Hello, and welcome. I'm Amy Cohen, Associate Director for SMI Advisor and a Clinical Psychologist. I am pleased that you are joining us for today's SMI Advisor webinar, Strategies for Successful Use of Clozapine, a Practical Guide. Now, I'd like to introduce you to the faculty for today's webinar, Dr. Yvonne Yang. Dr. Yang is an Assistant Professor and Associate Program Director of Residency Education at the UCLA Semmel Institute for Neuroscience and Human Behavior. Since 2016, Dr. Yang has been the Director of the Psychosis Clinic and Acting Deputy Chief of the Psychosis Section at the West Los Angeles Veterans Affairs Medical Center. Yvonne, thank you for leading today's webinar. Thank you for the introduction, Amy. Thank you so much to SMI Advisor for giving me the opportunity to speak with everybody today, and thanks to everybody who's joining the webinar. So, I have no financial disclosures to report. As an introduction, I just want to say this talk is mainly for prescribers, especially prescribers who've never prescribed clozapine but would like to, and also prescribers who already prescribe clozapine but would like to make their practice either more efficient or just become more comfortable with it, and hopefully so they can prescribe clozapine to more people. However, this talk is also for any mental health care professional who interacts with patients with severe mental illness. And the reason for that is not only does Clozapine REMS, which we'll discuss, allow for prescriber designees, but there are many people involved in the care of patients who can help contribute to the sense that Clozapine is useful to them, discuss risks and benefits, and make it more likely that our patients start Clozapine treatment. So, I think if you're attending this webinar, you don't need to be convinced that Clozapine is our most effective medication for psychosis. However, and you probably are aware that Clozapine is dramatically underused in the United States, so I'm only going to include one slide with a couple statistics. In general, only around two or even one to four percent of patients with schizophrenia receive Clozapine in the United States. Compared to other countries, such as the United Kingdom, one quarter of patients with schizophrenia receive Clozapine. Other countries, including Asian countries and Australia and other European countries, the rate is much higher than that. Now, the estimates in the literature for treatment-resistant schizophrenia range from 25 to 35 percent, so one could easily make the argument that at least 25 to 30 percent of any particular schizophrenia population should be on Clozapine. So, why is it so difficult for patients to receive Clozapine in the United States? The purpose of this talk is to try to make it more available to patients here in the United States through three main learning objectives for you, the listener. First of all, we're going to discuss the initiation, titration, and maintenance treatment with Clozapine. What is the nitty-gritty, the really finite details of treating somebody with Clozapine? Secondly, I want to talk about practical strategies, provide you with some practical strategies to overcome the logistical hurdles associated with prescribing Clozapine. Many, many prescribers find logistical hurdles really intimidating and they pose real barriers to prescribing Clozapine. Lastly, in terms, so let's say you've started a patient on Clozapine, one of the key factors to maintaining Clozapine treatment is making sure that we know how to treat the side effects that arise with Clozapine use, as well as when to, knowing when not to discontinue Clozapine because of a side effect. All right, so in the first of three major sections, I'm going to start by talking about initiation of Clozapine treatment. There are three very small steps to starting Clozapine. First of all, determining the patient's eligibility. This is very straightforward. There is only one criteria for eligibility for Clozapine, and that is to have an ANC greater than 1,500 or greater than 1,000 if somebody has benign ethnic neutropenia. Other SMI Advisor webinars have talked extensively about BEM, so I'm really not going to address it here, except to say that if you're a patient, you draw a CBC and their ANC is between 1,000 and 1,500, and they are of a minority population or of a Middle Eastern descent or Mediterranean descent, you should have a hematology consult and consider the possibility that have BEM. That helps increase access to Clozapine for those populations which historically have been limited in their access to this medication. I really want to emphasize there is no pre-existing condition that's an absolute contraindication to using Clozapine. That includes diabetes, a seizure disorder, obesity, even heart conditions, and I will explain why. The most important thing is that people just be started on Clozapine, and then a lot of those other conditions can be dealt with and worked through during treatment. All right, so what are the baseline checks that are generally recommended for starting Clozapine? Of course, a CBC with differential so the ANC can be determined, and