Alright, hello everyone and welcome. I'm Dr. Rob Cotez, Associate Professor at Emory University School of Medicine and SMI Advisor Physician Expert. I'm so pleased that you are joining us for today's SMI Advisor webinar, Keeping Up with Clozapine Rems, a guide to the November 15th changes. Okay, SMI Advisor, also known as the Clinical Support System for Serious Mental Illness, is an APA and SAMHSA initiative devoted to helping clinicians implement evidence-based care for those living with serious mental illness. Working with experts from across the SMI clinician community, our interdisciplinary effort has been designed to help you get the answers you need to help you care for your patients. Next slide. Today's webinar has been designated for 1.0 AMA PRA Category 1 Credit for Physicians. Credit for participating in today's webinar will be available until October 29th, 2021. Next slide. Slides from the presentation today are available in the handouts area found in the lower portion of your control panel. Select the link to download the PDF. Please feel free to submit your questions throughout the presentation by typing them into the question area found in the lower portion of your control panel. We'll reserve 10 to 15 minutes at the end of the presentation for Q&A. Now I'd like to introduce you to the other faculty for today's webinar, Drs. Jonathan Meyer, Donna Rowland, and Ray Love. Again, I'm Dr. Rob Kotez, Director of the Clinical and Research Program for Psychosis at Grady Health System and Associate Professor at Emory University School of Medicine. I am joined by Jonathan Meyer, Clinical Professor of Psychiatry at the University of California, San Diego. Donna Rowland, Clinical Associate Professor and the Director of the Psychiatric Mental Health Nurse Practitioner Program at UT Austin. And finally, Ray Love, Professor and Vice Chair of the University of Maryland School of Pharmacy. Here are our disclosure slides. Learning objectives for today, we're going to talk about the hypothesized mechanisms, risk factors, and team-based strategies for severe neutropenia due to clozapine. We're going to talk a little bit about a REM system, and we're going to review examples of REMs used for medication commonly used in psychiatry. And then finally, and most importantly, we're going to summarize the changes for prescribers and pharmacists with the changes to clozapine REMs. Next slide. Okay, so about an agenda for today's webinar. First, we're going to hear from Dr. Meyer about clozapine and neutropenia. We're going to hear from him also about benign ethic neutropenia. Then Dr. Rowland and I are going to summarize the changes for prescribers and the new clozapine REMs. Dr. Love is going to summarize the change for pharmacists, and then we're going to leave a lot of room for question and answer because we suspect that people may have many questions about this. Next slide. All right, I'll turn it over to Dr. Meyer. Hi, everybody. So one thing, the objectives really focused on severe neutropenia, but we actually felt that maybe more practically for most people is managing a more common issue of benign ethic neutropenia. So I'm sorry those two don't line up, but I think this will prove much more helpful to you in routine clinical management because people with severe neutropenia usually just go to the hospital. The question is, do we give them neupogen? So go ahead to the next slide, please. So here's the objectives for what we'll really be hearing. And I do want to encourage everybody to download the handout. There's some tables here, which I'm not going to read in detail, but I included them in my slide section just so you'll have them for reference. And to be honest, I think a lot of you will be not so happy with the next two sections, not because of the presenters who are wonderful, but because of a lot of the frustration all of us have with this new system. But I do want to say this before the complaining starts, that we are very fortunate with all the issues with REMS to still have the most modern prescribing guidelines for clozapine worldwide. And we'll talk about that in the next section. So we can go to the next slide and right after that. One thing, BEN has been recognized in other places in the world for a number of years. In fact, in Europe, they've had warnings in their package insert and some form of a modification well before we instituted ours in the middle of the last decade. So here's the warning. This is right out of the package insert. I'm not going to read it, but I will focus on the very last bullet. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN or BEN. And I think may is important. You can often diagnose BEN just based on clinical criteria and a healthy person of the appropriate heritage with no other causes for it. But there may be times where you need to do testing. We'll talk about which testing to do. And rarely do you need a hematologist unless for some reason it's mandated in your local health care system. It's not common to actually require that level of expertise. Next slide. This is the BEN chart for the U.S. And I mentioned before, whatever frustration we may have with RAMS, we are very fortunate that our monitoring guidelines are so simple and so clean. If you look at monitoring guidelines in other parts of the world, like the U.K., they still include total white counts. They still include looking at platelets sometimes in addition to neutrophils. They still have a minimum threshold for the general population of 2,000. Ours is 1,500. Many ways we're very fortunate. Yes, the new changes will bring lots of consternation and we're going to have lots of time for everyone to vent their anger. Again, we're just the messengers here. But this is great. Very simple, very clean. The only difference between BEN and other individuals for monitoring is that the initial threshold is 1,000 instead of 1,500. Then they have one step below, which is called BEN neutropenia. Below 500, it's severe no matter who you are, and everyone's going to have treatment stopped. And we go to the next slide, we can see that. This is BEN severe neutropenia. It doesn't matter if you're BEN or you're not BEN. If you're below 500, you got a problem, and you're probably going to go to the clean room for a little visit, certainly maybe get a shot of neupogen