Clozapine’s REMS Program on the Chopping Block at Upcoming FDA Meeting

Is a risk evaluation and mitigation strategy (REMS) still needed for clozapine? That’s what a joint meeting of two FDA advisory committees will discuss on Tuesday.

Risk management requirements for the atypical antipsychotic have evolved in the past 35 years to a REMS that manages the risk of severe neutropenia, which can lead to serious infections and death.

First approved in 1989, clozapine is the only medication indicated for treatment-resistant schizophrenia. It’s also indicated for suicidal behavior in those with schizophrenia or schizoaffective disorder.

But because it can decrease the number of neutrophils and potentially cause severe neutropenia (absolute neutrophil count [ANC] count less than 500 cells/uL), the FDA established one centralized REMS program in September 2015 — a transition from a previous six separate restricted distribution programs — to mitigate neutropenia risk.

During Tuesday’s joint meeting, the Drug Safety and Risk Management Advisory Committee and the Psychopharmacologic Drugs Advisory Committee will vote on whether clozapine’s REMS program is necessary, with the goal of minimizing burden on patients, pharmacies, and prescribers, while maintaining safe use of the drug.

When clozapine was first approved, no other antipsychotics needed frequent ANC monitoring and psychiatrists had generally little knowledge about managing neutropenia. Because of this, “additional strategies beyond labeling were necessary to educate healthcare providers and ensure that they completed the necessary ANC monitoring for patient safety,” an FDA briefing document pointed out.

“Severe neutropenia occurs in a small percentage of patients taking clozapine; however, neutropenia is associated with an increased risk of serious and potentially fatal infections,” a document from the Clozapine Product Manufacturers Group (CPMG) noted. “Therefore, early detection is important.”

As part of the REMS program, prescribers and pharmacy staff are required to complete training to become certified to prescribe and dispense clozapine. Prescribers also must obtain a baseline ANC for each patient and monitor this during clozapine treatment according to the patient’s risk category, ANC test results, and duration of clozapine treatment. During the first 6 months, patients are required to have weekly blood draws; in months 6 to 12, blood draws are every 2 weeks; after 1 year, they are monthly.

Prescribers are required to document the patient’s ANC test results using the web-based REMS system or fax a completed monitoring form to the REMS administrator. Only after completing the monitoring form with acceptable ANC results or the prescriber’s authorization can a patient be dispensed clozapine. This is done by electronic communication with the REMS website or by the pharmacy contacting a call center prior to dispensing.

However, “the REMS has not been fully implemented or functioned as intended” according to the FDA, which listed several problems including technical issues with the website and long call wait times. A new set of challenges also emerged when the REMS transitioned in 2021 to a new administrator. Some of these changes potentially caused treatment interruption and barriers to patient access.

“The CPMG suggests that over 45,000 patients per year could have their clozapine treatment withheld or delayed if all REMS safe use requirements were implemented as intended,” the FDA said.

Data also have suggested that severe neutropenia may not be the grave concern it once was. Though the 1989 clozapine label lists the cumulative incidence of severe of 1.3% at 1 year, an FDA literature review pinpointed this at 0.8%. A Veterans Affairs study said the cumulative incidence was 0.4% during the first year of treatment.

FDA-led retrospective observational studies also found very few deaths related to clozapine-induced neutropenia. A total of 34 severe cases of clozapine-related neutropenia were reported to the FDA Adverse Event Reporting System (FAERS) from January 2017 through September 2024, the agency noted.

The FDA affirmed that “frequent ANC monitoring remains necessary to identify neutropenia early so that healthcare providers can intervene and may prevent progression to more severe cases.” But whether frequent ANC monitoring needs to occur within the confines of a REMS program remains a question.

While there are other risks associated with clozapine — the drug has boxed warnings for orthostatic hypotension, bradycardia, syncope, cardiac arrest, seizures, myocarditis, cardiomyopathy, and pericarditis — they aren’t on the docket for discussion.

The FDA isn’t required to follow the recommendations of its advisory committees, but it typically does.