We have Dr. Steve Marder, Professor of Psychiatry at UCLA Semo Institute for Neuroscience and Human Behavior. And I am Rob Cotes, Professor of Psychiatry at Emory University School of Medicine. And we have additional information about all the presenters' bios on the registration page. All right. And just sort of as a housekeeping matter, if you have any questions, we're hoping to save about 20 minutes at the end of this presentation for your questions. Please put them in the Q&A in Zoom. Here are disclosures. All right. And here's a little bit of an outline. The first part of what we'll do is go over briefly Clozapine's unique role in the treatment of people with schizophrenia. We'll talk a little bit about how we got here from the regulatory standpoint with Dr. Love. We'll then have Dr. Ehret and Dr. Love talk about pharmacy perspectives. I'll give an update on latest evidence on hematologic monitoring. Then Dr. Marder and I will talk about clinical scenarios that we likely are facing now. And we'll all have some statements about moving forward and then we'll end it with questions. All right. So just very briefly, I wanted to highlight where Clozapine falls in the APA guidelines for the treatment of patients with schizophrenia. And it falls in three places. First, Clozapine is recommended after minimal or no response to two trials of an antipsychotic medication. Some literature even suggests maybe after the first trial of an antipsychotic, it could be warranted. Most of the time we see multiple, many more trials than two by the time someone gets Clozapine. The second place in the APA guidelines is for patients with schizophrenia if the risk for suicide attempt or suicide remains substantial despite other treatments. And then the third is not an FDA approved indication, but an important indication nonetheless, where patients with schizophrenia are treated with Clozapine if the risk for aggressive behavior remains substantial despite other treatments. Clozapine really is the only medication that's expected to work with people who have treatment resistant schizophrenia or TRS, which is poorly named, but it basically just means that someone is not responding to two antipsychotics with an adequate dose and an adequate duration. And really, you know, Clozapine's efficacy is unparalleled for people with TRS. About 40 to 60 percent of people will respond to Clozapine. It really wouldn't be expected that they would respond to other antipsychotics. And then also, if you talk to people who are taking it, they prefer it in comparison to other antipsychotics. So, you know, if you work with people with schizophrenia, you're going to see people who fall into this TRS category and don't respond to usual antipsychotic medications. And in one study, meta-analysis, looking at first episode schizophrenia, the TRS rate was about a quarter. And this is right in the early phases. So, there's also increasing data that suggests that minimizing the delay after Clozapine initiation improves Clozapine response. And there's a number of studies that have looked at this, but trying to identify people early after they develop TRS and initiating Clozapine is really key. Finally, there was a recent study published this year that suggested that people with first episode schizophrenia, if they switch to Clozapine after the first relapse, it significantly reduced the risk of a second relapse when compared to being on the same antipsychotic versus switching to a different non-Clozapine antipsychotic. Clozapine is highly underutilized for people with schizophrenia who have suicidal behavior or suicide attempts. We know that the lifetime risk of suicide for people with schizophrenia is around 5%. People with schizophrenia are about four and a half times more likely to die by suicide than the general U.S. population. The risk is highest among younger adults, which has important implications for Clozapine, and higher among men. We know from the Intercept study that there's less suicidal behavior with Clozapine in comparison to Olanzapine. We know this from RCTs and from naturalistic registry studies, including a Swedish and Finnish registry study. Now, if you buy that about 25% of people with schizophrenia have a version of treatment-resistant schizophrenia, in the United States, under 5% of people with schizophrenia are prescribed Clozapine, so it's highly underutilized. This is sort of 18% of who could benefit from it versus who's actually on it, and this is just for TRS, not its other indications. So this is the Clozapine underutilization gap that we only change by starting new folks on Clozapine. It's interesting, from the FDA data from the advisory committee in November, there was an analysis done looking at Clozapine prescriptions over time. Clozapine prescriptions are relatively unchanged since 2016. There was a dip in 2020 with 130,000 people, but then it kind of bounced back up to 147,000. So it's going to be interesting to see how Clozapine utilization changes with the changes in the REMS. Also, another interesting point here is that there's significant variation among Clozapine utilization across the states in the United States. A 13-fold variation, another study suggests 11-fold variation, and all of the states have had the same REMS process. So I think what this goes to show us is that the REMS is part of one of many barriers of accessing Clozapine, if different states can do it with different levels of effectiveness. And then finally, it's been shown that there's less Clozapine used in the Southeast and in the Southwest. All right, so with that primer, I will turn it over to Dr. Love, who will give us a history of how we got here. Dr. Love. Thank you, Dr. Cotez. If I can have the next slide. So Clozapine's been available in the U.S. for about 35 years, but the first REMS was instituted in November 2015, and really, even that REMS was controversial. The psychiatric pharmacists and APA both objected to a lot of the provision of