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. Narrator - ? 00:11 This podcast is 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 102 I'm your co host, Dr. Kane. Dr. Khyati Patel 00:35 I'm Dr. Patel. And with us today, we have our guest contributor, Dr. Srivastava. Thank you for joining us again. Thanks for having me. Dr. Sean Kane 00:42 And today's episode is entitled, when the Squatty Potty isn't enough, drug therapy for chronic idiopathic constipation. Dr. Srivastava, we've brought you on to this podcast episode as a content expert in constipation. So welcome. Thank you. So maybe we can start off today's episode with a simple patient case to set the groundwork for what we're talking about, because CIC or chronic idiopathic constipation isn't just your run-of-the-mill constipation caused by an opioid or something like that. So why don't we kick it off with this patient case to set the stage? Speaker 1 01:14 Okay, so we have this 40 year old female patient. She's come into her primary care physician for an annual physical and request drug therapy for her constipation. She, you know, is talking about how she's been having this constipation since she was a teenager, but she's never really gone to get help. She's tried random things over the years, and right now, she's not taking anything except MiraLAX, and she has no other really relevant past medical history. She says that she doesn't really have any pain or tenderness, goes to have a bowel movement about one or two times a week. But even when it happens, it's hard. It requires straining. She just doesn't feel good when she's going and so she says she's been drinking water. She uses an app for it make sure she gets her eight cups a day. She's trying to improve that diet, trying to get more fiber through her fruits and vegetables, and has been using MiraLAX most days of the week. Dr. Khyati Patel 02:02 So if we were to kind of set the stage and let our audience know, how is constipation defined? What is constipation, right? So a lot of the time, it's linked to the frequency at that you know, I haven't been able to go in a while, or it's been too long that I have since gone to the bathroom. So I guess there is some discrepancies when it comes to how patients define constipation versus how providers define constipation. Is that correct? Yeah. Speaker 1 02:28 You know, a lot of times, especially as clinicians, we often want to just put things in a box so it's like just a number an objective value. But patients, yeah, part of it is that they haven't gone in a while, but so much more of it is how they feel, or how it is, the quality of the stool, what it feels like, the pain may be associated with it, being able to not completely evacuate. They kind of try to go, but aren't able to go completely, yeah. So there's a lot of different symptoms that they're talking about. So maybe we can take a step back and talk just a little bit quick, quick review about how bowels happen. Dr. Sean Kane 02:56 So in terms of that physiology, 101, a bowel movement happens because you have adequate hydration in the intestinal lumen, you have to have colonic motility. And as part of that colonic motility, there's something called repetitive non propulsive contractions, and these are basically contractions that allow for mixing and absorption of the material in the stool. And then the second component is high amplitude propagated contractions, or hapcs, and these are very large coordinated movements that really get things moving toward the rectum. And these hapcs More commonly happen in the morning or after a meal, which is why some people will talk about having a bowel movement, like at the beginning of the day, for example, yep. Dr. Khyati Patel 03:37 And then, besides having the water regulation in the lumen and these motility contractions, we know that certain neurotransmitters — especially serotonin — play a key role in mediating peristalsis, and it's also associated with the pain stimuli that comes with IBS. Speaker 1 03:58 And in addition to this physical part of the physiology, we also have that whole brain gut connection. And so there's that conscious urge, and a lot of this is also connected to habits and maybe childhood experiences all around it. And so we're really approaching a patient with constipation, making sure there's no physical stuff going on, but then also, then talking about the behavioral as well, and trying to combine both techniques to help improve those symptoms. Dr. Khyati Patel 04:25 So having said, what is constipation? Let's talk about why that happens. We like to put things in a box and classify constipation — knowing the cause and etiology is important. As you mentioned, Dr. Srivastava, any physical issue that