Navigating the New Clozapine REMS

Bret S. Stetka, MD; Mitchell Mathis, MD


December 04, 2015

Editorial Collaboration

Medscape &

Specific Recommendations and Addressing Concerns

Medscape: What are the specific recommendations regarding neutropenia monitoring included in the new REMS?

Dr Mathis: These are as follows:

  • The ANC is used exclusively for patient monitoring per the following recommendations:

    • White blood cell counts are no longer accepted.

    • ANC thresholds to continue clozapine treatment are lower.

    • 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 to the clozapine REMS program within 7 days of the most recent blood sample.

  • Patients with BEN can be treated with clozapine and have a separate ANC monitoring algorithm.

  • Also, there are two ANC monitoring algorithms:

    • For general population patients (ie, those without BEN), interrupt treatment if neutropenia is suspected to be clozapine-induced for an ANC less than 1000 cells/µL.

    • For patients with BEN, interrupt treatment if neutropenia is suspected to be clozapine-induced for an ANC less than 500 cells/µL.

  • Substantial drops in the ANC do not require action unless the patient experiences neutropenia.

  • Prescribers have greater flexibility to make patient-specific decisions about continuing and resuming treatment in patients who experience moderate and severe neutropenia.

  • Prescribers can continue clozapine treatment for patients with an ANC less than 1000 cells/μL if the prescriber believes that the benefits of clozapine therapy outweigh the risk for severe neutropenia.

  • The National Non-Rechallenge Master File is discontinued. Patients may be rechallenged if the prescriber determines that the benefits of clozapine therapy outweigh the risk for severe neutropenia.

Medscape: Past research has reported underutilization of clozapine in treatment-resistant patients who could benefit from it. This is thought to be in part due to reticence about agranulocytosis risk, as well as concerns about extra paperwork and monitoring associated with prescribing the drug. Does this REMS address any of those issues, and if so, how?

Dr Mathis: We hope in the long term that utilization will improve because a broader population can now be treated and maintained on clozapine treatment. Monitoring ANC and documentation of the monitoring are the hallmarks of the program and minimize serious outcomes associated with severe neutropenia.

Once the website is working properly, the data are fully reconciled, and the automations for the outpatient pharmacy are implemented, we believe the new program will streamline some of the administrative aspects of prescribing and dispensing clozapine.

Medscape: Is there anything you want clinicians to know about safely prescribing this medication?

Dr Mathis: As with any new IT system and large data migration and reconciliation effort, there are challenges. Merging these registries was a huge undertaking for the manufacturer that encompassed merging data from over 50,000 prescribers, 28,000 pharmacies, and 90,000 patient records.

Currently, prescribers, pharmacies, and patients are in the process of transitioning to the new system. Transition is hard. There have certainly been challenges, especially with the website technology. We understand that some prescribers, pharmacies, and patients have had little to no trouble using the new system, whereas others have encountered many difficulties and frustrations. We do believe the combination of the changes to monitoring and the new program will better serve the public health once all the issues are worked out.

Thanks to the feedback we have received from practicing clinicians and their organizations, we continue to work with the clozapine manufacturers to identify, address, and resolve these problems. If you have experienced a problem or many problems, we hope you continue to work through it.

We also hope that, while the IT issues are being resolved, healthcare providers will use clinical judgment; determine what is in the best interest of the patient; and, as appropriate, continue to prescribe and dispense clozapine to patients with an ANC within the acceptable ranges.


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