the REMS. We continued to object. The FDA made only minor changes, but we all kind of labored through with the REMS. In the summer of 2021, we began to learn about a new version of the Clozapine REMS, and that was scheduled to be implemented in November. The new version looked like it repeated and compounded a lot of the mistakes in the first REMS, and eight organizations got together. We called ourselves the stakeholders, and we started objecting to the FDA and asking for changes. We were concerned about the burden of this new REMS, but more importantly, we were concerned about what the impact might be on our patients. Nevertheless, on November 15th of 2021, the new REMS went into effect. There were all sorts of issues, most of which we had predicted, and within that same week, the FDA suspended elements of that REMS. We continued to meet with both the FDA and the Clozapine product manufacturers. I think we had about nine meetings over the subsequent couple of years, and part of our meetings, we were saying this REMS was so problematic. We wanted to have an FDA advisory committee meeting to give input about the REMS, and we learned in late 2023 they were willing to do that, and the meeting wasn't held until late this past fall. Next slide, please. At that meeting on November 19th, there were a lot of advocates, a lot of patients, a lot of health professionals that spoke about the REMS and its weaknesses, and there were two specific questions that were posed to the advisory committee. The first was, do we need to keep these documentation requirements where you have to submit lab data or an indication of ANC direction to the REMS? Do we need to keep this provision where the pharmacy needs to call in or go online to the REMS to find out that the lab data is okay and up to date? And in both of those cases, the joint advisory committee said no, overwhelmingly. And then the last thing they asked was, do we still need to require education for those people prescribing and dispensing Clozapine? And again, the answer was overwhelmingly no. So we did not know what was going to happen after that. The FDA was pretty insistent and wanted to keep the product labeling the same. Next slide. So on February 24th, the FDA posted this announcement on its website. The FDA policy is to not send out letters communicating to pharmacies or communicating to prescribers, but it simply posted this announcement on its website saying that they intended to eliminate the REMS. However, they also said that they still recommend that prescribers monitor patients' ANCs. They did admit that by eliminating the REMS, that should reduce the burden on the health care delivery system and improve access. And finally, they had this one sentence, which we don't know what to make of. It said they'll work with manufacturers to update the prescribing information. We don't know whether that just means they're going to update the prescribing information to eliminate references to the REMS or whether there are other changes. We hope that eventually they'll make some other changes. Next slide. So again, the FDA doesn't communicate to anybody, and this includes payers and hospitals and insurers and pharmacies as well as prescribers. They don't communicate to those entities directly. So we have to assume that there are a lot of people that still don't know about the elimination of the REMS. So when a patient goes into the pharmacy to get a prescription filled, they could still be subject to limitations by payers or to pharmacy procedures or whatever, because while all of us are very aware, others aren't. The second point that I want to make is this is really an administrative change about documentation and procedures for dispensing prescriptions and not a clinical change in any recommendation. So I know there's been a lot of chaos and a lot of patients who say, well, now I don't need to get my blood monitored at all. That's not the case. There hasn't really been a clinical change. We hope that perhaps that will come in the future, but not now. So the FDA has still been very clear that blood monitoring is required, particularly at the beginning of treatment and during stabilization phases. What we do know is that we can forget about submitting the lab results to the clozapine REMS now. Next slide. And we also know that pharmacies no longer need an authorization from the clozapine REMS or the submission of lab data to fill a prescription. But I'm going to give you some caveats here. Chain pharmacies and payers may not have yet changed their procedures. Some have, but some haven't because they're not aware. Pharmacies often declined to dispense clozapine because of all the confusion and all the work. And it's likely that a lot of pharmacies, particularly if they don't have a lot of patients on clozapine, may not yet have clozapine in stock. So there could be a delay in filling prescriptions. And one of the nice things about the elimination of the REMS is the REMS did limit the number of days supply and patients may be able to get larger supplies. But this is subject to the payer. So if a patient's pharmacy benefit plan has no limits, then they could get a 90 day supply or they could get a 30 day supply, even at the beginning of treatment. So that's really something that we'll all have to consider when we prescribe what's appropriate for each patient. There are some other things that we don't know. We don't know when the REMS website will disappear. And that's important because there are some prescribers that rely on that website for historical data on their patients. And at some point that may may no longer be available to prescribers. So if you do use that or if you want to try and download that information, perhaps your patients switch providers and you need to get some historical information. Now's the time to do that because we don't know when that will disappear. And the other nice thing is that it used to be that a prescriber or pharmacist would have