Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 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 - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 169 I'm your co host, Dr. Kane, and I'm Dr. Patel, and I'm proud to announce today's episode entitled introducing HelixTalks 2023 drug superlative awards. So for the listeners that recall way back to Episode 128, in March of 2021 we actually had the debut of the HelixTalk drug superlative awards. These are awards that are kind of given because of a notable thing about a drug or a drug class. And we decided it was about time to have a new round of those awards. Dr. Khyati Patel 01:05 Dr. Kane, this is my favorite episode, because a, you know, they're hilarious, and B, we are learning something new. I am learning something new too. So I know back in March, we talked about, you know, things like drugs that is most likely to remember for covid 19 ineffectiveness, rather than its FDA indication, aka hydroxychloroquine. We were talking about commonly used but the worst antihypertensives that are in the market, like atenolol and hydrochlorothiazide. Dr. Sean Kane 01:36 And then we also covered the most confusing dosage form, which was valproic acid or divalproex or valproate sodium, all three. The same thing. We also covered the most innovative pro drug, which was valacyclovir. And then finally, the hottest inactive ingredient, which was actually a tie for sulfo butyl beta cyclodextrin, or s, B, E, C, D, the Excipient in remdesivir. And also tie for polyethylene glycol, or peg, which was one of the excipients in the mRNA vaccines for covid 19. Dr. Khyati Patel 02:08 So that's just the gist of what the superlative awards are. And you know, those are kind of voted upon by your co hosts here, Dr. Kane and Dr. Patel. And really they're just fun. I know in the long run, they're meaningless, but we are learning some nuances along the way, clinical pearls, pitfalls, weird study designs, whatever you call it. Dr. Sean Kane 02:34 And you know, I would encourage the listeners, as we kind of announce today's four awards, to think about before we say what the Award winner is, what would you award? So either, do you have kind of an innovative award that you would hand out to a drug or drug class or category, or as we announce what the award category is, what drug do you think is going to win that award? It's kind of fun to play along. And of course, if you have award suggestions, you think we've missed something. Go to our website. Helix, talk.com and reach out to us and let us know what award or recipient you think would be deserving of a future. Helix, talk, superlative award. Dr. Khyati Patel 03:12 Dr. Kane, I am totally ready. Let's roll these out. Dr. Sean Kane 03:15 All right, so. Dr. Patel, the first award is the most unique phase three patient population for a widely used medication. And just for context here, when we say widely used, we're not talking about orphan drugs. We're talking about a drug that is commonly used by a lot of people in the United States. And again, the award is the most unique phase three patient population. Dr. Khyati Patel 03:38 Drum rolls. What could this one be? So? Dr. Sean Kane 03:41 Dr. Patel, today's recipient is Pneumovax 23 or ppsv 23 the pneumococcal polysaccharide vaccine. Unknown Speaker 03:50 And why is that? Well, so let's Dr. Sean Kane 03:53 get some background here. So this was first FDA approved way back in 1983 but there are actually other variants or similar polysaccharide pneumococcal vaccines that came up before it, but those are no longer in the market. And the reason that this is winning the most unique phase three patient population superlative is that way back in the 1970s similar polysaccharide vaccines were studied and eventually led to the approval of Pneumovax 23 and it was studied in South African male novice gold miners that were aged 16 to 58 Speaker 1 04:30 and if I would think about that, Dr. Kane, it doesn't fit our normal patient population. So how did they even get approved? Dr. Sean Kane 04:37 Yeah, so let's go back a little bit of like, what exactly is the pneumococcal vaccine. And then we'll go back to what on earth are we doing with novice South African gold miners? So Pneumovax 23 is a capsular polysaccharide antigen vaccine, so it contains 23 common serotypes that are specific to Streptococcus pneumoniae or pneumo. Dr. Khyati Patel 05:00 And Dr. Kane, from what I know, we're kind of moving away from the polysaccharide vaccine, right? Because we have a lot of those conjugated vaccines out now. We have that PCV 713, 15 and 20 Dr. Sean Kane 05:12 and etc, totally, yeah. So this is somewhat unique in that we don't have very many polysaccharide vaccines, but this one is still on the market, and this is actually how it was originally studied in its polysaccharide form, again, way back in the 1970s in South African novice gold Dr. Khyati Patel 05:27 miners and those for our listeners who want to catch up on pneumococcal vaccine recommendation updates, we recorded that in our episode 152 so why does it really get the superlative award for the most interesting phase three patient population. Dr. Sean Kane 05:45 Yeah, so if you go back to 1977 and we actually have the original article