prevents defecation should be identified. Most clinical trials use the ROME criteria to help objectify functional gastrointestinal disorders. Broadly, constipation is grouped into three main classifications. Speaker 1 05:05 So we have IBS, and as we know, IBS irritable bowel syndrome, it can either be constipation dominant or diarrhea dominant, or mix. So for this, we're going to be focusing on the constipation. Then we have opioid induced constipation, very simply put, if you're starting on opioid and your constipation changes from baseline, it's probably because of the opioid or a dose increase, and then you have the chronic idiopathic constipation. Dr. Sean Kane 05:30 And CIC or chronic idiopathic constipation is, you know, idiopathic means we don't know what's going on. So this is basically the catch all for we don't know what your etiology of your constipation is. So we're going to put you in a box of could be a lot of different things, and we aren't sure which one. So I think one logical question then is for IBS, C so irritable bowel syndrome with constipation, how do we know that it's that versus CIC this, chronic idiopathic constipation? What is the main discriminating factor there? Speaker 1 05:59 So the biggest thing is going to be the predominant symptom, and there is much more pain associated with IBS versus the CIC. Dr. Sean Kane 06:07 And when you say pain, you mean abdominal pain, right? Yes, Dr. Khyati Patel 06:10 exactly. So then, how do we then hone in on the CIC diagnosis? What are the criteria for those diagnosis? Speaker 1 06:18 So what they're looking for to diagnose CIC is that symptoms must have been present for at least six months, with criteria met during the last three months. At least 25% of defecations should include two or more of the following: straining, lumpy or hard stools, sensation of incomplete evacuation or obstruction, need for manual maneuvers, or fewer than three spontaneous bowel movements per week — and there should be rare presence of loose stools (unless laxatives are used). Dr. Khyati Patel 07:07 So here is when we need to take patient perspective and consideration, as we talked about, it's not just about frequency, it's about how they feel around the bowel movement patterns, right? Absolutely. Speaker 1 07:19 And you know, there's apps for it. And so there's stool diaries, but there are apps to record it. And so what if your patients coming in and complaining about it, have them keep a diary, so when they see their provider, they can actually talk about all the things I've been going on and how long it's been going on. So then they don't have to wait for a diagnosis that may already be there. Dr. Khyati Patel 07:37 And then we talk about there is an app for everything. Like this really tells us there is an app for everything where you can even journal your constipation patterns. Dr. Sean Kane 07:48 So Dr. Srivastava, when we initially talked about this as being a topic for a HelixTalk episode, when I learned about chronic idiopathic constipation, I assumed all we would do is give laxatives and fiber to these patients. And I came to find out, as we'll talk about later, there's actually drugs specific for this indication. But before you get to those more novel drugs or CIC specific drugs, you do have to do the basic constipation stuff first. So where does that start? Speaker 1 08:14 Let's start with my favorite fiber. Do you know how much fiber we're supposed to get in a day? Dr. Khyati Patel 08:18 I know it's a lot, and I know we're not there. Most Americans are not there, especially the diet that we follow in this country, absolutely. Speaker 1 08:26 So it's 20 to 30 grams, and only 5% 5% get that amount of fiber in a day. And even from most people that do, if they do get it, they're getting less than half. So we got a long way to go. Dr. Sean Kane 08:41 So for our 40 year old patient, what you're saying is we should go from almost no fiber in the diet to maximize 30 grams a day of fiber, right? Speaker 1 08:49 Do you want your patient to like you? Yes, okay, then yes, but slowly, because if you do it all at once, they're gonna be miserable, and they're gonna think that you're trying to poison them. So make sure that we go slow and then get up there. And you know what? That patient, she says she's taken enough. Ask her how much she's taken, because it really may not be so. Dr. Sean Kane 09:08 And to your point again, there's apps that can track your dietary intake and how much fiber is a component of the food that you're taking in, in addition to any supplements and things Dr. Khyati Patel 09:16 like that, right? And this is a level B recommendation from the American Gastroenterological Association guidelines, and what they do recommend