Clozapine is the medication of choice for those with treatment-resistant schizophrenia. Clozapine is also FDA approved for the reduction in suicidal behavior in schizophrenia or schizoaffective disorder and effective for treatment-resistant mood disorders. Despite the clinical benefits of clozapine, hesitancy to prescribe the medication is not uncommon based on perceived dangers and rigorous monitoring parameters. One method to overcome barriers of clozapine use includes ensuring adequate education about the medication.
As an update to the previous toolkit in the MHC, this version contains important clozapine-related drug information such as:
Authored by CPNP members Jonathan G. Leung, PharmD, BCPS, BCPP, Greg Deardorff, PharmD, BCPP, Megan Trout, PharmD, and Robin Hieber, PharmD, BCPP, this toolkit is intended to highlight both the evidence base available as well as strategies of clinical decision making used by expert clinicians.
Changes to the Clozapine REMS occurred in November 2021. Certain provisions are still under enforcement discretion by the FDA meaning they are not currently mandatory. Most notably, this means that there is not a current mandate to obtain a REMS Dispensing Authorization (RDA). The dispensing quantities for inpatient pharmacies have also been changed to align with the ANC monitoring intervals in the product labeling.
The Schizophrenia and Psychosis Alliance spearheaded an effort with Congressman Brad Sherman’s office to coordinate a letter to FDA Commissioner Robert Califf urging the FDA to reduce clozapine-related barriers by shifting its REMS program to one with an educationally oriented focus for prescribers, pharmacists and front-line clinicians. The letter cites the overwhelming scientific evidence that the burdens imposed by the clozapine REMS program substantially outweigh the risk posed by the medication’s potential side effects. AAPP recently supported a Hill briefing coordinated by the Alliance on this topic with Past-President Deanna Kelly serving as the expert clozapine speaker. Thanks to the Alliance and participating members of Congress responding to concerns expressed by multiple stakeholders and consumers.
On February 14, CPNP joined 6 other national association partners in authoring a letter urging the Food and Drug Administration (FDA) to continue the temporary suspension of the Clozapine REMS (set to expire on 2/17) and provide an update on the Clozapine Risk Evaluation and Mitigation Strategies (REMS) implementation. The letter outlined the serious issues that remain unresolved and requested assurance that this suspension would continue past February 17, 2022. Stakeholders additionally requested at least a 60-day notice if the suspension is to be ended. FDA CDER responded back with a letter to stakeholders on February 17 indicating that the suspension of the REMS continues. Additional, new and favorable statements in the letter include:
CPNP and its advocacy partners met with the FDA again on December 16. CPNP Past President Ray Love, PharmD, BCPP, presented the concerns of the coalition which members can also view here. Specific challenges were detailed out in the presentation and also provided to the FDA in writing. Stakeholders concluded by reiterating that the transition to the new clozapine REMS has placed unjustified burdens on health care providers and health care systems and continued requirements of questionable effectiveness. The risk the REMS puts on patients and the fact that it discourages use of an underutilized drug that could benefit even more patients was emphasized. In closing, the stakeholders respectfully asked the FDA to eliminate or modify the most problematic elements of the REMS, or at the very least, to engage in a constructive dialogue (not just listening sessions) with representatives of the stakeholders regarding alternative, less burdensome strategies to preserve patient safety. The stakeholders further requested that the FDA devise a scientific forum to hear the concerns regarding clozapine product labeling that have resulted in a complex, burdensome REMS that places patients at risk.
CPNP and fellow stakeholders had the opportunity to engage with the FDA on December 2, 2021 in a listening session related to the new Clozapine REMS. CPNP Past President Ray Love, PharmD, BCPP presented remarks on behalf of the stakeholders noting the continued challenges related to the new REMS and stakeholder recommendations below. CPNP and stakeholders have another listening session with the FDA on December 16 and will keep the CPNP membership apprised of the discussion and any outcomes.
Read the prepared statement here.
Health care professionals continue to alert FDA about ongoing difficulties with the Clozapine REMS program, including a high call volume and long call wait times for stakeholders since launch of the program on November 15, 2021. We understand that this has caused frustration and has led to patient access issues for clozapine. FDA takes these concerns seriously. Continuity of care, patient access to clozapine, and patient safety are our highest priorities. We are working closely with the Clozapine REMS program administrators to address these challenges and avoid interruptions in patient care.
Due to problems with implementation and the potential impact to patient care, FDA is temporarily suspending certain Clozapine REMS program requirements:
Abrupt discontinuation of clozapine can result in significant complications for patient treatment. Health care professionals should use their clinical judgment with regard to prescribing and dispensing clozapine to patients with an absolute neutrophil count (ANC) within the acceptable range.
We encourage pharmacists and prescribers to continue working with the Clozapine REMS to complete certification and patient enrollment.
If you have questions or concerns about the Clozapine REMS Program or its website, please contact FDA at firstname.lastname@example.org, 1-855-543-3784 or 301-796-3400.
On Friday, November 12, 2021, the FDA sent several communications to CPNP and the other stakeholders regarding the Clozapine REMS Program. One communication asked the stakeholders to hold a date for follow up meetings regarding the REMS in December. The second communication addressed several issues that the stakeholders had posed in our communications.
