Speaker 1 00:00 Alex, welcome to HelixTalk, a podcast presented by the Rosalind Franklin University, College of Pharmacy. We're hoping that our real life clinical pearls and discussions will help you stay up to date and improve your pharmacy knowledge. This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - Dr. Abel 00:29 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 38 I'm your co host, Dr. Kane. I'm Dr. Schumann, and I'm Dr. Patel, and today we're talking about a new drug therapy, a whole new drug class just for insomnia. Speaker 2 00:42 Yeah, so, so, just to go over a little bit of an overview, many, as many of you know, sleep is a big issue, but for anyone working in outpatient pharmacies or retail pharmacy, any anywhere, it's something that people come asking about herbal medications, for prescription medications, for a lot of things. And we know that even looking at some of the branded medications and their sales through June of 2015 sales of Ambien CR, the one of the brand name products available for sleep total $46 million just in, just in that time period alone. It's sort of one of the top 100 medications. Speaker 3 01:14 And that's very interesting. You know, like nowadays, we say there is an app for that, or there is a pill for that. And I feel like, instead of really tackling what's really going on patients life that's keeping them from sleeping properly, doctors just usually throw medications at them. It's like, try this. You know that they don't enforce the sleep hygiene, the education that's needed. And these meds, as we will talk, are not benign. They carry a lot of side effects, Dr. Sean Kane 01:40 and it's a complete aside, but I think smoking cessation is often the same way of instead of talking to you about strategies to stop smoking that don't involve giving you a pill, is this easier for a physician or for any prescriber to give a pill instead and avoid some of the non pharmacologic counseling that comes with it? We can really see that and the agents that have been approved or not approved, but still used for insomnia very frequently in the United States. Speaker 2 02:05 Yeah, and then, and even with those lately, those are the markers. Been increasing concerns about some of the side effects, about the kind of, you know, having a laissez-faire attitude about medications, you know, just throwing them out there. You know, not concerning. For example, many of these medications were approved and studied, really, for only 14 day courses. And yet, you know, we sort of see the inertia with them being on board for months, even in years, in some cases. And so as time has gone on, as people have carried these medication regimens later on, later into adulthood and into, you know, ages over 65 you start seeing, yeah, that there may be problems with them. Some examples, as we know, in the news lately with Ambien or zolpidem causing parasomnias, or sleep behaviors where the individual is somewhat asleep and has no recollection of what they're doing, but they're doing things like cooking. I've had patients say that they stood the notice. They noticed that their wife got up, went, and they were just standing there frying up an egg in the kitchen, no recollection whatsoever. Others I know that woke up because the cop was knocking on the window of their car. They were pulled up on some median 30 minutes away. Sleep-driving, sleep-sex, walking around, going into other houses. I've had other patients knocking down doors of other of other houses, getting confused, thinking they're even back in some sort of a combat situation. So there's definitely some issues with that. We also know about benzodiazepines, temazepam, diazepam, Oxazepam, some of the ones that are used more in the evenings. They can have respiratory depression, a big issue with some of the opioid safety initiatives we're taking and as well as they can worsen sleep apnea. Dr. Sean Kane 03:34 Dr. Schuman, I know one of your pet peeves is the use of Quetiapine, or Seroquel, which is an atypical antipsychotic to use for sleep in someone who really has no indication except for insomnia. So no bipolar disorder, no schizophrenia. And as you were saying, you know, these agents have side effects, right? So in the case of Seroquel, as you know, we can see things like metabolic syndrome with weight gain, diabetes, dyslipidemias, if we're just trying to treat insomnia, it comes with a lot of baggage associated with it. Speaker 2 04:03 Yeah, and that's going to be the thing. Another one like that would be mirtazapine, with its potential for weight gain that may also impact sleep apnea. But yeah, that's the thing. You know, we need to consider these as medications to be used. But again, count the cost, look at the risk benefit. Speaker 3 04:17 And surprisingly, I've seen so many patients being on multiple medications, let's just say not for the indication of sleep itself. But for example, there'll be an Ambien for sleep, but then they'll have trazodone, they'll have another sedating medication that they're taking at the same time at sleeping, and the providers are not really evaluating what is the effect of all these medications on their wakefulness the next morning, yeah, Speaker 2 04:41 and that's gonna be a problem. And trazodone can often cause some of that residual sedation that then that can be further impairing the next day. And then, you know, we only occasionally start looking at, how do we address that pharmacologically? And then we continue in this vicious cycle of prescribing for the last thing that we screwed up. Speaker 3 04:57 Yeah, exactly. So then this new. Class we're talking about is supposedly knight in shining armor. Speaker 2 05:04 Yeah, this is one that it's been around, really, for the last 10 years or so they've been studying this, this medication. So we we know that orexin, or hypocretin is, is this neurotransmitter, and it was effectively discovered in in 1998 and then suvorexant, or the brand name of it, Belsomra is