is to get this fiber slowly from dietary sources, if possible. Diet modification should be part of treatment. Patients can't continue the same fast‑food, high‑sugar, refined‑carbohydrate diet — that needs to change first. If diet alone isn't enough, over‑the‑counter fiber supplements can be considered. Dr. Sean Kane 09:56 think one logical question is, you know, it's one thing to say 20 to 30 grams. Of fiber per day. Like, what does that actually look like in terms of, if you were getting nothing else in your diet, what would you have to eat to get that much fiber of 20 to 30 grams per day? Speaker 1 10:09 So you have foods like broccoli, one cup is two grams of fiber. So not very much, but at least some. So you can start there, to get the full amount, you'd need 12 cups. So it's probably better to mix it up a little bit. Mix it up a little bit. Dr. Khyati Patel 10:24 What about those Cheerios cereal they say, like, Oh, great source of fiber, heart healthy. Like, how many do I need to eat? Speaker 1 10:32 So one cup gives you three grams of fiber. And actually, the recommendation is you want to try to choose cereals with at least five grams. So this only gives you three grams in one cup, which means you need seven cups, but then you're probably maxing out your carbohydrates. So I wouldn't go there. Dr. Khyati Patel 10:46 And even about those fiber bars, right? Like Fiber One, what about those one? One should be enough, right? Dr. Sean Kane 10:51 So we're doing better with fiber one bars. You need two to three of those bars to get your daily intake. Each bar is about nine grams of fiber, depending on which product you're looking at. So that's better, but not going to get you all of the way there. And you also don't want to have your entire diet be fiber bars. Dr. Khyati Patel 11:06 So along with fiber, the next "F" is fluid — increased fluid intake. When we say fluids, these should be non‑sugary beverages because sugar can worsen constipation. The goal is about six to eight glasses of water per day. Dr. Sean Kane 11:25 And if you're curious, you can't just double that and get diarrhea or something like that. There's a kind of diminishing return here. So inadequate fluid is going to be problematic. And then you basically need to have adequate fluid in order to just get that minimum amount of hydration. Speaker 1 11:39 And then, of course, physical activity, it's good for every single thing under the sky, including constipation. So doing any of the guideline recommended physical activity three to five days a week at least, will help, yeah. Dr. Khyati Patel 11:52 And my slogan when I'm trying to explain this to patient is, you know, if you move your bowels would move. It kind of sticks to them, you know. And the other thing that we can recommend is behavioral changes, right? Like we talked about earlier, like creating that bowel movement routine that works for the patient using some of the pelvic floor relaxation techniques, which is like the biofeedback technique. So this may require some consultation to providers who work on these behavioral changes. And then there is Squatty Potty. Dr. Sean Kane 12:24 So this is popularized in a shark tank. I believe a shark tank episode, you know, is this something that has evidence behind it that it's something that a patient might seek out. Dr. Khyati Patel 12:34 So if I go way back and look at outside of United States, certain Middle Eastern or Asian cultures actually have been practicing this. They have those sitting toilets. They're not the standing toilets. They're the Western toilets, per se. And so I believe that there was some thought behind sitting, the way they're sitting when a bowel movement occurs, to actually help defecate better. And I guess that's the concept the Shark Tank investors are bringing in, Speaker 1 13:02 and while there may not be necessarily randomized control trials that look at this anecdotally, people say it really, really helps. And it's about $20 and you can either build a toilet that's closer to the floor, or you can buy this, which elevates your feet. Dr. Sean Kane 13:17 And I would say that there's basically no harms, except for the cost of the product, right? So if a patient tries it and loves it, great. If they try it they don't like it, the only harm is the money that they Speaker 1 13:25 spent, which maybe they can return it fair enough. So, you know, Dr. Sean Kane 13:29 there's plenty of non pharmacologic therapies that are really essential, that are recommended for these patients, also some of these dietary interventions. What if that isn't enough? And presumably that's not enough for our patient here. What are some over the counter, especially laxatives that are available to us. Dr. Khyati Patel 13:45 