in our show notes, there are a couple different studies at the time, but one of the ones was published in JAMA 1977 and they technically studied a six valent ppsv vaccine. So again, we have the 23 valent, 23 different serotypes that are covered. This was a six valent ppsv vaccine that was eventually the, you know, it was the predecessor to Pneumovax 23 so it turns out that in the 1970s in South Africa, if you were a gold miner, you were at a ridiculously high risk of getting Streptococcus pneumoniae or pneumococcal pneumonia. This was actually a fairly common disease at the time. Unknown Speaker 06:29 And when you say common, how common was this? Dr. Sean Kane 06:32 Yeah, so in that JAMA article, the attack rate in South Africa was about 90 cases per 1000 person years. And again, just for context, in the US at the same time, the risk was about one to five cases per 1000 so it was literally 20 to 90 times more common to get strep pneumo pneumonia in South Africa if you're a gold miner versus if you were in the United States. Dr. Khyati Patel 06:58 So then it, of course, makes sense. You know, in order to study the vaccine or a drug, you know, it's best studied in a population that has this condition the most Exactly. Dr. Sean Kane 07:08 So it makes sense that the vaccine manufacturers would want to study in a high risk patient population, which happened to be those in South African mines. In terms of men, it turns out that not a lot of women in the 1970s in South Africa were gold miners. So that's the study. Doesn't explicitly say what percent were men, or that they were only looking at men, but in the package insert, it does say that men were exclusively included in the study. Dr. Khyati Patel 07:35 And so that makes sense. But then what is the deal with young miners and not the old miners. Dr. Sean Kane 07:42 Again, they they looked at novice or young gold miners. And the rationale here is that if you've been a gold miner in the 1970s in South Africa, long enough, you've probably been exposed to enough pneumococcal disease that you have developed kind of a natural immunity. So they were focusing on identifying patients essentially, or study subjects that hadn't been gold miners long enough to develop that natural immunity, so that they would derive benefit from a vaccination. Dr. Khyati Patel 08:09 Well, so that makes sense, too. But if I were to look at that study and try to think, oh, now I'm going to apply those results to my patient population, I wouldn't think it holds a whole lot of external validity, Dr. Sean Kane 08:21 totally, and that, of course, is like the concern, right? So it's great in the vaccine was super effective in South African gold miners, but is it equally effective in the 60 year old COPD patient who lives in Michigan, right? Fast Forward 50 years from that 1977 study, we've actually studied a variety of different pneumococcal vaccines in a variety of different patient populations that aren't South African gold miners. And of course, the incidence rate outside of that South African population is a lot different. And of course we want to have data supporting that. It's a vaccine that will work and is effective and cost effective in a variety of patients. Dr. Khyati Patel 09:00 So in that sense now the CDC vaccine recommendations have changed, as we said. You know, we have recorded that in episode 152, so we're now going with PCV 15. And if you are using PCV 15, you got to follow it up with the ppsv 23 a year later, in some high risk group. It's a little bit shorter time interval between the two, or you can consider just PCV 20 and be done with it. Dr. Sean Kane 09:28 And of course, we still have PCV 13 for children on the market, and you'll still see things like PCV seven, which is an older version that's not recommended anymore in literature. In terms of there are a variety of different vaccines that have been developed over time, so naturally that can tell, you know if we have these in the US, and if we've been vaccinating in the US, hopefully, at least have some data that vaccinating either kids in the US or high risk adults or older adults, that it is effective, right? That would be the thing that we'd like to prove. In clinical studies in the US, not just in South Africa, yes. Dr. Khyati Patel 10:03 And that's the effectiveness that would be, you know, we were kind of gaging. Or maybe CDC would be, look a CIP would be looking at to then say, you know, let's approve it or make a recommendation on it. What is the effectiveness for these vaccines in adult and children population? Dr. Sean Kane 10:21 Yeah. So we have two meta analyzes that are linked in our show notes. Obviously there's a variety of different serotypes, patient populations, things like that. So we are very much abbreviating The effectiveness and efficacy of these vaccines, but generally speaking, in adults, which is typically the patient population studied, is going to be 60 or 65 years and older. So we're really looking at older adults. The meta analysis that we've linked looked at the vaccine efficacy, so how well it worked in a clinical trial, then also the effectiveness, which is how well it worked in observational studies after the trial was done in terms of a real life patient population, and