We're at the top of the hour, so we'll go ahead and get started. Welcome and hello. I'm Dr. Megan Ehrt, professor of pharmacy at the University of Maryland in Baltimore and pharmacy expert for SMI Advisor. I'm pleased that you all are joining us today for today's SMI Advisor webinar, Updates in Proper Use and Administration of Long-Acting Injectable Antipsychotics. Next slide, please. 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 for the care of your patients. Next slide, please. We're going to go back. There we go. Today's webinar has been designated for one AMA PRA category one credit for physicians, one continuing pharmacy education hour. This is our first CPE, so welcome to all of our pharmacists, and one nursing continuing professional development psychopharmacology contact hour. Credit for today's webinar will be available until October 9th, and information was just dropped into the chat as to how to claim CE. Pharmacists should claim their credit of participation after completing your evaluation. Your CPE certificate will be emailed to you by the end of the day tomorrow, and if you're claiming CME or NCPD credit, you'll find your certificate in your SMI Advisor account after completing the evaluation. Next slide, please. Slides from today's presentation are available to download in the webinar chat. Please click the link to view, and then the next slide, captioning for today's presentation is available. Click show captions at the bottom of your screen to enable. Click the arrow and select view full transcript to open captions in a side window. These are all things I normally don't educate people on, so bear your patience today. Okay, next, questions and answer slide. Please feel free to submit your questions. Please use the question area in the lower portion of your control panel, and we'll reserve about 10 to 15 minutes at the end to engage with Dr. Krause around any questions you have. And so now on the next slide, I'd like you to meet our faculty for today's webinar, Dr. Erica Krause. Dr. Krause and myself have been practicing together in psychiatric pharmacy, I hate to say this now, but over 15 years, and Dr. Krause serves as an associate professor at Virginia Commonwealth University School of Pharmacy. Her professional and scholarly interests are geriatric psychiatry, schizophrenia, and most recently I think substance use disorders, and she has a clinic there. So I want to thank Dr. Krause for leading today's webinar. It proves to be an exciting one. So I'll turn it over to you, Erica. Awesome. And Dr. Eric, thank you for that kind introduction and for inviting me today. I'm excited to, I guess, be the first pharmacist presenting for Pharmacy CE. So I do need to start by disclosing, in general, I don't have any conflicts with today's activity, but I have in the past received a trainer device from Janssen for some of the paliperidone palmitate products, and I'm pre-disclosing, I'm hoping that with some of the new products that have come out, that I'll have a chance to go and learn about some of the new products as they come to market. I will be discussing some off-label medication-related things today, including dosing for paliperidone palmitate and aripiprazole monohydrate that is outside the FDA-approved labeling, but I will make that clear. And I'm also going to talk about the investigational olanzapine subcutaneous. And generally speaking, we try not to use brand names in presentations, but given there are multiple brand names of some of the generic products, I am going to use them just so you know which product I'm talking about today. So at the end of today's activity, participants should be able to compare and contrast pharmacokinetic dosing strategies and administration techniques of our long-acting injectable antipsychotics to evaluate potential advantages and disadvantages of some of these newly-approved agents, and lastly, to prevent medication errors associated with the prescribing, administration, monitoring, as well as transitions of care of our long-acting injectable antipsychotics. And so before we get started, if you'll launch this first poll, I just want to know who's in our audience today. So in your day-to-day practice, how many of you, I guess, which best describes your practice regarding long-acting injectable antipsychotics? Do you dispense them? Do you directly administer them? Do you prescribe them, but not necessarily administer them? Or do you work collaboratively, either inpatient or outpatient, with nurses who administer the products? And you can select more than all or more than one option if needed. I'll give you guys about 30 seconds to reply to that. And I guess in my practice, I primarily work with medical residents and psychiatry attendings to provide dosing recommendations and choices of agents, as well as prepare transitions of care for these. In my practice, I've actually only ever administered one, but I will talk about that. All right, if you'll go ahead and give me the results to this poll. It looks like 11% of you have dispensed them, 35% directly administer them, about almost 40% prescribe them, but do not administer, and almost 60% work collaboratively with nursing to administer them. Awesome. Well, I hope you find some of this today useful information. Before we get started, this is just my all-inclusive list. We have two first-generation antipsychotics, both flufenazine decanoate and haloperidol decanoate. And of the second generations, you can see now, we have two different aripiprazole products. The first was the monohydrate, which is a bilifying maintenant made by the manufacturer of the oral aripiprazole. The aripiprazole loraxil is actually a pro-drug of aripiprazole, and that is marketed under the brand name Aristata. The olanzapine pamelate, at this point in time, has a single product, Zyprexa relprev. Paliperidone palmitate, all three are made by the same manufacturer, but we have a monthly preparation in Vega Sustana, the every three month in Vega Trinza, and in Vega Half Year is the new six-month product. And lastly, risperidone, which was the first second generation to be available as a long acting injection, now has four different products that we're going to talk about today. And I also want to highlight, all of them are approved for schizophrenia, but only the abilify maintena products and risperidone consta are the ones that are approved for bipolar disorder. All right, so what is a medication error? I know we have some nurses, prescribers, as well as pharmacists on this webinar. It is defined as any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of a healthcare professional, the patient, or the consumer. And today we're going to, the way I've got this set up is we're going to talk about errors that can occur during prescribing, dispensing, preparation, or administration. And so I'm going to start with prescribing and we're going to launch another poll. I want you to look at these options and tell me which of the following order potentially has a potential error with how it