So if I follow the guidelines again, the American Gastroenterological Association recommends non‑pharm measures first. If those fail, nonprescription products such as osmotic laxatives or stimulant‑type laxatives may be tried — start with osmotic agents like milk of magnesia or polyethylene glycol (MiraLAX). If those are insufficient, adding a stimulant‑type laxative such as bisacodyl or senna may help, but stimulants commonly cause cramping and are not recommended for long‑term use. Speaker 1 14:24 The strongest recommendation, and the evidence, is for the polyethylene glycol. So it just recently became OTC only, so there's no more prescription for it. And there's some pretty cool things about it, as how you can mix it. Dr. Sean Kane 14:39 So you can mix it literally in anything you want. To mix it in, coffee, go for it, juice, go for it, water, go for it, hot, cold. Doesn't matter. It can be put in whatever you want, right? Dr. Khyati Patel 14:50 But again, we should keep in mind that, you know, sugar beverages, so juice and stuff, if you can, we should avoid that too, Dr. Sean Kane 14:57 and we should highlight that one reason why. Mira lax or polyethylene glycol 3350 is so highly recommended is that it used to be prescription and by virtue of that, it does have a lot more evidence than some of these older laxatives, because it went through the FDA approval process for a prescription drug. And because of that, we just have a lot more experience and evidence for it than we would for, let's say Senna or docusate things like that, Dr. Khyati Patel 15:21 and we promise our audience that we would provide some over‑the‑counter, nonprescription fiber products too — for example, Metamucil, FiberCon, or Citrucel. There are different types of fiber if a patient's not getting enough in the diet. Speaker 1 15:34 And there's, if you go to any store, there's probably 12 to 15 different types of whether it's a bar or a cookie or so. Just really urge you to look at the label, because it's great to be like, Oh, this has fiber. It's in the fiber aisle. I'm just gonna have it, but there's just so much other stuff in it, so just make sure that it's appropriate. Like, somebody with diabetes probably shouldn't be having something with a lot of sugar alongside the fiber. Dr. Sean Kane 15:56 And even with these fiber supplements, depending on the product and things like that. If we take Metamucil as a typical example, a serving of that is only going to be five grams of your fiber, meaning that you're going to have to have multiple doses a day, presumably in addition to your diet, to get to that magic 20 to 30 grams a day of your soluble fiber. So that's kind of the over the counter realm. You know, the focus of today's talk is actually on these four products, many of which are fairly new. So any clinicians out there are likely to see some of these in practice if they haven't already, and some of these are actually or all of these are actually indicated specifically for CIC, chronic idiopathic constipation, in addition to some other constipation as well. Yeah. Dr. Khyati Patel 16:35 And again, if you kind of go along with the guidelines, the recommendation is you make sure your patient has tried all these over the counter, non farm remedies, appropriately, and if their constipation doesn't respond to that, we can move on to these prescription based products. So I believe Dr. shavassava, there are four different ones available in the US, yep. Speaker 1 16:57 So we have four available. The very first one was approved in 2006 and the latest one was approved last December, in 2018 and so they all work differently. There's three different mechanisms of action, so two of them work the same and then the other two work differently from that. How are these typically studied? So they were all studied against placebos. Most of the trials lasted 12 weeks. The very first one that got approved, it was a shorter trial of was a shorter trial, at four weeks. And some of them we've had a little bit longer studies, but they're mostly all 12 weeks. The patient population has mostly been all female, or majority female, majority white, mostly in their 40s. And then Dr. Sean Kane 17:37 in terms of efficacy endpoints, they do vary, but a typical is the percent of patients who have three spontaneous bowel movements per week and or having to have more than one bowel movement in addition to what their normal is per week. So if you normally have four bowel movements per week, but it's hard, and you have to strain a lot, then the threshold would be that you have five bowel movements per week for that endpoint. Yeah. Dr. Khyati Patel 17:59 And another thing to keep in mind as you're looking up the studies is that most of these