to do education before they could deal with Clozapine and get certified on that Clozapine REMS website. And that is also disappearing. Next slide. So what I would like to do now is introduce my colleague, Dr. Megan Aratt, and have Dr. Aratt try and address some specific pharmacy issues that have come up in the past and are probably still going to come up again until all of this shakes out with the REMS. So, Dr. Aratt, I have some questions for you and we can have a little bit of discussion about some REMS issues related to pharmacy. Dr. Aratt, I know that there's some pharmacies that require prescribers to submit ANC values to the pharmacy before they're willing to dispense Clozapine. What's going to happen with the elimination of the REMS? This is a good point. It's been brought up in our question and answer as well. Pre-REMS, so if we think back to the initial approval of Clozapine, the process was for physicians or prescribers to provide that data to the pharmacy. And so I think that still has hung around in some places, especially in the last couple of years with the REMS maybe not functioning as well. Prescribers may have just gotten into the habit and pharmacies got used to getting that. So hopefully with the elimination of the REMS, that practice of having to submit to the pharmacies should go away. But let's also think that maybe some of our pharmacies may not know this. We may need to do some education with them as well, that ultimately they don't need those anymore when they get them. Thank you. So another issue that came up with this was there were some pharmacies that started this practice because there was a provision in the REMS that allowed the pharmacist to fill a prescription, even if they didn't have the patient status form that came about through the REMS. And they could override that, but they had to have the patient's lab value in front of them to do that, the most recent lab value. And so that was another reason that added to that practice. And I think we both agree, at least we know that'll disappear soon. Hopefully. Yeah. Another question, Dr. Aratt, is how might the policies for no REMS be addressed by chain pharmacies? That's an interesting question. When we think about many of the different places our patients access clozapine, and you had mentioned, what does all this mean? Many chains may be bound by corporate policies or contracts with PBMs, such that they may require that RDA or that PSF to be submitted in order for the pharmacy to receive payment for dispensing of the clozapine. Some independent pharmacies may not have some of those binding contracts. So I think it's going to be very different across the board. And I think it's being different every day. Just last night, Dr. Kotez sent a text that said he had one pharmacy that filled a prescription and didn't require an ANC. And we all were very excited because we saw one change, but yet this other pharmacy down the street is still using the REMS and the PSF to make sure that they get an RDA before they dispense. So I think over time, we're going to see some hopeful changes as the stakeholders group work with these payers and pharmacies so that everybody's just dispensing without it. And Dr. Ayer, what about things like emergency supplies and limits on the number of days? Are those likely to change? And when will they change? They are likely to change. In all reality, there shouldn't be a restriction based on the day supply that can be dispensed. So if a prescriber wanted to write for a 30 or 90-day supply, they should. There shouldn't be a holdup at the pharmacy or barrier. Whereas previously, that PSF or RDA may have hindered that ability to do that. The timeline on that is going to be up in the air at this point because that website is still functioning and there hasn't been a large shift in PBMs at this point or pharmacy policies. we still may encounter that limitation on prescribing. Hopefully this will ultimately change too for our inpatient hospitals and our discharge ability to send them home with more meds. But I'm hopeful that Dr. Kotez and such will start to speak a little bit at the end, a little bit about the ability to maybe have your patients have a couple extra days, so we don't always run into this Friday night, I'm out of clozapine, my pharmacy won't give it to me situation. Doctor, what about the fact that a lot of pharmacies have not in the past stopped clozapine? Could you talk a little bit about why that occurred? Was that the REMS or something else? Is that likely to change? So a couple of different, I think, reasons why pharmacies may have not stopped clozapine. One, you needed to be enrolled as a clozapine dispenser, so there was a system, I mean it does require that, so pharmacies may have hindered away from that given time and burden. But also if there isn't a lot of people on clozapine, right, why do you want to keep a medication on your shelf that's just going to go out of stock? And so I think it's important as prescribers, if you have the ability to work with community pharmacies that are close to you so that they know that this potentially could be coming so that, you know, they can order it, you're not prescribing it on a Friday night when they can't get an order the next day. It probably be more problematic in our rural areas as well. I know you've worked in acute care hospitals as well as state-operated psychiatric facilities. Could you discuss how things were likely to change in those systems with the elimination of the REMS? I think this is a great point. As many of us work within health systems, whether that be academic health systems or state hospitals or other areas, keep in mind that there are pharmacy and therapeutics committees that may have established policies and that they might have been based on the REMS. And so those old REMS provisions are still going to be in place until we work with our state P&Ts and our hospital P&Ts to potentially alter some of those policies and