Elimination of the Risk Evaluation and Mitigation Strategy for Clozapine, an Antipsychotic Drug That Lowers White Blood Cell Counts

In 1989 the Food and Drug Administration (FDA) approved the oral drug clozapine (CLOZARIL, VERSACLOZ and generics) for treatment-resistant schizophrenia.[1] In 2002 the drug was also approved to reduce suicidal behavior in patients with schizophrenia or schizoaffective disorder.

People who take clozapine are at increased risk of neutropenia (low white blood cell count), which weakens the immune system and makes it more difficult to fight off serious or life-threatening infections. For this reason, clozapine prescribing has long been subject to a Risk Evaluation and Mitigation Strategy (REMS) protocol requiring that patients taking the drug undergo regular blood testing and reporting of their absolute neutrophil (a type of white blood cell) count to detect neutropenia.[2]

In February 2025 the FDA announced that the REMS program for clozapine would end, although the agency still recommended that clinicians monitor patients’ absolute neutrophil counts at the frequency described in the drug’s prescribing information.[3] The FDA’s action will make it easier for clozapine to be prescribed.

Although the FDA noted that the risk of severe neutropenia with clozapine has not changed, it decided that the REMS program was “no longer necessary to ensure the benefits of the medicine outweigh that risk.”[4] The prescribing information still includes a boxed warning, the FDA’s strongest warning, about severe neutropenia and other serious adverse effects.

Background on clozapine

Schizophrenia is a debilitating illness typically involving hallucinations, delusions, diminished verbal and emotional expression, and other cognitive challenges.[5] Treatment resistance is assigned to the diagnosis of schizophrenia if at least two other antipsychotic drugs (for example, quetiapine [SEROQUEL and generics]) have failed to reduce symptoms and functional impairment to below moderate levels.[6]

Clozapine is a second-generation antipsychotic that is believed to work principally by acting on the dopamine and serotonin neurotransmitter systems in the brain.[7] The label highlights two clinical studies.

The first study involved 268 participants diagnosed with schizophrenia with a baseline Brief Psychiatric Rating Scale (BPRS) score of at least 45 who failed to improve after treatment with the first-generation antipsychotic haloperidol (HALDOL and generics) and who previously showed inadequate response to three other antipsychotics.[8] The BPRS ranges from 0 to 126 — 18 items scored from 0 (no symptoms) to 7 (severe symptoms) each. Participants were randomized to receive six weeks of clozapine (n=126) or chlorpromazine (generics only; n=142), a first-generation antipsychotic. The mean decline in BPRS score was 16 for the clozapine group and 5 for the chlorpromazine group.

Support for clozapine’s effect on suicidal behavior was established with an open-label randomized study comparing clozapine with olanzapine (ZYPREXA and generics; second generation).[9] The trial included 956 patients with either a suicide attempt or hospitalization (in the prior three years), or serious and recent suicidal ideation (in the prior week). Trial participants were diagnosed with schizophrenia (62%) or schizoaffective disorder (38%), and 27% of the participants were treatment resistant. By week 104 after starting treatment, the clozapine group was significantly less likely than the olanzapine group to have a suicide attempt, hospitalization, or a completed suicide (24% and 32%, respectively).

Beyond neutropenia, adverse effects highlighted in clozapine’s boxed warning include low blood pressure and heart rate, syncope (fainting), seizure, myocarditis (heart inflammation), cardiomyopathy (weakened heart muscle), mitral valve regurgitation, and increased mortality in elderly patients with dementia-related psychosis.[10]

The most common adverse effects associated with clozapine (occurring in at least 5% of users) are central nervous system reactions such as sedation, dizziness/vertigo, headaches and tremor; autonomic nervous system reactions such as sweating, aberrant salivation, and visual disturbances; gastrointestinal reactions such as constipation and nausea; fever; and the cardiovascular symptoms noted in the boxed warning (for example, low heart rate).

Background on the clozapine REMS program

Before the February 2025 policy change, the FDA-mandated REMS program required clozapine prescribers and pharmacies to be certified in, and patients to be compliant with, regular testing and reporting of absolute neutrophil counts. For individuals with normal neutrophil counts (at least 1,500/microliter) prior to clozapine initiation, blood tests were required weekly for the first six months, biweekly for months 6-12, and monthly after that.[11]

The FDA’s updated neutropenia analyses

In November 2024 the FDA convened its Drug Safety and Risk Management and Psychopharmacologic Drugs Advisory Committees to consider whether the REMS program for clozapine should continue. At the meeting, the FDA discussed observational studies about the neutropenia risk of clozapine.[12],[13] A literature review identified 13 studies published through July 2024 showing that clozapine use correlated with a severe neutropenia risk of about 1% (with up to a 6% death rate among those with severe neutropenia).

Additional studies reviewed by the joint FDA advisory committee included data from tens of thousands of clozapine users compiled by a Massachusetts teaching hospital, the FDA’s Sentinel System and the Department of Veterans Affairs (VA). For example, the VA study showed that among 6,488 outpatient clozapine users from 1999-2023, severe neutropenia was observed by month three in 9.6 per 1,000 patient-years reviewed, or slightly less than 1%.

In response to the new information, the committee voted 14 to 1 to recommend that the FDA scale back the REMS program for clozapine, leading to the FDA’s decision to eliminate the program in February 2025.[14]

What You Can Do

Clozapine should only be prescribed as part of ongoing care by a psychiatrist or other clinician with expertise in serious mental health disorders. Your clinician should monitor your absolute neutrophil count before treatment and thereafter at the frequencies described in the prescribing information. Contact your clinician immediately if you experience signs or symptoms that could indicate serious infection.[15]
 

References

[1] HLS Therapeutic (USA). Label: clozapine (CLOZARIL). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/019758s106lbl.pdf. Accessed March 6, 2025.

[2] Ibid.

[3] Food and Drug Administration. Frequently asked questions | clozapine REMS modification. February 24, 2025. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/frequently-asked-questions-clozapine-rems-modification. Accessed March 6, 2025.

[4] Ibid.

[5] Fischer BA, Buchanan RW. Schizophrenia is adults: clinical features, assessment, and diagnosis. UpToDate. July 5, 2023.

[6] Kane J, Rubio JM, Kishimoto T, Correll CU. Treatment-resistant schizophrenia. UpToDate. August 15, 2024.

[7] HLS Therapeutic (USA). Label: clozapine (CLOZARIL). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/019758s106lbl.pdf. Accessed March 6, 2025.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] Ibid.

[12] Food and Drug Administration. Transcripts for the joint meeting of the Drug Safety and Risk Management Advisory Committee and the Psychopharmacologic Drug Advisory Committee. November 19, 2024. https://www.fda.gov/media/185361/download. Accessed March 6, 2025.

[13] LaCivita C. Summary of the studies conducted for FDA’s re-evaluation of the clozapine REMS. Drug Safety and Risk Management Advisory Committee and the Psychiatric Drugs Advisory Committee meeting. November 19, 2024. https://www.fda.gov/media/183654/download. Accessed March 6, 2025.

[14] Duerr HA. FDA committees vote to dismiss clozapine REMS. Psychiatric Times. November 21, 2024.

[15] HLS Therapeutic (USA). Label: clozapine (CLOZARIL). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/019758s106lbl.pdf. Accessed March 6, 2025.