Gerald Lee, MD (Host): Hello and welcome to a special episode of Allergy Talk, a roundup of the latest in the field of Allergy and Immunology by the American College of Allergy, Asthma and Immunology. On May 16th, 2025, the FDA issued an alert regarding a rare but serious side effect of severe pruritus after discontinuing long-term use of cetirizine and levocetirizine. In this episode, we'll discuss the background of this important announcement and what it means for our patients.

Well, hello again. My name is Gerry Lee. I'm an Associate Professor at Emery University and an Assistant Editor of Allergy Watch. We're very fortunate today to be joined by Dr. Michael Blaiss, a Clinical Professor of Pediatrics at the Medical College of Georgia, and a previous holder of the Presidency and Executive Medical Director of the American College of Allergy, Asthma and Immunology. Michael, thank you so much for joining us on the podcast.

Michael S. Blaiss, MD: Well, thank you for having me, Gerry. It's great to be here with you today.

Host: And you know, I particularly thought of you when I was trying to design this episode, because I know of your experience with being a consultant on antihistamines, could you tell us a little about your background expertise in this topic?

Michael S. Blaiss, MD: Sure. So in fact, when these products, the second generation antihistamines, before they were launched, in fact, I had consulted with most of the companies that were producing those. I was also at Pfizer at one time in their OTC division related to what they called it at that time, respiratory or better breathing.

So I had interaction there related to over-the-counter products like antihistamines. And now I am a consultant with companies that in fact manufacture three of the second generation antihistamines that are presently on the market. So it's something that I've had a passion about antihistamines in fact, uh, throughout my career.

Host: Oh, well again, I really appreciate you sharing your expertise and your insights. So let's get started. I think just so everyone is up to date, could you just review again what the FDA actually announced on May 16th of this year?

Michael S. Blaiss, MD: Sure. So the FDA issued a warning, that patients that in fact were stopping their oral allergy medications, and two specifically, and that is cetirizine or Zyrtec, levocetirizine, which is Xyzal, which we know is the active in acter of cetirizine, after long-term use; and I think that's key here and we'll talk about that more, that they may experience, in fact, when they stop it, a rare but in fact severe itching.

Now we know these medications are still available by prescription, though again, they're all over-the-counter also. So the itching that's reported in these patients, in fact, the FDA said where these were patients that were taking it daily and typically they were taking it for at least several months and often years.

And what I also thought was very interesting is the patients had not experienced itching before starting these medications, which we can talk about, you know, suggests that the itch mechanism here is different than the typical itch mechanism that we would have related to allergies in some cases.

So, very clear here, and I think the FDA made this point in their paper is that the reported cases are very rare, but they are sometimes serious. And these patients were experiencing very widespread, severe itching that really did require a medical intervention. So because of this, they're revising, in the prescription cetirizine and levocetirizine, their prescribing information.

There'll be a warning now also that'll be placed on the OTC versions, that'll be placed in the drug effects label. So that is in a nutshell what the FDA came out with related to these two products.

Host: Okay, so I mean, first I have to ask the big question here, Michael, cetirizine was FDA approved in 1995. We're talking about almost 30 years ago, and levocetirizine is 20 years ago, 2007. So I have to ask the question, why are we learning about this now, like decades after the drug was approved?

Michael S. Blaiss, MD: Well, in fact, you know, the FDA, and we can talk about this more, collects data from patients, healthcare providers through their FDA adverse event reporting system or what's called FAERS. And if you really go back now and I was able to get some more information here. In fact, this is not something new. The first report, and this was published in a journal called Drug Safety, and this came out in the Netherlands in 2016, and in fact there were 12 cases of this severe unbearable itching several days after withdrawal. In fact, all 12 of these cases were levocetirizine. And this was picked up by the database in the Netherlands, the Netherlands, a pharmaco vigilant center.

And they described these patients. They were mostly women. There was one man, and again, every time they would stop the antihistamine that they'd been on months or years, they would have this severe itching. And then in 2019, Chung et al, and all these individuals that were on this paper were at the FDA, and in fact, they published a retrospective study to identify and describe cases of itching that occurred after discontinuation of cetirizine. This was all from the FDA adverse event system, their database. And they reported at that time in 2019 that there were 146 cases. The mean age was 38. They had patients from six to 71 years of age.

And again, they reported that it was primarily seen in the female population. But why now the FDA decided to put this warning out, I can't give you an answer to that. But nevertheless, it has been noted, from the FDA, that these rare cases of the severe itching after stopping these two drugs has in fact been going on.