they typically look at invasive pneumococcal disease, which means getting meningitis caused by strep pneumo or pneumonia caused by strep pneuma, where you're also bacteremic. So it's not just pneumonia, but you have to have pneumonia with bacteremia. They also separately look at pneumococcal pneumonia, so those with or without bacteremia. So if you look at the conjugated vaccine, PCV 13. It's the best so it's effectiveness, and efficacy ranges about 50 to 75% so that means that it reduces the risk by 50 to 75% of getting invasive pneumococcal disease, and the reduction for pneumonia is about 40 to 70% reduction. So it's pretty effective for both invasive pneumococcal disease and also for just run of the mill pneumonia. TPS fee is not as good. So for invasive disease, its effectiveness is about 50% or so. And to prevent pneumonia, pneumonia caused by strep pneumo, it's much lower. So the vaccine efficacy is about 18% which is pretty poor. And there's some irony Dr. Patel that usually, just for simplicity, we call this the pneumonia vaccine. But actually in adults, it really isn't that effective for pneumonia in terms of ppsv 23 Dr. Khyati Patel 12:14 that's very interesting. And when we look at the data and in kids, where these vaccine, again, you know only the conjugate vaccine has been studied in this patient population, not the polysaccharide. We were looking at kids younger than two years of age. And so if you look at the efficacy again, that's, you know, invasive milk, cockle disease, it's about 90% pretty good. Kids tend to have ear infections, so otitis media, 55% efficacy. And then the radiograph confirmed pneumonia, about 30% efficacy. Dr. Sean Kane 12:47 So again, kind of interesting that we clearly see a pattern that both the conjugate and polysaccharide vaccines are really, really good at preventing these more invasive diseases, like especially meningitis or a pneumonia that causes bacteremia, and really, they're not nearly as effective at preventing pneumonia caused by strep pneumo that doesn't give you this severe bacteremia and things like that. Dr. Khyati Patel 13:11 Well, that was pretty neat to learn. Dr. Kane the history behind the pneumococcal vaccine and how it was studied before I'm ready to move on to our next one, if the first one was that good, Dr. Sean Kane 13:22 all right. Dr. Patel, the next one is the most misunderstood boxed warning award. So this award goes to a drug with a boxed warning, where you look at it and you think one thing, but really, there's a lot more going on under the surface. Unknown Speaker 13:36 Hmm, what could this one be so? Dr. Sean Kane 13:40 Dr. Patel, the winner of this award is all of the doacs, but specifically rivaroxaban and apixaban. And the box warning that we're focusing on is, quote, premature discontinuation increases the risk of thrombotic events. And if you read on, it says premature discontinuation of any oral anticoagulant increases the risk of thrombotic events. Dr. Khyati Patel 14:01 So then this should apply to other anticoagulants, such as enoxaparin or Warfarin as well, right? Dr. Sean Kane 14:08 So you'd think so, but they actually don't carry that boxed warning. And you know intuitively, and this is why it wins the superlative award. It's kind of a no duh scenario, right? So of course, if you stop an anticoagulant, your risk of thrombosis goes up because you're stopping something that thins out your blood and prevents clots, so you're more likely to have clots. And this is where the misunderstanding comes in terms of the doac box warning. Dr. Khyati Patel 14:33 So in theory, that does make sense, but is there data to show that it really does increase the risk of thrombotic events? Dr. Sean Kane 14:41 It does, and most of this data actually comes from non valvular AFib studies for doacs, again, more specifically with rivaroxaban and apixaban. But theoretically this is a concern for all of the doacs, and really what happened in these clinical trials. Just to give you context, Dr. Patel, so when rivaroxaban was first studied for afib. And the patients that were in that trial, they got either a doac or they got warfarin. At the end of that phase three trial, riveroxaban, as an example, was not an FDA approved drug yet for non valvular afib. That's why they're doing the study. So if you're a patient in the study and you're on riveroxaban, you can't continue rivaroxaban because it's not a drug approved in the United States yet. So you would then, if you still are indicated for an anticoagulant, you'd have to switch to warfarin, which would be the most common scenario, that you'd go from your study drug of rivaroxaban to now warfarin. So the reason for this box warning occurring is that they did analyzes of that transition period where they looked at people who were randomized to riveroxaban or pixabane or another doac, and when they were transitioned from doac to warfarin, they looked at their bleeding and clotting risk over the next 30 days and compared that to people who were randomized to Warfarin in the trial and then continued Warfarin after the trial was done, and again, looked at bleeding And clotting risk in that 30 day post study period. Dr. Khyati Patel 16:05 And so basically, it turns out, based on the results