then standard metabolic measures such as lipids, HbA1c, weight, BMI. Now, I include EKG here because it's almost always recommended as being obtained at the starting point of Clozapine treatment. However, we generally don't recommend that it be something that holds up somebody's treatment. What I mean by that is only the CBC is absolutely necessary. All these other measures can be secondary. In the case of patients with known histories of prolonged QTc or heart disease, EKG becomes a higher priority, but in general, only the CBC is absolutely necessary. The third step is simply prescribing Clozapine. It is helpful at that time to set expectations with the patient. And of course, you need to obtain informed consent from your patient, which does mean discussing important side effects, especially things to watch out for when they first start treatment. And we'll go over those when we discuss side effects in the third section. All right. Now, this all being said, if you as a prescriber are not yet registered with Clozapine or your patient's Clozapine REMS or your patient is not yet registered, that step does need to be taken. So, you as the prescriber need to enroll with REMS if not already registered. Of course, REMS is a risk evaluation mitigation system. Here's the website for it. And the patient, the prescriber, and the pharmacy must all be enrolled. Fortunately, all of this can be done online. Many, if not most pharmacies are already enrolled. Furthermore, the pharmacy can enroll your own patient for you. But in general, there does need to be some regular contact between either you or the pharmacy or a designee and REMS in order to report the ANC on a regular basis. Okay. So, let's get a little bit into the nitty gritty of actually using Clozapine. Standard starting doses usually are 12.5 or 25 milligrams daily at night. However, this really should be patient dependent. For instance, patients sensitive to side effects of other medications or who are really anxious about starting Clozapine, especially with respect to side effects, starting as low as 6.25 milligrams is not out of the question. I've actually done this with two different patients and it was successful for us. Similarly, titration is variable and patient dependent. So, I'm going to show you three sort of potential titration schedules and the scenarios in which each one might be used. And as you can see from the citation at the bottom, the full citation will be available at the end of the talk. A lot of this information can be found in a handbook called Treatment-Resistant Schizophrenia edited by Oliver Howes and myself and one of my mentors, Steve Marder. He directs the psychosis clinic at UCLA and I direct the psychosis clinic at the VA here in West Los Angeles, put this together. So, a rapid or often known as inpatient titration is generally thought to be increasing the dose of Clozapine by 25 milligrams a day. 50 milligrams a day would be the very fastest one would ever titrate this medication. If you look up a very standard and easy to find Clozapine titration online by Teva, the standard is increasing by 25 milligrams per day and this achieves a Clozapine dose of approximately 300 milligrams total daily dose by around two weeks. Now, the scenarios in which this is applicable are inpatient because there's so much close monitoring ability to look for side effects, including highly concerning side effects, on an outpatient basis, it really means having a high confidence in that particular patient's ability to manage a complex regimen. It's not really easy to increase a dose by 25 milligrams every day and keep track of that. So, you know, you want your patient to be organized, know how to keep notes, maybe even have the support of family or other staff at wherever facility they live. A more moderate approach would be to increase by 25 milligrams every other day. This pace allows for achieving a total daily dose of about 200 milligrams by the end of 16 days or almost two weeks. This is generally well tolerated by most patients. The advantage of doing this is it's a more manageable pace, which means you don't have is it's a more manageable pace. However, you're still allowing the patient to reach a therapeutic dose and therefore achieve some of the benefits of Clozapine within only a few weeks, which is really important. The most conservative option that I have used and actually use frequently here at the VA is to increase by 25 milligrams PO weekly. Now, this can be problematic in a sort of healthy, better functioning SMI population, as it were, because there are side effects even at low doses, but the benefits of Clozapine may not be experienced very early on. However, in a cognitively impaired population, in a population that has a lot of other medications on board that are likely to increase the risk for side effects, and especially things like sedation or orthostatic hypotension, being cautious is recommended. Another scenario in which this might be recommended is Clozapine re-challenge, and we'll talk about that more again when we talk about side effects in the third section of this talk. How long should a prescriber continue