FDA: Major Prescribing Changes for Clozapine

FDA: Major Prescribing Changes for Clozapine
FDA: Major Prescribing Changes for Clozapine

The Food and Drug Administration (FDA) announced changes to prescribing information for clozapine and a new shared risk evaluation and mitigation strategy (REMS) due to continuing safety concerns and current knowledge regarding the risk of severe neutropenia. Clozapine is an atypical antipsychotic agent indicated for the treatment of resistant schizophrenia and to reduce the risk of recurrent suicidal behavior in schizophrenia and schizoaffective disorders.

The requirements to monitor, prescribe, dispense, and receive clozapine are now incorporated into the new shared Clozapine REMS Program, which replaces the six individual clozapine registries. The REMS program includes all clozapine medicines in order to provide a centralized point of access for prescribers and pharmacists in managing the risk of neutropenia. Starting October 12, 2015, clozapine will be available only through the Clozapine REMS Program.

Important changes to the neutropenia monitoring recommendations and treatment algorithm for clozapine include:

  • Absolute neutrophil count (ANC) is the only test result accepted in the Clozapine REMS Program to monitor for neutropenia.
  • 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) can now be treated with clozapine.

For general population patients, i.e., those without benign ethnic neutropenia (BEN), interrupt treatment if neutropenia is suspected to be clozapine-induced for ANC less than 1,000 cells per microliter. For patients with BEN, interrupt treatment if neutropenia is suspected to be clozapine-induced for ANC less than 500 cells per microliter.

Although re-challenging 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 National Non-Rechallenge Master File (NNRMF) will be discontinued on October 12, 2015. Patients were listed in the NNRMF if they had a WBC less than 2,000 cells per microliter or an ANC less than 1,000 cells per microliter.

All patients listed in the NNRMF will be automatically transferred to the Clozapine REMS Program and clearly identified.

Prescriber Certification in the Clozapine REMS Program


Starting October 12, 2015, health care professionals who wish to prescribe clozapine to outpatients or inpatients must be certified in the Clozapine REMS Program. To become certified in the Clozapine REMS Program, prescribers must:

  • Review the prescribing information for clozapine,
  • Review Clozapine and the Risk of Neutropenia: A Guide for Healthcare Providers,
  • 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 at clozapinerems.com, 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 Clozapine REMS Program will contact current prescribers to provide instructions on how to access the Clozapine REMS Program website.

Prescribing Clozapine


Managing existing patients:

  • All patients registered in any of the existing clozapine registries within the last three years and all patients listed in the NNRMF will be automatically transferred into the Clozapine REMS Program.
  • Starting October 12, 2015, prescribers will no longer be able to enroll or manage patients through the other clozapine patient registries. All patient management activities will be handled through the Clozapine REMS Program.

Managing new patients:

  • Prescribers must be certified in the Clozapine REMS Programdisclaimer icon in order to enroll new patients.
  • Generally, to enroll a new patient prescribers must provide the patient or caregiver with What you Need to Know about Clozapine: A Guide for Patients and Caregivers, inform the patient or caregiver about the risk of severe neutropenia associated with clozapine and about the Clozapine REMS Program requirements, and complete and submit Patient Enrollment Form.
  • Prescribers can enroll patients through the Clozapine REMS Program website at clozapinerems.com, or by faxing the completed Patient Enrollment Form to (844) 404-8876.

Prescribers may designate other health care professionals or office staff to enroll patients and enter ANC results on their behalf.

For more information visit FDA.gov.

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