we have, that that transition from doac to Warfarin was the danger part. And so we have data from for apixaban from Aristotle study and for roxaban from rocket AF study. Can you summarize what we found? Dr. Sean Kane 16:21 Yeah, so in short, so we looked at hazard ratios. So this is like quantifying the risk of certain events. If you started on a doac and got converted to Warfarin versus stayed on warfarin and continued on warfarin. So if you went from doac to Warfarin and Aristotle with a pixabane, your risk of stroke or systemic embolism, was 4.1 times higher if you had that transition versus if you just continued on warfarin. So literally, four times the risk of having a stroke if you transition from doac to warfarin. Interestingly, the risk of major bleeding was also quite a bit higher, too, about two and a half times higher if you made that same transition. And this is kind of interesting back to tell, because usually we don't see in a clinical trial of an anticoagulant, but we have an increased risk of bleeding and clotting. Usually it's kind of a trade off, that if you increase bleeding risk, usually the cladding risk goes down, or vice versa. It's unusual that we see both bad things going up with this transition Dr. Khyati Patel 17:21 and the river rock Sabian in the Rocket Air trial wasn't too far from the results of the Aristotle study. Is that right? Dr. Sean Kane 17:29 Yeah. So again, in both cases, it was basically three to four times the risk of both having clotting events, so stroke or embolism and major bleeding events. So the hazard ratio is 3.7 and 3.6 so again, very elevated risk of having these very dangerous adverse effects or lack of efficacy when you're transitioning from doac to Warfarin that we did not see in patients that were on warfarin and stayed on warfarin. Dr. Khyati Patel 17:56 And it makes me wonder why that was the case. That's really interesting. Dr. Sean Kane 18:01 Yeah, and we don't know for sure. We do have some data with doxedan that says that maybe it was because we didn't plan that transition as well as we could have in Aristotle and rocket AF and these two trials, they didn't really provide a lot of guidance to the investigators on how to go from the doac to warfarin. So because the investigators didn't have a lot of guidance. There's some data that says maybe they didn't check INRS as often as they probably should have. They didn't overlap in some cases in terms of, you know, stopping the doac, starting warfarin. So these patients probably had some period of time where their, you know, INRS were not therapeutic, and the doac was completely gone from their body. And there's a lot of thoughts in terms of maybe that transition could have been tighter. And in the case of edoxaban, they did have more explicit transition instructions, and they actually did not see this increased risk of bleeding and clotting during that transition period. Dr. Khyati Patel 18:54 And so Dr. Kane, you know, in my clinical scenario, most of the time I'm getting requests to change from Warfarin to a doac because they're tired of INR monitoring and drug interactions and stuff. In some instances where cost is a concern or maybe a doac failed, I would get it across to change doac to Warfarin based on the data, though it seems like you know that is a little bit of a risky switch, and only consider in certain patient population Dr. Sean Kane 19:21 absolutely so if you can avoid doing this, you should avoid doing it. Obviously, there's going to be a couple of patients where they now have valvular afib, instead of non valvular AFib because of, you know, more severe mitral stenosis, or they were on a doac and now they have a mechanical heart valve. Or they were on a doac and now their renal function is so poor and they can't take a pixodan that they really need to be on warfarin. So as clinicians, we just need to be aware that this is a really high bleeding and clotting risk when this happens. And again, the box running only talks about the clotting risk, but it really doesn't emphasize that transition period enough, in my Dr. Khyati Patel 19:56 opinion, and that transition should be. Done really carefully. And so, you know, normally what we do in this instruction, perhaps wasn't available to the study investigator, is that we overlap the doac and warfarin, until Warfarin is started to work and we see an INR of, you know, the therapeutic INR above two, so two, between two and three. And we know Warfarin takes a few days to get to that INR, so you're going to have a patient taking both the doac and Warfarin during that period of time. We know that doacs are anti 10 days, especially your rock Saban and apixaban, and they tend to end up affecting the INR depending on when the last dose was taken. So know that INR might be falsely slightly elevated, but as long as your patient is above two, then it's okay at that time to discontinue the doac and then continue the warfarin, perhaps in this scenario too, as we alluded, probably checking the INR a little bit more frequently, would be advised too. Dr. Sean Kane 21:05 Yeah, and Dr. Phil, this is a very similar approach to if you have a patient taking warfarin that has a new drug interaction, that is a manageable drug interaction, the easiest