Federica Santoro 0:10

Welcome to Drug Safety Matters, a podcast by Uppsala Monitoring Center where we explore current issues in pharmacovigilance and patient safety. Choosing the best medicine for a child is no easy feat. Some drugs are inappropriate for young patients, while others require special consideration or monitoring. And for years, clinicians had only historical dogmas, word of mouth, and their own experience to guide their choices. But a valuable new resource promises to change pediatric prescribing for the better. I'm your host, Federica Santoro, and this episode is part of the Uppsala Reports Long Reads series, where we select the most topical stories from our magazine, Uppsala Reports, and bring them to you in audio format. Our pick for today is the article Improving Medication Safety for Children, The Kids List, written by Rachel Myers, Robert Hellinga, and Kelly Matson. The article appeared online in December 2020 and in print in issue 84 of the magazine. After the read, I sit down with Rachel and David Hoff, the senior author on the original Kids List publication, to find out more about medicine safety in children. So make sure you stay tuned till the end. But first, let's hear the article. Adverse drug reactions have been observed since the dawn of medicine. Assessing their risks and identifying populations most at risk is a constant challenge for healthcare practitioners. The BIERS criteria for potentially inappropriate medication use in older adults is one such attempt at addressing that challenge. First published in 1991 and most recently updated in 2019, the BIERS criteria have led to significant improvements in medication safety for the geriatric population. Until recently, however, no similar list of medications existed for the pediatric population. And with this in mind, the Pediatric Pharmacy Association commissioned a group of seven authors to accomplish this goal. The result was key potentially inappropriate drugs in pediatrics, the Kids List, published as an open access article in April 2020. The creation of the Kids List is a result of nearly three years of work by the authors of that paper, which included the three of us, along with input from multiple experts and the membership of the Pediatric Pharmacy Association. Our research included collecting information from a literature search, pediatric safety communications from the US Food and Drug Administration, and a search of the Lexicomp database. Medications were only included if they were commercially available in the United States. They posed a unique risk to pediatric patients, a safer alternative was available, and the adverse drug reaction was clearly attributed to the medication and documented in the medical literature. Examining the literature and reaching a consensus among the author group was challenging, and often came after hours of discussion and consultation with outside experts. In many cases, we faced a shortage of data from the literature, often just case reports from which to make a decision. The selective serotonin rheuptake inhibitors, or SSRIs, are just such a case. These medications for depression have been associated with an increased risk for suicidality in children. This risk is not well understood, and whether or not any individual agent has a higher risk than the others is unknown. Given the undeniable benefit that these medications provide to children with depression and the lack of any solid evidence implicating any particular medication, the decision was made to keep them off the kids' list. With better evidence, we hope that future iterations of the kids' list will provide better guidance. Other medications, such as those used for cough and cold, were left off the list because concerns about their use stem from lack of efficacy rather than documentation of harm from labeled doses. While the FDA recommends that they be avoided in young children, reports of toxicity were found to be due to overdoses. This example draws attention to an important point. Exclusion from the kids list should not be mistaken as an endorsement for a medication safe use in children. The kids list is limited to drugs marketed in the United States, and readers from other countries should keep this in context when incorporating the list in clinical decision making. Alternative medications which are available in the United States may not be as easily accessible in other parts of the world. The use of medications in the pediatric population frequently involves a comparison of risks and benefits, and for this reason, we intentionally cited all literature that contributed to a drug's inclusion on the list to allow healthcare practitioners to independently assess the available evidence. Since 2007, the WHO model list of essential medicines for children has been a reference for the minimum medication needs for basic healthcare for children. Several medications from the kids list appear on the model list. For the majority of them, bapproic acid, sulfamethoxazole, and ceftriaxone, to name a few, the kids list suggests age restrictions. For others, such as Lamotrigene, caution is advised due to the higher risk of skin rashes in the pediatric population. It should be noted that inclusion of these medications on the kids list does not mean that they should not be used in all children. Rather, the kids list strives to clarify which age groups are at greatest risk and identify drugs which have a higher incidence of adverse effects in children than in adults. For three drugs, chlorpromazine, haloperidol, and metochlopromide, the kids list recommends exercising caution for all children. The addition of these dopamine antagonists to the kids list was based on evidence of extrapyramidal symptoms and increased risk of respiratory depression in children. As therapeutic alternatives are readily available in America, the expert panel moved to include them on the kids' list. However, use of these medications in other countries may be warranted under specialized care, such as chlorpromazine and haloperidol, or with age restriction, such as metochlobramide, as recommended in the model list. Assessing the risks of adverse drug reactions in the pediatric population is a continuous process and one that is in great need of better evidence and more research. It is our hope that the kids list may serve as inspiration for others to create similar lists which take into account local data and drug availability. For those who care for children, it should also serve as a reminder of the importance of documenting and sharing experiences so that we may work together to improve medication safety for children around the world. That was the article, but as usual, I couldn't resist contacting the authors to learn more. So I reached Rachel Myers and David Hoff at their home offices in the US. Rachel is a clinical professor at the Ernest Mario School of Pharmacy at Rutgers University and a pediatric clinical pharmacist at St. Barnabas Medical Center. While David is the Director of Clinical Pharmacy Services at Children's Minnesota and an assistant professor at the University of Minnesota. I hope you'll enjoy our conversation. Hi Rachel, hi David, and welcome to Drug Safety Matters. Before we dive into the kids list that we just heard about, I'd like to take a step back and give our listeners a little background on the issue of medicine safety in children. So, as you point out in the introduction to your publication, adverse drug reactions seem to occur more frequently in children than in adults. Why is that?