is currently prescribed. And we're just focusing on dose with route of administration. So the first one says risperidone, that should say 90 milligrams. I am. The second one paliperidone palmitate 234 intramuscular, flufenazine decanoate 25 milligrams subcutaneous, haloperidol decanoate 100 milligrams intramuscular, flufenazine decanoate 100 milligrams intramuscular. And lastly, risperidone 100 milligrams subcutaneous. And again, this is a select all option. Give you guys time to get your answers in. And to think back to your practice and what you've seen. Again, about five more seconds. And if you'll go ahead and launch the results for me. All right. So, and I'll say A was risperidone 98, which should have been 90 milligrams intramuscular is correct. Those of you who chose that, that should actually be the subcutaneous dose. Haloperidone palmitate 234 milligrams IM is actually the initial loading dose for in vagus astena. So that is a correct order. Flufenazine decanoate 59% of you chose as being an incorrect or potential error, but flufenazine decanoate actually is labeled to be given subcutaneously, even though the majority of us probably do administer this. I am. Haloperidol dec 100 IM is a correct dose. 15% of you though, wondered if there was an error with that. 20% question, flufenazine decanoate 100 milligrams IM. And I would argue that as a very high dose of flufenazine decanoate. We'll talk about that in the next few slides. And lastly, 70% thought there was a potential error with risperidone, 100 milligrams subcutaneous. And I'm actually glad a lot of you chose this because it is actually the dose of the new use any product. And we will talk about that product as we go forward. So probably did not look familiar to many of you, but it is actually the correct dose. All right. So looking at the routes of administration, again, the majority of our LA eyes are available for intramuscular use. Flufenazine decanoate was the first product labeled to be given subcutaneously, but my understanding of this product, the subcutaneous actually caused more irritation than the IM injection. And now at this point in time, we actually have two products of risperidone subcutaneous. And the other thing just to think about as we go forward, as a lot of our IM injections, and as we know, second-generation antipsychotics can cause weight gain and increase the risk of obesity, that there is a growing concern that some of our deep IMs, we're having a hard time with the needle size, actually getting to the muscle depending on a patient's BMI. So we'll talk about that as well. All right. So starting with our first-generation antipsychotics, just wanted to compare their dosing. And if you think about haloperidol PO to flufenazine PO, in general, they're very similar dosing, right? Anywhere from five milligrams to 10 milligrams to 20 milligrams oral. When it comes to converting them to the long-acting injection, it is very different. And so haloperidol, we usually give 10 to 20 times the oral dose, whereas flufenazine decanoate, we're only giving 1.25 times the oral dose. So this equates to typical doses of haloperidol decanoate being between 50 to 200 milligrams, whereas flufenazine decanoate is a much lower dose of about 12.5 to 50. So that's where I was saying the 100 milligram dose of flufenazine decanoate was probably too high. Comparing the frequency of these two agents, halodaldec is usually given every four weeks. However, there are patients who are on higher doses where we may give it every two weeks just to divide up the dose. And then flufenazine decanoate has a shorter half-life and is actually designed to be given every two to three weeks. And I do want to have a caveat here. If you are converting somebody from oral halodal to the IM and say they were on 10 milligrams twice a day, so a total of 20 milligrams per day, that would convert to anywhere from 200 to 400 milligrams. And because it is a long-acting, usually our max initial dose is going to be 100 milligrams because once you give a long-acting injection, you cannot take it away. And so we do limit that first initial dose. All right. So moving on to other initial doses, we're going to talk about paliperidone palmitate. So this is a 57-year-old patient with schizophrenia who is treated with risperidone one in the morning and two at bedtime. Due to past adherence concerns, we're transitioning them to a paliperidone palmitate. Their labs of concern include a serum creatinine of 0.9, which is within normal limits, but a creatinine clearance of 62 mils per minute. Based on this, what is the recommended initial dose of paliperidone? Would you say 230 milligrams, 156 milligrams, 117 milligrams, or would you recommend sticking with risperidone and giving a risperidone long-acting instead? And if you guys want to go ahead and launch the results of this. And again, this is the initial dose for the loading dose of Invegas-Astena. So my results are all over. We have 27% who chose 234 milligrams, which is the typical initial dose if somebody is not renally impaired. 35% who chose 156 milligrams, which in this case scenario is the correct initial dose because their creatinine clearance is less than 70 mils per minute. 16% of you chose 117 milligrams, which is actually dose two of that initiation regimen. And lastly, 22% recommended sticking with risperidone, which I think is a reasonable option. And we'll talk about that as we go forward. So I wanted to highlight, I think a lot of people are unaware because when we think about our long-acting injections, the majority of antipsychotics are cleared through the liver. However, paliperidone palmitate being the active metabolite of risperidone actually does have dosage recommendations for patients with renal impairment. And so they use the cutoff of if your creatinine clearance is less than 80. So if it's between 50 to 79, you actually are going to dose reduce down to 156 milligrams for that initial dose. And that second loading dose is reduced to 117 milligrams. It is actually not recommended for use in patients with creatinine clearances less than 50. I will say there's probably more evidence with risperidone and moderate to severe renal impairment. And I have since read a couple of case reports of providers who have considered using paliperidone palmitate and somebody whose creatinine clearance was less than 50. But the manufacturer does not actually recommend that. So if their creatinine clearance had been say 46 mils per minute, I agree we would have wanted to stick with a risperidone product. The two microsphere options, normal renal function, we're going to start at 25 milligrams IM every two weeks. And if there's renal impairment, you can consider starting at that lower dose of 12 and a half every two weeks. However, if a patient tolerates two milligrams of oral, you can actually start at the typical starting dose of 25. And in the patient case we were just discussing, even though they were mild renal impairment, we could still start at 25 because they were on three