thing is to just check INR more often, because you know that you're going to potentially need to titrate that dose a little bit more often than you normally would. So if anything, I think just awareness that this transition period is a dangerous period and that you have to be on your toes a little bit more than maybe you you might think you need to be. Dr. Khyati Patel 21:31 Yeah, you know, my anti coax service Doctor Kane is mainly Warfarin management, but any patient transitioning from, you know, Warfarin to doac, or even the other way around. I'm always offering that closer monitoring and say, you know, we will, we'll help you come up with the dose. We'll help you transition. We'll come up with a regimen for not just dosing, but also monitoring. And that's all based on, you know, this data, where that that transition is pretty risky, absolutely. Dr. Sean Kane 22:00 Well, Dr. Patel, our third award is the biggest difference between pharmacokinetic properties and pharmacodynamic effects. So again, this is a huge difference between how long the drug stays in the blood versus how long the drug acts on your body. Unknown Speaker 22:16 I have some guess for this one. Dr. Sean Kane 22:20 Alright, so aspirin is our winner today. And really we're focusing on the anti platelet effect as opposed to the analgesic effect, but we'll certainly use both to kind of draw the contrast between its pharmacodynamic properties. And you know, if you look in UpToDate, Micromedex, anything like that, aspirin has like a weirdly short half life. So aspirin itself has a half life of 15 to 20 minutes, but it's quickly hydrolyzed to kind of its active component, which is salicylate. And so esterases in your body convert aspirin to salicylate very quickly. But even if you look at salicylate, its half life is still fairly short. So we're looking at three to six hours. And it does depend on how much drug is in your blood. So the higher the concentration, the longer the half life will be. Dr. Khyati Patel 23:08 And for most drugs, the therapeutic effects you know, usually will last a few half lives until the drug is nearly completely out of your body. In this case, you know, if you're thinking about half life of three hours, three to six hours, let's go with three hours. We would expect that the aspirin therapeutic effect would wear off in six to nine hours. But that's not the case. Dr. Sean Kane 23:33 Yeah, it's not the case for the anti platelet effect. So from an analgesic effect, usually you're going to dose aspirin every four to six hours. So if you're taking it for headache, for example, or fever, which is not commonly used anymore, but if you were to it would be about every six hours that you're needing to redose, which is what you would expect based on its half life. But for the anti platelet effect, patients take this once a day, so every 24 hours, which isn't in line with that half life of kind of lasting six to nine hours. And when we actually look at the anti platelet effect itself, the anti platelet effect will last for up to 10 days. So somewhere seven to 10 days ish, depending what reference you look at. So that's actually not what you'd expect. You'd expect it to not last up to a week or longer, based on a half life of three hours, Dr. Khyati Patel 24:22 and the plot thickens as to why that is the case, right? So, Dr. Kane, we talked about NSAIDs in general, way back in May 2019, Episode 95 and where we covered a little bit of that pharmacology, of how NSAIDs work, we know that they inhibit Cox two enzyme and Cox one enzyme, the Cox two is primarily responsible for blocking that pain, inflammation and fever versus Cox one inhibition leads to that antiplatelet activity, and Dr. Sean Kane 24:55 it turns out that many of our NSAIDs block both of these pathways, but at different. Ratios with aspirin, it does bind to Cox two, but not very well, so you need much higher doses, and it doesn't stick to the Cox two enzyme and inhibit it for as long of a time as compared to its Cox one inhibition. So this is why when you treat a headache, for example, you're going to give aspirin at 325 all the way up to 1000 milligrams every four to six hours for pain or fever or headache, you need these higher doses to be able to inhibit Cox two effectively. And even when you do it, it's kind of a weak binder, so it doesn't really stick to the Cox two enzyme very long, which is why you're having to redose it based on the frequency of its half life, which is kind of what you'd expect. Dr. Khyati Patel 25:41 Now, if we turn around to Cox one, the story is much different. It binds to Cox one, really, really well, even at lower doses. So we are talking, you know, 81 milligrams once daily, for its anti platelet effect. And this, this finding is irreversible. So literally, the aspirin is bound to the platelets forever, until the platelets are gone. And so really, then we're looking at that 10 day, that seven to 10 days generally the lifespan of platelets in your body. Dr. Sean Kane 26:15 So literally, the body has to make new platelets. It can't use the existing platelets, because those existing platelets have been bound with aspirin. So this is a great example where even though, if you drew an aspirin drug level of a patient's blood, and