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 154 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is what's new with paxlovid drug interactions, pharmacist prescribing paxlovid mouth and a brief drug review, Dr. Khyati Patel 00:47 it looks like we have a great potpourri to review paxlovid from just overall perspective of pharmacology, efficacy, safety. You know, where we stand for pharmacists authority to prescribe this drug, drug interactions, things to monitor, and then some of the issues, quote, unquote, we have noticed with that, such as the ADRs or even the rebound symptoms after paxlovid therapy. Dr. Sean Kane 01:13 Absolutely So, Dr. Patel, we know that paxlovid has been out for a while now, and it's been prescribed a lot. So the focus of today's episode is more on what's new or different or something that providers need to know about paxlovid, as opposed to the very nuts and bolts of paxlovid and going through the initial clinical data for it. Dr. Khyati Patel 01:31 So as we understand, paxlovid is a combination of two different medications, so not necessarily co formulated, as in two molecules and one tablets, but they're co packaged, or combo blister packs available. So we have the nirmatrelvir and ritonavir as part of this combination blister package. Yeah. Dr. Sean Kane 01:56 And the new drug here is near mitrellavir, and this is a protease inhibitor. This is the drug that is active for the covid 19 virus. It's actually a protease inhibitor. And what that means is that when viruses make their proteins that they need, they have a protease enzyme that will cut up or chop up that protein, long strained molecule into kind of the individual components of functional units. So for example, the spike protein, the nucleocapsid protein, the envelope protein, the membrane protein, all of these proteins come from a long strand that has to be chopped up for them to become functional units. And clearly, a protease inhibitor is going to make it so that the viral particles can't chop that long protein up into the functional units, therefore those protein molecules don't form and nothing viral happens when you take the medication. And we've seen protease inhibitors for a long time out on the market in HIV therapy, we have durunivir, atazanavir, lopinavir, and a bunch of other ones. So this drug class is not new, but near montrelvir is a new medication just for this covid 19 virus, Dr. Khyati Patel 03:03 and then it stops me in its tracks. Dr. Kane to hear ritonavir as combination too, because technically that's a protease inhibitor too, right? So what is the purpose of ritonavir? It's part of paxlovid, yeah. Dr. Sean Kane 03:15 And we've seen this before with HIV medications, so it's really not a new concept. But although ritonavir is a, technically a protease inhibitor, we dose it really, really low where it's actually not really doing much protease inhibition, but we, at these kind of sub therapeutic doses, were able to achieve hepatic CYP enzyme inhibition. So we're inhibiting metabolism of other drugs that are metabolized to the liver. And I love this. In the paxlovid prescribing information, they call ritonavir a pharmacokinetic enhancer. Sometimes it's also called a booster, where, basically it boosts or enhances drug levels of other medications. Dr. Khyati Patel 03:54 And so in a nutshell, you're using drug interaction to your advantage for this combination therapy, exactly. Dr. Sean Kane 04:00 And just to put a number to it, nirmatrelvir, if you didn't have the ritonavir, its half life is about two hours. But when you boost it with ritonavir, it goes up to six hours. Or the AUC goes up by about a factor of sevenfold by taking ritonavir. So it allows you to take fewer tablets per day. It makes nirmatrelvir last longer, so the pill burden is better. Wow. Dr. Khyati Patel 04:22 That's that's incredible change from just using it alone versus adding the return of your on top of it. So all that you know, cool, pharmacokinetics and combination nuances aside, let's talk about how effective paxlovid is. Yeah. Dr. Sean Kane 04:37 So the main study that got paxlovid, the emergency use authorization or EUA, was called the epic HR study. It was a double blind, randomized, controlled trial, and north of 2000 patients who were adults with covid 19, and these were all people who had confirmed covid 19. They were not hospitalized. They had symptom onset within the past five days, so fairly quick and. Terms of getting the medication on board, and they try to target a higher risk patient population. So these were patients either who were older, 60 years or older, or any adult that had additional risk factors, like diabetes, obesity, a variety of chronic conditions, things like that. Dr. Khyati Patel 05:16 And I think these inclusion points are important to consider, because when the EUA for paxlovid came out, they kind of suggested to use medication in this type of population rather than anybody else. So these were the kind of things we looked at to evaluate whether patient qualifies for paxlovid therapy or not. I have to say, though, Dr. Kane the very interesting and notable exclusion was those people who've had either previous infections of covid 19 or who had received covid 19 vaccination. And so this particular trial did not include those patients, Dr. Sean Kane 05:52 and that's a huge criticism, and we'll talk about a newer study in a second. But if you think about it, the