as well. Next slide. This is just a little bit of history of BEN, just because I think it's very interesting. It was not recognized until the 40s. Seemingly, we've had people of African descent for a long time during which we've had laboratory medicine, but it was not picked up or at least not described in the literature until 1941. And even then, it wasn't pursued for another quarter of a century until 1966, when we got really one of the only articles to actually discuss it and the implication. And the implication was these people are otherwise healthy. It says they're actually normal. They just have norms, which are not the same as the other norms in the laboratory, which were normed, of course, on white people. And here's our modern definition of BEN. Recurrent ANC, less than 1,500, in the absence of other secondary costs. And that'll be the hang-up sometimes when we see people who we think have BEN and we're saying, well, there might be a secondary cause. It's rarely anything other than medications. Everyone gets screened in most hospitals for HIV, if there's any suspicion of it. An interesting point is that you can have BEN and still be above 1,500 at times, because there's a range for all human beings. You fluctuate. Depends on the time of day. Depends on whether you've exercised. You can boost your neutrophil count just by exercising. It's transient, but the idea is that there is a range. There are people, though, who actually live between 500 and 1,000. And sometimes that freaks folks out. Like, well, this guy's neutrophil count is 800. He's going to die. Like, well, he's had this neutrophil count for probably 35 years, and he hasn't died yet. It's a benign condition, but there are some people who live even below 1,000. It's just part of BEN. You don't see it a lot, but it's important to recognize that this can be part of BEN. Again, assuming you've eliminated other causes. And next slide. So who gets this? Well, it comes from a certain part of the world. The strongest association is being from Africa, but adjacent populations also have it for some reason. A lot of Yemenite Jews have it in certain Arabic populations as well. It's not race that makes the diagnosis. It will be, in fact, genetics. Now, genetic testing is not always necessary. We'll talk about whether you ever need it, but it's clear that there is a single nucleotide polymorphism, which gives rise to this phenotype of benign ethnic neutropenia. These people are not at increased risk for infection. They have normal bone marrow morphology. Their leukocyte counts otherwise for other cell lines are normal. And one thing that's been proven by the folks at Maryland, including Dr. Love and D. Kelly, is that people with BEN are at lower risk for actually developing severe neutropenia during clozapine treatment. So people wonder, well, his baseline neutrophil counts 1,000. Isn't he going to have severe neutropenia? No, he's probably at lower risk. There may be other factors which are associated with severe neutropenia risk, which are more prevalent in the white northern European population. Next slide. This is an associational graph showing the association between the self-identified race and what we see based upon genotype and really phenotype as well. Because most of the time, you're not going to order the genetics. You're going to order the red cell antigen testing, and I'll tell you how to do that. And this is what the report will look like. You can see about two-thirds of the people who self-identify in this U.S. sample as African American had the minus-minus phenotype, really, and they had low neutrophil counts. Once one of those were positive, then you are phenotypically normal. In order to have BEN, you actually have to be minus-minus or null-null, depending on the nomenclature. And once you have a change in one of those and you're expressing one of those antigens, that means you no longer have the association. And it's not surprising. The U.S. is a melting pot. Many people self-identify with a certain heritage, but they may have ancestors from all parts of the globe, regardless of how they self-identify. Next. What the antigen is that you're going to look for when you order testing is called the Duffy blood group antigen. Everyone's familiar with ABO. There's all sorts of other markers on red cells which are expressed, which are more or less significant, really, to the hematologists that have to do with transfusion reactions and other things, which I'm not going to get into. But this is one which has been known since the 50s. Just like the ABO major system, this is just another antigen. For whatever reason, they couldn't think of another system besides A and B. So it's just the same thing. Either you express A or you express B or you express neither. And if you express neither, you're called minus minus or null null. Very common among people. If you go to Africa, 88 to 100 percent of black Africans. But in the U.S., as I showed you before, it's about two-thirds due to admixture. They figured out what the antigens were in the 60s. And then in the 2000s, they found the single nucleotide polymorphism. This SNP is actually being studied mostly to see if there's a real easy test that can be ordered for the future when people want to do testing, as opposed to having to do red cell antigen testing, which is actually fine. But maybe if we have a simpler and a more specific test with this one SNP, 2814778, that'll give us the exact thing we need. And not surprisingly, you think, well, what's the evolutionary advantage of this? If you are minus minus, you are less likely to be infected by Plasmodia vivax and no less. Again, you don't get malaria of those types if you're minus minus because they use those antigens to hook onto the red cells. Next slide. How do you diagnose it? For those of you who don't know what I do, in addition to be affiliated with UC San Diego, I'm a psychopharm consultant to the state hospital system in California. I am just a humble clinician working in the state hospital. It just happens to be a state hospital system which has 6,700 people in it, of which at any one time we probably have roughly 800 people on Clozapine. Much of the time, we don't need a diagnosis from a hematologist or even a blood test to tell us this person has BEM. The common scenario is