procedures. And so there may be limitations on how much you can prescribe at discharge. And so while none of these are necessary anymore, we really need to make sure we work on that. We also want to make sure that as we're editing these, we aren't introducing any new policies that can further reduce access to clozapine or perpetuate the burden on health care professionals. Yeah, I think that's a real important point about making sure we don't worsen the problem by putting in place new restraints and restrictions. You know, you brought up about facility policies. I think that in many practices and in many clinics, they also have policies and procedures and special documentation and use designees and things like that. So I think that almost regardless of setting, we're going to need to rethink how we do things and whether there's changes we want to make. Because while we a lot of us found the REMS a burden, some people did find that that kind of backup plan of the REMS is a crutch and we need to decide how we're going to how we're going to proceed without that that process that helped to make sure things were were documented. Dr. Eric, thank you for helping us to understand how how pharmacy and health systems might respond to the elimination of the REMS. And I'm going to turn it back over to Dr. Kotez. Thank you, Dr. Love. I actually have one question for Dr. Eric before we move forward, which is, you know, we have been, I guess, in my experience, I've been communicating with the pharmacies about the new changes. What is the best way to actually do this? You know, like what would you recommend? What resources would you send them to? I think at this point, we're what we have is the FDA information and saying that the REMS is no longer required. And I think providing that to them, many of them may not have seen that or even are aware of that. Ray, Dr. Love and his stakeholder group are working on some additional education. And how do we get this out to the masses? Because I think it's more than us just all individually calling our pharmacies, there needs to be some directed education at everything. And I'm hoping the stakeholders group is developing some processes. So Dr. Love, if you have something that you're thinking to the major chains and things of that sort, that would be helpful. Yeah, and actually, we have, I think there's about 14 organizations participating, including advocacy, state government through NASHBD, various psychiatric and pharmacy groups are all working together. And we have started to construct some some outreach to the National Association of chain drug stores, the pharmacy associations, the PBMs, the insurers, organizations like that to try and let them know that some of the old audit criteria that they had and some of the old processes and and their software are all things that need to be changed to, to improve access to clozapine and, and get rid of these REMS holdover practices that that led to patients having their, their, their treatment interrupted. Okay, thank you all. And I'm going to go ahead and jump into the next section and provide a little bit of a quick review on clozapine and neutropenia. And I think that this will be important as we go to some of the clinical scenarios. And if you are, say, a medical director in your system, and you're thinking through policies and changes, I want to include some of the references here for you all around some of the updated information about neutropenia. And I think that in some ways, you know, there's been such a focus on neutropenia, we run the risk of missing other potentially life threatening side effects from clozapine. So this really is about like, this is about neutropenia, but there's a lot of, you know, there's other monitoring that we should be doing, and we should be doing them sort of in concert. Okay, so first, you know, neutropenia has an immune mediated mechanism. And from a 2018 meta analysis, it's it's, you know, the the incidence of severe neutropenia, which is an ANC of less than 500, is around 0.9%. I often quote this statistic, the risk of death due to neutropenia and clozapine exposure is one in 7700. We know that this is more likely to occur early in treatment. 89% of cases of severe neutropenia occurred at one year. And then on the right hand panel, I have sort of the cumulative incidence and you can see that as the number of months of follow up decreases, the cumulative rate of neutropenia decreases. So early monitoring is essential. This is why we do weekly monitoring. There's been some new studies which I want to bring to your attention that were published last year. The first study is a study looking at a Finnish cohort who's, you know, was led by Jose Rubio. This study basically found that after three years of clozapine treatment, the risk was comparable to that of non-clozapine antipsychotics over the initial six months of treatment. So clozapine does have an initial like a greater risk of neutropenia than other antipsychotic medications. But after time that risk reduces to that of non-clozapine antipsychotics, particularly starting new antipsychotics. The next study I wanted to talk briefly about was from Dan Siskind and Corin Northwood, looking at a large cohort from Australia and New Zealand. And they basically found that the peak risk of neutropenia was at nine weeks, and then the risk became negligible at two years. And another important point of this study was that clozapine retrial after interruption with two years of unremarkable testing might not require further testing. So you might not have to start all the way back over to weekly testing. I now wanted to just highlight very quickly some of the findings, some of the FDA data that was presented at the advisory committee. This data hasn't been published, it's available on the FDA website. But they commissioned a number of studies to look at neutropenia and clozapine, which I think are important for us to have a sense of. This first study is a VA