Mental Health
Olivia C. Welter, PharmD
In November 2024, a joint FDA advisory committee voted 14–1 to eliminate the REMS program for clozapine. The advisory committee meeting included testimony from FDA staff, professional organization representatives, and members of the public including patients and their caregivers.
REMS requirements for clozapine
The clozapine REMS program, begun in 1989, was originally created to address the risk of neutropenia and agranulocytosis as adverse effects of clozapine.
For a patient to receive a clozapine prescription, both their provider and pharmacy must be certified in the modified clozapine REMS program. Each patient must also be enrolled in the modified clozapine REMS program. Additionally, the provider must assess the patient’s absolute neutrophil count (ANC) at varying intervals over the patient’s course of treatment. For the first 6 months of treatment with clozapine, patients must undergo weekly ANC monitoring. For the next 6 months, providers conduct monitoring biweekly. After the patient has been stable on clozapine for 12 months, they must receive monthly monitoring before pharmacies can dispense their prescription.
Previously, inpatient pharmacies could only dispense a 7 days’ supply of clozapine to a patient upon discharge. However, as of November 2022, FDA clarified that they will not object if the patient is discharged with a days’ supply consistent with their monitoring frequency.
Pros and cons
According to the FDA advisory panel, the REMS requirements for clozapine pose unnecessary barriers for patients. Because clozapine is the only approved therapy for treatment-resistant schizophrenia, timely access is imperative. Currently, patients may need to wait several hours to several days before their blood work is properly assessed.
Many patients and caregivers testified during the FDA advisory committee meeting that clozapine refill denials have led to instances of psychosis-induced self-harm, violence, incarceration, and even suicide attempts. In fact, one FDA advisory committee member changed his vote to be in favor of eliminating the REMS requirements after hearing the emotional testimony provided during the public hearing period.
According to Jesse Upton, PharmD, a mental health clinical pharmacist practitioner at Minneapolis VA Medical Center, the COVID-19 pandemic offered scientific and anecdotal evidence that extended monitoring intervals may be reasonable. “During the pandemic, patients were not able to attend in-clinic appointments due to safety, and the restrictions from the REMS clozapine program were loosened,” said Upton. Upton also emphasized that literature from this time period does not indicate any increased incidence of agranulocytosis or other severe adverse effects in stable patients being monitored at 28-day intervals.
However, Upton also recognizes the importance of regular clinic visits for continuity of care among his patient population. “One potential negative [if the clozapine REMS program is eliminated] is that, due to less frequent provider visits, veterans may be more susceptible to dropping out of care, medication nonadherence, and risk of missing potential harmful side effects,” said Upton.
The only FDA panelist who voted to keep the REMS program indicated that there is a role for regular blood work within the first 18 weeks of treatment when neutropenia risk is highest. Similarly, Upton said that monitoring ANC is especially important during the initiation and titration period, but Upton also believes that current monitoring intervals can be significantly extended once patients are stable to reduce barriers to care.
Will REMS be removed?
As of February 2025, the clozapine REMS website advises that the REMS program is still required for clozapine prescribing. The website notes that further guidance from FDA is required before any changes can be made to the program. Historically, FDA follows their advisory committees’ recommendations, but FDA has not yet reacted to the vote in favor of eliminating the clozapine REMS program. ■