that we have a healthy person who gets admitted to our state hospital, which is predominantly forensic. They come usually from jail on no medications and their neutrophil count is low. Of course, we've screened them for HIV and they're otherwise healthy. What else could it possibly be? There's literally no other possibility. Yes, we'll order another CBC just to confirm it, but it's pretty clear this individual has BEM. We will encode the diagnosis on the chart in case they ever need Clozapine just so people realize it when they're giving them other medications. The reason it's important to note this in the chart and give them the diagnosis is that all antipsychotics have a class warning about Leukopenia and Neutropenia going back more than a decade, maybe even 13 years. Yes, we only monitor people on Clozapine for Neutropenia, but there are case reports that FDA gets for all antipsychotics. Most of them are exceedingly rare. Maybe Quetiapine, Olanzapine, and the old drug Chlorpromazine have a bit more. It's not common with any of these by any stretch of the imagination. I've been consulting to the state hospital system in California almost a dozen years and I've literally encountered one case of an antipsychotic-related Neutropenia other than Clozapine. But this does complicate the diagnosis. Let's say this individual comes from jail. She self-identifies as having a heritage which is associated with BEM and she's on Risperidone. Well, could Risperidone cause it? Yeah, I'm sure there's a case out there. There's probably a couple, but it's really rare. On the other hand, you can't say absolutely it's not due to the Risperidone. Sometimes we'll suggest, hey, do you mind switching your antipsychotic for a month, see if your white count changes? If the patient says yes, that's fine. If her white count's still low, we know she has BEM. If she says, no, I'd rather stick with the Risperidone, it's working well, then we'll just go ahead and order the appropriate testing, which we'll discuss in a second. The biggest offender by far and away for Neutropenia though, in case you did not know it, is Divalprox. Everybody knows, or most people know, it causes Thrombocytopenia, but it's in a serum-level dependent manner. It causes Neutropenia. And we get these consultations all the time in the state hospital. They want to put this gentleman on Clozapine and they're wondering why his Neutrophil count's low. And they're often perplexed because he's white too. It's like, why does this white guy have benign ethnic Neutropenia? We don't think that's it. Yeah, we think it's the Divalprox. And then like 99% of the time, it's the Divalprox, it's not the antipsychotics, it's not the other medicines, it's the Divalprox. And that's important because there's often an option to not being on Divalprox. If you have mood stabilization needs and your renal function is adequate, you could be on Lithium and maybe somebody put them on it prophylactically for a seizure, which they've never had and possibly they don't need at all. Next slide. The question then is, okay, look, I have a person, I think they have been, we don't want to mess with their meds. They came in on meds. It's possible it could be the meds. We're skeptical, but we figure we'll just get the confirmatory test. What is the easiest thing to do? The test you should order is called red blood cell antigen testing, but specifically you have to say for the Duffy antigen. We just had a case where we told the provider to order this and they didn't specify Duffy and it got kicked back from the lab like, well, which antigen do you want us to test it for? And it just delayed the patient getting on Clozapine. Specify that it's for the Duffy antigen. If you're not sure how to code it and just ask the lab, they'll know what to do because they get these from time to time. Very, very rarely do you actually have to get the genetic testing. Now that may be changed if we have rapid point of care testing for this SNP, and then this discussion will be very different. But if you look at the table down below, this comes from a journal, which I'm sure most of you subscribe to, the Hematology, Transfusion and Cell Therapy Journal. If you didn't look at the issue from November of last year, I suggest you take it out of the plastic. This is a great study because it came from Brazil. Large proportion of people with African heritage, they see Ben all the time. Their infrastructure is like ours. You order genetic testing, it's going to take a long time, but they can do the red cell antigen testing fairly quickly in most major hospitals. You can see the accuracy of the antigen testing is almost exactly the same as it is for genotyping. There are some weird other rare genotypes, which I'm not going to get into, but antigen testing is fine. It's efficient. It's all you need to do. If you get something that just doesn't make sense, then maybe you will order the genetic testing. I have never seen this, but you might get a patient who comes back, say, look, this gentleman self-identifies as African descent. As far as we can tell, this is correct. We think he has been, he had low neutrophil count on no medications, but we just wanted to get the antigen testing. It came back as FYA minus B plus. Well, what is this? This doesn't make sense. He should be minus minus. There are some people who have weak B antigen expressing, so the antigen testing may come up with a weakly positive B, which they report as positive, but they really do have been the antigen testing. I've never seen this, but there you go. You've heard about it. If you ever need to order the test, this is the test you would order. Next slide. Lastly, we're going to talk about what happens when people dip below their thresholds, which then necessitate additional monitoring. If we go to the next slide, this has not been specific. These are situations which can happen to everybody. Of course, it's a pain in the neck. If you have a non-BEN patient who goes below 1,500, or if you have a BEN patient who goes below 1,000, they have to be monitored three times a week. It's a whole nuisance. What can you do to possibly prevent it? Well, the biggest thing, of course, is trying to get rid of offending agents with valproic acid being far and away the biggest problem we see. We have patients who are on