Understanding the Black Box Warnings for JAK Inhibitors - Episode 4

Risk of Systemic Absorption with JAK Inhibitors

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Clinicians provide insight into the risk of high systemic absorption levels with JAK inhibitor treatments.

Linda Stein Gold, MD: You might ask the question: If we potentially have oral JAK [Janus kinase] inhibitors that we get by mouth for atopic dermatitis, are you worried about systemic levels? I mean, does that worry you if it’s a transient increase?

Matthew Zirwas, MD: It’s a hard question. For the immunosuppression, I’m really not. It’s hard for me to believe that the amount that’s getting into the blood with topical ruxolitinib [Jakafi] is enough that it really is immune-suppressive. Clotting risk for blood clots are such a black and white phenomenon: you had one and then you didn’t. Maybe this increases your risk of a blood clot by 1%, but right now, if your risk at baseline is 1 in 1000 per year, and that increases it by 1% so it’s 1 in 999 people versus 1 in 1000, that’s not a very meaningful effect. But it might be 0, or it might be a tiny increase. I could imagine it. But it’s a really interesting question. The way that I phrase it for patients is that “I don’t think this has any effect on how your blood would clot, but I can’t tell you 100% that it has 0 risk. It may have a very small effect. We just don’t really know.”

Linda Stein Gold, MD: We did that maximum use study, but we also did some pharmacokinetic analyses from the phase 3 clinical trials where, again, they use it between 3% to 20%. Matt, as you mentioned earlier, we saw much lower systemic levels that were way lower than what we would expect to see orally. So I think from this basically what you’ve said, and what the data shows us, is that if you stay within the packaged label, the 3% to 20%, you can be fairly confident that the amount of systemic exposure that your patient would experience will be quite low and well below the oral levels. However, if you push it, and instead of doing 20%, you do 60%, you could potentially get a level that would be similar to what you would experience taking the struggle early. This drug is approved orally for other indications outside of dermatology. It’s not something that can’t be used by mouth because we certainly have it available by mouth.

Matthew Zirwas, MD: I always think about what the instances are where insurance and package size are actually protecting us. So it comes in a 60-gram tube, you know what? At most, you’re never going to get insurance to pay for more than 1 tube a month. So at 30 days in a month the most you’re going to get daily is 2 grams, and we know that 2 grams can treat probably 5% to 10% body surface area. So by the size of the package it would be almost impossible to treat more than 10% body surface area with this drug.

Linda Stein Gold, MD: Right. That’s definitely a good thing. You mentioned that we saw some rare systemic side effects with topical rux [ruxolitinib], but there were a few cases of thromboembolic events. On the label, they talk about serious infections. This really mirrors what we see with the oral JAK inhibitors, but they mentioned you want to watch for a serious infection. If that should occur, you want to stop taking it. They talk about TB [tuberculosis], however no cases of TB were reported in the clinical trials with topical. They talk about viral reactivation, and there were a few cases of varicella- zoster virus that did occur in the clinical trials. We saw it, so what do we make from it? It’s really kind of hard to know. And then they go into the other things like lymphoma and other malignancies. This is more appropriate to talk about with the orals, but the label includes the massive events, again more appropriate to talk about with the orals, but it’s on the label. I’m kind of going down what we’ll see in that box warning, and we did see, rarely, some cases of thromboembolic events with ruxolitinib. They didn’t find any clear relationship of the thromboembolic events and the platelet count, so we’re not really sure. For laboratory abnormalities, we very rarely saw some thrombocytopenia, some anemia, and some neutropenia ,but it’s not on the label that it is mandatory to be checking any types of blood counts, so it’s left up to the individual physician to do what you think is appropriate. That kind of goes over what we see on the label, and where that comes about. It’s not unusual that we have things on a label that are associated with the oral route, but not with the topical. We’ve seen, for instance, with minocycline, if you look at the topical minocycline foam, we know that there’s almost no systemic levels of minocycline when it’s applied topically. Yet, when we look at the package insert, they have exactly the same label as oral minocycline, even though it states on the label that none of these particular side effects have been seen with topical minocycline, yet it’s still in the label. So, this is something, and I think Matt, you would agree, that we’re used to seeing. We’re used to seeing labels that are very conservative and cause us to kind of stop and think for a minute.

Transcript edited for clarity.