other professional groups. “I was really glad to see that the FDA took this action, and if it is going to make significant changes in the hematological monitoring requirements, this [reevaluation] is the way it will happen,” said Robert Cotes, M.D., “I think it’s an example of effective advocacy by APA and other professional organizations to get us to this recent update from the FDA.”

Cotes is an associate professor of psychiatry at Emory University School of Medicine and physician expert for SMI Adviser, the clinical support system for serious mental illness that is funded by the Substance Abuse and Mental Health Services Administration and administered by APA.

Last year APA filed a Freedom of Information Act (FOIA) request to the FDA seeking information about administration of the REMS and the REMS website and how the FDA is assessing whether the REMS is even still necessary (see Psychiatric News).

APA filed the FOIA request on its own but has worked in concert with other organizations concerned about the REMS, including the American Association for Community Psychiatry, American Psychiatric Nurses Association, College of Psychiatric and Neurologic Pharmacists, National Alliance on Mental Illness, National Association of State Mental Health Program Directors, and National Council for Mental Wellbeing. In letters to the House Energy and Commerce Committee and the Senate Health, Education, Labor, and Pensions Committee, APA and its partners requested a wholesale reconsideration of REMS.

APA will host a Policy and Practice Insight webinar about the clozapine REMS on January 17. Click here for information about registration.

Neutropenia Risk Exaggerated

“It’s not an exaggeration to call clozapine a miracle drug, yet few psychiatrists prescribe it, and it’s not a mystery why,” said Melissa O’Dell, M.D., an assistant professor of psychiatry at the University of Nebraska Medical Center (UNMC). “The clozapine REMS is a nightmare for prescribers and patients alike.” She added, “The number of patients with treatment-resistant schizophrenia who could benefit from clozapine but don’t have access to this lifesaving drug is unacceptable.”

She is the founder and director of Active Support for Psychosis in Recovery (ASPIRE), a multidisciplinary clinic for people with psychotic disorders at UNMC, and an APA Assembly representative from Nebraska.

O’Dell said that aside from many administrative problems with the REMS, the requirements for lifelong monitoring for neutropenia are unjustified. “It just doesn’t make sense when you look at the actual risk of neutropenia,” O’Dell told Psychiatric News. “It’s a lot lower than we used to think it was, is comparable to other antipsychotics, and neutropenia tends to happen in the first year of treatment. There is very little justification for how the REMS program is currently set up, and in my view it’s questionable whether there is any justification for a REMS.”

After the updated REMS went into effect in November 2021, prescribers experienced increased administrative time navigating the REMS website, seeking authorization for prescriptions, and trying to get questions answered. Pharmacies had problems with the enrollment process and delays and difficulties getting authorization for individual prescriptions.

Because of those problems, the FDA temporarily suspended some of the revised REMS requirements through “enforcement discretion.” The suspension, still in place, allows pharmacists to dispense clozapine without a REMS Dispense Authorization (RDA) and wholesalers to continue to ship clozapine to pharmacies and health care settings without confirming enrollment in the REMS.

But O’Dell and Cotes both said that, for a variety of reasons, in practice the “enforcement discretion” has had little or no effect on making it easier to prescribe clozapine.

“I have had patients who were directly harmed by the REMS because they were not able to get their clozapine in time and suffered withdrawal and worsening psychosis,” O’Dell said. “As a clozapine champion, one of my biggest frustrations is that there is a very limited number of psychiatrists willing to prescribe clozapine because the REMS makes it so hard.”

Cotes said he believes lifelong blood monitoring should not be required. “The risk of severe neutropenia at two years treatment becomes negligible,” he said. “That could be a substantive modification to the system.”

He added, “I think the FDA could consider a different implementation of REMS. An educational REMS might require that prescribers review educational material, attest that they understand the monitoring requirements, but then do the monitoring themselves. I think psychiatrists and other prescribers can monitor this on their own without a system that mandates they submit labs to the REMS.” ■