vast majority of the US patient population has either gotten covid 19 and they knew it, they got covid 19 and it was asymptomatic, and they don't know that they previously had an infection, or a lot of people got vaccinated. So although the drug manufacturer probably picked a non vaccinated, non previously infected patient population because they were hopeful that their drug would work better, and those people who were more susceptible. It also limits the external validity, because theoretically, maybe the drug won't work as well if you've been vaccinated as an example, right? Dr. Khyati Patel 06:30 And so looking at the interventions they had given paxlovid, again, this is a combination taken twice daily for five days, or the placebo, the primary endpoint of the study was looking at covid 19 related hospitalizations or died. So pretty Meteor outcome. You're not just looking at, you know, how much viral suppressions, level suppressions you achieve, but really, like, how many hospital visits did we prevent? How many covid 19 related deaths we prevented? And so the result was actually pretty amazing. Can you share that with us? Dr. Kane, yeah. Dr. Sean Kane 07:04 So among the patients that received paxlovid, they had a 0.8% incidence of being hospitalized or dying from covid 19, and in the placebo arm, it was 6.3 so point 8% versus 6.3% a huge difference, statistically significant. That is almost a 90% relative risk reduction. That is a ridiculous effect size for any medication. Just to put it into context, the IV infusions of monoclonal antibodies, which is one dose as an outpatient or even outpatient IV remdesivir, both of those had similar effect sizes in terms of roughly 90% reduction in hospitalization or death. But the benefit here with Paxlovid is it's oral, and you can take it from home, and you don't have to have an infusion. So kind of a big deal in terms of an oral medication that has this pretty profound effect size. Dr. Khyati Patel 07:57 So Dr. Kane, you know, pretty large study. This is a PO drug, showed almost 90% improvement in hospitalizations or deaths related to covid 19. But as we kind of talked about, the biggest issue was that they didn't include patients who've had previous infections of covid 19 or vaccination. And so there was a another study done, a retrospective study which looked at patient who had previous infections or vaccination, right? Dr. Sean Kane 08:26 Yeah. And this is literally hot off the press. This is herbal et al, New England, Journal of Medicine, in August of 2022 and basically this is a retrospective study of people who got paxlovid versus people who did not. And they were trying to show whether, in real life practice, not a randomized controlled trial, whether paxlovid is effective or not. Dr. Khyati Patel 08:46 And what they found that yes, the reduction in hospitalization was true. However, most of that effect came from those inpatients who were 65 and over. So again, good efficacy was shown in the paxlovid group. This was regardless of any immunity status, meaning whether they were, you know, naturally immune by having an infection or previously vaccinated, which is slightly different than our earlier study that we described, epic HR study. So this is promising that the medication works in people who were previously vaccinated or infected, Dr. Sean Kane 09:24 and we'll talk about kind of who who deserves or who's indicated for paxlovid later. But it's not actually that surprising that the older patient population in this retrospective study were the patients that benefited the most, and the younger patients tended to not have an obvious benefit. Age is by far the biggest risk factor for doing poorly with covid 19. So I would say, if anything, this study argues that probably we should have some minimum thresholds from an age perspective generally. But we'll get more into that in a little bit. Right? Dr. Khyati Patel 09:57 So, Dr. Kane, we know, you know we're talking about. Paxlovid here, but there have been some other studies that are used for treating covid 19 outpatient in that grand scheme, where does paxlovid really fit in? Dr. Sean Kane 10:10 Well, thanks for tell. If you look at the NIH guidelines, they say among patients who are at high risk for progressing to severe covid 19, paxlovid is the preferred therapy, assuming there are no contraindications, no major drug interactions that can't be dealt with. So really, this is the preferred therapy. The next preferred therapy, by those NIH guidelines, is outpatient remdesivir, which is an IV infusion that has to be taken every day for three days, if that isn't reasonable. The next preferred is a monoclonal antibody IV times one dose. The name of that monoclonal antibody currently is beb, televillab, and there have been a variety of different monoclonal antibodies, but that's the one that is currently recommended. And then finally, the least preferred therapy, because the efficacy is not nearly as good as those other therapies, is another oral therapy called molnupiravir, which is really effectively not recommended, because you have three other much more effective therapies, again, the main one being paxlovid, right? Dr. Khyati Patel 11:12 And then, depending on the status of supplemental oxygen use, you could use steroid like dexamethasone. So dexamethasone is recommended for those who are, you know, discharged from the emergency room. So again, these people are not hospitalized, but