study, looking at clozapine new starts over a period of 23 years. All the visions, so the entire VA network, they found that severe neutropenia occurred in 0.4% during the first year, the risk was highest during the first three months. And interestingly, a low percentage of patients that were started on clozapine remained on clozapine at 13 years, actually only 4.1% of initiators. There were 48 cases of severe neutropenia, and two of those were fatal. This is not a complete study, and they're incorporating inpatient data, which may yield another case of severe neutropenia or two potentially. Some of the cases of severe neutropenia, there were other issues going on like the, you know, possibly cancer and chemotherapy. The next study I wanted to just very briefly mention, was a Brigham and Women's Hospital study, looking at neutropenia related hospitalization. And sometimes, you know, I think on one end of this clozapine discussion, there's a question like, well, maybe the risk of neutropenia due to clozapine is similar to that of other antipsychotic medications. And, you know, I think this study kind of shows that clozapine is more likely to cause neutropenia than elanzapine, particularly earlier on. This study looked at actual patients who were admitted to the hospital with the diagnosis of neutropenia, and they found that clozapine initiators had a higher risk of neutropenia related hospitalization than elanzapine initiators. And it was about twofold, the risk of elanzapine. The rate remained low, but persisted over five years, and there was an attenuation over time. So, this next study is from the Sentinel database that the VA did, that the FDA did, that looked at adherence to monitoring during different eras of the REM system. And I think what's important to point out here is that even with the REM system, adherence to monitoring was not perfect. In fact, adherence wasn't perfect, and some people received medication, like received clozapine in the enforcement discretion, and actually didn't have any monitoring that was reported at all. I mean, personally, I didn't see any patients who were part of the enforcement discretion, but enforcement discretion has actually been in place with the prior clozapine REMs. And that just meant that the FDA did not tend to object if you didn't get blood work before. You could still put into the REM system that the patient refused. You could put that as many times as you wanted. I think sometimes it was just a question of whether or not the pharmacy would fill it for you, because sometimes they needed to have an ANC. So, I think, you know, there was flexibility before, adherence wasn't perfect, and I think it's impossible for us to expect perfect adherence in the post-REM system. Just to highlight some of the numbers here, they found that, you know, during the first six months of treatment, the median monthly ANC tests decreased from 2.3 to 1.6. And you would expect that number to be 4. So, the monitoring was in, it was, you know, it wasn't perfect. And then also, it's sort of surprising that 20% of people in the Sentinel study actually had no monitoring whatsoever. I'm not sure exactly how that happened. But the next part I just wanted to touch on briefly was a little bit about benign ethnic neutropenia, which has been a barrier, I think, for, you know, people of African, Middle Eastern, and Yemenite Jewish ancestry to receive clozapine. And, you know, without the REM system and without the clozapine and the risk of neutropenia guide for healthcare providers, we're going to have to have, I'm not sure if this will exist moving forward, but it's going to be important to have, you know, really clear information about, you know, how to continue to monitor for people with benign ethnic neutropenia, sometimes called benign neutropenia or benign familial neutropenia. Important to recognize that a hematology consult is not always needed for these patients. And then Deanna Kelly did a great study, and I think Dr. Love was also on this study looking at clozapine in patients of African descent across, you know, the United States and Nigeria, showing that clozapine could be used safely in this population. 25% had an ANC less than 1.5, but there was only one case of severe neutropenia. All clozapine new starts. All right, so we asked, you know, the SMI advisor group, just sort of hypothetically, if there was no REMs in place, how often would you do ANC monitoring? And now here we are in a place where there's no REMs in place. So I thought it was important to present this information. And essentially, almost everyone said that they would continue to follow the recommendations in the product labeling for at least the first year of treatment, which I think is important. And then there were some differences around how long people would continue to do the monitoring. Okay, so one of the first questions I got asked after this happened was, well, now what's the monitoring frequency going to be now that there's no clozapine REMs? And the answer is the monitoring frequency is the same. This, like Dr. Love said, is an administrative change rather than a clinical change, and still clinical vigilance is necessary. There will be some, you know, forthcoming recommendations from the clozapine ANC Delphi guidelines, which are under review. But I wanted to first present sort of the US package insert information that shows weekly, every other week, monthly cadence, sort of indefinitely. There was a paper published in 2025 from the European Clozapine Task Force, which suggested a more lenient monitoring protocol weekly at zero to 18, then monthly from 18 to a year, quarterly from year one to two, and then yearly after year two. And you see sort of the caveats there. Again, I think, you know, one of the next steps of advocacy is to align the monitoring frequency in the package insert with some of the latest evidence. And the European Task Force guidelines are sort of one, you know, potential