Implications of Boxed Warnings of Topical JAK inhibitors

EP: 1.Treatment Options and Targets in Atopic Dermatitis (AD)

EP: 2.Factors Guiding Treatment Selection in AD

EP: 3.Patient on Long-Term Steroidal Use in AD

EP: 4.Durability of Topical Steroid Use in AD

EP: 5.Challenges Faced by Non-Dermatologists When Using Steroids

EP: 6.AD Treatment Options for Patients Moving Away from Long-Term Steroids

EP: 7.Patient With Limited Disease Activity in AD

EP: 8.Efficacy Data for Topical Treatment of AD

EP: 9.Durability of Response to Treatment in AD

EP: 10.Time to Response in AD

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EP: 11.Implications of Boxed Warnings of Topical JAK inhibitors

EP: 12.Treatment Goals in AD

EP: 13.Treatment Options for Patients With Moderate Disease Over 10%-20% BSA

EP: 14.Monitoring AD Treatments in Various Age Groups

EP: 15.Guidance for Topical Treatment Use Based on BSA in AD

EP: 16.Emerging Treatment Options in AD

EP: 17.Keeping Physicians Up to Date With AD Advances

Raj Chovatiya, MD, PhD: Just to dig a little deeper into topical JAK inhibition, one of the talking points you guys have all had a chance to share your thoughts on is the idea of implications of boxed warnings, the dreaded black box warning that’s found on the JAK-STAT class, of which topicals are no exception. What do you think should be communicated with other health care providers, primary care physicians, even patients, to give them an adequate sense of balance when it comes to why you’re selecting a therapy for them based on some scary words that they might be seeing on a box or prescribing information? Dr Lio, I’ll ask you first.

Peter A. Lio, MD: Thank you. I think this is a big question because one thing we can’t do is, we can’t just not talk about it and hope for the best. Because inevitably someone along the way will mention it or they’ll see the package insert, and then they’ll call you at 10:00 at night and say, “Wait a minute, I finally just picked it up from the pharmacy, but you didn’t tell me about any of this.” So, you have to be anticipatory to some degree and address it. But what I like to say is, “First of all, we’re always trying to get the right patient to the right treatment, so this is not for everybody.” I often start by saying something like that. “The reason I want to use this is because, yes, it has some potential risks, but I think the benefits greatly outweigh them, otherwise we wouldn’t be having this discussion.”

The second thing I talk about is that, particularly for our black box warning on our topical calcineurin inhibitors and our topical JAK inhibitors, these are reflective of the systemic versions of these drugs. And it’s there as a precaution and a warning, and yes, it is possible that some of these adverse effects could happen even if topically used, especially if we are going to blow past some of the guidelines on how to use them. If you’re going to use it on much more than 20% of body surface area, we know you can start to approximate some of the systemic levels, although even in the maximal use study, we found that they weren’t even half the levels needed to get some of the hematologic issues. But that being said, I think I would say these are really inspired by the oral and systemic versions, and so if we use them safely, we think these risks are minimal, but I still go through them all with the patient. I think it’s so important to go through them so that they’ve heard them from me instead of somebody else.

Raj Chovatiya, MD, PhD: I think it makes you a better clinician from that standpoint because you’re thinking about these things and about the patient history. Oftentimes questions may not necessarily be asked about comorbidities, but then you realize there is a lot more going on with this person with atopic dermatitis, thus given more credence to the fact that this is really a systemic disease from that standpoint. I want to ask Matt about this because I know you have a unique and very understandable way of talking about this kind of stuff. How do you have these discussions with your colleagues or your patients, particularly as it relates to the boxed warnings on topicals? Then once you get a chance to weigh in, we’re going to ask Adelaide what she’s thinking as well.

Matthew Zirwas, MD: My conversation goes like this, whether I’m talking to a patient or a colleague. First, if I’m talking to a patient, I very specifically do not start by saying, “You’re going to get warnings from the pharmacy that talk about heart attacks, stroke, death, etc.” What I say is, “You’re going to get warnings from the pharmacy that sound very scary, but I don’t think you need to pay attention to them because they’re talking about a different medication than the one we’re prescribing for you, and for people who have a different disease. And we have tons of information that show us you are not at an increased risk for any of those things with this medication.” Really what I’m saying there is, we’ve got tons of data now that even the systemic JAK inhibitors do not increase the risk of VTE [venous thromboembolism] or MACE [major adverse cardiovascular events].