milligrams. And the new risperidone subcutaneous actually have dosing based on their oral dose that they're taking. So this slide compares all three of the risperidone products that we have at this point in time. And I should correct myself, all four. I'm also going to date myself so you know when I went through training. I trained here at VCU Health back in 2003 to 2004 for my PGY-2 psychiatric pharmacy residency. And during that year, risperidol consta was approved. And it was a huge, I'd say, practice changer because it was the first second generation antipsychotic that was available as a long-acting injection. And I'm excited to see the original attending that I trained with is on today's webinar. So hello. Because we started some patients on this medication that year. So since then, we now have three additional products that have come out with risperidone. To the best of my knowledge, this Rikindo product that came out January of this year really tried to mimic the original risperidol consta. The dosing is the same. It's an every two-week injection. When consta first came out, it was for gluteal injection only. But over time, they did expand it to deltoid, whereas Rikindo at this point in time is only gluteal injections. They're similar concentrations. When we talk about oral overlap, that is one other difference between those two products. Whereas the subcutaneous, I think when the paliperidone products came out, we saw a major reduction in the prescribing of risperidol consta because we now had options for monthly and every three-month injections. So the two risperidone subcutaneous products, this first one, Perseris, came out in 2018. It gave us a monthly injection option, but only for patients who are on three milligrams of oral or four milligrams of oral. So our patients who are on higher doses were not candidates. You can see back to that original slide, 90 milligrams monthly subcu is an appropriate dose of risperidone subcu. The case we just talked about would also be a candidate for this since they were on three milligrams of oral. And the newest product that came out literally just a few months ago is Uzeti. And this one has expanded the subcutaneous dosage range from if they're on an oral of two all the way to an oral of five. And they have also expanded from a monthly dose to an every two months. So we have an extended interval as compared to what we used to. So again, we started with risperidone consta every two weeks, and now we have every two-month injection options. And this patient, had we decided to stick with a risperidone, could have been a candidate for either the 75 milligrams monthly or the 150 milligrams every two months. All right, so I'm going to switch gears from the paliperidone-risperidone products to some aripiprazole products. This is a 42-year-old patient with a history of OCD and schizophrenia who is currently treated with peroxetine 40 milligrams and aripiprazole 15. They are interested in transitioning to the long-acting injectable formulation. So what is the appropriate starting dose for this patient? Is it the monohydrate product, which is Abilify Mantenna, 400 milligrams IM monthly, 300 milligrams IM monthly, or 200 milligrams IM monthly? Or are they a candidate for Aristata 882 IM monthly? And if you're trying to read my mind, peroxetine is a cytochrome P450 2D6 inhibitor, and aripiprazole is a 2D6 substrate, if that helps you. All right, if you want to go ahead and launch the results. So I've got a pretty similar distribution. I've got 35% who want to go with aripiprazole monohydrate 400 milligrams monthly, 39% who want to go with 300 milligrams IM monthly, 23% of you all who chose the 200 milligrams IM monthly, and only 3% wanted to go with the Aristata monthly product. So the answer I was looking for based on the prescribing information is actually the Arapiprazole Monohydrate 300. And that is because of the drug-drug interaction with peroxetine that increases the concentrations of this agent. And we're gonna talk through that as we go through the next few slides. So at this point in time, we have two different brands of Arapiprazole Monohydrate. There's Abilify Mantenna and Abilify Asymptufi, which is the two month option. If somebody is just on oral Arapiprazole without drug-drug interactions, they recommend a starting dose of 400 milligrams monthly. And with the two month product, the recommended dose is 960 milligrams every two months. However, we do make dosage adjustments based on the concurrent medications they're on. So when this medication came out, they said everybody starts at 400 milligrams unless you're on a drug that interacts with it. Whereas the Aristata product, when it came out, they actually have dosing based on what oral dose of Arapiprazole they're on. And so the patient we were just talking about was on 15 milligrams per day. And you can see that they were actually a candidate for the 882 every six weeks, or their monthly dose would have only been 662. And the other thing, when we talk about the Arapiprazole products, I think it's always important to remember that its half-life is close to 70 hours. So it takes a good two weeks for oral Arapiprazole to hit steady state. So we need to be cautious about starting the long-acting injection too early because if somebody has a tolerance concern, it may not show up for two weeks after starting it. This slide just highlights all of the products we have now. So when Aristata and Abilify Mantenna first came out, they both recommended oral overlap. But now at this point in time, there are products that we have to maybe get around having to administer oral overlap. So the Aristata product has Aristata Initio, which is a 675 milligram loading dose. And this is my off-label slide. It's not in the US labeling, but it is in the Canadian labeling where they have given two 400 milligram injections concurrently in different sites to get away with having to do oral overlap. Of the Arapiprazole products, we have the monohydrates that are every four weeks or some of the Aristata doses are every four weeks. The Aristata 882 can be given every six weeks. And now we have either an every eight week or every two month injection with both of the Arapiprazole. So this slide is what highlights the drug-drug interaction from the case scenario I was talking about. So if somebody is on no medications that interact with Abilify Mantenna, you can see this is their typical PK curve. If you add in a 3A4 inhibitor, we do see an increase in the concentrations with those highlighted by the blue squares. Whereas if they're on a cytochrome P450 2D6 inhibitor, such as peroxetine, you can see it more than doubles the concentrations. And that is what's here in the light green X. And lastly, if somebody's on both the 3A4 and 2D6 inhibitor, it significantly increases the concentrations. Therefore, the manufacturer recommends a dose reduction with a single interacting agent down to 300 milligrams, or if they're on two interaction agents down to 200. So in the case of a patient on peroxetine, I