Host: Okay, so, clearly a lot of this is post-marketing surveillance. You mentioned the FDA actually knew about this even as early as 2019, but let's talk about post-marketing surveillance. Just because a lot of people may not be familiar. Could you talk a little bit about the system of the FDA adverse event reporting system?

Michael S. Blaiss, MD: And it's, very important because as you mentioned, post-marketing safety is, you know, extremely important to know what in fact is going on out there after a drug is released. So the FDA Adverse Event Reporting System is a database that physicians and other healthcare providers and the public can in fact report adverse events they've had with medications, medication error reports, product quality complaints, so any type of adverse event that's associated or believed to be associated with a drug, can be reported, by the FDA. So this gives us information as in this case, of extremely rare side effects that in fact can occur, with a particular product and that picked it up. The FDA also has an adverse event reporting system just for vaccine reactions.

And the same situation can be reported by either patients or by healthcare providers. And again, how accurate are these? You can't say, from this data, there is a cause and effect in all cases. But nevertheless, I think it is an extremely important system out there to pick up, the possibility of rare side effects associated with medications.

Host: So it sounds like, even though the FDA reported this on I guess 2019, even though it was up to 2017, this recent report is based on data since 2017. What's the data they actually used to submit this warning or what was the basis of it?

Michael S. Blaiss, MD: So the data that they reported for this warning is data they collected from April 25th, 2017 to July 6th, 2023. And during that time, the FDA had 209 cases, in fact, that were provided to them or placed by people on the database. Since it is worldwide, anyone can, 197 of those were in fact, from the US.

The other 11, were from other countries where patients stopped either cetirizine or levocetirizine and in fact had severe itching. And in that database, 180 of those cases were related to cetirizine, 27 of those cases were related to levocetirizine and there were two patients that in fact were on both medications, at least according to the report.

And I think it's important to note in these 209 cases this is a temporal relationship between discontinuing the antihistamine and the onset of the itch. And at least from the data that they had, the median time on onset was two days after stopping the antihistamine, and the range was from one to five days.

So this is going to occur very quickly, at least from all this data, after the antihistamine is stopped. They also gave some other information that I thought was interesting. They stated that 87% of the cases were submitted by individuals using the medicine and six, this was interesting, self-identified healthcare professionals, reporting their symptoms.

So in fact, there were six healthcare professionals that had this side effect, associated with either levocetirizine or cetirizine.

Host: Okay. It does sound like then that there's a consistent pattern over the years. Now it's just, getting more attention. But even with this latest report, we're talking about 209 cases. If that's the numinator, do we do a much about the denominator? Like how many patients take these medicines? I'm just curious of like the again, you said it's rare, so how rare is it?

Michael S. Blaiss, MD: When I go over these numbers with you, you'll see how rare it is. So I have data here from 2022. And remember these antihistamines you can still get by prescription. So we'll divide it into prescriptions and then over-the-counter packages. So if we look at prescriptions and we're talking about in 2022, there was 26.8 million cetirizine and levocetirizine prescriptions that were dispensed in US outpatient pharmacies during that year; 65%, were for the OTC version of the medicine, and 35% were for the prescription products. So that is through the pharmacist. Now, in addition to that, another 62.7 million packages of OTC cetirizine and levocetirizine were purchased by consumers, again, just off the shelves from the drug store or the grocery store or whatever, any other US retail outlet.

So you can see here, we're talking about basically almost a hundred million packages, prescriptions, a total of cetirizine and levocetirizine in 2022 alone.

Host: Man, I knew this was a popular medicine, but gosh, nearly a hundred million got what? 400 million people in the United States? That's, I mean, I'm not saying it's a one-to-one, but that's like 20, 25% of the population on this medicine. My goodness. It's like in the water. Okay. So I think overall, let's just clarify then. You mentioned the onset of the itching is quick, but how much cetirizine or levocetirizine would take, could you remind me again, of just what is the definition of long-term use? Like when does this risk might occur?

Michael S. Blaiss, MD: So what's been seen from the data, so far, where they have the data, again, they don't have all the data from those 200 and something patients, of exactly, the time that they were on the particular antihistamine, but they did have data in 106 of these patients.

And in these patients, the length in fact was more than three months. I think the other interesting part here is that generally the longer the person had been on the medication and then stopped, the higher the risk of the reaction. And I think that's one of the key points that at least from this data.

Host: Did they give any sense of how bad this itching was? I mean, is someone going to report this and they're just a little itchy for a day? How serious, when they mean serious, is this itching?