SPEAKER_01 9:36

Well, first, thanks for having us, Federica. And yes, as we pointed out in our article, adverse drug reactions do seem to occur more often in children, and there's a variety of reasons for that. One is simply that they're still developing and they're just simply not going to handle drugs and excrete drugs and metabolize drugs the same way that an adult would. Another reason would be that drug testing in kids is not going to be as extensive. Now, we've seen a lot of new legislation in the last 20 years that's really increased the amount of testing that is undergone for new drugs for children. But unfortunately, I would estimate in my day-to-day practice, about 80% of drugs that we use every day are older drugs, which may not have gone through some of the same rigorous testing that newer drugs have. And we know that because we often use older drugs so frequently, oftentimes we're using them off-label and just trying them out in kids when they really haven't been fully tested.

Federica Santoro 10:35

And because of all you said, it made a lot of sense then to come up with a resource like the kids list, which was modeled on the BIERS criteria, which addressed medication safety in another vulnerable population, the elderly. Now, the BERS criteria were published in 1991. The kids list only appeared last year. What took so long?

SPEAKER_00 11:00

Federica, I'm hoping that you could answer that question for us because I don't have the clear answer on that one. I think what everyone realizes when they get into pediatrics, whether they're in medicine, uh nursing, pharmacy, they understand that there are certain medications that children they behave differently with those medications, or they they don't handle them as well, or there are medications to be avoided. And so we all have this mental list in our heads when, you know, before we walk in the door on the first day that we start to practice. And I had a list of maybe five that I learned in school. Unfortunately, no one ever thought to put those into writing and publication. And when I was a young practitioner, I looked for such a list. I did not find the list. I don't think the internet was much of a thing then. And so I was going to the library looking for lists, a little bit embarrassed asking my colleagues if there was a list, because surely a list would exist. But apparently nobody thought to put the list together. It's something that I always thought that somebody else should have done, somebody with more knowledge, experience, more savvy, smarter than me. But as time went along and the beers list was published and gotten quite recognized, I thought, well, somebody should do it and um I'll be the one. And so that started the process of our team and uh getting the kids' list to publication.

SPEAKER_01 12:22

Yeah, I just think in pediatrics, there's always been this historical dogma that built on itself over the years, and you just sort of learn as you're going along in clinical practice as a student and as you go on to your residency in in all the professions, nurses, physicians, pharmacists, and it's just sort of passed down by word of mouth. There was no really good place where that was all recorded together. That's why we tried to put this together so there was a good, solid reference out there. And again, we hope that it'll be a living document that we can add to over the coming years.

SPEAKER_00 12:55

Correct, Rachel. I when I began, I had my list and I started growing my list based on my own personal experience, based on my conversations with others. And as I traveled the United States, I encountered others with similar lists in their heads, and their lists were different than my list. That's very interesting. And so this dogma is very uh haphazard, I guess. It's based on your own experience. It's not rigorous, it's not scientific, it's not vetted. And so that really uh said to me the need for such a list to exist.