they do need some sort of oxygen therapy. However, dexamethasone is not recommended if the patient does not need supplemental oxygen. So this is kind of like a landscape of, you know, where paxlovid is fitting in. That's, that's for the NIH guidelines. But let's look at some of the nuances in terms of like, the safety of paxlovid Dr. Sean Kane 11:46 and Dr. Patel. One of the reasons we wanted to cover this episode, kind of the update of paxlovid, is some of the reports that we read in the news or seen on the news about quote, unquote, paxlovid mouth. And I actually hadn't heard of this until you and I kind of talked a little bit about it. And this is basically like a literal terrible taste in your mouth during paxlovid therapy. And if you go to the original EUA, the emergency use authorization prescribing information, they do describe what they call dyscusia, which is basically a bad taste in your mouth at 6% with paxlovid, versus less than 1% with placebo. And all of these were grade one or two, which is a mild to moderate adverse event, with the exception of one case of a grade three or more severe dysgoosia. And you know, if you just kind of look at the package insert, at least for me, I kind of glazed over it, and I assumed, oh, you get a bad taste in your mouth. Not that big of a deal. 6% versus less than 1% but again, if you're in that 6% it sounds like this is a pretty bad adverse event of paxlovid, Dr. Khyati Patel 12:51 yeah, Dr. Kane, this is really interesting. I actually heard an NPR segment on it, and that was the first time I learned about this side effect. And then, you know, I do a little bit of research, and I found plethora of journal articles talking about how terrible taste this medication lives in your mouth to the point where patients rather wish they had covid, 19 symptoms and not take not having to take paxlovid. Can you describe some of the phrases that you found how bad terrible taste was described, Dr. Sean Kane 13:22 yeah, and again, just for context, just the word discusa in the prescribing information doesn't do this justice. So what I came across were patients describing the taste as quote, unquote, hot garbage, Sun baked trash bag, liquid mouth full of dirty pennies, rotten soy milk, grapefruit juice mixed with soap, just to give you a couple examples. So clearly, this is beyond just like a metallic taste in your mouth. It truly is like a garbage like taste in your mouth that is pretty intolerable to some patients, right? Dr. Khyati Patel 13:55 So the word yucky does not justify at all here. But as pharmacists, this is something very important for us to know and warn the patient. And if that happens, the answer is not to stop the medication, right? The answer is to provide some tools that the patients can sort of improve the taste in the mouth, and that would be eating foods that have a little bit of a stronger flavor. So those will be like lozenges or mints or cinnamon gum that kind of just covers and overpowers this terrible paxlovid mouth. Dr. Sean Kane 14:29 And I think, in all fairness, some of these patients that have the paxlovid mouth, if they knew it ahead of time because their pharmacist told them about it, I think that they would be more okay with it, versus if it's a complete surprise and they have no clue why they have this terrible taste in their mouth. So I think there is a role here for good patient counseling whenever the patient comes to pick up that prescription, right? Dr. Khyati Patel 14:51 And this would be a side effect that would be, quote, unquote, intolerance, meaning patient may quit the therapy, as opposed to some of the other. Side effects were noted in the in the prescribing information, but doesn't sound as severe. So we're talking about some diarrhea. So 3.1% with paxlovid versus 1.6% with placebo, some increase in the RE function test and hypersensitivity reaction, probably mainly coming from that return of your component that included anywhere from having rash to angioedema to anaphylaxis, or even skin related eruptions such as Steven Johnson Syndrome or toxic epidermal necrolysis. Dr. Sean Kane 15:34 Yeah. And again, this is a great role of the pharmacist to educate the patient that, for example, if they have a rash while on paxlovid, they should stop paxlovid and call their prescriber, because if it is one of those more severe allergic reactions, they could actually it could cause more harm than good, right? And the patient just needs to know that a rash is not normal and that they should probably hold therapy until they talk to their healthcare provider. Dr. Khyati Patel 15:58 Yeah, absolutely. And then kind of just the safety and efficacy information aside, there's been something else cooking in the politics and the policy world of paxlovid, especially how it pertains to pharmacy practice. And so we know that FDA expanded prescribing authority for pharmacists on paxlovid. We kind of want to dive a little bit deeper into it and then learn about the paxlovid timeline overall. Dr. Sean Kane 16:24 Yeah, and Doctor, I'm gonna be honest, I didn't know a lot about this, partially because I'm an inpatient pharmacist versus outpatient, but no, it's also fairly new. So our timeline, we're gonna start all the way back in April 2020 but the end of our story here is gonna end up in July 2022 so this is still fairly new stuff in terms of what's going on. So if we go all the way back to the spring of 2020, right in the