agents have multiple constipation related indication, and the dose might be different. And obviously the studies will be different too. For example, we will talk about lubiprostone and mattesa. The dose is different if you're looking to treat IBS related constipation versus CIC. So why Dr. Sean Kane 18:20 don't we start there? That's actually the only one that I was familiar enough with that I heard of both the brand and generic name. So lubiprostone (Amitiza) — this came out a little while ago, right? Speaker 1 18:30 Yes, it was approved in 2006. Lubiprostone (Amitiza) is a secretagogue that works locally in the intestines by activating chloride channels and enhancing fluid secretion into the GI lumen, which helps loosen stool, increase bulk, and improve motility. It was the first of these agents and remained the only option for several years. Dr. Sean Kane 18:49 and this should be taken with food and water. For many of these products, they work by pushing some ion into your GI tract, and then water kind of follows that. So you have to look out for dehydration. For these products in terms of efficacy. The main study that got this approved initially was a study over a four week time period. And their endpoint was, how many bowel movements did you have in weeks 123, and four, and basically throughout the entire study period, in any given week, this increased the number of spontaneous bowel movements by about two so if you were having one bowel movement per week, taking this drug gave you three bowel movements per week on average. Dr. Khyati Patel 19:26 Yeah, and if a patient wants to know, like, How soon after taking the first dose, would I have a bowel movement? The answer is about 24 hours. So it's also good to know, because they may plan things accordingly, and Dr. Sean Kane 19:38 as we'll talk about with all of these agents, just like almost all laxatives on the market, it's not uncommon to see GI‑type adverse effects — nausea, cramping, and flatulence. Those are common with many of the agents, including over‑the‑counter laxatives. Speaker 1 19:55 Specifically with Amitiza, it should be taken with food because many of its GI side effects are reduced when taken with meals. That's not true of all agents, but with Amitiza we often start at a lower dose and increase as tolerated. Dr. Khyati Patel 20:12 common side effects do make sense. They work in the GI tract. So a lot of Gi related side effects, but what about some serious ones? I've heard with a metiza as well something related to blood pressure. Dr. Sean Kane 20:22 So one thing is, and these are rare but serious side effects. One is syncopal episodes, usually due to hypotension, and usually this is with the high dose, 24 milligrams, twice a day. So that could be scary for a patient, if they take a drug for constipation, then they pass out. Probably the scarier one is dyspepsia, and it's not just GERD type dyspepsia. This is dyspepsia where a patient will experience chest tightness, difficulty taking a breath, and this can have an onset 30 to 60 minutes after taking, typically, the first dose, and it usually resolves within hours. But obviously that would be very scary for a patient that would feel like you're having a heart attack or having trouble breathing. So patients may need to be aware of this, but also know that this is incredibly rare for this drug. Dr. Khyati Patel 21:04 That was 2006, I believe, and then nothing until 2012 when linaclotide (Linzess) was approved. Speaker 1 21:12 Yes — linaclotide (Linzess) and plecanatide (Trulance), which was approved in 2017, share the same mechanism of action. They are guanylate cyclase‑C (GC‑C) agonists, similar to the endogenous peptide uroguanylin, which stimulates chloride and bicarbonate secretion into the intestinal lumen and increases luminal fluid. They also appear to decrease visceral hypersensitivity, which can reduce abdominal pain — an important effect in IBS‑C. Dr. Sean Kane 21:53 And at least for me, when I see a drug, and I'd never heard of these two drugs, to be honest with you, when I see a new drug, one of the first things I look at are boxed warnings and then warnings and then Warnings and Precautions, because I think that really highlights what, from a safety standpoint, are the most important things. And I was actually interested to read that both linaclotide and plecanatide carry a boxed warning: do not use in children under 6 years of age, and they should generally be avoided in children up to 17 years. The boxed warning is based on animal data showing severe dehydration in young animals. Speaker 2 22:27 What's that reason must be something crazy. So it turns out Dr. Sean Kane 22:31 that in very young neonatal mice, when they gave a single dose of these drugs