clozapine, and there's people out there who, unfortunately, still use valproate prophylactically for seizures, even though the rates of seizures, even above 600 milligrams, are well under 2%. They started unnecessarily. The patient never had a seizure, and they're running into trouble with the neutrophil count. We ask them to taper it off. Occasionally, it could be another antipsychotic too, but it's really, really uncommon. But if we feel like they are on the second antipsychotic, and it might play a role, we'll see if we can switch it to a different agent just to see if it makes a difference. If it doesn't make a difference, then what we do is look at agents to boost the neutrophil count of lithium is the easiest to use. When I trained a long time ago, people said, oh, lithium just causes margination of polys. That's not true. It actually causes you to make more neutrophils. It directly stimulates the production of colony stimulating factor within the therapeutic range. The only contraindication is you're not a candidate for lithium. Sometimes even that's not enough. And then we'll go to the big guns, which is neupogen or filgrastim. Very safe. I gave you some guidelines about when to use it, how often you use it will be quite individually dependent depending on really their response to a single dose and how durable that is. But you should know about these things because we want to keep people on Clozapine who are on it. And certainly if your patient is below the threshold for starting Clozapine, these might be strategies to get them up to the threshold. So I'm going to stop talking right here. Thank you all very much. I'm going to pass the baton on to the next person. Great. Thanks so much, Dr. Meyer. Before we get into the changes that are occurring effective November 15th, what I want to do is just briefly talk about the changes that occurred in 2015 that really helped to monitor. It really helped to modernize our monitoring system for Clozapine into really one of the most, one of the best in the world. So first, one of the big changes in 2015 was that the six registries that were previously kept by the manufacturers of Clozapine were then combined into one shared REM system, which is what we use now. And then the second change was about the hematologic monitoring itself. And instead of looking at the white blood cell count and absolute neutrophil count, we can now just use the ANCs. The threshold for starting Clozapine was lower using the ANC. And then there was the benign ethic neutropenia algorithm that was introduced in 2015. And all of this actually made a difference clinically. And there was a study done by Ryan Soltan and colleagues that suggested from a VA sample that the new guidelines actually increased the number of people who could take Clozapine without an interruption. So with that in mind, I'll turn things over to Dr. Rowland, who will discuss the changes for prescribers. Thank you, Dr. Cortes, for that perspective on the REM system history. I think it's important for us to remember. Now I'll walk everyone through in detail all of the information that we do have available so far regarding what prescribers must do in order to transition to the new system. Next. First of all, prescribers must recertify with this new REM system. And the new REM system will be the only official one beginning November 15th. So when you do register, you may add designees at that time if you wish, or you can return later to do that. Once you get registered as a clinician, all of your patients must also get enrolled. And finally, there is a new monthly patient status form. This is required for each patient to keep them current in the new system. And we'll review these steps in detail next. And you'll see at the bottom of this slide, there's a URL where you can find the main source document. Next. First, there's a transitional URL to use, newclozapineREMS.com slash home. On November 15th, or shortly thereafter, the usual URL that you also see on the slide will host the new REM system. In order to complete prescriber recertification, you must have the following identifiers. NPI, which will become your login user ID, and DEA is next. You can see why this might be problematic. A DEA number is not required to prescribe clozapine as it is not a DEA controlled substance. Residents, for example, who don't yet have a DEA number can't currently register with the new REM system. We're told, however, that REMS will be making this field optional in the near future. You'll also need a unique email address. This is required per site. And this could be problematic for clinicians who work in multiple sites where clozapine is prescribed. And the last step for prescriber recertification is taking the knowledge assessment test. This is composed of 12 questions. It should say 12. Your handout may say 13, but that's a typo. These questions are essentially the same that were required for the old REM certification. And all of the knowledge assessment content for prescribers is included in a downloadable document called Clozapine and Risk of Neutropenia Guide for Healthcare Providers. This is available on the new site. Most of the content also in these questions is covered in our webinar slides today, such as some details about BEN, required ANC ranges, clozapine dispensing procedures, etc. We may also have some time during the Q&A to review some of this content if that's helpful. Next. This slide details the process for adding prescriber designees, including office personnel, RNs, etc. Once a clinician enters their identifiers that you can see here, clinicians should send an invite through the new REM system to each designee to finalize a process. Designees can be very helpful, especially during this transition period. They can enroll patients into your account. They can also submit the monthly patient status form on behalf of the prescriber. Next. Unfortunately, each patient must be enrolled individually. There is no mechanism by which we can submit bulk data. The required patient identifiers are listed here. Note that race and ethnicity is required. Also, you must enter a baseline recent ANC result in microliter units with the date. And lastly, you'll know whether they should be flagged with BEN or in-hospice designations. Next. This is all the information that you need to