suggestion there. But right now in this era, I'm certainly recommending that people are getting their ANCs with no change in frequency to make sure that they can get their medication at the pharmacy, which if they can't, that's often one of the most, you know, catastrophic things that has happened with the REMS is treatment interruption. Okay. So with that, maybe I can turn it over to Dr. Marder. And he and I will have a discussion about some clinical scenarios. And maybe to kind of get started, I'm curious, Dr. Marder, your thoughts, like how big of a deal is this decision? And sort of what are your initial thoughts about kind of what's happening right now? Well, you know, I think it's a big deal, you know, in a clinic where I work, that specializes in psychosis, 35 to 40% of our patients are on clozapine, actually. So this this affects a lot of what we do. It also means that clinicians have a new type of flexibility that they haven't had before. It's a flexibility, Dr. Cortes, that I think is similar to other medications, that is that they have a product label. And they can make a choice about how closely they'll wish to adhere to it. So I think it puts, you know, more, it just gives both more flexibility, and more responsibility to the clinician in making decisions. I'm wondering if you can comment a little bit on the perception that, you know, the risk, you know, has somewhat, you know, maybe maybe this is, I think this is a perception that maybe the risk has shifted to the prescriber a little bit. And now that the pharmacy doesn't have to input the stuff in REMS now, like, how I wonder how, how that will affect people around this sort of perception issue around risk sort of shifting to the prescriber. Yeah, I, I think, you know, prescribers who deviate from the product label, you know, we'll have to, you know, you know, we'll probably absorb some risk. I think one way to deal with that is to have frank conversations with patients. And in many cases, patients with psychosis have caregivers, so that if a decision is made to deviate from the product label, that, you know, a process setting up shared decision making, where there's a decision that's made together with the patient and the caretaker is probably, you know, the best route to go. Yeah, I, I agree. I'm curious, like, what do you think this is going to do for clozapine utilization overall? Do you think that this decision is going to change clozapine use? Dr. Cortes, I hope, I hope so. You know, you know, I've been prescribing clozapine actually, from before it was actually approved for more than 36 years. And the, I've tried mightily to convince more clinicians to use Clozapine, and up until now with only minimal success. So I would hope that this increased flexibility will both from a patient standpoint and the prescriber standpoint, lead to really many clinicians trying Clozapine, getting experience with them, and just seeing how it could actually change lives and change the trajectory of the illness. I think getting clinicians to do that first or second Clozapine patients, and to see that despite all of the extra work it takes, that the results can be really life-changing, as I said. And I'm curious, if this decision, might it open the door to some people who were never Clozapine candidates because it was impossible to do the early monitoring, the early hematologic monitoring. Do you think that this decision opens up a door for some people that maybe never had access to Clozapine before because of that? Well, do you mean in patients where it's impossible to do the monitoring or patients who refuse to do the monitoring? Yeah. That'll be a difficult decision because the risks of Clozapine, both myocarditis and severe neutropenia really occur during the first few months of treatment. And maybe clinicians can make deals with patients to have a little bit less monitoring or something like that. On the other hand, and I'd like to hear your viewpoint on this, that we have cases that are really compelling where we think Clozapine could be life-changing. And when you weigh the possible advantages of Clozapine against the risk that you might actually consider starting them on Clozapine without monitoring. In our clinic, we've discussed that. We haven't done it yet, but maybe now we'll consider it more seriously. I don't know what your views are on that, Dr. Cortes. Yeah, I too have been aware of some really compelling cases where that might be a possibility, particularly during my days on the inpatient unit for, you know, and I think people were in some really sometimes life-threatening situations. I think one role that some professional organizations, maybe even like the APA can have is some templates around, you know, how do we set up that risk benefit discussion for our patients and, you know, maybe even pulling in some of the evidence about Clozapine and sort of giving some language in the documentation to be able to address some of these concerns. Yeah. Yeah, and I think weighing the overall welfare of the patient, you know, will be the primary concern, even though there's some risk. I wanted to get your thoughts on, you know, people who have been stable on Clozapine for, you know, years and years who have needed to get, you know, monthly hematologic monitoring. And I mean, I've had patients who have tried to go out of the country for long trips, who's, you know, had to cancel their trips because they only were able to get a month of Clozapine. So part of it is, you know, the dispense limits, I think will be gone. I think that will be helpful. But like the, you know, the stable, you know, people who are doing well, who are on Clozapine for a long time, the risk of neutropenia is low. How are you thinking about them in terms of hematologic flexibility and the monitoring? Well, first of all, I think many of our patients on Clozapine are relatively high functioning and they're going to learn that other clinicians are, you know, stopping monitoring