the patient's current antipsychotic while they're titrating Clozapine? Our recommendation is continue it at full dose until Clozapine reaches at least 100 milligrams. However, continuing too much longer than that does increase the risk for cumulative side effects of being on multiple antipsychotics. Lastly, we do recommend, and this is sort of a new recommendation, including the troponin with the CBC, with the weekly CBC for the first eight weeks. This is because this is one of the only ways to be certain that a patient's not suffering from myocarditis, one of the more potentially fatal side effects of Clozapine, and again we'll talk about that more in side effects. All right, so another common question. What dose should I be aiming to get my patient to before we sort of settle there for a little while and wait to see clinical response develop? It's very standard in the literature for a range between 250 to 300 milligrams total daily dose to be regarded as the initial target dose. In general, this roughly corresponds to a Clozapine serum level of 300 to 350. We will again in a few minutes talk more about serum level monitoring. In general, it's not very useful clinically, but this is also regarded as a target serum level at times. Like many other antipsychotics, what we consider a reasonable trial for efficacy is 12 to 16 weeks. But of course, like many other antipsychotics, many patients are going to start to feel better sooner than that within just a couple weeks. On the other hand, some patients may take as long as six months to experience a full benefit of Clozapine. Therefore, we recommend that if there is partial benefit, if there's a partial response to Clozapine in your patient, really to hang on for at least a full six months, even 12 months to see if they continue to improve. That really does happen quite often. And then there's other good news, especially for those who experience a lot of side effects on the medication. Doses as low as 200 or 250 milligrams can be effective once a patient is stabilized. You can back down on the dose just a little bit. So monitoring, in this case, I'm referring specifically to monitoring required by REMS. Most of you probably know this already. The United States REMS requires a weekly CBC for six months. After six months, the CBC plus diff frequency can be reduced to two weeks. And then after a full year of being on Clozapine, that means total cumulative months, including if there is an interruption, the cumulative months of actually being prescribed Clozapine and taking Clozapine, the CBC can be drawn only monthly. In terms of serum level monitoring, as I alluded to earlier, serum levels are highly variable from one individual to another and generally not closely related to dose, at least between individuals. Therefore, clinicians should base decisions about clozapine dosage on clinical response and side effect burden, not serum level. So we're treating the patient, we're not treating the number in this case. However, there are some specific clinical situations in which serum monitoring can be useful. For instance, if your patient is not improving on what seems to be a therapeutic dose of clozapine, drawing a level could help assess whether or not they're taking their medication. And as all of you know, medication compliance rates tend to be much lower than what doctors estimate. And in some cases, when the patient changes their smoking habit or starts or stops another drug with high levels of CYP enzyme activity, it can be helpful to see the impact that it had on the clozapine serum level and help physicians make a decision about what changes they might want to make to the dose. One thing I'll just state, it's probably obvious to most people, of course, the serum level should always be a trough, meaning either immediately pre-dose or at least 6 to 12 hours, preferably 12 hours post-dose. If you see a serum level come back as very high, like above 600 or above 800 or close to 1000, the first thing you should do is check the time that the dose was drawn and make sure it wasn't too, sorry, not the dose, the level was drawn and make sure it wasn't too close to the patient's last dose of the medication. So speaking of smoking, clozapine levels have been found to be decreased by up to 50% in smokers. In general, changing in smoking habits can dramatically affect clozapine levels via induction of CYP1A2 enzyme activity, and that includes not only a decreased number of cigarettes per day, but also changing from smoking cigarettes to the patch, gum, or chewing, and it even includes changing from smoking cigarettes to e-cigarettes. The reason for this is that the hydrocarbon that induces CYP1A2 is not nicotine, it's not, it doesn't have anything to do with nicotine, it's actually found in the cigarette itself, in cigarette smoke. So if a patient's intake of nicotine switches away from cigarettes to any other form that doesn't involve cigarettes or cigarette paper, they're likely to have a bump in their clozapine level, and therefore a change such as those mentioned here warrants reduction of clozapine in order to avoid toxic serum levels. Okay, so the