Michael S. Blaiss, MD: Yeah. Yeah. So what we don't know is how many people have mild itching because from looking at this data from the database, it really looks like these people that reported it really had severe itching over a significant area of their body and really affected their quality of life and ability to function.

In fact, they had data that 48, of these patients were classified with disability, that they had a debilitating itch to the point that they were bedridden. And there were three that were hospitalized, and, they had thoughts of suicide and self harm in fact had been reported in two of the patients in the database. So, at least from what is being reported, this is a severe itch problem.

Host: CThat raises the level of concern. Obviously, if you're having that level of severity, I can understand why they want to bring this to our attention, but does that make sense biologically? Do we have any theories of why long-term antihistamine use might cause this?

Michael S. Blaiss, MD: There are definitely some theories out there. Again, none of this has been proven. I'll give you at least, my thoughts. The one that seems to make the most sense, and the one that at least I've heard others suggest maybe a possible cause is basically, and I'd put this under the category of a histamine receptor upregulation.

And one of the things we know is that long-term blockade of the H1 receptors, by cetirizine, may lead to an upregulation, or an increased sensitivity to these receptors. So when cetirizine is withdrawn or levocetirizine is withdrawn, now you have these hypersensitive histamine receptors that respond strongly to just normal levels of histamine that could cause an intense itch.

Because remember, we have small levels of histamine being produced at all times. So it's not like only when you're having an allergic reaction. And the reason this one tends to make probably the most sense, this type of phenomena has been seen with proton pump inhibitors, where patients have been on them for a long period of time.

And then they come off and they start developing severe GERD symptomatology. So that's one of the theories. There's some others out there too. One is the suppression of endogenous antihistaminergic regulation. And what may be going on here is that chronic antihistamine use, and again, remember, these are patients taking it long term, may affect mast cell stabilization, or histamine degradation pathways has been thought. And therefore, when one discontinues the antihistamine, this could result in some transient deregulation of histamine activity. And again, this may exacerbate itching. And one other theory that also I think has a possibility because we do know that this has to do with the central nervous system.

We know that cetirizine does have some limited CNS penetration and chronic use therefore may alter the neuronal process of itch in histamine signaling in the central nervous system. So possibly stopping the medication may increase that itch perception, due to central sensitization. So these are at least some theories out there of exactly, what may be going on. But we have no proof of any of these at this time.

Host: Michael, how good are these reports? Meaning like, do we specifically ask these patients, did they have rash associated with the itching? Because one of the things I initially thought was, could they have been on daily antihistamine and then have like chronic urticaria that they just didn't recognize, and then they stop their treatment and then boom, they got uncontrolled chronic hives? I mean, you know, again, I'm just going for the lowest hanging fruit here, but I, I don't know. How good do we know about these cases or they don't provide that information?

Michael S. Blaiss, MD: No, it's what you voluntarily give. So that's why they don't have information on everybody of how long they were on the medication and that's why this is probably underreporting the mild to moderate patients because they're probably not reporting this. So, unfortunately we just don't have that particular type of information.

Host: Now these reports are centered on cetirizine or levocetirizine, but a lot of what you are saying is just talking about histamine blockade. So has this been reported with other antihistamines? Is there any reasonable belief that other antihistamines could cause this side effect?

Michael S. Blaiss, MD: So if you look at the database, we're really not seeing that with the other second generation antihistamines like, fexodenadine and loratadine.

Now we know all of these are inverse agonists of that H1 receptor. So they all bind to the inactive confirmation of the H1 receptor and stabilize it. So, we know the mechanism of action here. It prevents histamine from binding, it reduces spontaneous receptor activation.

We also see that can lead to a greater suppression of allergic symptoms. So it shouldn't be from that. So what could be the difference here? So even though they all have similar pharmacologic properties, if you look at their chemical structures, there are some significant differences here.

And this could affect the metabolism, the duration, and those side effect profiles. So just to tell you, if we look at the chemical structure, the core ring of these antihistamines, if we take cetirizine and levocetirizine first, they have a piperazine ring. If you look at fexofenadine, it has a pepperdine ring, so a completely different ring.

And then if you look at loratadine, it has a tricyclic core with the pepperdine ring, with ethyl ester. So the chemical structure of these agents is completely different. So my guess is, and it's just my guess, it's related to a difference in the chemical structure between cetirizine and levocetirizine and the other second generation antihistamines.

Host: Oh, that's really interesting. Okay. Well, clearly we have this report out. It sounds like it's biologically plausible and not a new thing. It's just being brought to our attention, but it's been around for a while. So do we bring this to the clinic? Is there ways we can avoid this side effect in our patients?