complete the new monthly patient status form. You'll see this section. Prescriber must authorize continuation of therapy if one or more ANC results are missing for the month. It is unclear how tightly this will be followed or whether certain pharmacies will be stricter than others with late ANCs, probably really similar to how things are now. This patient status form essentially replaces the ANC lab reporting form. Next. Okay. Again, this patient status form is required monthly. There seems to be an option to authorize continued clozapine therapy with missing ANC results. This form will also be used for treatment interruptions, for designating a patient with BEN or on-hospice status, and for including a treatment rationale when the ANC is below the required range, indicating mild, moderate, or severe neutropenia. Next. This is what the top of this patient status form looks like. And the PSF is available at the site newclozapinerims.com now. Here you can see the patient information required that we have gone over. Next. This is an example of the PSF that would be submitted for a patient requiring monitoring every two weeks. You'll notice that the lab information is entered along with any reasons for missing labs. The prescriber must sign this form in cases of continuing therapy with a missing ANC or for treatment interruptions. And the treatment rationale and signature is also required at the bottom if the ANC is below the required range. Next. Options for submitting the PSF are detailed here. Clinicians will log in, select manage patients, and upload the form. This function is not yet enabled. I last checked yesterday. RIMS does tell us, though, that there will be an option to input lab information digitally without a file upload for months subsequent to each patient's first submission. So, that first submission will need to be uploaded. Alternatively, you can fax in the PSF. Please do note that ANC lab result submissions do not replace this required form. Next. Unfortunately, there's currently no plan to transfer data between the old and new RIMS systems. This includes no transfer of designations of do not re-challenge. We recommend at this time that clinicians or their designees review the ANCs in the current system, making note of low ANC results, dates, and treatment interruptions. Again, the new RIMS system will be effective on November 15th. We anticipate that in the interim, especially in November, we may have to do some double entry into both systems to assure that our clozapine is dispensed appropriately to our patients. And with all of that, I'll now turn it over to Dr. Love for an update for pharmacists. So, Dr. Rowland, thank you very much. In the next few minutes, what I'm going to do is discuss some of the changes in the RIMS that relate to pharmacy. However, many of them are going to be important for other members of the team to understand so that you can be aware when there are complexities that occur when patients are trying to get their prescriptions filled. Next slide. So, just as prescribers need to re-enroll and patients need to re-enroll, pharmacies need to re-enroll in order to continue to dispense clozapine when this new system goes into effect in November. And I would hope that all prescribers of clozapine have some relationships with pharmacies in their area that they use for their clozapine patients. And if they do, it's worth making sure that they go ahead and re-certify. Some pharmacies are not aware that this new system will be in effect. We'll talk in a few minutes about the registration process for inpatient and outpatient pharmacies. There are, if you work in a hospital setting, there is a different set of policies, procedures, and a different registration process that occurs for inpatient pharmacies versus outpatient pharmacies. And just like the new guide for healthcare providers, there's also a separate guide for pharmacists, which goes into some issues in the dispensing process. Next slide. So, when clozapine first came out, we had a system where the pharmacist actually looked at the white blood cell count. Then we kind of emerged into a system where the pharmacist could see most recent white blood cell counts. And the current REMS uses what's called a pre-dispense authorization. And this has changed now to something new called a REMS dispense authorization. So, each time the pharmacist is going to dispense clozapine, they've got to either call or go online to get this REMS dispense authorization. So, it's kind of a separate process. Now, there are some important things that take place. This process does verify that the pharmacy is certified, that the patient is enrolled, and that the patient's treatment is not in a interrupted or discontinued phase. So, this is kind of a safeguard to make sure that patients who shouldn't be getting clozapine don't get clozapine even with a current prescription. So, there's an initial RDA that the pharmacist has to obtain. And then after that, each time the pharmacist attempts to fill the prescription, there's a new RDA they have to obtain. And that RDA also makes sure that that patient's status form that Dr. Rowland talked about is current. And the definition of current is that it's completed within the last 37 days. The pharmacists obtain the RDA by going to the Clozapine REMS website or by calling the Clozapine REMS contact center. Now, it's important to note that this Clozapine REMS contact center number is different than what you may have for the current number for Clozapine REMS. So, if you've had occasion to call Clozapine REMS and ask a question in the past, this is a new number for the new REMS. And the fax number that you'll obtain is also new. So that when you're submitting paperwork, you're going to have to deal with new telephone numbers. If you have those programmed into your phone or fax system, they'll need to be changed in November. And there used to be a switch system where pharmacists could obtain the pre-dispense authorization. That has all gone away in the new system. Next slide. So, this is something that is of particular interest. The pharmacist actually can override the system if it says not to dispense it. And in the old system, a pharmacist could do that three times for a given patient in a six-month period. In the new system, they can only do it three times