would recommend starting at 300 milligrams IM monthly. And I really liked this slide because it shows you if somebody's on an inhibitor and then you discontinue it, it takes about two weeks for your cytochrome P450s to come back to their normal metabolism routes, and then all of them will have the same routes of elimination. So comparing the drug-drug interaction with the monohydrate product to the loroxyl product, I want you all to recall that this is a pro-drug, and so it's converted to aripiprazole. And so, excuse me, they have different dosage recommendations. And so if somebody is on a 2D6 inhibitor, such as peroxetine, you would reduce to the next lowest dosage strain. And so this patient who was on 15 milligrams oral daily would have been on 882 every six weeks, but because they're on peroxetine, we should probably recommend them being on 441 milligrams monthly. So flip side of that, what if somebody is on aripiprazole long-acting and they're treated with an enzyme inducer, such as carbamazepine 200? And I like to highlight this because I don't think we always think about some of the drug-drug interactions when medications reduce the efficacy of our agents. And so Abilify Maintenant is actually recommended to not be combined with carbamazepine because it is such a significant drug-drug interaction that it is hard to maintain therapeutic concentrations for the dosage interval. Whereas again, aripiprazole loroxyl being a pro-drug, they don't recommend dosage adjustments if you're on the highest doses. However, if you're on one of the lower doses, they recommend increasing the dose. And so I just wanna highlight the concentration differences. This is with the aripiprazole monohydrate or Abilify Maintenant product. This is somebody who has no drug-drug interactions, and this is how much concentration they get if they are on carbamazepine. So again, I would argue this is not a combination of medications that you should prescribe. It's very expensive to not be working. All right. And then looking at some of the extended intervals of aripiprazole loroxyl. When it first came out, I actually took care of a patient who'd been stable for two and a half years on the Abilify Maintenant 400 milligram monthly product. But she was tired of coming to visit the CSB every 12, sorry, every month or 12 times a year. So her CSB decided let's go ahead and switch her to the every six-week product of aripiprazole loroxyl. At this point in time, the every eight-week product was not available. And unfortunately, following that first injection, she actually decompensated between weeks four and six, and she was admitted at the hospital for the first time in two and a half years. Hindsight is always 20-20. And today we have the option now of the Abilify Asymptote, if I can say that correctly, the every two-month product she might have been a candidate for, but she did not do well when we switched her from Maintenant to Aristata. And so I went back and looked at kind of, there's not a head-to-head comparison of these two agents, but looking at the concentrations of these two. And so she was on the 400 milligram here of the Abilify Maintenant, which if you look at, sorry, its average concentration, its range is significantly higher than the 882 every six weeks. So I think that even though she was transitioned to a dose, it was probably too low of a dose because that's equivalent to about 15 milligrams per day of oral aripiprazole. And so I think that's part of what led to her decompensation was that she was not achieving a high enough dose of the medication. All right, so I'm going to switch gears and talk about dispensing. I spent a lot of time on prescribing. So this is, we're going back to our first generation. Long-Acting Antipsychotics. And I think it's interesting, we have short-acting as well as long-acting injection formulations of haloperidol and flufenazine. So I have listed here the difference of how they come. Decanoate has a 50 milligrams per ml and a hundred milligrams per ml. Single-use vial as well as multi-dose vials. And flufenazine decanoate comes as a five ml multi-dose vial. Whereas the immediate kind of short-acting injections, haloperidol comes as a five milligrams per milliliter as does flufenazine. And they both come as single-use vials and multiple-dose vials. If we were to give flufenazine decanoate, this is how it would show up in the medical record where I work. It's a 25 milligram route of administration IM, which is appropriate. And the correct should have been a one ml dose. Where I work, we do not have flufenazine short-acting on formula, but we used to store it. And we had, I'll say over time, potential dispensing errors where a short-acting was ordered and somebody sent up the decanoate product. And so kind of red flags when you're looking at the chart, you can see if somebody only administered a 0.2 ml dose, did they give the decanoate when they were trying to order a five milligrams of the short-acting? And I've also seen where this is a five ml vial. Unfortunately, somebody thought it was 25 milligrams in the entire vial and not that it was per ml. And we had a nurse, this was a state hospital who called and consulted us here in Richmond that the patient actually got 125 milligrams because they thought they were supposed to administer the whole vial. So things to think about. And I've also seen errors where it's not clear with held all deck, it just says two mls, but they don't specify if it's the 50 milligram product or the a hundred milligram product. So hopefully that makes sense. All right. So we are gonna move on to a different case scenario. This is a 67 year old patient with mild renal insufficiency schizophrenia who is on risperidone 0.5 twice daily. So she's on a very low dose and has some renal impairment. So they decided to go with the risperidone microspheres, 12.5 milligram dose. They ordered a once dose and pharmacy sent to the floor a 25 milligram product stating that it would carry the 12.5s. Nursing called the prescriber who said, sure, it's okay to go ahead and give half of the injection. So my question to you all, sorry, if you'll go ahead and launch that poll is, can you give half of a risperidone constant 25 milligrams to equal the 12.5? Would you say yes, no, or I'm unsure? All right. If you wanna go ahead and launch the results, the straighter, hopefully. So I've got 24% who says, yes, you can do it. 37% who say, no, you cannot. And 40% who are not sure. So I'm glad we're talking about this. And this occurred again, back many years ago when we used a lot of risperidone constant. But if you can see here, I'm gonna go ahead and launch the results. So I've got 24% who says, yes, you can do it. And if you can see here on the product, it comes as a pre-filled syringe that needs to be mixed. So this is the powder, this is the diluent, and you have to push it into here, mix it, and bring it back to the syringe. It is not a marked syringe, and this is a suspension. So you actually do not know what half is. And if you were to attempt