a dual orexin one and two receptor antagonist. Speaker 3 05:25 And so the name kind of makes sense. Belsomra, generic is suvorexant, so orexin, orexin antagonist, yeah. Speaker 2 05:33 And again, even looking at Belsomra, it immediately comes to mind with some of the Latin deriv is bell or, you know, sleep is beautiful, beautiful sleep. So they found the neurotransmitter itself in 1998 and then what they were able to do is kind of tag back, looking for DNA fragments to find out from there what the weather receptors could be working on and what they found yet. So there's this chemical that fits into the key of this receptor, and then what it does is that can then produce sedation. So if you end up with, you can end up with with narcolepsy by changing the by changing the function of this receptor. And so they said, Okay, so if abnormal receptors can cause narcolepsy, then if we block this, perhaps then we could get some beneficial effects on sleep. Dr. Sean Kane 06:15 And so suvorexant and Belsomra was born. Then Right, correct. Speaker 2 06:19 And obviously it's not to be used in patients with narcolepsy, but yes, it's one that can can produce sleep. Dr. Sean Kane 06:25 And this is the first drug in this class of a dual orexin antagonist. And at least one resource that I found called the drug class DORA, a dual orexin receptor antagonist. If other drugs do make it to the market in the same drug class, I think we may be using the phrase DORA, just like we do, non-hypnotics and things like that. But I think at this point, until at least two drugs get to the market, the use of DORA, I would say, let's hold off on that correct, Speaker 2 06:50 because I know with things like the SSRIs, the NaSSAs, we keep changing the acronyms anyway, so we'll kind of keep up with one until we're forced to change it. Dr. Sean Kane 06:58 Fair enough. So in terms of dosing, what is our dosing range, and what kinds of things do we think about with Belsomra? Speaker 2 07:04 So this is medication that we're starting with about 10 milligrams, 30 minutes before bedtime. One thing to note with it also is that food can delay the absorption and potentially delay the effect of this medication. So it's come up a couple times with patients that I have on an Ambien as well, as a result. And the same thing applies that you just want to be aware of that. So if you're somebody that snacks before bed, has a fatty meal, that can delay the time, so you may be waiting there a little bit long until the medication kicks in. So assuming we're probably going to want to take it on an empty stomach, 30 minutes before bed, you can go up to 20 milligrams, but sometimes doses above that can have more ADRs, as we'll talk about, and doesn't really seem to necessarily show a higher efficacy with dose. Speaker 3 07:45 So I know for Ambien, looking at the STOPP criteria and the Beers list, there is the maximum dose recommended. Is there such dosing recommended for orexin and elderly patients? Or currently, we don't have any provision, so at Dr. Sean Kane 07:59 least in the packaging and in the clinical studies, when they looked at age, it wasn't a big contributor for elimination of drug and metabolism of drug. The big things that did impact exposure AUC of the drug itself was women had higher exposure than men, and obese patients had a higher exposure than non-obese patients. And then finally, if you had any drug interaction with a CYP3A4 pathway, it was susceptible to that pathway. So as an example, if you take amiodarone, you should expect a longer half life with Belsomra than if you're not on amiodarone. So those are the three main things, although I will say that generally with any of these sedating medications, we typically do see that elderly patients do have either higher sensitivity or prolonged half life, and it could be that once we go into more phase four trials, that we'll start seeing some of that. But at least in the packaging right now, it's pretty clear that elderly didn't have a dramatically different effect than non-elderly patients. Speaker 2 08:55 And again, it's going to come to the same monster we've been now using with Ambien is going to be about the minimum effective dose. So again, if you can, you know, even if you go up to 10 milligrams for a time period, can you dial back the dose again? So we're watching that overall dose burden over a long period of time. So that's gonna be something important to Dr. Sean Kane 09:13 consider for patients. Timing. Again, balsamira is approved to help you fall asleep quicker and stay asleep longer. Given that, like you said, Dr. Sherman, it makes sense that you wouldn't want to want to take it with food in your stomach, because it's going to delay how quickly you can fall asleep from the medication. But also, we don't want patients taking it at 4am and having to wake up at 8am while the drug is still active. So with many of the non hypnotic benzodiazepines like Ambien or zolpidem, we say eight hours of sleep is what you should plan for. In this case, the packaging says seven hours of sleep. But with that said, we'll talk about it later that some patients still do have even after nine hours, some patients still do have kind of sedating qualities when they wake up the next morning, right? Speaker 2 09:54 And again, that we're, you know, it's difficult to necessarily know which patients are going to have or not have that. So it's still. Is going to be somewhat of that trial and continue to try alternative medications and see it's the same thing. I've, you know, some patients that trazodone 100 milligrams is a complete joke. Others, 25 milligrams and boom, they're groggy still the next day. So, you know, we don't have, you know, a guarantee, even with this medication, that we know for a fact, it's going to be completely benign in those regards. Dr. Sean Kane 10:21 So, Dr. Schuman, in terms of the studies, I understand that there is one main study that you looked at that dealt with the efficacy and safety