Michael S. Blaiss, MD: So, if we look at some of the reports that are out there and the two articles that I mentioned in journals, there was also some talk about this. And so one of the ways, that they talked about is you could just restart that patient back on that antihistamine and the symptoms in fact will improve.

So that's one way. Another way would be to restart the antihistamine, but then wean them off slowly. And there is some data, but not in all patients, doing that, will allow you to get the patient off levocetirizine or cetirizine and the itch to go away. Another way to do this, would be to start them on a different H1 antihistamine.

Loratadine and then taper, off the levocetirizine or cetirizine and that may reduce receptor bound sensitivity. And then I saw one report where they tried weaning them and adding a short course of corticosteroid to help with the withdrawal. So those are at least some possible ways of helping patients with this problem.

Host: So you know, we have to keep in mind one reason people on long-term antihistamine, we tell them to stop it suddenly is skin testing. So should we be including something in our skin test instructions or pre-visit instructions just to make sure patients don't actually get a side effect from this?

Michael S. Blaiss, MD: Yeah, I think that that can be very important so that we, you know, we tell the patients that when they stop their antihistamine, if they start developing severe itching obviously, to let us know. So we can tell them what to do. Now it could just be mild itching and maybe they could tolerate that till the time that they got skin tested.

You could have them use some topical emollients to try to help with the itching. So I would warn the patients that, again, if they start developing a severe itching coming off either cetirizine or levocetirizine before skin testing, they get in touch with you as far as what the next step should be.

Host: So it hasn't happened to me yet, but a patient on cetirizine or levocetirizine might ask what to do now that they're on it, or if you prescribe it or recommend it, they might come back to you about the warning. So how would you address patient concerns about this report?

Michael S. Blaiss, MD: Well, I guess the question is why are they on the medication? And so that's going to be the first thing. And are there other medications if the patient wants to come off that could take care of the problem? So, one example would be if the patient's really only having seasonal allergy problems, which is why they're taking the antihistamine, then, you know, just taking it during that particular season, so that they're not taking it chronically for months or years. If they had severe, allergic rhinitis, they're taking it for that, they're mostly having nasal congestion, then we know antihistamines aren't that helpful for nasal congestion.

So maybe a topical intranasal corticosteroid would be better. And if someone was having like severe eye itching, maybe a topical, ocular antihistamine may be better. I think, you have to look at the particular conditions. Another one would be, and we see this a lot, patients on antihistamines for atopic dermatitis, and we know in fact, that it's not histamine that is leading to the itch of atopic dermatitis. So, an antihistamine's not going to help those patients. So, we as allergists can get that history and determine in fact, with that patient, what is the best treatment for their allergic condition.

Host: Well, Michael, again, I really appreciate your expertise and teaching me a lot about this topic and what I can do if this comes up my clinic, or again, being proactive to prevent this side effect, but now that this is out, what are the next steps? What should we do as a specialty? What do you see happening in the future?

Michael S. Blaiss, MD: Hopefully we'll learn what exactly the mechanism is and is there ways to prevent it? I think what we're doing today though is what's extremely important, and that is I think every allergist out there needs to know about this. We all use antihistamines and, so many of our patients come in on antihistamines, so we need to be able to explain to them that in fact there is this rare side effect now. And that doesn't mean they need to stop the medications, but in fact they just need to know about that possibility of it occurring. And again, all medications that we use for our patients, we always are weighing that risk benefit ratio here. And again, we can see here it's a very small number of patients compared to the number of prescriptions and over-the-counter use of these medications. So we don't want to cause alarm out there, but we just want people to understand that there is that rare possibility.

Host: Well, that's really good things to keep in mind. And again, Michael, thank you so much for joining us on short notice about this recent FDA alert. You may have further questions about this topic or just want to give us your own anecdotes or feedback. The email to contact us, it's allergytalk one word,@acaai.org.

If you do like what you hear, if you subscribe and rate to us, that does help the podcast. And remember, we also continually give you up-to-date information about what's important in our field. The Allergy Watch publication website is college.acaai.org/publications/allergywatch. Again, this is Gerry Lee from the American College of Allergy, Asthma and Immunology.

Dr. Blaiss, thank you so much for your time and I hope you enjoy the rest of your day.

Michael S. Blaiss, MD: Thank you for having me.

Host: The ACAAI is presenting this podcast for educational purposes only. It is not medical advice or intended to replace the judgment of a licensed physician. The college is not responsible for any claims related to the procedures, professionals, products, or methods discussed in the podcast, and it does not approve or endorse any products, professional services, or methods that might be referenced.