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Navigating the New Clozapine REMS

Bret S. Stetka, MD; Mitchell Mathis, MD December 04, 2015

Editor’s Note: On September 15th, 2015, the US Food and Drug Administration (FDA) approved a new, shared risk evaluation and mitigation strategy (REMS) for the atypical antipsychotic medication clozapine in order to help address ongoing concerns about the association between the drug and neutropenia. The FDA announced that they would be extending the original November 23, 2015, prescriber certification deadline and the December 14, 2015, pharmacy certification deadline to help ensure that healthcare professionals have sufficient time to complete the certification process and that patient access to clozapine is maintained.

Medscape recently spoke with Mitchell Mathis, MD, director of the Division of Psychiatry Products in the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research (CDER/OND/DPP), about the intentions of the new REMS and its potential influence on patient care.

Medscape: What indications are clozapine currently approved by the FDA for?

Dr Mathis: Clozapine is an antipsychotic drug used to treat schizophrenia in patients whose symptoms are not controlled with standard antipsychotic treatment. It is also used to treat recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Treatment with clozapine may help improve the symptoms of schizophrenia in patients who do not respond adequately to standard antipsychotic treatment. Symptoms of schizophrenia include hearing voices, seeing things that are not there, and being suspicious or withdrawn.

Clozapine may also help reduce the risk for repeated suicidal behavior in patients with schizophrenia or schizoaffective disorder.

Medscape: What is the risk addressed by this REMS?

Dr Mathis: Clozapine is associated with severe neutropenia, which can lead to serious and fatal infections. A REMS is required to ensure that the benefits of clozapine outweigh the risk for severe neutropenia.

Medscape: What was the rationale behind creating a unified clozapine REMS program? In other words, why this, and why now?

Dr Mathis: There are two main reasons for creating a unified clozapine REMS program. First, substantial changes were made to the prescribing information with regard to how to monitor for neutropenia and manage clozapine treatment on the basis of the patient’s absolute neutrophil count (ANC). These labeling changes were going to cause substantial effects on how the six previous registries operated. The changes provided an opportunity to revise and consolidate the six registries at the same time that the monitoring guidelines were modified.

Second, each of six previous registries had similar requirements but subtle differences with regard to how they operated. In addition, prescribers, pharmacies, and patients were required to enroll in each one separately to be able to prescribe, dispense, or receive the specific clozapine medicine available from that manufacturer.

The shared REMS was created to reduce the burden and possible confusion related to having separate registries for individual clozapine medicines. With the unified or “shared” REMS, prescribers, pharmacies, and patients are able to enroll in a single shared program that provides access to all clozapine products regardless of the manufacturer.

Medscape: What are the components of the new REMS program, and how is it different from the previous programs?

Dr Mathis: The new shared clozapine REMS program has similar components to the previous registries in that prescribers, pharmacies, and patients must be enrolled to prescribe, dispense, or receive clozapine. Prescribers and pharmacists are still required to check a patient’s ANC on the basis of the patient’s monitoring schedule, to make sure it is current and within the acceptable range as described in the prescribing information before dispensing.

There are also many differences in the clozapine REMS program from the previous registries that have been put in place to support the changes to the prescribing information. For example:

Patients with benign ethnic neutropenia(BEN), who previously were not eligible for clozapine treatment, will now be able to receive the medicine. Prescribers can identify patients with BEN in the new program, which places those patients on a different monitoring algorithm with lower ANC thresholds than the thresholds for the general population.

Prescribers have greater flexibility to make individualized treatment decisions about continuing and resuming treatment in patients who experience moderate to severe neutropenia if they determine that the risk for psychiatric illness is greater than the risk for moderate to severe neutropenia. The decision to continue treatment needs to be documented with the clozapine REMS program before an outpatient can continue treatment.

The prescribing information with regard to how to monitor neutropenia and manage clozapine treatment have become more complex. It includes two different monitoring algorithms and increased flexibility to continue or resume treatment in patients. For this reason, the clozapine REMS program was designed with an enhanced infrastructure, which was determined necessary to support communication between prescribers and pharmacists.

Once fully operational, the clozapine REMS program will require a “predispense authorization” (PDA) in order for pharmacists to dispense clozapine in an outpatient setting. The PDA is an electronic code indicating that the program’s safe use requirements are verified (electronically) and it is safe to dispense the drug. Outpatient pharmacies have a choice as to how to obtain the PDA, and some pharmacies are incorporating this verification step into their pharmacy management systems, so that this verification is done at the same time (and in a similar way) as electronic insurance claim adjudication is taking place.

In the previous registries, prescribers and pharmacists enrolled as a “treatment team,” which meant patients had to continue to fill their clozapine with a specific pharmacy. In the new program, prescribers and pharmacies are not linked, and a patient can fill his or her clozapine prescription at any pharmacy that is enrolled. Similarly, any certified prescriber can write a prescription for a patient.

Medscape: What does this mean for existing patients currently receiving clozapine? Do they have to be reregistered?

Dr Mathis: Patients who were previously treated with clozapine were automatically transferred to the new clozapine REMS program. We do understand that there were some challenges with migrating all previous patients, especially those who had incomplete information or different information across multiple registries. The clozapine manufacturers continue to work through these data reconciliation issues. To resolve the issues, it often requires contacting the call center to speak to a representative directly.

Because of data issues like this, the clozapine REMS call center has been extremely busy. Wait times are improving, but this has been a source of frustration for healthcare providers.

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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