of Belsomra or suvorexant, and that this was published a couple years ago, Speaker 2 10:31 right, right? So the main one, I was able to look at 2012 one where they were really starting to piece together, you know, what doses should they use? And they looked at a wide swath of patients. So this one, they looked at non-elderly individuals with diagnosis of primary insomnia, and they were given a seven day running phase. And in that seven day phase, they looked at all these number of patients, 723, that were screened, and they only included those with a greater than 20 minute time to onset of sleep and an average wake time after falling asleep those greater than 60 minutes. So for example, it took them 20 minutes to fall asleep, and then through the course of the night, they were up for at least 60 minutes after that initial time they fell asleep, which is interesting, because that's more stringent than the criteria we have for diagnosis of insomnia, right? Insomnia really need to have one or the other. Primary insomnia can be those that have trouble falling asleep or those that have trouble maintaining sleep. But because of we'll get to it, some of the objectives they wanted to look in the way they designed the primary and secondary outcomes. They really wanted to capture those that had both issues, and that was assessed via polysomnography, Dr. Sean Kane 11:33 which is a sleep study, yes, yes, excellent. As I understand that they had four different doses that they're looking at, 10, 2040, and 80 milligrams. And as we said earlier, based on FDA approval, 20 milligrams a day is the maximum dose. But they did study higher doses, and it would appear, based on this and other studies, that efficacy wasn't that much better, but you get more ADRs as you exceed the 20 milligram per night dose, right? Speaker 2 11:56 And then a lot of it is going to be these early studies where they're trying to find out, you know, yeah, where is that risk benefit going to be at? And you know, is that sometimes they'll even just as a way, as an extra placebo, almost they'll use a very, very low dose of it, of the drug, just to see if it had any effect at all. But yeah, they did a wide swath four different doses. And even in each case, they had a group that received the drug first and then placebo, they had a group that received placebo first and then the drug. So really, there were a total of eight groups receiving four weeks of the drug and four weeks of the Unknown Speaker 12:25 placebo, and this was a crossover study. Then, Speaker 3 12:27 yes, that's interesting. So you mentioned that polysomnography was used as a criteria to make patients eligible for the study, and this was probably one of the criteria to evaluate the efficacy as well, in addition to certain questionnaires and scales on patient satisfaction, correct, right? Speaker 2 12:45 They really, they used both. So they tried to objectively look at it the sleep efficacy, that was one of the CO primary endpoints. They looked at percent time in bed that the individual was actually asleep again, using the polysomnography to detect that. And they looked at interestingly. They kind of picked one base point at day one of that phase, and then at the end of week four. And those were actually co primary endpoints, instead of just looking at, for example, you know, a lot of times you look over a long period of time and look for the total change. So instead, they were kind of using day one as a snapshot of what they had been on before, and then Week Four is snapshot of, okay, that this next intervention, what is that doing? And so because of that, they have these co primary end points, but again, and the main one again, being assessed by the objectively looking at, you know, the polysomnography sleep studies and the secondary endpoints they looked at time to onset of sleep and average wait time after falling asleep, again, using similar mechanisms. And then there were these additional, as you mentioned, Dr. Patel, there were some initial assessments they did, looking at disability scales and insomnia severity indices to again see how the patient feels. Do I wake up in the morning and feel refreshed? Do I notice changes in the day? Am I feeling more depressed? How are things going on just to again, to see, because once again, and I know Dr. King, you harp on this a lot, is, do we have these surrogate endpoints of, you know, numbers? Are we chasing after the numbers, or is it actually benefiting the patient? And so they, they really did to their benefit, try to look at both the subjective and the objective Speaker 3 14:08 ones here. And this is more to figure out whether they have the restorative sleep. They call it right, fulfillment of the sleep. Yeah. Speaker 2 14:15 Because, again, that can be very subjective there. So wanting, wanting to be able to capture that. Dr. Sean Kane 14:19 So if I understand correctly, they had basically eight groups that you could be in, and then they had two co primer end points, which means that we should have seen, let's say, 16 p values just for the primary endpoint. Then, is that right? Speaker 2 14:32 Yes, and that's the thing about it is when you're, you know, as you know, Dr. King, you're doing multiple comparisons, you know, we can have that potential increase in our our type one error or finding a difference when there really isn't one. And so a lot of times, what you're trying to do is do adjustments for that. So, you know, maybe so we make sure that we're being fair of the data and not making it look like everything's a lot better than this, because you keep looking at something over and over and over again, or keep assessing multiple things, you're gonna be more okay to find a difference. What's interesting here? Year, though, is my experience. They're usually, you know, we use specifically a Bonferroni correction as a way to do that, where we're kind of dividing the initial P value by the number of endpoints, and so therefore making them