heart of the beginning of the pandemic in the United States, there was something called the public readiness and emergency preparedness act, or the prep act. It was declared, and it had a variety of different components to it, but one of it was it expanded the scope of practice of pharmacists. So this is what allowed pharmacists to order and administer covid 19 tests, and also it protected pharmacists from liability. So it provided immunity from liability for pharmacists, for, you know, giving out covid 19 vaccinations and doing the testing associated with that. Dr. Khyati Patel 17:22 And fast forward from there until September 2021 there was an amendment to this particular act that authorized license promises to be able to order and administer covid 19 medications that were either subcutaneous form, intramuscular form or oral however, the nuance was that the oral therapy was not yet available until paxlovid came out in December 2021 Yeah. Dr. Sean Kane 17:49 And again, the US government obviously knew that covid 19 treatments were coming, and this was a way to kind of get things ready so that if we needed to, we could rapidly administer whatever covid 19 therapeutic became available. So in December 2021, paxlovid EUA was authorized. But in the EUA itself, even though back in September, the prep act amendment allowed pharmacists to order and administer oral therapies, the paxlovid EUA said that only state authorized prescribers could prescribe it, so that specifically excluded pharmacists from being able to prescribe paxlovid, because it was in the EUA that it must be from a state authorized prescriber. Unknown Speaker 18:33 Well, this wasn't confusing at all. Dr. Kane. Dr. Sean Kane 18:36 And then what happened next was, back in March 2022, the test to treat initiative was launched, and the goal of this was to allow a patient to be tested, and if they're positive, to receive effective covid 19 therapy, basically in the same visit. So it was supposed to expedite the whole process. The process itself, testing and treatment was free, regardless of insurance status, and although this didn't change who could prescribe paxlovid, it was intended to kind of expedite the whole thing, where a patient wouldn't have a test in location A and then get treatment with Person B in two different areas. The intent was to kind of expedite the whole process, right? Dr. Khyati Patel 19:18 So I think what escalated back in July of 2022 so just a month ago is that the paxlovid EUA was finally updated to allow additional healthcare provider, like the state licensed pharmacist, to prescribe it. What the EUA did is they ended up recommending that patients still seek care from their regular healthcare provider or go to specific test to treat sites, perhaps in order to improve the access to the medication and testing at the same time. Dr. Sean Kane 19:50 Yeah, and you know, in part, this new initiative of updating the paxlovid ua to allow pharmacists to prescribe was partly prompted by. Pharmacy groups advocating for pharmacists to play a role in prescribing paxlovid Different pharmacy groups actually conducted analyzes showing that especially in underserved communities, those underserved communities have higher risks of covid 19 infection, high risk of covid 19 hospitalization, and also they have a lot more barriers to equitable patient care services. So they said things like, 90% of the US population lives within five miles of a pharmacy. And in these analysis, they kind of showed that if they allowed for pharmacist prescribing, that you'd be able to impact a lot of these underserved communities. And that was the main rationale to allow pharmacists prescribing impacts of it. Dr. Khyati Patel 20:41 I think it makes sense for a pharmacy who's already providing covid 19 testing, and they're kind of enrolling themselves as a test to treat size and so if authorized and approved, then they can go ahead and prescribe paxlovid as appropriate. Dr. Sean Kane 21:00 Dr. Mattel, shouldn't surprise the audience that it's not just like, hey, you know, Dr. Patel, you can now prescribe paxlovid. There's actually a lot that goes behind that, and there are also a lot of barriers to getting the pharmacist prescribing authority into that EUA. So one of those is a checklist. So the FDA actually has a checklist to help pharmacists identify who qualifies for this pharmacist based Pax sub Ed prescription, and we actually have a link in our show notes for what that checklist looks like. But there's a bunch of other things partially in that checklist that I think is worthy of discussion. Dr. Khyati Patel 21:35 And so in addition to or what's part of this checklist is looking at specifics such as lab work. So we need to have access to patient's lab work within past 12 months that's looking at patient's liver function and kidney functions. Obviously, because we talked about earlier, you know, the dose needs to be adjusted, and it does end up increasing liver function. And so these are the two main lab parameters that we need to look at. Let's say that the lab cannot be accessed. The pharmacist actually needs to refer the patient to the prescriber, assuming that prescriber would have access to these labs. And so again, kidney function is looking at the EGFR, and then liver function is to make sure that the side effects is not pronounced. So here we are looking and making sure a patient doesn't have the child pew score of C in order to