to these mice, they actually died of dehydration after that single dose. And again, all of these products can potentially cause dehydration. But because of those animal studies, there's a concern that if you give this to someone who's too young, they may get dehydrated, and that could actually cause potentially death in those patients. So this is pretty much an adult only constipation drug, which is our target market for CIC in most cases. Speaker 1 22:59 Anyway, absolutely none of them have any FDA indications for children, but these specifically, like you say, have a box warning that nobody under the age of six should be taking it. Dr. Sean Kane 23:09 And I guess you might consider, you know, if you have a mother taking this product and her child is constipated, she may be thinking that maybe I could give this for constipation of my child. And I wouldn't say that you would counsel every person on this who has a child, but maybe that's where some of that warning comes from. Dr. Khyati Patel 23:28 Ideally, these drugs are not going to be used in post delivery type of constipation, you know. And so if you are questioning whether this, you know, medications are going to show up in the milk supply and they're going to be transferred to babies, probably not, because the way these work, they work in the GI tract, and they're not they're minimally absorbed in the systemic circulation of the mother, so chances to pass it on in the milk supply to the their young ones is pretty low. Dr. Sean Kane 23:53 So in terms of efficacy, the main endpoint for these two drugs was, basically, did patients achieve three or more spontaneous bowel movements in a given week, and an increase of one or more bowel movements from their baseline. And really, both the drugs showed roughly at least a 10% increase all the way up to maybe a 20% increase, depending on what study you look at and the placebo rates range from all the way down to 3% up to 10% so a typical patient, if they were enrolled in these studies, maybe about 5% of them were having three or more spontaneous bowel movements by taking the drug, you go from about 5% to all the way up to 15, maybe 20. 25% which, if you think about it, we're still not actually hitting most patients having the goal of three or more spontaneous bowel movements per week. You know, probably 70 plus percent of patients will still be non responders based on that particular endpoint, right? Dr. Khyati Patel 24:43 And just like I'm a teaser, if a patient asks, How soon after taking the first dose, it can start working? It's, again, about 24 hours. Speaker 1 24:51 And the side effects similar the abdominal cramping, the flatulence, but the most common one is diarrhea. So you have your patient and they've been constipated. And now they have diarrhea, and I don't know, they might be excited at first, finally able to go, but is it really safe? Dr. Sean Kane 25:07 And again, that's going back to dehydration, right? So if you're having a lot of diarrhea, you absolutely have to maintain your fluid and take otherwise you will get dehydrated, and that can cause electrolyte problems and things like that. So on the surface, a patient might actually laugh at you and say, like, I would love to have some diarrhea. I am miserable, but at some point it is too far, and you would have to make an adjustment at that point in addition to maintaining hydration. Dr. Khyati Patel 25:28 And at that point it could be dose decrease or even stopping the drug for a while, until the diarrhea resolves, obviously. Dr. Sean Kane 25:36 So are there any differences between Linzess and Trulance? They're in the same class and have similar safety profiles; no head‑to‑head trials exist. Dr. Khyati Patel 25:46 Dosing differs by indication. Linzess (linaclotide) has different doses for CIC versus IBS‑C and must be taken on an empty stomach at least 30 minutes before eating. Trulance (plecanatide) uses the same dose for both indications and can be taken with or without food. Speaker 1 26:11 and both of these if people aren't able to swallow tablets or capsules, they can both be or if they have an NG tube, it can be used via the tube, and there's very specific instructions and how to do it. So if any of your patients do need to take it that way, just make sure that you look it up. But it's good option for certain patients that if they need to do that, Dr. Khyati Patel 26:29 and the pipeline keeps getting better — in December 2018 we had the most recently available agent, prucalopride (Motegrity), approved for the indication of CIC. Dr. Sean Kane 26:42 So only CIC for this one. So how does this one work versus the other one? So we Speaker 1 26:46 were talking about serotonin earlier. So about 95% of your serotonin is