per year on an outpatient basis. In an inpatient environment, it's assumed that the pharmacist has access to the patient's laboratory data and is in closer contact with the treatment team. And therefore, there is no limit on this override. However, if the pharmacist is going to do this, they need to have an ANC that's less than 30 days old. And they also need the prescriber's NPI number. And with these two things, they can override it in case the PSF gets lost when it gets faxed in or there's another issue. Next slide, please. Pharmacy training has also changed. It used to be that all the pharmacy staff had to be certified in the system. Now, it's the pharmacy itself that's certified. And this is often done by owners or in the case of a chain pharmacy, a corporate representative. And in the new system, they don't have to keep recertifying, which is kind of nice from the pharmacy point of view. But there's another point about certification that's important. And this is why, if you have pharmacies that you regularly deal with, you should have a conversation with them. And that is that the REMS program is working with the wholesalers from which pharmacies buy drugs. You may have heard of the McKessons or the Cardinals of the world. But those big corporations are being encouraged to not sell Clozapine to any pharmacy that is not certified. So, this is just another reason why pharmacies need to get certified and why you need to make sure that pharmacies that serve your patients are certified. Next slide. So, some of the other important changes. Again, this is a reminder that the old national non-rechallenge master list, what we call the do not rechallenge list, is disappearing. And that there are no lab values that will be retained from the old system. So, that when you start your patients, it's important that you get the best information you can historically from the medical records you have available from family members, because we won't have this safety net. And of course, this is a bit unfortunate because this actually started when Clozapine was approved before the advent of any REMS systems. Other important changes, we talked about the changes in the telephone number and the fax number. The designee system that Dr. Rowland talked about has also changed. It used to be that you could have your nurse or the pharmacist that you worked with or a medical clerk go into the system and it would alert you that someone wanted to be your designee and you could approve them. So, that system is now gone. And as Dr. Rowland pointed out, you now need to actively enroll any designees that you have, including pharmacies. Next slide. So, what hasn't changed is the knowledge assessment really hasn't changed. There are some changes to the language in one of the questions for pharmacists about all the things that you need to do to dispense to encompass this RDA. But otherwise, the questions still are quite similar. Next slide. So, one thing that's important, if a patient is admitted to an inpatient facility and is already enrolled in the program, is already on Clozapine and registered in the REMS, there is no need to re-register the patient just because they're now an inpatient. However, if they're going to be started on Clozapine while they are an inpatient, then that patient enrollment process will need to take place. Again, that can be the prescriber. It can be the designee. If you make the inpatient pharmacy a designee, they can do that. If the patient is a BENS patient, however, it will need to be the prescriber that does that. Next slide. One of the things that is nice about the new system is they are putting together a feature where you can find pharmacies that are already enrolled and certified. Now, there was a previous certification lookup feature, but you needed all sorts of numbers on the pharmacy like their DEA number or their National Council of Prescription Drugs number. You don't need that now. You can do this geographically, and I understand that there's a hope that this will be made available even to patients. Next slide. So, that concludes the first part of our presentation, and we thank you, and we'll now turn it over to the moderators. Thank you so much, Dr. Love and everybody else. Before we shift into the Q&A, I want to take a moment and let you know that SMI Advisor is accessible from your mobile device. Use the SMI Advisor app to access resources, education, and upcoming events, complete mental health rating scales, and even submit questions directly to our team of SMI experts. Download the app now at smiadvisor.org slash app. All right, and now we'll go to the Q&A section. We've got a number of great questions from the audience. Let's go ahead and dive right into it. This is a question for, let's see, Dr. Love. Can you clarify RDA for inpatient pharmacies? We are working with a psychiatric state hospital with inpatient dispensing and outpatient discharge prescriptions. I was advised to register the pharmacy as an outpatient pharmacy so that I'm not sure how we can obtain an RDA prior to dispensing. Okay, I'd be glad to take that. So, the RDA, well, first of all, I would encourage the hospital to register twice, once as an inpatient facility and once as an outpatient facility. The reason for that is if they're dispensing to outpatients, they will need to be registered as an outpatient facility because when a pharmacy fills an outpatient prescription, they can only fill seven days' supply of clozapine according to the provisions of the new REM. So, if you have a patient who's getting a two-week supply or a four-week supply, you would need to do that through an outpatient pharmacy. So, they should register twice. The reason they should register also as an inpatient pharmacy is because that RDA only needs to be obtained once. That is, the first time that clozapine is dispensed as an inpatient, they'll need to get an RDA and keep that on file, but they won't need to for the remainder of the patient's stay. So, the advantage of having an inpatient registration is that you don't need to keep getting those RDAs. The advantage of having an outpatient registration is that you'll be able to give your patient a larger supply eventually. So, I would recommend that you do both. All right. Thank you so much. Next question is about, how do you actually