Clozapine: FDA Acts to Address Neutropenia Risk

Megan Brooks

September 15, 2015

To address "continuing safety concerns" about severe neutropenia associated with the atypical antipsychotic clozapine (multiple brands), the US Food and Drug Administration (FDA) is making changes to requirements for monitoring, prescribing, dispensing, and receiving the drug, the agency said in a drug safety communication posted on its website today.

The FDA has "clarified and enhanced" prescribing information for clozapine to better explain how to monitor patients for neutropenia and manage clozapine treatment, and it approved a new, shared risk evaluation and mitigation strategy (REMS), called the Clozapine REMS Program.

The shared Clozapine REMS program replaces the six existing clozapine registries maintained by individual clozapine manufacturers and requires that prescribers, pharmacies, and patients enroll in the single centralized program.

Prescriber Action Required

"The revised prescribing information and the Clozapine REMS Program will improve monitoring and management of patients with severe neutropenia," the FDA notes. "The shared REMS is also expected to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. The requirements to monitor, prescribe, dispense, and receive all clozapine medicines are now incorporated into the Clozapine REMS Program."

Clozapine is used to treat schizophrenia in patients whose symptoms are not adequately controlled with standard antipsychotic medication. It is also used to treat recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Starting October 12, 2015, healthcare providers who want to prescribe clozapine to outpatients or inpatients must be certified in the Clozapine REMS Program. To become certified in the program, prescribers must review the prescribing information for clozapine and the Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers. They must also successfully pass the Knowledge Assessment for Healthcare Providers and complete and submit the one-time Clozapine REMS Prescriber Enrollment Form.

Prescribers can be certified through the Clozapine REMS Program website or by faxing completed forms to 844-404-8876. For more information or to request materials, call the Clozapine REMS Program at 844-267-8678.

Prescribers who currently treat patients with clozapine will have additional time to complete their certification and will have access to the Clozapine REMS Program to manage current patients, the FDA said. The Clozapine REMS Program will contact current prescribers to provide instructions on how to access the Clozapine REMS Program website. Patients who are currently taking clozapine will be automatically transferred to the Clozapine REMS Program.

The FDA has also made the following changes to the neutropenia monitoring recommendations:

  • Neutropenia will be monitored by the absolute neutrophil count (ANC) only, rather than in conjunction with the white blood cell count. The REMS program will only accept the ANC.

  • If the patient is an outpatient, the ANC must be reported to the Clozapine REMS Program before clozapine is dispensed. If the patient is an inpatient, the ANC must be reported within 7 days of the most recent blood sample.

  • Patients with benign ethnic neutropenia (BEN), who previously were not eligible for clozapine treatment, can now be treated with clozapine.

The two ANC monitoring algorithms are as follows:

  • For general population patients, ie, those without BEN, treatment should be interrupted if neutropenia is suspected to be clozapine-induced for ANC less than 1000 cells per microliter.

  • For patients with BEN, treatment should be interrupted if neutropenia is suspected to be clozapine-induced for ANC less than 500 cells per microliter.

The FDA says although rechallenging patients who develop severe neutropenia during treatment with clozapine is not recommended, under the revised prescribing information, prescribers will have more "flexibility to make individualized treatment decisions for their patients if they determine that the risk of psychiatric illness is greater than the risk of recurrent severe neutropenia."

The FDA encourages healthcare professionals to report adverse events related to clozapine to MedWatch, the FDA's safety information and adverse event reporting program, by telephone at 1-800- FDA-1088; by fax at 1-800-FDA-0178; online at; with postage-paid FDA form 3500, available at; or by mail to MedWatch, 5600 Fishers Lane, Rockville, Maryland 20852-9787.


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