initiate prescribing of paxlovid. Dr. Sean Kane 22:29 The other criteria, which makes sense, is that the pharmacist has to be able to have an accurate med list, including over the counter medications, and if drug interactions are present, and oftentimes there will be, because of the right to another component, the pharmacist has to refer to the prescriber if one of those medications needs to be modified, typically, this is going to be a dosing modification. Or if the medication can't be modified because it is needed and it can't be withdrawn, those conversations need to happen with the patient's provider. And what's kind of neat about this is that there are a ton of resources, some of which are recommended by the CDC or the FDA for evaluating drug interactions with paxlovid. So there's a bunch of websites out there that, basically, you type in the patient's medications and it will show you what are some of the major or less major interactions with paxlovid, right? Dr. Khyati Patel 23:23 And I think one thing as an outpatient pharmacist to emphasize as patient using a singular pharmacy in order to capture the accurate drug list, right? But if you think about urban area or people who are shopping for pharmacies for better pricing, that patients prescriptions might potentially be at five different pharmacies, and so the pharmacist that reviews medication lists to go through this drug interaction may not have a complete list. And I can be on the soapbox and talk about importance of continuity of care for all medication and not just paxlovid prescribing, but this is really important that, you know, patient either provides a complete list to the pharmacy, or that they go to a singular pharmacy where all medications can be simultaneously assessed Dr. Sean Kane 24:11 absolutely so you know, those are components of that checklist. There are also big barriers to consider in terms of getting pharmacist prescribing period. And interestingly, Dr. Patel, one of the biggest barriers was actually from the American Medical Association, or AMA, and they released a very controversial press release in response to the government adding pharmacists prescribing a paxlovid. I'm going to read it and kind of emphasize the end here. So the press release said, quote, while the majority of covid 19 positive patients will benefit from paxlovid is not for everyone, and prescribing it requires knowledge of a patient's medical history as well as clinical monitoring for side effects and follow up care to determine whether a patient is improving requirements far beyond a pharmacist scope and training. Dr. Khyati Patel 24:59 Well, obviously. Whoever made the statement do not realize what the current curriculum of a graduating pharmacy school looks like. So Wow. In this day and age, the statement is very surprising. Dr. Sean Kane 25:13 Yeah, so clearly, the EUA was updated despite the AMA's controversial opinion about the role and the expertise and the scope and training of a pharmacist, which is good. I think that that kind of mentality is really holding pharmacists back, because we do have that kind of training, and oftentimes we are actually consulted by prescribers to help understand how to manage a drug interaction. So I'm not not loving that, that statement from the AMA, I Dr. Khyati Patel 25:41 think we're all in the same boat. Dr. Kane, I agree with you. However, I think drum roll process here is who's going to pay for the service that pharmacist is able to provide improve the access to the care, and that's where the buck stops, because we don't have a clear mechanism for billing. Now, these organizations who advocated for pharmacists to be able to prescribe paxlovid have asked the CMS to issue a guidance on how clearly pharmacists are going to be able to reimburse we could bill under Medicare Part D for David, which is pharmacy benefit. However, paxlovid billing does not occur under Medicare, Part B for boy, which is usually used for clinical services. And Medicaid is kind of like the same way over here. This is just sufficing, you know, what the CMS can do and third party commercial plans, it's a whole nother ball game, Dr. Sean Kane 26:40 of course, like a cash paying patient could be billed for this kind of service, because you can do whatever you want to do with a cash pay patient, but you cannot charge for the packs of the drug itself. So the cognitive service is what we're talking about here. Pharmacists can't bill under Part D, because that's for the actual drug itself, which you can't bill for. And pharmacists are not providers under Part B for clinical services, so there's really no way to get reimbursed. This is like, literally, the story of the clinical pharmacist. Lies right here that a reimbursement has always been a big challenge when we do have this increased scope of practice to be able to be reimbursed for our cognitive services. I think Dr. Khyati Patel 27:20 this, this likely is a disincentive for a lot of community and independent pharmacies to say, hey, yes, you know, we are the only pharmacy in the community, and we realize our low and we're going to do it, but hey, you're not getting paid for it. So why would you invest your time and resources into it? And so that's a big question here, Dr. Sean Kane 27:40 absolutely, and it speaks to, obviously, a larger issue within pharmacy that is not going to be solved tomorrow, but clearly the reimbursement component needs to be connected to