have to, you know, maybe shoot into a smaller target there, hitting a smaller P value. They didn't really discuss exactly how they did it here. And again, my opinion is that it, you know, wouldn't have been necessary to do these somewhat confusing multiplicity adjustments if they had just, you know, maybe designed a little bit of a more cohesive study in the first place with with single primary input. Kind of muddles things and always makes me kind of wonder why they, why they went to those lengths to do that. If there was, you know, if they were, you know, there's some issues with the data otherwise. Or what kind of was the game, the end game here? Dr. Sean Kane 15:41 So given that there were potentially some limitations to the study design and how the data were analyzed, what were the results generally for the study? Speaker 2 15:50 Okay, so again, with both of the CO primary endpoints, looking at their sleep efficacy, looking at the period of time, so how much of the time there were sleep versus the time in bed, both of those endpoints, it was significantly more improved relative to placebo, and that was across the board, at all doses, 1020, 4080, and the same was with improvement in time awake after initially falling asleep. But what they did find was some inconsistencies in the time in regard to sleep onset, so that sleep latency, per how long it takes you to fall asleep, wasn't really dose dependent. And they mentioned that some of the ones they weren't able to do the multiplicity assessments because they didn't meet their original criteria finding Dr. Sean Kane 16:27 a difference. So in addition to that study, the FDA used at least two other studies for the approval of the drug, and generally speaking, in these studies, they looked at 20 milligram doses for most patients, or they gave a 15 milligram dose for elderly patients. Because interesting that in the packaging they don't really say that elderly matters or not, but they did give them a lower dose, at least in many of the phase three trials. Speaker 2 16:51 And again, I sometimes wonder, you know, a lot of times there's, honestly, there's their data. We're not always seen where there may have been some preliminary data saying, you know, in the elderly, you may want to target this. You often see that even you know, there seems to be something guiding them, even though you may not have any published data available that says we tried a few patients. And here's Dr. Sean Kane 17:07 what happened. Agreed in terms of the studies, it's interesting that they were placebo controlled trials as opposed to active comparator so we did not compare them to the hypnotic agents like zolpidem or Ambien. But what we did see was, generally speaking, for these patients, it took them about 60 minutes to fall asleep, and if they got the drug, it reduced that somewhere around eight to 10 minutes sooner. So instead of falling asleep after lying in bed for 60 minutes, you lie in bed for 50 minutes. And this was similar at different time points that they looked at in the study. The other main end point that they looked at was how long it took for you to wake up after you fell asleep the first time. And generally speaking, these patients woke up about two hours after they fell asleep. So they had two hours of sustained sleep as an average, and then woke up, and if they took the medication, they got basically another 20 to 30 minutes out of it. So instead of waking up after two hours of sleep, they woke up after about two and a half hours of sleep. So I think at least that second endpoint matters, the first one eight to 10 minutes falling asleep sooner, because it's taking these patients so long to fall asleep. Clinically, you know, I'm on the fence in terms of how much I really care about that endpoint, Speaker 2 18:13 and that's going to be, you know, the issue with it, and is, if that 10 minutes is going to be worth the potential side effects, and some of that, admittedly, there's going to be some inter patient variability there, but it's so it certainly needs to be considered that if you're taking this medication and you're not seeing a big benefit, you know, does that warrant switching? Do you keep adding on medications, hoping that each one's going to add another 10 minutes? Because it may not. They may just continue to stick with you've gotten 10 minutes better, and that may be it. And again, we have to consider, what are the side effects here of these medications as we start to add them, Speaker 3 18:44 and it's really subjective. I mean, 10 minutes to us, clinicians might not look whole lot for but for a patient, a 10 minutes of sound sleep might be work as just as good of a 10 minute nap at night, true. Dr. Sean Kane 18:56 So Dr. Sherman, what are some of those adverse effects that we're trying to weigh this 10 minutes of falling asleep sooner and 30 more minutes of sustained sleep, what are we weighing against that in terms of adverse effect? The first Speaker 2 19:07 thing to look at is going to be, they looked at withdrawal assessment, and then also looked at assessments of psychomotor function. So they wanted to know, if you stop this medication, are you going to have rebound increases in sleep? That has been an issue, you know, with some of the other medications that are already on the market, and also, as I mentioned about ones like Trazodone, is going to be the residual effects the next day. Are you waking up refreshed? Are you still waking up groggy, so that you're having problems with your job? I've had patients that, yeah, had to, you know, they were fired or quit their jobs because they were now getting better sleep, but they couldn't wake up the next morning. So what they found is there was no significant effect of residual sedation the next day in this study. However, other studies did mention it. In fact, it's also described in the package insert. And then furthermore, they did find that there were there were no withdrawal symptoms, and that one seems