Federica Santoro 13:28

That's really interesting. And obviously, that kind of experience you describe and the word of mouth is certainly important, but there's the evidence aspect that you want to take into account. And we're certainly glad you took it upon yourselves to compile such a resource. Now, what does it mean when a medicine is on or off the kids' list?

SPEAKER_01 13:52

So, items or drugs that made the list were drugs that specifically showed risk in children. It was well documented in the literature, and also a really key point is that the risk had to be greater than it was in adults. So there are plenty of medications out there that show risk for all populations. And that wasn't our goal here. We wanted to show what was riskier in pediatric patients specifically. Um, I think a good example of a drug class that didn't make the list was fluoroquinolones. And I know as a student, we always learned, you know, you don't use fluoroquinolones in children under 18 except in very special circumstances like in cystic fibrosis, for example. Um, but what we found when we were looking at the data is that there are a lot of risks in adults as well. The United States FDA has come out with several warnings about fluoroquinolones over the last few years. And so when we looked at the evidence in total, we found that they really didn't seem to have a higher risk in children where we felt that it would be worthwhile to put them on the list. Now, again, this is a living document, so maybe in the next couple of years something will come out that will make us want to add them. Another example would be the SSRIs or selective serotonin reuptake inhibitors, which are used for depression. Those medications have been linked to increases in suicidal thinking. And we are very concerned about those, but at the same time, we knew that they show definite benefit for children, and we didn't want to put the whole class on the list because, again, we didn't want anyone to think, oh, this is a drug that should not be used. We didn't want anybody to hesitate to treat a child with depression. And what we were really hoping to find was maybe one or two of them showed more risk than the others. But unfortunately, while there is some data looking at that, there just wasn't enough to really put one or two from that class on the list. So we decided, and this was probably one of our hardest decisions. I think Dave will agree with me on that. Um, but we decided to leave them off. But we're hoping that because we know there is some risk there, that in the future we'll be able to sort of piece out a couple of them that maybe are riskier than the others to help guide clinicians and their decisions.

SPEAKER_00 16:08

Yeah, I agree, Rachel. We have to have an alternative. Just because a medication or medication class causes adverse reactions in children doesn't mean it makes the list. We have to have an alternative from which to choose. Chemotherapy is incredibly toxic, but it's not on the list. It's not on the list because it's similar to adults, and in many cases, we don't have good therapeutic alternatives that are less toxic. And so there you go. I would also add a few other categories to what you said. And I think if uh the reader would like uh to go through the paper, the kids list, you can kind of see what the inclusion and exclusion criteria are, and you can be very crisp on that. We were using the World Health Organization definition of adverse drug reaction, which is very specific. It talks about a noxious or unintended uh consequence from a medication being used in the normal course of the treatment of a disease. And so we eliminated anything from the literature that was an overdose or something that was uh used improperly. We also avoided getting into the weeds on deciding whether a drug was a good drug or a bad drug based on therapeutics. So we weren't looking at clinical outcome, only at adverse outcomes. Um, also, the medications on the list had to have a use in children. I think the cough and cold products are a good example of that, Rachel, where we saw a lot of adverse reactions in the literature around dextromethorphan and some of the cough-cold products, but the products are not effective in children. And so we would argue that they shouldn't be used in children. And most of the reactions that we saw were overdoses as well. So for two different reasons, we excluded the cough-cold products from our list, even though they're well known to be hazardous in the pediatric population.

SPEAKER_01 18:01

Aaron Powell I think that brings up another point, too, is that just because a certain group of drugs is not on the list doesn't mean they're safe to use. We pointed out in our article, but I just like to stress that that just because it's not on the list doesn't give it a green light.

Federica Santoro 18:15

Absolutely. And that's an important point to make. Were there any surprises while assembling the list?