the cognitive service for this to be a successful program. I'm sure pharmacists will still do it, but you can't expect this to be a wildly successful program if you're asking pharmacists to take 10 to 30 minutes of their day per patient and not have any reimbursement for that Dr. Khyati Patel 28:08 100% 100% and I think another kind of sort of long term barrier to look at is the perp act is not a permanent act. You know, it's due to expire in October 2024 but it could expire early if we lift the public health emergency declaration. So does that mean that at that point pharmacists are no longer able to prescribe paxlovid kind of stands up in the air right now. Dr. Sean Kane 28:33 So lots of interesting things to think about for the listeners. You might be curious, you know, whether under the EUA for pharmacist prescribing, or just in general, who kind of qualifies for getting paxlovid. What's interesting here is there are some obvious indications or inclusion criteria, but it's actually a fairly gray area. So obviously you have to be covid, 19 positive, you have to be 12 years or older. So not just adults, but they did include some adolescents. You have to be at least 40 kilograms, mostly for proper dosing, and then the the gray area is, quote, high risk for progression to severe disease. So we'll talk about that in a second terms of who should not get it? You can't get it if you're already hospitalized for severe covid 19, and you cannot get it if your EGFR is less than 30, again, for dosing reasons there, right? Dr. Khyati Patel 29:23 And I think you mentioned Dr. Kane the high risk for progression, right? And this is not going to be as black and white as I assume. It's going to be kind of like a judgment call by the prescriber who's treating the patient to look at the patient and decide whether the patient is high risk for progression, looking at the trial that we discussed earlier, and as you mentioned, age by far is the biggest risk factor. The older you are, the higher risk you have of complications for covid 19, leading to hospitalization. So again, age is going to be the deciding factor here. Dr. Sean Kane 29:58 Yeah. And. What I kind of like about this Dr. Patel is that, although sometimes nice to have black and white criteria, the EUA basically allows the provider to have discretion here. So there's going to be a variety of different comorbidities and different things to think about, and they're trusting in the prescriber, which could be the pharmacist or the PA or the MP or the physician to decide whether this patient is likely to benefit from paxlovid. So just to put a number to it, in terms of how important age is in the calculus here, compared to someone who's less than 40, someone who's in their 40s is about two fold more likely to have severe covid 19, someone in their 50s all the way to 64 it's about four fold different. And if we keep going up, it's a linear relationship. When you're 85 years and older, your risk is about 10 fold higher of having severe covid, 19 requiring hospitalization, compared to someone less than 40. So age is a big deal, and it's a linear relationship. It's not like once you turn 65 that that risk starts to happen. That risk goes up from your 40s and up Dr. Khyati Patel 31:05 right again. So in the paxlovid EUA, you know, there is no specific age mention, again, to emphasize this is going to be the provider discretion or prescriber discretion. Dr. Sean Kane 31:17 And you know, some of the other things to think about are comorbidities of our patients. So risk factors would include things like lung disorders like asthma, COPD, having cancer, having history of stroke or CKD or diabetes or heart failure, coronary artery disease, any kind of immunosuppression. There's a bunch of kinds of immunosuppression, even being obese, so a BMI greater than 30, all of those are considered pretty significant risk factors for progression of your mild to moderate covid 19 into severe covid 19, requiring hospitalization Dr. Khyati Patel 31:50 and throwing more gray lines. You know, we do have some potential and mixed risk factors, like, what if a patient's not obese, but patients overweight, right? So we're looking at BMI 25 to 30, or those who have hypertension, and single handedly, this comorbidities only increase the risk, maybe, like, 1.1 to 1.3 fold. But if you have multiple comorbidities, then the risk increases quite a bit. And so we're talking about, you know, for example, if you have one condition, 1.5 times the risk. But if you have two to five of these underlying conditions, then the risk increases to, like, 2.6 fold. You know, so and again, it has that linear relationship. Dr. Sean Kane 32:33 What I thought was so interesting. And again, we linked all of this information in the show notes for episode 154 the risk is about four fold higher if you have 10 conditions that are known risk factors, that is the same risk as being about 50 to 64 years old, or in other words, being 50 to 64 years old increases the risk of severe covid 19 as if you had 10 plus chronic health conditions. So again, age is by far the biggest risk factor, right? Dr. Khyati Patel 33:04 So I think that's the underlying message here to look at the patient's age, and not so much the health conditions, but definitely age is should be looked upon. So having discussed all of that, let's say Dr. Kane we have a patient, we deem that patient eligible for paxlovid. How do we assess