to be fairly across the board with that one. But then they also found some other side effects, headaches, somnolence, which, to me, is kind of an obvious one, that what we're going for, especially in the evening, dizziness, abnormal dreams, it defines a little bit of increase in respiratory tract infections, and interestingly, urinary tract infections in this study, and then an increase in some of the ALT or some of our liver enzyme assessments. Speaker 3 20:19 And from what we said before, because we did some dose ranging study, we found out that the higher doses were associated even more significantly with the side Speaker 2 20:27 effects correct. And one interesting piece that I pulled out, that they mentioned was that there was one patient who did have a, quote, mild visual hallucination lasting 30 to 60 minutes, and that did lead to discontinuation. They stopped the medication. Speaker 3 20:41 And this was in the 80 milligram control group, right? And so that was Speaker 2 20:45 when they said it didn't happen again. It's something to monitor for the you know, these. Anytime you're working in sleep phases, you're bouncing people between rem and non REM sleep, and sometimes you can trigger episodes. It's thought that perhaps nightmares, traumatic dreams are in non rem and vivid the non traumatic dreams are in REM sleep. In either case, you can see some vivid dreams that could be relatively certain to individuals, depending on which which part of that sleep stage they're in. So it is something to caution with a lot of these medications. Dr. Sean Kane 21:12 And I love that adjective on visual hallucinations were mild, as opposed to visual hallucination that is not mild, which I guess it's like the amount that you hallucinate in terms of what you see. But I don't know that any visual hallucination can be all that mild, unless it's waviness versus seeing a cat walk across the room. I don't Speaker 2 21:30 know, but correct? I think that was just a word to kind of smooth over the data a little bit, but it's certainly hard to quantitatively say, you know, you know what is, what is, you know makes a mild versus, oh, that's quite bad, agreed. The other interesting thing is they really did a good job when they came in and did this study, knowing the issues with benzodiazepines and the Z drugs or our ambient Lunesta Sonata. They really tried to look at some subsequent analyzes, to look at what are the effects on patients with COPD, what are the effects with sleep apnea, and again, as I mentioned about driving performance. So, so among 26 patients with sleep apnea, there was no change in what I call the apnea hypopnea index after a single dose. So not seeing any changes in the amount of time that they're they're breathing versus no, you know, or less, less breathing, or more labor breathing. And then there was a small increase in that, in that index after repeat doses, so maybe a little bit of a change in sleep but for the most part, if you look at the Cochrane reviews, it doesn't seem that this is a major issue with patients with sleep apnea. However, of course, in the package insert and then clinical practice, you're going to want to be really, really, really careful using in a patient with sleep apnea. Speaker 3 22:39 I'm particularly interested in finding out how they actually did the study to evaluate the effect of this drug on driving pattern the next morning. And they're talking about this scale, it says standard deviation of lateral position. SDLP, so do they have some sort of monitor that they put in patient's car and that would assess as to like, how much they're deviating from a straight line. Speaker 2 23:02 I believe what they do is they do a simulation of a driving test. And, yeah, and do, I don't believe it's an actual car, but using a simulator, are able to detect, you know, with that line down the middle, how far they are they deviating from that line, and then go, and again, was the standard deviation laterally left to right on it. So, yeah, they're in a crude way, that's exactly what they're doing, is testing, you know, you take this drug and the next morning Are you going to be weaving back and forth? And so what they ended up finding is that, and you know, other studies with Ambien zolpidem at a dose is like 7.5 milligrams, there were increases in that weaving when they were given the morning after dosing, and they didn't seem to have any clinically meaningful increases nine hours after taking a suvorexant, depending upon regardless of the dose, or even after two to nine days of consecutive administration. Speaker 3 23:49 So I'm guessing the label includes a warning saying, please be careful in driving or operating having Speaker 2 23:55 right now, even though that you know, again, the site didn't show that they still have to be careful in it. In fact, under Dr. Kane, you and I were talking about that, there was also some intro. Also some interesting findings in that study as well. Dr. Sean Kane 24:05 Yeah, so in the study of really, there weren't that many subjects that were doing this driving test, but four of the female subjects actually couldn't complete the test, this standard deviation of lateral position driving test, because they were too sleepy. So had they done the test? We don't know, but I would assume that they would not perform well on the driving test to show that they were or were not impaired while driving. Unknown Speaker 24:28 So basically, they self withdrew from the driving, right? Speaker 2 24:31 So because of things like that, you can say, okay, even though the data looks okay, we still out of precaution. Gonna want you to really be careful with these medications the next morning. And that's something they do emphasize, both on the commercials, the websites, the package and such. Dr. Sean Kane 24:43 So Dr. Truman, as you mentioned earlier, and kind of relates to this, is that sometimes in the clinical trials, we can see some of the adverse effects, but the drug company