There’s no information that shows an increased risk with medications such as abrocitinib, upadacitinib, and there are no data around ruxolitinib topically increasing the risk either. So VTE, MACE, cancer, mortality, all of those, there’s not 1 shred of data that suggest there’s an increased risk with any of the drugs we have in dermatology. So that’s exactly what I tell patents, “We have a ton of information that shows that there is not an increased risk in people on this medication. But the FDA does want you to know that a distantly related medication did increase those risks in people with a different disease, but like I said, all of the information we have about this medication and this disease, none of it shows any increased risk.” And that is true, if somebody taped that and played it in court, I would be very comfortable defending it. So, notice I didn’t say, “It has been proven there’s no increased risk,” because that would require a specifically designed safety study that would be placebo-controlled and all this stuff. But we can very much say, “With all the information we have, none of it has shown any increased risk.” We can absolutely say that.

Raj Chovatiya, MD, PhD: I like that because that definitely is something that’s easy to understand, particularly for our adult patients. As somebody who sees a lot of children, Adelaide, particularly when we’re thinking about topical ruxolitinib in adolescents who are ages 12 and up, what does that discussion look like to you? What do you like to emphasize or think about, knowing the data?

Adelaide A. Hebert, MD: Well, I wanted to give some specifics on ruxolitinib. Many of you may know it’s been available as a systemic agent since 2011 for polycythemia vera, myelofibrosis, and graft vs host disease that is resistant to steroids. And the systemic drug does not have a black box warning. Here we have this interesting juxtaposition where the topical carries it as a class FDA warning, but the systemic, again, with 11 years out in the public domain, treating patients with these 3 disease states, we do not have a black box warning on the systemic drug. So that’s the conversation I have. If the FDA really had concern, it would have come out as a black box for the systemic agent, but we don’t have that.

Now, in terms of the oral JAK inhibitors, I do talk about some of the adverse effects. Like Matt, I don’t jump right into that, but having done the clinical trials and seeing the data and having had at least 3 years of experience with some of these drugs, I feel very comfortable, and I give my reassurances to the patients, not only based on the data but based on my own experience. We’re all clinical investigators, so I think that puts us in a unique comfort zone where we can have these discussions.

Raj Chovatiya, MD, PhD: I like it, and I think this is the reason we have a very diverse group here. People have had a chance to use these in very different capacities. I think that with much of our new therapies, particularly ones targeting JAK-STAT, it’s that use that gives you a lot of information on how that might fit into your practice. So oftentimes it’s just breaking through and trying something new for someone who might be a little less likely to adapt to something. I know we’ve had this topic discussed quite in depth, but I want to give Dr Noor a shot. Is there anything that was not mentioned that you find resonates well with patients or providers alike?

Omar Noor, MD: I appreciate it. I agree, I think the interesting part about medicine, especially with dermatology and our ability to communicate with patients, is everybody has their own kind of art to it. But I think the core value behind all these things, and I think Dr Hebert just mentioned it, is our own experience and our own confidence, individually. That confidence and experience is based on, obviously, our individual experience with the medication in our own patients. But it also starts with that framework of the data. Matt went through that as well, the data are there to make us feel comfortable that yes, these boxed warnings are due to a distant relative, which by the way, I totally love. But the real data behind the medication, and like Adelaide said, with the oral ruxolitinib, you’re not even having the boxed warnings. So, when I talk to my patients about what they might see if they Google the drug, or if they open the package insert in what comes in the box, I tell them I’m comfortable with it, they should be comfortable. And a lot of times, depending on the individual I’m speaking to, it’s enough.

Raj Chovatiya, MD, PhD: I think that summarizes it really well. I feel by and large, as I’ve had more time to think about what that discussion looks like, as I’ve had more time to use these medications, it’s become an easier conversation. And frankly, when placed in the right context, I can’t say that I get that much pushback from patients, which I think everybody theoretically worries about. Because again, it sounds very scary on the surface to say the adverse effects are mortality, malignancy, major adverse cardiovascular events. This is where the power is in the user, and I feel like the ability to walk through that prescribing information is so user dependent. So I think educational things like this, conferences, you name it, hearing about how differently it’s done from person to person, can really be helpful.

Transcript edited for clarity