right? That's the one thing that FDA really wants us to do, is monitor the therapy and how do we assess the renal function and hepatic function for these patients? Dr. Sean Kane 33:34 So the FDA says that you have to have labs within the last 12 months. Otherwise you can't prescribe. So you have to have proof that their EGFR is at least 30. If it's below 30, you can't give paxlovid. If it's the EGFR is between 30 and 60, they get a reduced dose. If it's 60 or higher than they get a normal dose of paxlovid. And also, they can't have very advanced liver disease. And at least from my standpoint, most people know that they would have advanced liver disease, but they do want lab findings proving it, so you're going to need that bilirubin, albumin, INR, presence of ascites, presence of encephalopathy. Again, generally speaking, patients don't just walk around with ascites encephalopathy and don't know that they have some degree of liver dysfunction. But per the prescribing information, the pharmacist does need these lab values to prove that they still qualify for paxlovid, because if they have very advanced liver disease, they won't clear the drug as well, right? Dr. Khyati Patel 34:32 And I think the other important thing that pharmacists are really at advantage of evaluating is drug interaction. Again, if their medications are all obtained from one pharmacy. There are plenty of drug interactions that are very common with paxlovid, and these drug interactions will increase potential risk for the ADRs and the toxicity. And so I've been consulted in the clinic too, when our prescriber is prescribing paxlovid to. Like take a look at the patient's medication list and make sure that we can provide some advice on how to avoid some of these drug interactions. And the first and foremost that comes to mind is statins, as this is not a surprise to you having the CYP-based mechanism, the statins also have that, so that interaction is coming in; however, particularly in the prescribing information, they're saying if the patient's on simvastatin and lovastatin, we got to hold it 12 hours prior to starting paxlovid, and then five days after finishing the paxlovid. And then for all the other statins, the recommendation is to just hold it while taking paxlovid. So this is a very important advice to give to patients if they are on statins and Dr. Sean Kane 35:45 doctor tell you know, one, I think it's important to know that the simvastatin and lovastatin that you have to continue holding it for five days after paxlovid. But two, statins represent a medication that these are taken chronically over years and years and years to have benefit over literally, a 10 year time frame. So if a patient doesn't take their statin for five to 10 days, it's really not going to cause any trouble. And that, to me, is like one of the easy interactions to Dr. Khyati Patel 36:12 deal with. Yeah, so this is very similar. Dr. Kane, I'm glad you mentioned and provided perspective. We do the similar approach. When patients on Clarithromycin, for example, just hold the statin for that time period. Dr. Sean Kane 36:23 But unfortunately, many other medications, we can't do that. So alpha blockers for BPH, for prostatic hypertrophy, something like tamsulosin or Flomax. You know, if you hold that which it does interact with paxlovid, the patient may have trouble urinating, and that in itself could cause a problem, or certain calcium channel blockers like Amlodipine. You don't want a patient to stop Amlodipine and then have a sky high blood pressure that causes some other side effect, right? Dr. Khyati Patel 36:52 And additional drug interactions that are seen are digoxin, quetiapine, most of the antiarrhythmics like amiodarone, so you got to watch out for our anticoagulants, like rivaroxaban and warfarin, again, I'm assuming, for you know, these type of agents, we're going to have to monitor the INR a little bit closely and look out for any kind of abnormal bleeding or bruising. And some immunosuppressants like tacrolimus, the anti rejection medication, and even PDE, fine inhibitors such as Viagra are interacting with paxlovid. Dr. Sean Kane 37:28 And then on the opposite side of things, there are some drugs that will actually cause an interaction with Paxlovid itself. So any CYP inducers, like St John's Wort, which is over the counter, phenytoin, carbamazepine, these are all CYP inducers that will make paxlovid not work as well, because it will increase the metabolism of paxlovid. Dr. Khyati Patel 37:47 So one interesting other interaction is with estrogen based hormonal contraceptive, where paxlovid ends up decreasing the effect of those contraceptives such as ethanol estradiol, which then increases, obviously, the risk of pregnancy. We don't need the mechanism of action. But, you know, patient are on these type of contraceptives, and the recommendation would be to additionally use barrier method as well. Dr. Sean Kane 38:12 And Dr. Patel, this one's particularly interesting because you'd actually predict the opposite. You'd predict that Paxlovid being a CYP inhibitor would increase estrogen levels and give you side effects of too much of your oral contraceptive. But in actuality, it's a decrease in efficacy of your oral contraceptive and higher risk of pregnancy. Dr. Khyati Patel 38:33 That is very interesting. For sure. One other thing that I want to talk about Dr. Kane, maybe it's a pop culture. Maybe there is an evidence behind