they have no aspirin left over, because they've metabolized it all off, it's been all eliminated within, you know, six to nine hours, the pharmacodynamic effect of its anti platelet will last for the duration of the platelet life, because it's a covalent, permanent bond that will never let go, and the body literally has to make new platelets. Dr. Khyati Patel 26:49 And how do we translate that into clinical practice? So in in patients who are on aspirin, you know, and if they are going under surgery and stuff or procedure where, you know, bleeding risk is higher, and we would want to stop the aspirin, we would typically tell them to hold it for seven days before we can, you know, they can, quote, unquote, go under the knife. Dr. Sean Kane 27:09 And of course, it's going to depend on the type of surgery and things like that. There's many surgeries that you can do while they're on aspirin, but it does absolutely depend on the kind of surgery and other patient specific factors, right? Dr. Khyati Patel 27:21 And that's where you will lay out the risk versus benefit of continuing versus stopping, absolutely. All right? Dr, Kane, I'm kind of sad we are coming towards the last superlative award, but I'm also excited to hear what that would be, yeah. Dr. Sean Kane 27:36 So kind of in the spirit of a HelixTalk, superlative award, this one's a little funnier, I guess. But this award is entitled The drug that should be dispensed with extra toilet paper. Dr. Khyati Patel 27:49 Now we wouldn't be talking about this if we were talking about that toilet paper spike that happened in post covid, right? Dr. Sean Kane 27:56 Absolutely so in the maybe in the context of the days and things like that. We'd have to change the award, but at least for in a post covid environment with plenty of toilet paper available in the grocery stores, we're going to go with the extra toilet paper award. And this is actually a tie. Dr. Patel, so the CO winners of this award are I run a T can and clindamycin. Dr. Khyati Patel 28:17 Oh, I remember I even on T can. We learned that as I ran to can Dr. Sean Kane 28:22 or the toilet, right? So we'll start with I run a T can. The brand name is camp to SAR, and this is a chemotherapy agent for a variety of cancers, mostly GI cancers, but also ovarian, pancreatic, lung cancers, things like that. And to be fair, I learned the exact same thing of I ran to the can or the toilet. I ran a T can Dr. Khyati Patel 28:42 I guess both of our schools have taught it the same way. I don't remember this chemo regimen, but I do remember irinotecan really well. And so some examples of chemo regimen where you can spot irinotecan is foleyri or folferinox, where the IRI part stands for irinotecan. And how does it end up causing diarrhea? Yeah. Dr. Sean Kane 29:06 So in terms of its mechanism as a chemotherapy agent, it's a topoisomerase one inhibitor. So topoisomerase one is an enzyme that's responsible for kind of breaking apart double stranded DNA to allow for DNA replication. So what happens is irinotecan will bind to that enzyme, inhibit it, and the cell will accumulate what's called cleavable complexes. It's basically where it's trying to replicate DNA, but it can't, and it just kind of stops because it doesn't have this enzyme responsible for DNA replication. And eventually the DNA strands will break or become damaged, and that causes cell death. Dr. Khyati Patel 29:43 I assume that this diarrhea side effect is significant enough, because it has even earned its place in the box warning, Dr. Sean Kane 29:52 yeah, and I'm sure there are other drugs out there that have box warnings for diarrhea. But in the spirit of I run to the can where I. T can, I think we have to give the award to this drug. And just for completeness' sake, docetaxel. And again, oncology is not our area of expertise, but I think it's worth mentioning more for the NAPLEX studies out there that Irinotecan also has a box warning about myelosuppression. But again, we're focusing on the diarrhea here, right? Dr. Khyati Patel 30:20 And normally we see that early diarrhea. And so in the case of, you know, chemotherapy in general, you have the acute diarrhea, which we call it the early diarrhea, and we have the delayed diarrhea, which we call delayed diarrhea, and it's very similar to the acute nausea versus delayed nausea as well. And so with this drug, the early diarrhea usually happens within 24 hours of infusion has to come from drugs cholinergic symptoms. So anticholinergic, everything is dry, cholinergic everything is wet. So here we're talking about rhinitis, you know, increased salivation, sweating, flushing, bradycardia and diarrhea is also caused by increased peristalsis, which is a cholinergic effect. So we are seeing that, you know, post 24 hours infusion, and I bet you, you know, in any given patient education material where this is part of their chemo regimen, they will be warned about this, and they will be given medication to reverse if that happened. Yeah. Dr. Sean Kane 31:26 So if this does happen, atropine would be the typical drug given. Atropine is an anticholinergic, so it's going to block those cholinergic effects of that earlier, within 24 hour of infusion, diarrhea. This is actually very preventable and treatable. This