obtain Duffy antigen testing? And the question from the audience was, does a place like Quest or LabCorp do this? And the answer is, I know that LabCorp does have this service available. For our lab, where I work at Grady Hospital, I actually have to call the blood bank in order to get the Duffy antigen testing and order a type and screen, and then call the blood bank and say, give us the Duffy antigen testing instead of having it just go through hematology. So, these, to my knowledge, they are available at LabCorp and other sort of places like that. Yeah. If I could add to that, I think what Dr. Kote says is important is that if it's unclear when you're ordering, you're not sure, call whoever it is who's going to process your labs or the Quest or whatever, or virtual local community hospital, just so they know what exactly you're asking for, because you don't need all the red cell antigens. You just need the Duffy antigen, and you don't need other things, which might be done with a blood bank specimen or some other testing, which is unclear. Once you've done it the first time, then you'll exactly know how to do it. But if you're not sure, just call the lab and they'll tell you how to order it. Okay. Thank you, Dr. Myer. This is also in regards to the Duffy antigen. How do Duffy antigens physiologically relate to benign nethic neutropenia? It's not the antigens itself. What happens is that when you have this single nucleotide polymorphism, which is actually in the promoter region of gene, which is controlling the presentation of the antigens, having this polymorphism essentially prevents you from forming normal A and B Duffy antigens. And so you just don't have those on the surface of your red blood cell. And that's why you just don't see them when you do the phenotyping or the antigen testing. So it really just relates to a feature that for some reason, we see lower circular neutrophil counts. Now how that happens, which is I think it's just your question. We're not entirely sure. All we can say is the association with this single nucleotide polymorphism is robust, but the exact molecular mechanism why there are fewer circulating neutrophils, I'm not sure is entirely known, or at least it's not known to me. That's probably a better statement. Okay. Thank you, Dr. Myer. Next question is when should providers or prescribers start to re-enroll in this process? Maybe to Donna. Sure. The system is open for prescriber enrolling now. So I went ahead and did that several weeks ago and it was fairly simple. I mean, it just takes a little bit of time, but you can go ahead and get in there now and add yourself and you can also already add designees. I already added a couple of designees to my account. The only thing you can't do that's not functional yet is upload the patient status forms. All right. Thank you so much, Dr. Roland. Next is a question about designees. This question is I have heard a rumor that each designee can only be attached to one prescriber. I'm hopeful that that's not true. If so, any suggestions how to handle this? In this person's agency's primary medication clinic, there are fewer nurses than psychiatrists as most of the psychiatrists are part-time. This one may be to the group. I'll take that, Dr. Cortez. Originally, that was the way it seemed to be that you could only be a designee for one prescriber. We have not tested this yet, but in conversations with the REMS, we have been told that by the time this rolls out in November, one prescriber may have many designees and one designee or one individual may be the designee for multiple prescribers. So they understand the need for that. It was not operational early, but that is supposedly changing. Thank you so much. Actually, a number of people had that concern. Let's see. Another question is, you know, if the group could kind of wave a magic wand and get the FDA to do anything regarding the new REMS system, what kind of things would be on the wish list? Well, I think part of it is a lot of this is not going to happen. So it does become an exercise and futility to think about this. But I think one thing is that we really wish there would be access to the old database, even if it was kept in a parallel system and even if it was a little clunky getting to it. But having all that old ANC data, I think would just be really helpful as people move forward. We're going to get somebody who said I was on it and they stopped it. And you don't have the medical records. It'd be nice to have that. I'll mention one more thing or maybe two more things. A number of organizations, including the Psychiatric Pharmacists and APA and the Psychiatric Nurses and NAMI and the State Mental Health Program Directors and the American Pharmacists Association. I'm sure I'm missing some other national council, have all written the FDA and a group called the Clozapine Product Manufacturers Group, CPMG. They're the actual ones that administer the REMS and ask for changes. Maybe the first change we'd like to see is a delay in the implementation date. Dr. Rowland talked about this patient status form has to be done every 37 days at the least. And if you look at November 15th, 37 days is December 22nd. That means if something breaks down and a form isn't submitted, we're going to be in the middle of the winter holiday season. So I would like to see things be delayed or at least the dispense authorizations not be enforced until that time. So that's one thing that all of these organizations have requested. Another thing I think that we'd like to see is looking at how long do we have to do ANC monitoring. And Jonathan can speak to this better than I can. But we know that there is a period of increased vulnerability where we see neutropenia early on. But the question is, after six months or a year, should the patient then be able to opt out of the system? So that's still another issue where I'd like to see some changes eventually. And in conversations with the FDA and less with CPMG, more with the FDA, I think they are interested in looking at that eventually. So those are some changes I'd like to see. And if I could add a thought, we certainly know, even from the early 90s, that the rates, once you get past six months, drop precipitously and certainly after a year. They're not zero, but they approach zero. The hard part, of