In their response, the FDA indicates that there will not be a delay in the implementation of the REMS. However, they do indicate that there will be a transition period that will allow a pharmacist to obtain a REMS Dispense Authorization (RDA) even if the patient has not been enrolled in the REMS. Depending on the specifics, this would be an important comprise. The problem is that they supply no details on how this will work and whether it will work for unenrolled community pharmacies. We will probably not find out until Monday, November 15, 2021. They also indicate that they will continue this transition policy regarding RDAs longer than 90 days if necessary.
CPNP urges any members who learn more about these changes to the RDA system on Monday, November 15, 2021 to share their experiences by emailing email@example.com.
The FDA asserts that the RDA “ensures providers are monitoring patients and documenting their absolute neutrophil count and risk/benefit analysis for continuing treatment.” The stakeholders have stated that a 37-day retrospective view using a Patient Status Form (PSF) does not ensure this in a manner that promotes patient safety. It also inappropriately assigns pharmacists roles as “enforcers” rather than collaborative team members.
CPNP is aware that many pharmacists were unaware of any prior policy limiting clozapine discharge supplies from hospital pharmacies to seven days. The FDA says that this a carryover policy. They are willing to further discuss this matter. They are also willing to discuss the issue of classification of pharmacies.
Finally, they note that the REMS has made changes to the designee system. They ask for further information regarding the problems with pharmacists and prescribers also fulfilling roles as designees. CPNP will respond to this request for information in coordination with the other stakeholders in the coming days.
CPNP has taken a leading role in addressing the challenges of this new Clozapine REMS. Please continue to send us your questions and experiences so that we may share them with both the FDA and our colleague stakeholder organizations. The information that you have provided has helped lead to the changes we have seen pre-implementation. It will be essential as we continue meeting with the FDA.
The full text of the FDA’s response appears below:
1. At the meeting, CPMG discussed a 90-day transition period. The stakeholders were accepting of a transition period but noted the potential challenge of the single transition measure offered by CPMG.
FDA Response: Regarding the 90-day transition period after the modified Clozapine REMS goes into effect, this is to allow a pharmacist to obtain a REMS Dispense Authorization (RDA) even if the prescriber is not yet certified and patient has not yet been enrolled in the modified REMS. We will continue to monitor the REMS very closely after launch and evaluate the need to extend this transition period after we have additional data.
2. The difficulties that patients would face if hospital pharmacies were only able to dispense a seven-day supply of medication upon discharge.
FDA Response: Inpatient pharmacies only being able to dispense a seven-day supply of medication upon discharge was carried over from the current program that has been in effect since 2015. We were just made aware of this issue and we are interested in listening to your concerns on this issue.
3. The need for the pharmacy classification system to change.
FDA Response: We would like to listen to your thoughts on proposed changes to the pharmacy classification system.
4. The stakeholders suggested suspending the RDA component of the REMS until implementation issues are resolved. The stakeholders have stated that this is an obvious potential barrier to patients obtaining medication (unless pharmacies just ignore the new REMS).
FDA Response: We will continue to monitor the transition of the REMS and determine if the 90 day transition period post-implementation of the modified Clozapine REMS, needs to be extended. However, we do not want to have an adverse impact on patient access to clozapine, this temporary method of obtaining an RDA during the 90 day transition is intended to avoid interruptions in patient care.
The RDA ensures providers are monitoring patients and documenting their absolute neutrophil count and risk/benefit analysis for continuing treatment. We urge pharmacies to work the CPMG and make the best decisions for their patients.
The CPMG has worked to address concerns with prescriber designee system and these changes have been made on the REMS platform. This will allow designees to initiate enrollment and the ability for a designee to associate with multiple prescribers. You were notified of this communication on November 10, 2021.
If would be helpful if you could describe the difficulties with pharmacists serving as designees and prescribers serving as designees for other prescribers, so we can explore ways to address this.
We understand that stakeholders continue to receive reports that parts of the new REMS are not working. Full functionality of the modified REMS will not be available until November 15, 2021.
Due to the complexity of the implementation and the change in vendors, we are not able to delay implementation. The modified Clozapine REMS program is being implemented on November 15, 2021.
The FDA would like to continue our communication with you and will be setting up meetings in early December to gather feedback on the implementation.
As part of our ongoing dialogue with the FDA regarding the New Clozapine REMS (NCR), we have received further guidance on the issue of prescriber designees. In the initial release of the NCR, there were many important components of the current system that were problematic. In particular:
Details regarding a recent update to the REMS addresses these two issues. A many-prescriber to many-prescriber-designee relationship can now be established. And, a potential prescriber designee can now initiate the prescriber-prescribe designee relationship. However, they need the prescriber's NPI to initiate this process. This is accomplished by a new prescriber designee account creation process. Meanwhile, the prescriber uses the "Manage Personnel" button on the prescriber page to deal with their designees.
One CPNP member who tested this system notes that the prescriber is not actively informed of the prescriber designee request, but has to check the through the "Manage Personnel" button for new designee requests.
To the best of our knowledge, this change still does not allow an individual enrolled in NCR as a pharmacist to serve as a prescriber designee without the use of a second email address.