second of three major sections, I'd like to address some specific logistical hurdles associated with clozapine and provide you with five strategies for success to help you create your own prescriber clozapine infrastructure to help facilitate getting medication to your patients. I think certainly myself and certainly in the literature and probably many if not most of you from personal experience find the logistical hurdles intimidating, maybe a hassle, certainly time-consuming, at times frustrating, so I want to try to provide you with some tools to help with that. I'm going to start by showing a basic diagram of coordination of clozapine care. There are five components, five entities involved in clozapine prescribing. Since this talk is directed towards prescribers, we'll put prescribers sort of at the center of the discussion. Of course your interaction with your patient is key. The laboratory is going to have to do regular lab draws for the patient. The patient is going to have to go to the laboratory every week for the first six months. This is a big commitment and involves communication between the prescriber and the laboratory. Similarly, the prescriber is going to have to communicate to the pharmacy when, how much clozapine coordinated titration, and of course the patient's going to have to receive medication on a weekly basis from the pharmacy for the first six months. Finally, the fifth entity is REMS. There's a reporting requirement and of course the prescriber, patient, and pharmacy all need to be registered with REMS at the beginning. So let's start with strategy for success. For success one, the laboratory. You, the prescriber, do not need to have a database of all the labs. In my case, for instance, in Southern California. Ask your patient what lab they already use. They almost certainly have a laboratory they already use because they need to get blood drawn for their primary care physician appointments. Great news for clinician, you do not need to write a CBC lab draw order every week for the lab. Most laboratories, if not all, accept standing weekly orders that can be standing for six months or 12 months or just ongoing. Perhaps the most important and key tip here is to have the laboratory send the lab results directly to the pharmacy. Now a little bit more in the future, although some health care systems already have implemented use of these, point-of-contact CBC analyzers are machines that allow an ANC to be determined on the spot without having to have a full lab drawn done, instead with just a finger stick for the patient. Also the results can be available in as short as 5 to 10 minutes compared to the hour or two that is standard for many regular labs. So my hope, and already happening in some places in the country, is that labs can be cut out entirely from the process of getting clozapine to a patient. So to return to our diagram, if you apply strategies for success, one, for the laboratory, that helps reduce the burden of communication between the prescriber and the laboratory. And in fact with a standing lab order, really on a day-to-day, week-to-week, month-to-month basis, there's no interaction with the laboratory. Have the laboratory send the results directly to the pharmacy, and the patient can choose their own lab. Any lab is fine. And again, hopefully in the future, point-of-contact CBC analyzers will eliminate the laboratory entirely from the picture. Okay, so let's talk about strategies for success to a pharmacy. This is maybe one of the best tips I can offer. Find a pharmacy already enrolled in REMS and experienced with clozapine. In my own experience, many pharmacies already have these systems in place, and that includes CVS, Walgreens, Kaiser, any pharmacy that you or your patients may interact with. Something really wonderful is that many pharmacies will dispense clozapine to the patient after checking the ANC themselves. They don't need to communicate on a weekly basis with the MD. Furthermore, even though technically a new clozapine order is required every seven days with no refills, some pharmacies will allow prescribers to order a 30 or longer day supply of clozapine and refill only seven days at a time for the patient. So basically, some pharmacists will take on the management of dispensing only seven days at a time and take that away from the off the hands of the prescriber. Furthermore, prescribing pharmacists can help with side effect management and titration, and may even run specialty clozapine clinics, as is the case in the Los Angeles VA clinic downtown here in LA. Okay, so applying Strategy for Success 2 means that the prescriber's relationship to the pharmacy can now resemble a much more normal relationship as you would be prescribing any other antipsychotic or any other medication. And instead, a lot of the work is just done between the patient and the pharmacy, who coordinate on a weekly basis to get their medication. So as you can see from the diagram, a lot of the coordination is just done directly between laboratory, pharmacy, patient, and back. Next, let's talk about REMS. So initially, it can sound kind of intimidating that clinicians are