SPEAKER_00 18:22

Well, the big surprise for me was that my list looked nothing like the list we ended up with, right, Rachel. We ended up with uh 67 drugs or drug classes and 10 excipients. And I probably had 40. And a number of mine didn't make the list. I long suspected that. I guess it didn't occur to me how much the list differed from the list that I had in my head until we actually went into the literature and uh pulled data. And I think of the ones that were on my list that I kind of changed over time. I changed perspective a little bit, where the fluoroquinolones, I was pretty comfortable with their use in PEDs. And after speaking with our team and going over the data, I felt even more comfortable leaving them off the list. Uh, aspirin was one, right? It's the very first one they teach you in school. Don't give aspirin to kids who have a flu-like illness. It'll cause Ry's syndrome. And some of our more seasoned uh professionals remember very well and speak loudly about the days when Ryze syndrome was among them in children in the hospital with Ri's syndrome. Though over time, I think some of the cases that were diagnosed as Ri'Es syndrome were really perhaps previously unknown, unrecognized, unstudied metabolic disease that we now have names for. And now that we have names, Ry's syndrome, I haven't seen a case in spite of using aspirin in appropriate indications in infants and children. The other one was tetracyclines. We all learned from the beginning that you don't give tetracycline to children, it makes their teeth mottled gray uh and brown. It's uh not to be used. But over time, research emerged that the semi-synthetic uh doxycycline was probably okay. And we were pulling data and we came to that same conclusion, really. And so when we wrote the tetracycline class, we had tetracycline and dameclocycline, made the list. There's evidence showing harm, but not doxycycline or monocycline. And so we specifically left doxycycline off the list. And no sooner did we make that decision within our subgroup than the United States came out with some sort of communication saying that doxycycline could be used in children. And so I felt good about that. Sometimes when we were working through a process, my thoughts on that came to change a little bit over time.

SPEAKER_01 20:52

Yeah, I just wanted to add to the aspirin piece, that was the one that really surprised me the most because it's taught to you as a hard and fast rule. You really can't use this. And it did make the list, but what was surprising to me was how we ranked the evidence. And the evidence just wasn't as strong as we had thought, or as I had thought it would be, based on how I had been taught and how strong that recommendation had been repeated to me over the years.

Federica Santoro 21:19

Um And you say the kids list is a living document. How do you hope it will be used in practice? And uh, have you received any feedback from clinicians or patients, perhaps, since it was published?

SPEAKER_01 21:33

I think the feedback that I was most glad to hear was from our pediatric medical residents. They thought it was really interesting, and they were just glad to know that it was there and that it was a reference and something that they could look at and refer to as a guide for them in their practice. I think one piece that Dave and I have been kind of talking about lately that we're trying to work on in terms of incorporating into practice is reaching out to our Retail pharmacy and community pharmacy partners because sometimes this kind of information doesn't disseminate down to them. And I still hear from my physician colleagues that they get called about doxycycline, they get called about aspirin, and we're struggling to find a way to kind of uh reach out to those community partners and help them learn. And I think it's going to start in schools, unfortunately, too. And so we hope that this document will help change how we educate our pharmacists and our physicians. Um and slowly that will work its way down.

Federica Santoro 22:32

Now you're both based in the United States, therefore the list is specific to the US. Can readers in other countries make use of it? And do you know if similar lists are being developed anywhere else?

SPEAKER_00 22:46

That's a great question. I would say please follow the lead. You know, a lot of what we did in developing the kids list was based on the methodology and work already done and sort of the breadcrumbs that was left by the beers list. And so I would hope that our colleagues from other countries consider that and develop their own lists or an addendum to this list. The reason we stayed away from an international list is I don't claim to know anything about other countries' formularies, um, medications that are used that I have had no experience with. I feel like it's not my place to go and tell Sweden how they should be doing things. And so I would look to partner with our international colleagues on this. I think there are medications that are not used in the United States that are freely used in other parts of the world. I think that lists from other countries would be quite useful. And so I would say please follow our lead or join together with us or give us suggestions to improve our own list. And to that end, I am unaware of any effort to generate lists from any international sources.

SPEAKER_01 24:06

The other piece to add to that is that there are just other options in other countries, and maybe they have an alternative that we don't have in the United States, or maybe we have an alternative drug therapy in the United States that doesn't or isn't available in other countries. And so we may list a drug because we have a better alternative, but it's just not available in other countries. And so that's why you just have to be careful and consider what's available in your own practice area.

Federica Santoro 24:32

The list is a really important step forward, but obviously it's not the end of the story. Children deserve better information on the drugs they take, and for that we need more research and better evidence. How do we get there though?