this is the rebound symptoms of covid, 19 with paxlovid. This is much been talked about in the in the media as well, or what's the details behind it? Dr. Sean Kane 38:51 Yeah, so a lot of this kind of was already out there. But then when President Biden tested negative after having paxlovid, and then he tested positive again. Three days later, he was completely asymptomatic. This came up in the news because he was considered a rebound case because of paxlovid, Dr. Khyati Patel 39:09 and I believe Dr. Fauci had a similar case as well. Dr. Sean Kane 39:13 Yeah, and this is become such a big deal that there's actually a Health Alert network or H A N publication from the CDC, which we've linked in our show notes, and it basically talks about this rebound phenomenon. A couple things to know about it. One, if it occurs, it usually happens two to eight days after your initial recovery. Two, we don't know, but it's possible that this rebound may actually be part of the normal infectious process with covid 19, regardless of paxlovid therapy and Dr. Patel actually saw a tweet from a pharmacist who had covid 19. Did not receive paxlovid, they got better, and then they actually got worse, two to eight days later, and they kind of were just commenting that, you know, had they had paxlovid, everyone would have branded this as a paxlovid. Rebound, but they did rebound. They didn't get packs of it. So this could actually be part of the disease process itself. We don't know, right? Dr. Khyati Patel 40:07 I think the bottom line here is that, let's say you did have paxlovid five day course, and you did have rebound. It doesn't warrant the case to extend the duration of paxlovid beyond the five days. So there's still the course is still limited to five days of therapy. Dr. Sean Kane 40:23 And of these rebound cases, Dr. Fauci, President Biden, these are good examples where the rebound itself is generally completely asymptomatic, safer that positive test or very, very mild symptoms. It's extremely unusual for someone to take paxlovid and then have this rebound and progress to a severe disease, that's very unusual, right? Dr. Khyati Patel 40:44 And you gotta kind of compare your risk versus benefit, right? So kind of reminding the audience about our epic HR study, we found almost 90% 88% to be precise, relative risk reduction in hospitalization or death within 28 days. And so that, in itself, outweighs the asymptomatic or minor rebound cases that are occurring. Dr. Sean Kane 41:09 Yeah, you know, with a five day of paxlovid therapy, and we'll call it about a week, where you could have that rebound effect that's captured in the 28 days of the study. So even if everyone had rebound with paxlovid, you still get a 90% reduction in hospitalization and death with paxlovid therapy, so the benefit is definitely still there. Dr. Khyati Patel 41:30 Well, Dr. Kane, this was a great episode to just kind of summarize it. Paxlovid is the preferred outpatient therapy now for covid 19 in patients who are at high risk for hospitalization due to severe covid 19, and when we look at some other therapies, like the IV monoclonal antibodies and IV outpatient remdesivir, the efficacy is similar, but we can't, you know this wasn't obviously studied head to head, and it makes the comparison a little bit different because of The difference in vaccination rates in these underlying patient population. And so it's direct comparison. It's not really easy to make. Dr. Sean Kane 42:09 And one thing for me, Doctor Patel is that I was not familiar with this paxlovid mouth or this terrible trash like taste in your mouth that some patients may have. And if they have that, it usually resolves very quickly after stopping therapy, and there are some simple interventions like lozenges and strong tasting gums that can help patients get through it to finish their five day course. Yeah. Dr. Khyati Patel 42:31 And then the exciting thing is, as of July 2022, the licensed pharmacist in the states have authority to access patients for paxlovid and prescribe the medication. However, we don't have clear reimbursement criteria in place, which kind of makes this clinical service execution a little bit difficult. Dr. Sean Kane 42:50 And then finally, in the news, the rebound covid 19 with paxavid. I would say it isn't completely clear that paxavid is causing the rebound, but if it is, it's almost always mild or asymptomatic, and it does not require additional treatment. So thanks to tell I think that rounds out today's episode quite nicely. We actually have a lot of show notes, because this is kind of an emerging topic, and even something as simple as risk factors for severe covid 19 and therefore indications for paxlovid, it's on a website that is frequently updated, so we have all of the websites, the checklist for pharmacist prescribing everything in our show notes. And the listeners can see that by going to HelixTalk.com and clicking on episode 154 we're also on Twitter at HelixTalk, where we release some clinical pearls. And anyone who wants to get an inbox message in their email whenever we release new episodes, we have a mailing list, and you can subscribe to our mailing list again through our website, at HelixTalk.com so with that, I'm Dr. Kane Dr. Khyati Patel 43:49 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 43:53 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 - ? 44:04 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.