actually found in the gut, and so that's what's targeting. And it's a selective serotonin type four agonist in the GI tract, and it's a prokinetic it stimulates colonic peristalsis. So remember those H A PCs that Dr. Kane was talking about? They help increase the bowel motility. And so these help increase that, that, in turn, increases the bowel motility. Dr. Sean Kane 27:11 So in terms of dosing, this can be taken with or without food, there is a renal adjustment for it. In terms of efficacy, it had a similar end point. Basically, did patients have at least three or more spontaneous bowel movements per week, and we basically saw a similar efficacy response to what we saw with other agents, where it roughly increases your percent responders by about 10 or 20% and the particular trial of this one, the placebo rate was pretty good. So the placebo rate went from about 10 to 20% all the way up to about 20 to 30% with the drug. Dr. Khyati Patel 27:43 So in addition to having some GI related side effects, this one also has headache as one of the possible side effects. No. Dr. Sean Kane 27:52 Dr. Patel, I know that every drug in micro medics has headache listed as a potential adverse effect. So is truly a headache, or is this kind of background noise in terms of an adverse effect, Dr. Khyati Patel 28:02 it might be it says about 19% headache noted in clinical trial versus 9% in the placebo arm. So I'm going to take that as a pretty significant headache side effect. Dr. Sean Kane 28:15 And even the package insert mentions that if headache does occur, it typically happens within the first two days of therapy, it typically resolves within a few days in about two thirds of patients. So most patients will have this, and most patients it will go away if they continue therapy. Speaker 1 28:29 So it's probably important to just let them know, so they know to expect it. Try it for a couple more days and then see what happens. Dr. Sean Kane 28:36 You know, there are some rare but serious side effects as well with this agent — one reported concern was a numerical imbalance in suicidal ideation signals in trials. The data are limited, but if a patient has active depression or suicide risk you might avoid prucalopride. Prucalopride shares some prokinetic properties similar to older drugs such as cisapride, which was withdrawn for QT prolongation; clinical data for prucalopride do not show a clinically relevant QT signal. Speaker 1 29:47 And then they also did a large observational study of about 35,000 patients (approximately 5,700 on prucalopride) and looked at MACE outcomes; they found no evidence of increased MACE risk for patients treated with prucalopride compared with those treated with PEG. Dr. Sean Kane 30:03 So we have four new agents. We have a lot of laxatives. Where do we go from here? So what is kind of our preferred therapy? If there is one based on the AGA guidelines or any other treatment approach that's out there? Dr. Khyati Patel 30:16 Well, it seems that none of these four agents have been compared directly with each other. The AGA presents individual placebo‑controlled data and does not recommend one agent over another; if laxative therapy did not provide relief, you can move on to any of these prescription options. That brings us to cost considerations — how different are they? Dr. Sean Kane 30:52 So if you look at the AWP (average wholesale price), we're looking at roughly about $15–$17 a day for these agents — they're all very comparable. The AGA estimates costs closer to $7–$9/day depending on pricing assumptions. Either way, cost can be significant for patients, and even though lubiprostone has been out the longest, list prices are similar across the agents. Dr. Khyati Patel 31:24 Well, these are daily costs. How long are they going to incur this cost? Meaning, how long are they going to be taking these medications? Because, Hello, we're treating chronic constipation here, right? Speaker 1 31:36 And so, I mean, these studies that we saw were mostly 12 weeks. We did have a 24‑week study for one agent, but for the most part trials were 12 weeks. The guidelines recommend treating for about 8–12 weeks and then reassessing for maintenance or stopping to see how the patient is doing. Dr. Khyati Patel 31:54 So the assessment should occur at eight to 12 weeks. The patient should not be put on uninhibited or given infinite number of refills without questioning. Hey, how is this working for you? Can we re evaluate? Can we try a hold, kind of like a drug holiday type of an approach here and see if your bowels are regular enough to do on their own, along with your non farm behavior modification type of approach. Speaker 1 32:21 Unfortunately, the guidelines right now do not tell us the