to give half, we really don't know if you're giving 10 milligrams, 12.5, 20, et cetera. So the correct answer is no, you should not split it. It's usually not an emergency to give a long-acting injection. We need to order in the 12.5 milligram dose for the next day. So this slide highlights which ones are solutions, which are your two decanoate first generations. And I wanna highlight they're in sesame seed oil. So if somebody has an allergy to sesame, they technically should not receive these products. Whereas all of the second generations are suspensions, and it's extremely important to make sure that we suspend the medication well before you give it. The majority of these products cannot be split. The two exceptions are the olanzapine product and aripiprazole monohydrate. If you have the vial, the vial has specific instructions on how to mix it and pull out a separate dose. But if you get a pre-filled syringe, you should only give the dose that is ordered. All right, so moving on to preparation. As I mentioned, a lot of these are suspensions. And so aripiprazole monohydrate, olanzapine, risperidone microspheres and subcutaneous risperidone do require reconstitution before administration. So this slide just expands the previous slide showing how they come. A lot of them are gonna send a diluent along with the powder in the packaging. And so it's really important to follow the direction. So I just wanna highlight some of the errors I've seen over the years associated with dispensing. So haloperidol decanoate, somebody was on 150 milligrams IM. Pharmacy sent three of the 50 IMs, which is a total injection of three MLs. Those of you who are nurses probably know this better than me, but you should not exceed two milliliters in the deltoid. And I think the larger the volume, the more painful it's gonna be in the gluteus. It does say in some of the literature though that there is less pain with the 50 milligram product, but I would argue in this case, it would be less painful to give 1.5 milliliters of the 100 milligram product than three milliliters of the 50. We had a case with the risperidone consta when it first came up. I showed you how the package came. She just took out the prefilled syringe and put a needle on it, administered the diluent and never mixed it with the powder until she went back to chart it and realized that the vial was there. So she had to go back and tell the patient, hey, I need to give you another injection. I just gave you essentially a placebo. And lastly, aripiprazole monohydrate. We had the pharmacy actually open the package and send up just the diluent and not the actual medication. Luckily, our nursing staff knew that a piece of it was missing. All right, so this is another scenario. We had a patient who was on paliperidone palmitate 234 monthly for nine months. And when Invegatrinza, the every three month formulation came out, they were transitioned to that. The first injection cycle went really well. And then they showed up three months later for their next 819 milligram injection. And about six weeks later, the patient was severely psychotic, decompensated worse than they had in a while. So the first question I was asked is were they transitioned to the correct dose? And so being on the 234 monthly, the equivalent three month dose is 819. So that was correct. And this was early in the days of Invegatrinza. So the team was actually very worried about adding medication since they were on, had just received such a high dose potentially of an antipsychotic. But when I contacted the manufacturer, I learned that there have been drug failures with administration errors. Essentially that it was not shaken hard enough or the particles of medication were not dispersed well enough. So in this case, we recommended going back to the monthly just because she had done so well on it. But my question to those of you who have reconstituted paliperidone before for the Invegatrinza product, do you need to shake it vigorously for at least 10 seconds, 15 seconds, 20 seconds or 30 seconds? And do you need to administer it within two, five, 15 or 30 minutes? All right, if y'all go ahead and share the results of this slide. All right, so 16% said 10 seconds within two minutes, 43% said 15 seconds within five minutes, 22% 20 seconds within 15 minutes and 19% chose option D. All right, so the correct answer, the majority of you guys got it correct. The three month product needs to be vigorously shaken for 15 seconds and administered within five minutes. So I think where we sometimes see errors with this is if we're trying to prepare the medication ahead of time, say in the medication room, we shake it, we set it down, go get the patient, bring them back to the clinic room or like take the medication to the room and they're not ready for it. If this two minutes for Risperdal-Consta, five minutes for paliperidone, three month or six month, sorry, monthly or three month goes by, the aripiprazole within 15 minutes or aripiprazole monohydrate within 30 minutes, you need to pick up that syringe and re-shake it really hard. And when we say vigorously, this is where I have gotten those training devices from Janssen, from Vegas Astana. It's not just a light shaking, like you really need to shake this medication hard to make sure that you suspend the medication. And so originally that was thought with some of the potential product failures with this was. The new Invega half-year or six month product, they recommend 15 seconds and then a second 15 seconds to make sure you really shake it well. All right. And olanzapine pamawate, I couldn't find exact time but they actually have what you need to have a consistent texture and color. And if you don't use it right away, again, you need to re-suspend it. All right. So this is some examples of good shaking versus poor shaking. This is the Aristata product. So this is when you set it down on the counter, you can see it all settles onto one side of the syringe. Good shaking, it should be homogeneously dispersed versus poor shaking, it can actually cause it to clump and that increases the risk of clogging your needle. This is the new every six month product for paliperidone. And you can see if it's well suspended, it's gonna be a uniform thick and milky white versus if it is not, it's gonna have kind of a clumping on the side and an uneven mix looking to the liquid. All right. So coming back to all of our risperidone products, one thing that is very different about them is they require refrigeration. And so depending on how many patients you have in your clinic setting or hospital setting, this can take up a lot of room. And it also limits thinking about if a patient picks it up from the pharmacy and brings it to your clinic, you wanna make sure that they have been properly storing it. So the original Risperdal Consta as well as Rikindo are good outside of the fridge for up to seven days, whereas Perseris actually is good up to 30 days outside of the refrigerator and the new product Uzeti is actually up to three months. So