course, is the manufacturers being risk-averse and worry about litigation, may feel that this is protective, even though it's not evidence-based. And that's some of the difficulty you may have because, to some extent, they set the rules in many ways for what they want in terms of monitoring. I'm not saying they're impervious to feedback. But one way it might be around this, because the old database won't be destroyed, it will still exist, would be a reanalysis looking at late-onset neutropenia cases so we can come up with a base rate and really make an argument about whether, in fact, there is any rationale in monitoring people beyond a certain time point and whatever the data shows it shows. And it's a hope. We'll see if we can get access to the data. Clearly, analyses have been done with this data previously, which allowed us to get to these new lower thresholds. It's certainly possible. It just may not be possible in the near future. Great points, everyone. Another question that came up, and I've never understood this either, but for an inpatient, can maybe Dr. Love speak a little bit to the idea of the pharmacy only being able to dispense seven days of clozapine post-discharge? And I assume this is someone who perhaps has been on monthly monitoring or something before. That is a great question, Dr. Kotez, and I don't know the answer to it. It's interesting. The only place that appears that we can find it is in the pharmacy enrollment form for inpatients. And we do not have a rationale for why clozapine REMS put that in there. It makes no sense to me either. If you have a patient that's only being monitored every four weeks, why are you going to restrict them to a one-week supply of medication? Certainly, to me, that's risking an interruption in treatment. And we also know that when patients are discharged sometimes, and certainly in my experience often, it takes longer than that for them to get a follow-up appointment. So I don't understand the rationale for that. Yeah, I think that's a great point. It's often a big challenge in that inpatient to outpatient transition. You know, as a person who runs an outpatient clozapine clinic, when people are discharged from the hospital, it really is sort of a race against time to get them in. And sometimes, you know, people need to be seen on a weekly basis. They're on weekly monitoring. So it's very challenging to try and predict, you know, how much staffing you actually need in order to sort of work with new people who are discharged on clozapine. One final question for the group is a little bit about, you know, the changes that the FDA made during the COVID-19 pandemic, essentially about not, you know, not going after clinicians who aren't updating the blood work. If people have had, you know, consistent absolute neutrophil counts, non-neutropenia, but the risk sort of going to get blood work may be greater than not getting blood work due to the pandemic. And I'm curious if anybody has any ideas about what the new clozapine REMS kind of philosophy will be about COVID. I'll venture a comment, but not a guess. And that is, I don't think that they have gotten that far yet. If there were to be, you know, a new variant that posed danger again, I would bet they would look to the FDA for guidance rather than making that decision themselves, because the FDA is the one that determines the need for REMS. In the case of clozapine, it's the CPMG that determines how the REMS will be implemented, them and their vendor. In this case, Sineos Health, I believe, is the vendor. So I think that's going to be more of a question for the FDA than the REMS as to what they would do if severe pandemic circumstances and shutdowns emerged again. On kind of a side note, you asked a risk benefit question, and we pose the same risk benefit, all of the organizations, to the FDA. And that is, is the risk of not treating people with clozapine, which can be a potentially lifesaving medication, worth the risks of the drug not being used because of the monitoring requirements? And I think that's a question that's still up for debate. All right. Thank you, Dr. Love. Excellent point. So we'll see what happens. And I just wanted to thank all the panelists. And we'll go ahead and wrap up now. So if you have any follow-up questions about this or any topic related to evidence-based care for SMI, our clinical experts are now available for online consultations. Any mental health clinician can submit a question, receive a response from one of our SMI experts. Consultations are free and confidential. Next slide. SMI Advisor is proud to partner with the American Psychiatric Association on the Mental Health Services Conference, which takes place on October 14th to 15th. The keynote address of this conference features Miriam Delfin-Rittman, the newly appointed Assistant Secretary of Mental Health and Substance Use for HHS and administrator of SAMHSA. The conference agenda features topics like climate change and mental health, sociopolitical determinants, structural racism, mental health in rural and indigenous populations, and much more. I encourage you to check it out and register at psychiatry.org slash MHSC. To claim credit for participating in today's webinar, you'll need to have met the requisite attendance threshold for your profession. Verification of attendance may take up to five minutes. You'll then be able to select next to advance and complete the program evaluation before claiming your credit. Join us for a follow-up conversation next Wednesday, October 6th for SMI Advisor's Clozapine and LAI Virtual Forum. Bring your ideas, questions, and concerns about the November 15th changes to Clozapine REMS and discuss with national Clozapine experts. To join, click on the link in the chat and download the calendar invitation. And finally, please join us tomorrow on September 30th as Dr. Lisa Rossano and Brandon Hill present Inclusive Evidence-Based Practice in Gender Non-Binary Mental Health Services. Again, this free webinar will be September 30th, 2021 from 3 to 4 p.m. Eastern time. So thank you again for joining us and until next time, take care.

webinar

Clozapine REMS

changes

re-enrollment process

prescriber recertification

patient enrollment

monthly patient status form

REMS dispense authorizations

limitations on overrides

challenges