maximum amount of time to use it. Anecdotally from gi specialists or patients that are using it, sometimes they're on it for six months, sometimes they're on it for closer to that 12 weeks. But there's no absolute guideline that tells us, okay, this is how long the maximum should be. And just Dr. Sean Kane 32:39 for clarification, I assume these patients are continuing their over the counter laxatives in addition to these agents. Is that correct? Speaker 1 32:47 They should really only be continuing their fiber intake, but if they are on these agents, there's not any other laxative they should be taking alongside it. Dr. Sean Kane 32:56 Well, let's go back to our patient case. So just to reiterate, we had a 40 year old female who were saying, has chronic idiopathic constipation, and she's tried laxatives and it's not working. Assuming that she's tried multiple different laxatives at higher doses, I would say it's reasonable that she could be a candidate for one of these four newer agents that we discussed Absolutely, Speaker 1 33:17 if we want to put numbers to it, they say an adequate amount for four to eight weeks and see what happens. And then we go to these agents. Dr. Khyati Patel 33:24 So the guidelines don't differentiate any of these, the cost as we covered earlier, kind of come about the same. So what do we go with that? Dr. Sean Kane 33:34 So I think one easy thing is, what does the insurance cover? If she has third party insurance, typically, you're going to have one of these agents that is a cheaper copay for the patient versus another agent. So I would probably start there as a you know, cost could be a factor for a patient if it's not covered, or it's on a high tier with a very high copay. Speaker 1 33:53 And then we could look at side effects or patient risk factors. There's a dehydration risk with several agents, particularly the guanylate cyclase‑C agonists linaclotide and plecanatide (boxed warning in young children). If there is concern for depression or suicidal ideation, you might avoid prucalopride. Dr. Sean Kane 34:17 And I would argue that lubiprostone (Amitiza) has been out the longest, and that alone might be a reason to favor it — we have more post‑marketing (Phase IV) data and a clearer side‑effect profile. Newer drugs sometimes reveal rare adverse events only after wider use. Speaker 2 34:43 Seems like we're going with Amitiza for our patient. I think that would be reasonable, Dr. Sean Kane 34:47 assuming it's covered with insurance and things like that. Speaker 1 34:50 Great and important to note, there are no generics right now, and Dr. Sean Kane 34:53 hopefully at some point there will be. And that would also, in the case of ametiza, make that an even more attractive option. Dr. Khyati Patel 34:59 I. Kind of wrapping it all up for our audience. What we learned in this episode today is, Speaker 1 35:06 so I'll start — you know, I think it's important to emphasize that constipation is truly a problem and needs proper assessment. Many people assume it's "no big deal," but when a patient raises the issue you should take their complaint seriously. Dr. Khyati Patel 35:27 and it probably starts with home housekeeping measures such as improving fiber intake. We talked about fiber, fluid, and exercise, and guiding patients to replenish fiber with over‑the‑counter options as needed. Products like MiraLAX can help as well. Dr. Sean Kane 35:49 And then my take home point is that these four new agents, you know, they're great, but they're also not miracle drugs. So again, in the clinical trials, they basically increased the percent of patients that had three more spontaneous bowel movements by about 10 or 20% in a typical patient, you know, maybe a third of them became responders, and two thirds of them remained non responders, where they were still not having three or more spontaneous bowel movements per week. So I think that that's important to talk to a patient about, that this isn't going to be night and day difference, but it may be enough that even increasing by one or two bowel movements per week, or reducing straining, other things like that may be advantageous to the patient, and you really have to try it out to really see if that patient's a good responder or not. So with that, that wraps up today's episode, Episode 102, you can read our show notes at HelixTalk.com we're on Twitter at HelixTalk, and we love those five star reviews in iTunes. So with that, I'm Dr. Kane, I'm Dr. Khyati Patel 36:41 Dr. Patel, and I'm Dr. Srivastava. Thank you for being with us again, Dr. Srivastava, and with that said, study hard. Narrator - Dr. Abel 36:49 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 - ? 37:00 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.