that is a big difference as compared to the other. I have here highlighted the difference again on how long to shake. The Perseris is actually two syringes that you put together and the Cycles is pushing the medication back and forth between the two syringes. And the Uzeti product comes as a pre-filled syringe that you just literally flick three hard times and there's a bubble that you'll see come to the top. So very different between all of them. All right. So next we're gonna talk about administration of these. So in general, most of our long acting injections, we're going to do a nice slow and steady injection and it is apparently less painful if Haldol and flufenazine are given at about 30 seconds per ml. The exception to that is the Aripiprazole Loraxil product which they recommend pushing rapidly. And the reason for this is again to reduce that risk of clogging the needle. So this needle shows you that if you shook it well and it's well dispersed and you push it really quickly, you're more likely to have a successful injection and that you won't clog the needle. Whereas if you push it too slow, you do have a greater risk of clogging the needle. And you can see here the olanzapine pamawate and risperidone microspheres also suggest slowly withdrawing from the vial to the syringe. All right, I'm going to move on to another case scenario about injection sites. So this was the first ever in vagus systena I gave. We had a 27 year old patient who had been on paliperidone 12. I have the renal function for you there. It was above 70 or above 80, so it didn't require any dosage adjustments. They were being switched to the monthly formulation. They pulled up the medication record and c-palipiridone was given in the right gluteus. So if you want to answer this next poll question, what medication occurred? Did we give the wrong dose, the wrong route, incorrect volume or incorrect location? And I will say in this case, I actually went up and talked to the nurse because I knew it was the first time we were giving it. I went over the instructions with her and I'm gonna give it about 10 more seconds. We'll see what you guys think. All right, if you want to launch the results. So we have 15% of you believe it's the incorrect dose, 4% the incorrect route, 26% the incorrect volume and 56% the incorrect location. Those of you in the majority are correct. So if you recall in vagus systena, those first two injections, generally speaking need to be given in the deltoid because it increases the concentrations quicker. And so this is the PK curve just showing why we give the loading doses in the deltoid instead of the gluteus. And so the gluteal peak is in the gray here, whereas the deltoid injection is what's highlighted in red. And so you see a 28% higher C-max with deltoid injection, which the whole kind of thought process behind the loading doses of paliperidone palmitate is so you do not have to give oral overlap because you're more likely to achieve therapeutic concentrations quicker. So in the case of this medication error, we did actually continue them on oral overlap because we figured there was a lower likelihood that they achieved a therapeutic concentration with that first injection being given in the gluteus. We gave the second loading dose injection and made sure to give it in the deltoid. And we did monitor for EPS because we kept the oral on board. So just kind of summarizing these different agents and their location, paliperidone palmitate can be deltoid or gluteal, but again, those first two loading doses need to be administered in the deltoid. The palmitate, three months, it depends on the dose, but generally speaking, you're going to be doing gluteal for those larger, like 8, 19 milligram doses and deltoid can be for some of the lower ones. And then the half Euro product, the 15, 16 milligrams I want to highlight is a 5ml injection. So that's pretty large. And it's also one of the larger needles. If you recall the smaller your gauge of needle, the larger the bore is. So it's a very large needle and a very large volume for your half Euro product. Looking at the risperidone products, you can see that the IM injections, again, constant when it first came out was gluteal, but then over time, it was also deltoid. Rikindo currently is only gluteal. Perseris and Uzeti. Originally, Perseris was just around your abdomen, but it has gained approval for the back of your upper arm. And you can see here, similarly, Uzeti can be abdominal or the back of your upper arm. And I've been told, especially with the kind of paranoid population of schizophrenia, that the out of sight, out of mind on the back of arm seems to do better for some patients than when they can feel the little nodule around their belly where it was administered. I also want to show here this new Uzeti product. The gauge needle is much smaller, sorry, than the Perseris one. And the volumes of injection are also a lot smaller. All right, coming back to our first generation agents, I'm sure you're all familiar with Z-Trac, but that's where you pull your skin to the side, put the needle in, push in the medication and pull it out. And that reduces the risk of some of the medication leaking out. Of the different Aripiprazole products, I want to highlight the difference again in the needle size. So you can see here, the Aristata, those extended intervals are for gluteal only because again, they are larger volumes. And then the Monohydrate product, this new Asymptufi is gluteal only for the every two month product. I want to highlight too, Olanzapine Pamoate is a very large injection volume as well, 2.7 mLs. And it's a 19 gauge needle. So again, that one needs to be gluteal only and you need to use that 19 gauge needle because it could potentially cause clogging. All right, I haven't talked much today about Olanzapine Pamoate. Probably as we all know, it has a significant REMS program. And I wanted to highlight a case that's been published in the literature of somebody who had been successfully treated with Olanzapine Pamoate for a very long time. She was on 300 milligrams every 15 days, so twice monthly and they actually set up her discharge appointments in the emergency room. So she had access to that acute care if needed and she would sit in their ER for three hours after she received her injection. She was stable on it for one and a half years. And if you recall the dosing she's on was probably equivalent to either 15 to 20 milligrams that she was on 300 milligrams every two weeks. Unfortunately, following her 31st injection, 10 minutes after receiving it, she had difficulty walking. She slipped into increased sedation. She was hard to arouse, very agitated, slurred speech, became tachycardic and her RAS score was between positive two and negative three. It took about nine hours, but her vitals did eventually stabilize. And she, despite this, was willing to continue the Olanzapine Pamoate and came for her 32nd injection without event. So there's actually criteria for the post-injection delirium sedation syndrome. I highlighted in blue what this patient case was experiencing and it did occur within 24 hours of receiving her Olanzapine Pamoate. A lot of the symptoms are consistent with Olanzapine overdose. And this slide highlights of the published case reports how quickly they occur. About 48% occur within 15 minutes of the injection. So that case was 10 minutes. 