say at two years or even earlier. So I think they're going to be aware and they're going to be asking questions. I believe that I think we need to have conversations with patients who've been on Clozapine for two or more years, inform them about the changing risks and the new flexibility. And again, make a decision together using a shared decision and decision-making model. I think that will probably lead the great majority to want to sort of stop monitoring or make it less frequent. The other thing is, Dr. Cotterson, I don't know how you've thought about this. How can you articulate the risk of Clozapine to a patient and to a caregiver in this setting? I mean, it's hard to say that the risk is 0.4 per 1,000 patient years or something like that. That's a difficult sort of a message for many people to interpret. I think we're going to have to find language that says that the risk is minimal or very low or similar to other medications that we prescribe without monitoring. I think those conversations are going to be interesting and we've already started them in our clinic. Yeah, I agree. I agree. And I tell people, it's interesting because for people who have weekly monitoring and then who have progressed and are on monthly monitoring, some of the people that I talk to really feel like the monitoring adds an element of safety. Like we're doing this blood work. It helps them feel confident that this medicine is not causing any significant problems. We're monitoring it. We're on it. So there is a group that certainly appreciates the ongoing effort. I think it's despite all the logistical issues that can occur with the sort of frequent monitoring. The other thing that I tell people is like, this monitoring is sort of part of it, but the most important thing is if you get a fever, you give me a call. Yeah. You call me. It's just sort of an easy thing. I think not just because of the risk of neutropenia, but if somebody has a fever or an infection, you can have changes in the clozapine level that increases in the clozapine level that I would wanna know about. So I tell my patients that instead of, it's sort of a different way of thinking about it, to have a sort of a, the first person you call if you get a fever is your psychiatrist, but that's the way I tell them to think about it, rather than your primary care doctor or whatever, you call me and then we'll figure out if there needs to be a dose adjustment or, cause I think that part of the problem, part of what we see with life-threatening agranulocytosis is that it occurs quickly. It occurs over an eight day period. And if you're just randomly doing monthly monitoring, there's possible, you just won't pick it up. So really sort of looking at the key symptoms, signs and symptoms of infection, fever, big CRPs, things like that are probably really important. That's something that I've learned from the hematologists over the years. I agree. Okay, well, maybe what we could do is, each of us can have a little reflection on moving forward and kind of where are things going and let's see, maybe Dr. Lovell, you wanna start off with that? Sure, thank you, Dr. Cotez. I'm gonna try and address this from the perspective of all of these stakeholder organizations that have been working together and they've continued to work together, actually even more intently since February 24th to decide how to go forward. And I think what they're looking to do in the short run is to try and make sure all of these remaining barriers to the use of clozapine are removed. And it involves things like changing audit criteria for PBMs and pharmacies changing software systems and documentation procedures and things of that. But in the long run, what they're really trying to do is work with the FDA and work with the clozapine manufacturers to try and increase communication about clozapine, increase education about clozapine. As Dr. Cotez showed in his slides earlier, we're all convinced that clozapine is drastically underutilized. And we feel this is the opportunity to really promote clozapine use as an alternative for those patients that can benefit from it. At the same time, we wanna make sure that it's used safely and educate people how to do that. Part of that is also trying to work to get some of the portions of the product labeling change that deal with dose titration or that alert people to increase susceptibility to pneumonia. So those are the things that I think are gonna happen in the future. But I think it's gonna take all of us to try and move forward towards those goals. Thanks, Dr. Love. Dr. Ehret. Dr. Cotez, maybe I'll keep it in the very near future. I think I'll just ask that we all have patience and grace as we navigate this system because it's changing on a daily, hourly basis. And so let's all work together as a care team, understanding that pharmacies may have different restrictions, prescribers, healthcare settings, all may have different policies and procedures that they are trying to untangle. And as we're untangling and disassembling some of what might've been put in place for REMS, let's advocate for our patients and not assemble new barriers and hurdles for our patients so that we can increase access to clozapine. Yeah, excellent points, Dr. Ehret. And I think that the tendency maybe for some systems is to say, okay, well, let's create something that's like clozapine REMS internally for us. And then the problem is that, one, it might not be necessary. And then two, if everybody develops a lot of separate systems, there's a lack of standardization across the systems. And then what we end up with is something even more challenging. Okay, Dr. Marder. Yeah, again, I hope that we get more patients receiving clozapine earlier in their illness and that more clinicians begin to feel comfortable using clozapine. And I think it's also important that we sort of put in perspective the risk of severe neutropenia, the risks of more people die from bowel obstruction and ileus on