has really interesting adverse effects. It may have happened, let's say one out of 1000 patients, and if only 1500 patients were ever given. The drug, then you don't know if that's a true, meaningful thing that you should pay attention to or not, until you get more patients taking the drug in Phase four clinical trials. So sometimes you can see those really unique adverse effects within the package insert that you don't really see in those phase three clinical trials. And oftentimes you don't have enough information to know how common it is, but you know that it's something that you should be aware of right? Speaker 3 25:21 One of them catches my attention. We talked about the hallucination with the 80 milligram dose. You know, we talked about mild versus extreme hallucination, but sleep paralysis, they're saying that you after waking up, you might have to just be laying straight, or you can't move after you wake up. That sounds a little extreme to me, and Speaker 2 25:39 they can, you know, that sometimes occurs in individuals with sleep behavior disorders on its own. But yeah, that's going to be about that time in which you're, you know, you're changing the you know, how your body is shifting in and out of REM sleep. So in that REM sleep, when you're having a rapid eye movement, active mind, quiet body, so in that period of time, you're somewhat paralyzed. And if we're changing the body's ability to come in and out of that, we may see that that changes, and where the individual may start to be aware but, but now we can't move there. So yeah, that's gonna be a facet of as we start to you know, these are not again, these are not benign. These have wide reaching effects. So you're gonna see some of that collateral when you when you're adjusting these neurotransmitters. Speaker 3 26:15 So you're saying it's a combination of cognitive paralysis on top of being a motor function paralysis, because some like weakness, is also noted as part of the side effect. Speaker 2 26:25 Yeah, I think again, you may have that you're getting that subjective awareness of what's going on, but then your body is now unable to unable to move. So again, now the mind is active, but, and you're cognitively away, awake and but, yeah, again, you still have some of that lead in paralysis that was still an effect of again being in the sleep stage. Dr. Sean Kane 26:42 So Dr. Patel, to put your mind at ease, the paralysis, the inability to speak, or the weakness, particularly in lower extremities, only lasts for a few minutes after awakening. So if you just kind of hang in there, it'll go away on its own. Speaker 2 26:55 But as you can imagine, that can that can be very disturbing to have that I've had come up a couple times with patients who have mentioned feelings like that, yeah, that could be very disconcerting. Would probably lead somebody to discontinue, right off the bat, if they did Dr. Sean Kane 27:08 have, I mean, think about if that was you, you'd think you're having a stroke, right? Like, exactly, or a TIA, no, you have a whole Tia workup if you're within kind of the group of patients that are at risk for that. Like, that's kind of a big deal. And like I said, this is extremely rare, but it's in the packaging for a reason. It's because they saw this in the clinical trials. Speaker 2 27:27 And then another one to look at is going to be a suicidal ideation. So once again, we're blocking certain neurotransmitters, and if they are, you know, these that are accounting that ability to regulate that sleep wake cycle. And we know that, you know, a lot of these, you know, with serotonin moving to melatonin, there's a lot of play between neurotransmitters and their involvement in mood, and then they're also involved in sleep. And so we did see some suicidal ideations based upon questionnaires here. Dr. Sean Kane 27:52 I think it's important that, like you mentioned, questionnaires versus number of suicides, but also the number of times that patients affirmed positive suicidal ideations was extremely rare, and there was no clear like dose dependent effect on this or anything like that. It's something that I think I'm sure will be monitored in Phase four trials, but it's very unclear, because it's such a rare adverse effect, whether the drug therapy actually promoted this, or if it was kind of a background noise that just happened to come to the surface, because it's something that we're monitoring. Speaker 2 28:24 Certainly this the old adage of correlation, not, you know, causation, that's gonna be the same thing. But you definitely mentioned that, you know, through the FDA MedWatch, and through a lot of these post phase four marketing, we're gonna, we're gonna see if things like that do come up over time. And then I already mentioned about the complex sleep behavior, sleep-driving, sleep-cooking, sleep-eating, sleep-phone calls, sleep-sex, with or without, loss of the memory during the time period have been reported, and that's been seen with a whole lot of medications, or non-benzodiazepines, as we already mentioned. And so it's included in the warning globally for a lot Speaker 3 28:55 of these. Seems like there should be a wristband made for patients who are taking such drugs to say, you know, I'm on such medications that cause me to have such behaviors, and so you know they don't get in trouble, or if they do, then you know there's someone that can help them or guide them. Dr. Sean Kane 29:10 And then finally, we talked a lot about OSA or obstructive sleep apnea and COPD patients and things like that, where we're concerned about depressing the respiratory drive, at least in the packaging. They say that they've tested doses up to 150 milligrams, which, again, the highest approved dose is 20 milligrams, and they did not see a change in oxygen saturation for healthy volunteers. With that said, though, I can tell you that in the hospital setting, oxygen saturation is one of the last things to go when your respiratory drive is very low, a