25% in the next 15 minutes and an additional 18% within that first hour. So overall, 91% of the PDSS events occur within an hour of the injection. The reason that we have the three hours that we have to watch the patient is because there are some case reports that have occurred greater than two hours later. And there's actually one case that's been documented six hours after injection, which is why patients need to be driven home from their appointment and ideally have somebody spend the afternoon with them. So major difference, thinking about Clozapine and the risk of severe neutropenia, the longer you're on the drug, your risk of neutropenia goes down. In the case of Olanzapine Pamoate, the longer you're on the injection, the incidence goes up. So it's roughly 7, sorry, 0.07% of injections, which is about 1.4% of patients. As of 2017, there is almost 450 reports of this. And that is why everybody needs to be trained to give this medication. And the thought process behind what happens is Olanzapine Pamoate itself is actually very soluble in water. And so if you inadvertently hit your vein, it dose dumps that entire 300 to 405 milligrams of Olanzapine into the bloodstream, which is why it looks like an Olanzapine overdose. And this is where I wanted to bring up again, currently under investigation, they're looking at a subcutaneous dosage form to see if it can hopefully reduce this risk. These are some of the case reports of the PDSS. You can see how high within six hours of the injection, this concentration of Olanzapine got as compared to where the typical peaks were. This is multiple reports of patients who had the PDSS events in the clinical trials. So if your typical peak here is what, around 35 to 40, you can see this is more than four to five times that peak concentration. So this is the REMS related to it. Again, everybody needs to be registered. You need to ensure proper training of who is gonna be administering it because we wanna make sure we avoid inadvertently hitting a vein. And they need to be in a facility with easy access to emergency response services. Cause as you saw, it can occur within 10 to 15 minutes of the injection. And you need to keep the patient in the clinic or site for at least three hours. All right, I'm switching gears for the last few minutes of this presentation. This was a report out of the University of Australia that looked at some of the medication errors associated with long acting injections. Some included, there was a lack of knowledge of the injection technique, which is why we discussed that today. Omission of the depo antipsychotic from the med list. So we give a once dose, but we don't keep it on the med list. So maybe we don't know that they're still on it. Receiving additional depo injections because of documentation. So they got them in different systems. Failure to taper off the oral medications. Unfortunately, somebody, a wrong patient got it. So I'm gonna wrap up this with transitions of care, discharge prescriptions and documentation. So again, long acting injections, not all of them work immediately. A handful of products do not require oral overlap. One week or less is flufenazine decanoate, paloperidone palmitate. Sometimes we will do that one week off label before we give the second injection. And this new Rikindo product only requires one week of overlap versus risperdal consta is three weeks. And then the two Abilify products, you can see our aripiprazole products. Abilify Mantenna is two weeks, and Aristata is three weeks. And Havlodac is usually four weeks. I always like to highlight why risperdal consta was a 21 day overlap. The little microspheres actually take about three weeks before they start to release the medication. And this is the PK curve, and that's why we give it every two weeks. This is the perseris or risperidone sub-Q. You can see that it actually achieves target concentrations within four hours of that first injection. And I would argue some patients even one to two. So therefore they do not require an oral overlap and neither does the new Uzeti product because they also saw therapeutic concentrations within the first day. Looking at the aripiprazole laroxyl initiation strategy, I've had some patients who are discharged from an outside hospital and received a dose of aripiprazole and they're discharged and either they don't pick up their oral overlap or they picked it up and never took it and they end up in our hospital a week or two later. So that's when we need to think about, are they a candidate for that like initio dosage strategy, which I have listed here or potentially, I don't know, a way to get the medication in them so they don't need the oral overlap. And I've actually once saw somebody try to order 675 monthly which is the initial dose and should not be monthly. And this just shows you the difference between the Aristata products. The extended interval has a little bit more fluctuation versus it does take a few months of consistent injection to start to build up your concentrations. So they do not occur immediately. This one shows with that loading dose of the 675, they do achieve therapeutic concentrations within that first day or two, which is why they don't need oral overlap. And some just transitions of care I wanted to share before we get to the questions and answers. I had one person who received Abilify Maintenna 400 10 days later, an additional one while in an ED at a different hospital. That person did experience akathisia. I had one person who was on the floor who was on oral Risperidone. The team started Risperidone microspheres 25 on a Thursday and just ordered a once dose. So it wasn't in the med list. The covering weekend attending thought he had done a great job and convinced the patient to get along acting and ordered paliperidone palmitate instead. Did not flag in the medical record because technically they're different medications, but luckily our pharmacy resident was working that weekend in the pharmacy and had documentation that the patient had received the constant and she stopped them from getting the Invegas and Stena. This was a patient who had three hospital stays in three different hospitals in a three week period. Unfortunately got held all DAC, Risperidone, Consta and Abilify Maintenna all within a three week period. And if you think about it takes Consta three weeks to start working, Abilify Maintenna two weeks to start working. So we got him as all these medications were starting to peak. All right, I'm gonna skip that one. And then as I was preparing this presentation, I also had a patient where the case manager had wanted to transition somebody to the every three month paliperidone and