required to report the ANC to REMS with the same frequency that the patient's monitoring interval is. So weekly for the first six months, every two weeks for the next six months, monthly thereafter. However, pharmacies report the ANC values directly to REMS themselves. There's no need for prescriber to actually do this themselves. And also, just a quick plug for the VA, where I work and prescribe clozapine, there is no REMS reporting. It's all coordinated through the VA through an agreement between the VA and the REMS system. So effectively, after the prescriber and patient and pharmacy are registered with REMS, the prescriber can have no more contact with REMS moving forward after that, because the reporting is done by the pharmacy. All right, let's talk about the most important relationship, the prescriber and the patient. Strategy for success for working with a patient, maybe you're asking yourself, all right, if I start my patient on clozapine, does that mean and they get their medication every seven days, do I need to see them every week? Definitely not, definitely not. A weekly check-in by phone can be sufficient during the initiation phase. Sometimes that's more than is necessary, or that's only necessary for the first couple weeks. In general though, you as a clinician or whoever the prescriber is, needs to be available to their patients to evaluate for side effects and to help adjust the titration schedule if it seems too fast or maybe too slow, and to help patients navigate obstacles. Also, there's lots of literature showing engaging family support is useful. This is no exception. Having family members aware that the patient is undergoing a titration or starting a new medication like this, getting their support and helping the patient commit to using the medication, helping them with transportation, helping them keep track of the medications, and in general supporting them through this time is really highly useful. I could have a whole 60-minute presentation on this point, I think. If you, listener, are not 100% convinced that clozapine is our best antipsychotic, then I highly suggest going back to look at some of the very large effectiveness, real-world effectiveness studies that have come out over the last few years, many of them from Scandinavian countries, that really demonstrate that clozapine and LAIs are the best agents we have for our patients at preventing rehospitalization. I worry that sometimes there are certain studies that have shown clozapine really isn't too different from olanzapine and risperidone, but I don't think that that is really true. Believing that clozapine is our best agent and is your patient's best shot at getting better and being able to communicate that to your patient will help them have confidence and be willing to tolerate more things like side effects moving forward. In general, once clozapine maintenance is established, the frequency of visits is the same as for any other patient. So, applying strategy for success four, the prescriber-patient relationship becomes the same as a patient who wasn't on clozapine. To take things even one step further though, there are many other forms of help for prescribers in the form of coordinated clozapine services, designees, and clozapine clinics. So, I will mention one private pharmaceutical service here called Integrated Clozapine Pharmaceutical Services, only as a potential resource to listeners, certainly not as an endorsement. This is just the one that I happen to know about, but this type of service coordinates all five parties that I was just telling you about involved in clozapine management. The patients pay $95 a month, but the MD or the prescriber is the one who initiates contact with ICPS. This service in particular has been around for almost 30 years, has served over 10,000 patients with schizophrenia, and this one in particular has a lot of experience. If wherever you are in terms of your geographical region, you should look to see if there's a service like this in your area as well. I referred previously to pharmacists-run clozapine clinics. They can facilitate titrations, manage side effects, and tend to have a psychiatrist as sort of the supervisor, the meta-supervisor. Lastly, REMS does allow a designee. This could be somebody in your office, it could be a pharmacist, it could be another non-prescribing clinician, and these are people who can order labs, double-check the ANC, and help do the coordination that we mentioned above. So, applying this final strategy for success means that a designee, clozapine clinic, or other coordination service, can help manage a lot of the coordination. But whether or not you choose to go that route, or just a more standard coordination of clozapine care, I hope that I've convinced you that by building your own infrastructure, finding the pharmacies that you can build a relationship with who are experienced with clozapine, by setting up the relationships in a certain way, it can be very similar to prescribing any other medication.

Clozapine

prescribing strategies

psychosis treatment

ANC monitoring

Clozapine REMS program

communication in care coordination