better metric is either respiratory rate, or even better than that, would be exhaled carbon dioxide or your pCO2 level. So they only looked at O2 sat, which isn't the best one, but it is reassuring from kind of an overdose standpoint, that we don't see massive respiratory depression with one. Would be a fairly significant overdose of basically eight tablets of the highest strength, certainly with more than that. We would expect to see that, but at least within the packaging, we don't see that Speaker 2 30:10 certainly and again, though, given the limited data we have, it's still going to be room for monitoring it in cases of polypharmacy. So if you're on other anxiolytics, maybe benzodiazepines during the day, or you're on opioid medications for pain, or if you're on other medications for sleep on top of it, then you really do want to be aware of the potential for the any kind of synergistic or additive effects. Dr. Sean Kane 30:32 So a couple other things to note about Belsomra. One is it is a schedule, a DEA schedule IV medication, and the reason for that is they actually gave patients a questionnaire about how much they liked the drug. And this was similar in how much you liked it compared to a pretty big dose of Ambien or zolpidem. To give you reference, 15 to 30 milligrams of zolpidem was very similar in how much patients liked the drug compared to a pretty big dose of Belsomra. Speaker 2 30:59 The one thing I have to get to and Dr. Patel, you mentioned this at the beginning about, you know, someone who's being concerned about increased reliance on medications versus treating non pharmacologically. And I have to say, I really do not like the commercials for Belsomra, if anyone's seen it, we have this nice white cat and then this mean, nasty gray looking cat. And the nice white cat's what helps you to sleep, and this gray cat is what helps keep you awake. And it seems to me to convey this image that the onus is on the individual to go get the medication, something to help me get my sleep back, versus what kind of non pharmacologic, what kind of things can am I doing that is making my sleep harder? They say, you know, it seems to be okay, you know, there it's not, it's not you as an individual that sleeps just running out the door like a cat, and you've got to somehow get the good cat to come back and get nothing about sleep hygiene, nothing about, you know, being caffeine intake, or the environment. It's just, it's just something that's there or you're not. It's just buying or anything. I don't have sleep. I want sleep and take a pill. It gives me sleep. And that's it. Dr. Sean Kane 31:55 This goes really well to, you know, direct to consumer advertising. Of is that the right message, legally, they're allowed to do that. But is that really the right message that we're trying to send the patient, and is it appropriate that we have the ability for a direct company to provide that message to a patient? Speaker 3 32:12 Because if you look at most of diabetes medication commercials, you will see that they portray the person being active, eating salads or engage in some sort of physical activity, and it's a behind the scene message that, yes, the medication is going to work if you have an active lifestyle, if you have the good lifestyle modifications working for you. But there was no such thing shown in this commercial. And besides the fact that those cats were just pretty much creepy, yeah, very creepy. Dr. Sean Kane 32:38 And unfortunately, from a critical care point of view, there's very little direct to consumer advertising, so I feel very left out of the who's got better, worse commercials, but guess I'll have to deal with it. So Dr. Schuman, what are, let's say, four pearls that you would either encourage a provider to know about or something that you'd actually tell a patient to really emphasize and drive home during patient counseling, Speaker 2 32:59 driving home is actually one of the things we do talk about is, yeah, is going to be being careful of the next day drowsiness, as I mentioned, you know, especially on the higher doses, like 20 milligrams, being careful while driving, especially, you know, until you do have a complete idea about what it what it's doing on you and and minimal dose, effective dose, for an individual, that I would consider, if You are on it long term and you are finding benefit, to consider, or for your patients to consider, going down on those and giving a trial of it to then see if the individual is able to take that dose instead. Because, once again, they're not benign, and there can be that additive, cumulative effect of a medication over time. So to mitigate that, bring down the dose a little bit, and then also being careful with alcohol and other CNS depressants. So again, as I mentioned, opioid medications, benzodiazepines, other medications for sleep, even other sedating antidepressants, for example, being aware that you have to be careful about the number of all these other medications, and some of them may have their own effects on sleep apnea, have their own effects on sleep latency, or residual sleep the next day. So just to be aware of that, and the Speaker 3 34:04 most important thing you mentioned was to make sure they take it without food in order to have the onset of action start as soon as possible. So that's one of the counseling points correct. Speaker 2 34:15 We talk a lot of times about other medications that take it with food to decrease stomach upset, but a lot of these, medications, I said both Ambien, zolpidem and then suvorexant, or Belsomra Empty Stomach to then help with that absorption rates. Dr. Sean Kane 34:27 Just to drive that point home again, think about the efficacy of the drug. So if the drug helps you fall asleep, let's say 10 minutes quicker, but if you take it with a high fat meal, that may extend out the onset of the drug by 30 to 60 minutes, which almost certainly would negate that benefit of quick onset of sleep, Speaker 2 34:44 