clozapine than other illnesses. So this should be part of a sort of a broad safety monitoring, some of which is sort of loaded in the front, the beginning of clozapine treatment, myocarditis and neutropenia, and then constipation and pneumonia, later on in the illness. Yeah, really great points. And then I guess I would also add that this is really the time for education sort of, and really having a lot of our professional organizations work together around education, around education, not just around neutropenia, but around all the other things that we need to be monitoring. And I really, and I think that the education is sort of one part of this, but I think maybe we as a system need other sort of incentives to increase clozapine use and maybe education alone won't be enough. I really think that, I really feel strongly that every psychiatry resident or other, sort of prescriber in training should have experience with at least one patient who's on clozapine or at least get some sort of education about clozapine within their training. Because really, I think if you have, if you see sort of what clozapine can do early on, that's something that's gonna stick with you for the rest of your career. And I think that that's something that happened with me and it was an important part of my work in clozapine and sort of, so I think the training pieces is really, really important. All right, why don't we go to, we have a lot of questions and maybe we can go to some of the questions. I'll jump in on one, Dr. Kotez. One was about timing, about when's all this gonna disappear? The FDA has until I think two more weeks to really finish charging the manufacturers to get rid of the REMS. And then the manufacturers will have up to six months to actually dismantle everything. So right now, it's really gonna be in the manufacturer's court. So we don't know when all that, those websites are gonna disappear and the REMS is gonna go away. Another common question is, will there be new standards of practice? Will APA come up with monitoring guidelines? Things along those sort. Dr. Kotez, maybe you could address that. Yeah, I think that the European Clozapine Task Force guidelines and then the forthcoming Delphi Consensus guidelines will be informative in helping to, develop new practice guidelines. But right now, we don't have those and I'm really not recommending a lot of changes in the monitoring frequency, particularly in this sort of era where some pharmacies still may require the ANC. So I think the most important thing is in the short term to make sure that our patients continue to get their Clozapine. I'd love to see some new practice guidelines out there and I think there's gonna be important source of advocacy moving forward. I think Dr. Kotez, if you just want, I think one thing to keep in mind, although the FDA and the manufacturing groups have times to change all of the things and dismantle, the statement, the way it reads from the FDA should, I think people at this point today don't have to submit to the REMS unless their pharmacy is requiring it. So keep in mind, you don't have to wait six more months for something to happen in the labeling. That will all come, but as of the 24th of February when that announcement was made, then the REMS ceased to be a requirement to prescribe Clozapine. And then just sort of the other thought about the REMS is we talked about this a little bit, but the REMS does have historical ANC data and I don't know how much longer the REMS is going to be up. And I know some clinicians who are downloading some of the information that's sort of available in REMS in PDF form and putting it in somewhere secure so they can just sort of have access to that data, particularly if you have someone in multiple health systems and you don't have all the ANCs just sort of right in front of you. We're gonna have to figure out a way to keep track of when has somebody been on Clozapine for six months? When has somebody been on Clozapine for a year? I think we've probably already been doing that, but now it's also gonna still be up to us. Were there any other questions we wanted to get to? There's a lot in the chat, Rob. I do know the APA is going to take note of these and so there will be future resources made available based on this, because I think we could probably sit here and talk about Clozapine for the whole rest of the day based on all these questions. There was one I'll take a stab at. Somebody said that their hospital didn't have Clozapine on the formulary and what could they do about that? And I think that now is the time that all of these administrative procedures are disappearing for people to reconsider it if it's not on your formulary and have a reanalysis done of what the hospital has to do. They have to do a whole lot less than they used to have to do. And that makes it a lot easier to manage, particularly when you're only seeing a patient for a short period of time during a hospitalization. So if it's not available in your health system, now's the time to ask for a reevaluation. And I think there's enough data out there to point people in the right direction about how to use it safely and appropriately. We know a lot more about Clozapine than we did years ago when a lot of these decisions were made. I think that's a great point. And we're at the top of the hour. So I just wanted to thank our audience for the excellent questions that came through in the chat. And I wanted to thank the APA for this format to be able to have this discussion. And thanks to my co-presenters, Dr. Ehret, Dr. Marder, Dr. Love. I think we had a really great discussion. Hopefully we can do this again because things may be in a different spot in a few weeks from now. But so, again, thanks to everybody. And we'll hopefully see you soon. Thank you.

clozapine

schizophrenia

treatment-resistant

FDA recommendations

REMS

suicide prevention

pharmacy challenges

neutropenia

educational outreach

prescribing practices