is not really what irinotecan has earned its superlative award for, but of course, it is a form of diarrhea caused by the medication. Speaker 1 31:52 And then what's the deal with the delayed diarrhea? Dr. Kane, Dr. Sean Kane 31:56 so this is where most of that box warning comes from. So late or delayed diarrhea. This is happening more than a day after the infusion. This is a completely different animal. We see a ton of diarrhea, and it's less treatable. So basically all but if you look at the package insert, we're looking at, 80 plus percent of patients will report having this late diarrhea, and of the people who receive the medication, about one in three will have grade three or four, which is severe, late onset diarrhea. So we're talking like many, many stools per day, which would be grade three or four diarrhea. Usually this happens, not, you know, 25 hours into it, but usually this happens one to two weeks into therapy, and it probably is not caused by those cholinergic problems, but more just cell death of the GI tract and things like that. Dr. Khyati Patel 32:46 And so Dr. Kane, you know, when I'm thinking about grade one, grade two, diarrhea, I'm thinking me and dehydration, you know, rehydration fluids and stuff. But grade three and four sounds way out there. There has to be some severe complications that are resulting from here? Dr. Sean Kane 33:02 Yeah, and there definitely are. And you'll see that this is the most common dose limiting factor when it comes to irinotecan. So if a patient can't tolerate irinotecan or they need a dose reduction, diarrhea is the most common reason why, and that's despite the treatment that we'll talk about in a second. And of course, the the concern here isn't so much the inconvenience of diarrhea and needing a lot of toilet paper, but there's actually like life threatening complications caused by the diarrhea. So these patients can get colitis, ulcerations in their GI tract, bleeding, perforations, dehydration, sepsis, all things related to having many, many stools per day caused by this severe diarrhea, and that's really the concern with the drug. Dr. Khyati Patel 33:46 And the go to medication for this late diarrhea from irinotecan is loperamide. And you know loperamide, if you use it just generally, not even in the case of this drug induced diarrhea, the dosing is different. But when we're going to use it for this like grade three, grade four, severe diarrhea, you're going to be a little bit aggressive with your loperamide dosing. Dr. Sean Kane 34:08 Yeah. And just to give context to the dosing, most patients that take loperamide for kind of acute diarrheal illness, they don't need that many doses. Like sometimes one or two doses will get the job done. But in this case, the dosing recommendation is four milligrams up front and then two milligrams every two hours, until the patient doesn't have diarrhea for half a day or overnight. Instead of waking up every two hours, they can take four milligrams every four hours. So basically, this is just a more aggressive dosing frequency than what you'd normally see for acute diarrheal illness that isn't related to irinotecan. Dr. Khyati Patel 34:43 And there are some small studies that show that, you know, there are patient who would have loperamide resistant diarrhea from irinotecan, meaning they dose that no higher doses of loperamide, and it still is not working for them. This is a, you know, you. Wants cherry on the top, but you could also use subcutaneous injections of octreotide. Dr. Sean Kane 35:06 So clearly, irinotecan is deserving of this superlative award of the drug that should be dispensed with extra toilet paper. But this is a co‑winner here, and the other winner of this award was clindamycin, and it's actually for a completely different reason, in terms of what's going on with the diarrhea with clindamycin. Dr. Khyati Patel 35:26 I knew that was gonna come out. So we know clindamycin can increase the risk of C Diff diarrhea. And the acronym for that is, you know, C dad, so Clostridium deficield associated diarrhea, Dr. Sean Kane 35:41 yeah, and really, like any antibiotic can harm the GI flora, and when you have these imbalances in the GI flora, that's a huge risk factor for overgrowth of Clostridium difficile in the gut. And if that Clostridium difficile has the DNA to be able to make certain toxins, we end up with diarrheal illness and fever and white count, things like that. We call that that C Diff associated diarrhea. It just so happens though, that clindamycin is literally one of the worst ones for that. And of course, there are going to be other risk factors and patient specific factors to think about, but clindamycin is definitely one of those. Dr. Khyati Patel 36:15 And those risk factors are, you know, older age, hospitalization, number of times I've been exposed, or number of days they've been exposed to the antibiotic. Just to put in perspective how clindamycin fares with other antibiotics, most antibiotics have odds ratio about five. That means you know, if you are taking antibiotic, then the risk of having C Diff diarrhea will be about five times compared to people who are not taking antibiotic. What is it like for clindamycin? Dr. Sean Kane 36:46 Yeah, so for clindamycin, the