and then again. And then out of that, though, what does the individual do? If that's the case, they take a higher dose of the drug. And now what we're seeing is now we're more likely to see the residual sedation the next day, and so by either taking it earlier in the day, or, in this case, taking without food, we can we're. We can get it, get better efficacy in the beginning, and then hopefully not have further issues down the road in the morning. And then lastly, there does not appear at this time to be any major concerns about withdrawal dependence or rebound insomnia, although this is something that is going to come out a lot in post-marketing reports, and I'm sure Dr. Kane and things like ER visits for some of these effects, or as we're looking at addiction facilities, it'll see these reports and number of patients admitted on this on medications, that would be the kind of places where this data would come out, whether or not it was an issue. Speaker 3 35:33 So Dr. Schuman, looking at the evidence we have available so far and the risk and benefits from these trials that we have available. Where would you put this in the therapy cube? Speaker 2 35:45 I would, again, first, first thought always is going to be about sleep hygiene. So we're going to look at, have we limited caffeine later in the day? Are we on are we on medications that increase alertness, whether it's a stimulant, certain kinds of antidepressants? What are they like? What is housing environment like? Is temperature discrepancies, loud music? Are we texting in bed? Are we reading in bed? Other behaviors that you get the mind thinking, Oh, hey, I should be active for this. And so then you now created this association where now your body likes to be active when you're supposed to be asleep, looking at all those things, looking at different lights, whether they're in sight, even looking at blue lights and different kinds of bright lights in the room. Have we eliminated those things then and only then? Do we start looking at medications? And I think, honestly, I believe that I think this one may be, may be appropriate as kind of a first line for treatment of primary insomnia in individuals, right along with short courses of your your Z drugs, or perhaps some of your antihistamine anticholinergic medications, like our diphenhydramine, hydroxyzine, things like that. Some of these other ones that, again, may be more off label, but they can be considered as well trazodone again, and then it's going to come down to a lot is individualization based upon the patient specific factors. So once again, you know, looking at the age of the individual comorbidities of other medications that that will guide which one you choose, but I think it honestly can be in that conversation with those others, cost, Though admittedly, is going to be one thing, and so I do, I cannot get away from fact that, yeah, it's going to be a lot pricier than those other medications, so that, in and of itself, may be prohibitive for a lot of individuals, but if insurance is covering it, or we're thinking down the road, and cost is not an issue, again, I think it could be listed in the same breath as some of those others. Dr. Sean Kane 37:31 So Dr. Patel, I would imagine, if you haven't been visited already, that this would be kind of green pastures for drug reps, right? Speaker 3 37:37 Yeah, we have seen the reps in the clinic so far, and what they have provided is the patient assistant called a card. Dr. Sean Kane 37:44 So at least for me, I'm a little afraid of the the idea that it's kind of a new therapeutic target, and I'm curious to see what happens down the road in terms of what other unique adverse effects pop up that we didn't see with those Z drugs. And we don't have any comparative data to say that this is definitely better or worse than anything else that we have. So I would kind of echo what you said. Is probably fine, but if it was me, I would probably use the things that we've been using for a long time just to wait and see what happens as patients begin taking this more often, Speaker 3 38:13 absolutely and without the comparative data available, I think it will be really hard for the insurance company to put this on the formulary, and even if they do, they probably will be a non preferred brand, which could be a higher copay that might not fit patients pocket, Dr. Sean Kane 38:27 or that you have to prove that you failed a Z drug before you're able to qualify for this drug. Absolutely right? Speaker 2 38:32 And then other things that you had mentioned just at the beginning, Dr. Kane is about you know that the potential for other medications, whether it's me-too drugs or to start looking at those more selective orexin receptor antagonists. And again, as you mentioned, you know, down the road, do we learn more and more? Do we find out? Oh, no, one of those receptors is a problem, the other one's fine. Do we and therefore selectivity is better? You know, those are the kind of questions that may need to be answered down the road. Dr. Sean Kane 38:56 So you're saying we may see dex-suvorexant, or suvorexant Could be, well, I think time to wrap it up. So we've discussed suvorexant or Belsomra. It may appear to have some role in insomnia, very similar to some of the Z drugs that we've already discussed. Speaker 3 39:12 And it's still it's an infancy stage in terms of the label warnings and whatnot. So we're waiting for the phase four trials to come up to have further understandings of the safety parameters. Dr. Sean Kane 39:23 Yeah. So with that, if you haven't done so already, please go to iTunes, type in HelixTalk and give us a five star review. We love them. If you'd like to visit us online, we're at HelixTalk.com with that, I'm Dr. Kane, I'm Speaker 3 39:34 Dr. shoeman, and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 39:38 Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science. For more information about the show, please visit us at HelixTalk.com. You.