SPEAKER_01 24:49

Uh so I think that's an excellent question. The first step, um, which we've already taken, is better legislation to improve studies that we're doing for the new drugs that are coming out. And I think what we're seeing is some of these new drugs, when they finally get approved for children, we have data that we never would have dreamed of having 15 to 20 years ago. So what's coming out in the new drug realm is great. But what we need is better evidence again on those older drugs. So I would say a couple of things are happening. I know, at least here in the United States, the National Institutes of Health oftentimes will sponsor studies or ask manufacturers for more studies on drugs, even if they're older drugs. And in addition, I think we as practitioners need to take the initiative to publish and document what we see. And if we're trying an older drug in a new way, we need to study it and measure that and document it. Or if we are using a medication and we're noticing, you know, an adverse reaction that maybe isn't in the literature, we need to again report that to the FDA and also hopefully publish that. So we need to take the initiative ourselves as well as clinicians.

SPEAKER_00 25:56

I agree, Rachel. There are all sorts of different avenues that can be taken from this point. So we have now what we believe is an evidence-based reference. And then we're kind of throwing it out there. And I think one of the things that could be done with a list like this is to study the list. Is what we say actually true? So if you go ahead and implement this list in your health system, does it actually reduce adverse drug reactions? Wouldn't that be nice? I think that those who have access to large databases, our pharmacovigilance colleagues who are listening right now, if they have access to a database where you can use population, mathematical modeling to advance knowledge in this area, you can actively research what other drugs might be out there that we didn't get because it's not in the literature. We were limited by what was out there. We don't have the databases, we don't have the PhDs with the mathematical models. And so if there are those out there who have access to that and have that resource, I think identifying medications that are higher risk and have a higher risk of adverse drug reactions would be the beginning. And then other researchers can try to understand why those drugs behave that way. They can do other research to get to the bottom of it. Another area of potential use for the kids list is to better integrate the list with the World Health Organization model list of essential medicines for children. There are some medications on the kids list that are also found in the World Health Organization list. And if you read carefully the kids list, we're not saying that these drugs should be not used in all cases whatsoever in all age groups of pediatrics. Many of them, most of them, are neonates or premature neonates. And we would want to avoid that medication in that subpopulation of pediatrics, but it's still an essential medication. And we use it every day in pediatric hospitals. And so maybe that could be looked at a little bit more closely. I think the medications in the list could be integrated into information systems, like hospital information systems or national information systems. Pop-up alerts could fire based on the age of the patient and the medication being ordered, and we could have real-time synchronous alerts to reduce harm at the point of prescribing. These medications can be more integrated into drug information databases. Lexicomp, for example, partnered with us in this research. They actually let us have their database, and we were able to look behind the curtain, so to speak, to see what uh LexiComp had in terms of adverse reaction data for children. And Lexi has has adopted the list into their database, but there are other databases that could adopt this into their information systems. And then finally, uh Rachel mentioned it earlier. Not all drugs within drug classes behave the same way. The SSRIs, as she mentioned, study those more carefully. Try to tease out if there's a higher relative risk of harm of one medication within a category than another. Tetracycline is a good example I brought up earlier. Doxycycline, we're using tetracycline, demecrocycline, we don't use. There are just a whole host of possible uses and research avenues that can be taken from this point.

Federica Santoro 29:24

Sounds good. And we look forward to hearing about developments. You're welcome to come back to Drug Safety Matters anytime and tell us about future editions of the Kids List. Thank you both for taking the time to talk to me. It was a pleasure to have you on the show. Thank you so much.

SPEAKER_00 29:40

It's a pleasure being here. Thank you so much.

Federica Santoro 29:46

That's all for now. But we'll be back soon with more long reads, as well as our usual in-depth conversations with medicine safety experts. If you'd like to know more about the kids list and medicine safety in children, visit upsalareports.org or check out the episode's show notes for useful links. For more stories like this one delivered straight to your inbox every month, sign up for our free newsletter at upsalareports.org slash subscribe. And of course, if you don't want to miss future episodes of Drug Safety Matters, subscribe to the podcast in your favorite player and help us spread the word so other listeners can find us. If you'd like to get in touch, the easiest way to do that is on social media. Look for Uppsala Monitoring Center on Facebook, LinkedIn, or Twitter, and come talk to us there. For Drug Safety Matters, I'm Federica Santoro. I'd like to thank Rachel Myers and David Hoff for taking the time to talk to me, Matthew Barwick for post production support, and of course you for tuning in. Take care and till next time.