odds ratio is about 20x so your odds are 20 fold higher of getting C Diff associated diarrhea with clindamycin versus about five fold higher with other antibiotics. So you can think of it either as you know, 20 fold higher versus no antibiotics, or about four times the risk with clindamycin versus any other antibiotic, even carbapenems, fluoroquinolones, cephalosporins, whatever they're all about, they're all literally a fourth the risk of that with clindamycin. Dr. Khyati Patel 37:16 Wow. And as we all know, you know, C difficile, diarrhea, it's very similar in terms of like increased frequency and needing more toilet paper. So the the answer is, you know, use your clindamycin very carefully. Dr. Sean Kane 37:32 And probably what makes this so ironic or frustrating is that most patients that are prescribed clindamycin actually don't need clindamycin. So the most common scenario where clindamycin is prescribed is for skin and soft tissue infections, maybe also dental infections. And usually the clinician is picking clindamycin because the patient has a penicillin allergy. They're trying to pick a non beta actin. Dr. Khyati Patel 37:58 And as we all know, 90% of these patients are not truly allergic to penicillin, and a lot of those patients can actually be given cephalosporin without allergic issues. Yeah. Dr. Sean Kane 38:11 So in most cases, choosing a cephalosporin as opposed to clindamycin, would be very appropriate. The other kind of more frustrating thing is in patients that have skin and soft tissue infections where they're having Exudative ssti, so this is where they have pus draining out, or they have a deep abscess that can be drained. MRSA is our most common concern in those patients, and the IDSA guidelines actually say that you should have MRSA coverage if they have an abscess or Exudative kind of pus. So clindamycin, when you prescribe it for those patients, actually has a very poor coverage. For MRSA in the US, the resistance rates are really high in most areas of the country, and clindamycin is not an appropriate option. In actuality, Bactrim or doxycycline would be recommended therapy instead. So it's kind of a double whammy, that you're prescribing an antibiotic that has a dramatically higher risk of C Diff diarrhea, and also that same antibiotic is not nearly as effective as alternative agents that don't have that same risk. Dr. Khyati Patel 39:13 Well, bottom line to that one, what I learned, Dr. Kane is, you know, try to use your clinical medicine very carefully. Try to prescribe it really carefully, look for the alternatives when possible, because the C dad is real Dr. Sean Kane 39:26 absolutely Well, Dr. Patel, just for fun, why don't we go through our four superlative awards and then for the audience, we do have a number of references for what we've talked about today that are available in the show notes for today's episode. So the first award was the most unique phase three patient population for a widely used medication, and that was Pneumovax 23 or ppsv 23 and it kind of earned that award because it was originally studied in South African novice gold miners. Dr. Khyati Patel 39:54 And the second award was for the most misunderstood box warning, and that went to. All of the doacs, but notoriously for pixaban and rivaroxaban in particular, due to both the increased risk of thrombosis and bleeding. However, the warning only says thrombosis when we switch patient from doac to warfarin therapy. This was seen more in patients with atrial fibrillation, Dr. Sean Kane 40:20 and our third award was the biggest difference between pharmacokinetic properties and pharmacodynamic effects. And I went to aspirin with its really short half life and short duration of analgesic effect, yet it's very prolonged anti platelet effect, because it never lets go to those platelets, and the body literally has to make new ones in order for platelet function to return. Dr. Khyati Patel 40:40 And last, but not the least, the drug that should be dispensed with extra toilet paper. We couldn't pick one. So that was a tie between irinotecan and clindamycin. Irinotecan chemotherapy agent, its most limiting, dose‑limiting side effect is diarrhea, and we use the higher doses to treat that diarrhea. Clindamycin earns the award because it is the antibiotic out of all antibiotics out there that's mostly associated with the C difficile associated diarrhea. Dr. Sean Kane 41:14 Absolutely So again, for the audience, if you played along and you felt like a different drug should have earned these awards, let us know, or if you have an award of your own, some notable thing about a drug that we can then use to educate our audience about the nuances of a medication, please reach out to us. So our contact information is available at HelixTalk.com we're also on Twitter at HelixTalk, and we're looking forward to hearing from the audience. We love it. In addition, we love the five star reviews in iTunes, so keep those coming. So with that, I'm Dr. Kane Speaker 1 41:45 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 41:50 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 42:01 to suggest an episode or contact us. We're online at HelixTalk.com. Thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.