they wanted to know if we could give it in the hospital. And so I asked, well, when was their last injection? And interestingly, they had missed their past two monthly injections, had been at a different hospital, got a Flucentazine decanoate during that time. And so it was just, this is part of why I think it's so important to make sure that we document these. And I wanna wrap up with some additional thoughts, some great resources, always refer to the prescribing information in the products. We have a training program at the American Association of Psychiatric Pharmacists, which is a organization I'm a member of. And lastly, they are currently studying two other additional LAIs. And so I'll let you read the take-home points so we have time for questions. Dr. Kraus, thank you so much. I think you pointed out some excellent things that many of us get consulted on very regularly. So I greatly appreciate you taking the time to answer that. So before we jump into questions, if we could switch to the next slide, here's your acknowledgements and references. Yeah. And thank you. All right, so we'll go to the next one. So thank you very much. And before we shift again to questions and answers, you'll see on the next slide, the mobile app. So the mobile app has resources, education, upcoming events, mental health rating scales, there's a consult service, there's an LAI conversion tool that's now on the app. So I recommend if you haven't had an opportunity to look at that conversion tool, it will help you if you put an oral dose in, it will spit out an LAI dose. On the next slide, we are going to jump into questions. And so there's a couple of questions. The link for the slides, again, is in the chat. If you scroll up or maybe we can post that again if you joined late. There is a question going back to creatinine clearance. And I didn't know the answer, so I'm also intrigued if you knew, if a patient only has one kidney, does that rule out a long-acting injectable? And my answer, I'm thinking more of lithium, but if you have one functioning kidney, as long as it is working and you have good creatinine clearance, I think it's fair to go ahead and administer a long-acting injection. Again, most of them do go through the liver, paliperidone palmitate is the one that you just need to make sure you're monitoring for your extrapyramidal symptoms and side effects if you use it. Here is a question or scenario that we get very frequently for our maintenna and sustenna patients. You know, the patients may not be taking PO meds before starting the LAI, but maybe has a past history of taking the meds and they responded well. So how long or how many monthly injections do you anticipate it might take to reach steady state really to give the LAI a fair trial in that regard? I think that's fair. And if you go back to those two eripiprazole slides that I had, each month you see it go up. In my experience, it usually takes a good four to five injections. So for the monthly injections, that can be four to five months before you see it like fully at steady state. So even though I'm not gonna promote polypharmacy and having oral on top of the injection, in those cases, they might need a small oral dose on top of while you're waiting for it to like fully get into their system. Great question. I have, I think, two, if we can get them in. Do you prime the needle for Trinza, for a lansipine consta or any of them? Do you know if that is part of the package inserts? Ooh, I admit I do not. I know that, like I said, Uzeti, you have to get rid of that air bubble at the top. And so I think the biggest thing you wanna make sure you get the air out and kind of get it all the way up to the top so you're administering the injection and not an air bubble, but that's okay. I don't recall specifically if package inserts require priming. I don't think that that's in there as a requirement. Thanks. So our last question before we wrap up, that there is potential to start seeing an increase in galacteria and hyperprolactinemia with risperidone and now in vega injection. Are you seeing this? I'm gonna say- Give me some of your opinions on that. Absolutely. And I think we all know, right? Risperidone causes hyperprolactinemia, paliperidone, my understanding is it's actually more related to the metabolite paliperidone. So I would expect to see it within vega. Once had a patient, unfortunately we gave a risperidone constant and she had it. And so then you're stuck with, what do I do next? And so to me, those are the patients you either need to think about switching to aripiprazole and you're partial dopamine agonist or a medication less likely to cause it. But I don't think that the injection reduces that adverse effect. We definitely see it. So thank you for the great question. Yeah. Excellent. If you can switch to the next slide, we have a couple of things that we're gonna wrap up with today. So if there are any topics covered in this webinar that you have more questions or would like to discuss with your colleagues in the mental health field, you can post a question or comment on the SMI advisors discussion board. It's an easy way to network and share ideas with other clinicians. Additionally, if you have questions about the webinar or other topics, you can get an answer within one business day with the SMI advisors national experts on SMI. And this is available to all mental health clinician, peer support specialists, administrators, and anyone else in the mental health field who works with individuals with SMI. It's completely free and confidential service and the link is here on the slide. As mentioned on the next slide, there is the LAI conversion tool. And this is a tool designed to help provide dosing recommendations for both initial maintenance doses of LAIs based on your oral dose. And it's up to date with all of the new LAIs, including the two that Dr. Kraut spoke about today. So please utilize that resource. And again, to claim credit for participating in today's webinar, you'll see on the next slide, you need to meet the requisite attendance threshold to claim for your procession. And then after the webinar ends, please click next to complete the program evaluation. The system then verifies your attendance and it can take up to an hour and can vary based on the amount of users we have on our Zoom platform. Pharmacists should claim credit of participations after completing the evaluation. And again, that'll be available tomorrow for nurses and physicians. This will be in your SMI advisor account. And then the next slide, I welcome you to join us in two weeks on August 25th as Dr. Papa presents Silent Storms, Unraveling Perinatal Mental Health. So the free webinar on August 25th from 12 to one. So please join us. Thank you, Dr. Kraut for your time. We greatly appreciate your expertise and until next time, take care.

Dr. Megan Kraut

long-acting injectable antipsychotics

dosages

renal function

drug-drug interactions

administration

complications

medication errors

documentation

transition of care