I’m a bit obsessive about reading the labels/inserts for any medications I take, because sometimes I have weird reactions. Many years ago, before I started to pay attention to labels, I was taking Bactrim (antibiotic) for an ear infection, and after a day or two, not only was my ear infection no better, but my wrists started to feel weird. They weren’t swollen, but they felt like they were, and they had a tingly feeling, a bit like nerve damage. So I pulled out the label for the Bactrim, and sure enough, there was a rare side effect that involved joints. I discontinued the Bactrim, and the weird feeling went away.
So you can be sure that I read the label for burosumab when it was approved! Depending on where you get your burosumab injections, you may never have had the opportunity to read the label. You can see it here though: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761068s000lbl.pdf
If this is your first time reading it, you may end up feeling a bit anxious, given all the possible side effects listed. Don’t panic! Especially if you’ve been on it for a while with no problems. You should, of course, take it seriously, but also be aware of how those side effects end up on the label.
With a relatively newly approved treatment, the label is based on the clinical trial experience, which is, necessarily, limited in terms of number of people the treatment was tested on, and the limited timeframe of the trial (balancing the need to get treatment to the public with the need to make sure it’s safe/effective). The evidence is bound to be incomplete, in terms of both good and bad news. During a clinical trial, absolutely every little health event is documented, looking for patterns, and as a result a lot of ordinary things, like headaches and nausea, that people experience even without any type of treatment, get recorded. And then, if enough people have the experience, it gets listed as a possible side effect. Which it could be, but it could also just be that of course people will have common life experiences while on the new treatment but totally unrelated causally, since they would have had the symptom even if they weren’t on the new treatment. As a result, I’d be willing to bet that pretty much every single new treatment ends up with a label showing that headaches and nausea are possible side effects, simply those are such common events in daily life, and it’s impossible to see which are causally related to the treatment.
When you read a label, it’s easy to understand that something like headache or nausea may not actually be due to the treatment, and you can choose not to worry about them as side effects (absent evidence that clearly ties them to the treatment), but it can be more difficult to judge other types of symptoms, and whether you should be concerned about them. The FDA tends to err on the side of caution, listing all of the health conditions that might, by any stretch of the imagination, possibly be related to the treatment. That makes sense in most situations, but in others, I think listing certain side effects can be misleading, and could dissuade a patient from getting treatment they need. Several of the supposed side effects of burosumab fall in that category. They’re not common symptoms like headache and nausea that affect the general population, but are that common within the XLH population.
Here’s what the label says are possible side effects (also known as Serious Adverse Effects, or SAEs): “Most common adverse reactions (≥25%) in pediatric XLH patients are: headache, injection site reaction, vomiting, pyrexia [fever], pain in extremity, vitamin D decreased. Most common adverse reactions (≥5% and in at least 2 patients more than placebo) in adult XLH patients are: back pain, headache, tooth infection, restless leg syndrome, vitamin D decreased, dizziness, constipation, blood phosphorus increased.”
Of the most common side effects in kids, all but injection site reaction and decreased vitamin D are things that can happen to any XLHer in the absence of treatment (i.e., pain in extremity). Similarly, the most common side effects in adults are things that everyone with XLH experiences in the absence of treatment, except for restless leg syndrome and decreased vitamin D. (I really don’t understand why they mention the blood phosphorus increasing as being a side effect, since that’s the whole point of treatment, but they may mean when the phosphorus goes too high.)
The two scary-sounding side effects are back pain and dental infections. We all know that XLHers get both of those symptoms in the absence of treatment, so it’s not surprising that they would also get them during treatment. If anything, the back pain and dental infections are likely to be improved by burosumab (in the long term), rather than worsened by it. I can testify to my back pain improving on treatment, and I’m not alone, from what I’ve heard. (Some patients may experience a temporary increase in back pain until they adjust to the treatment, but it’s not a long-term worsening, and at some point, the pain lessens and is better than before treatment began.) There’s also recently published evidence that burosumab treatment leads to increased dentin, the lack of which contributes to our dental infections.
I’d just hate to think patients (and parents) who aren’t fully informed about the pros and cons of burosumab might be scared away from treatment by the prospect of permanently increased back pain and dental issues, when those aren’t really side effects of burosumab, and are even more likely to occur without burosumab treatment.
If those side-effects were deleted from the label or better explained, it would leave just two true side effects to consider: restless leg syndrome (RLS) and decreased vitamin D levels. The latter has a simple solution, that appears to have become fairly standard among experts treating XLH: add an over-the-counter vitamin D supplement to the daily regimen and check the vitamin D levels occasionally. The restless leg syndrome is a more complicated side effect to treat, from what I understand, but there are treatments available. And, for most patients, even if the RLS is untreated, it’s less of a drag on quality of life than the other symptoms of XLH.
Obviously, we need to know what the potential side effects are in order to make an informed decision about treatment. But care needs to be taken not to make those side effects out to be worse than they are. Sometimes too much information can, counterintuitively, be misleading, and I believe that listing back pain and dental infection as side effects of burosumab is a perfect example of misleading with too much information.
I believe the FDA will review the label in 2028 or thereabouts, after receiving data collected by Ultragenyx and Kyowa Kirin. I’d like to see Kyowa Kirin request (and then the FDA approve) the removal of the two scary adult side effects that are just part of living with XLH, nothing to do with burosumab. The label notes that the incidence was slightly higher compared to placebo, but I suspect that that’s due to a too-small sampling, and future data will likely confirm that. If KKNA won’t make that request, then patients may need to advocate for removing those supposed side effects, or at least clarifying that the increased back pain is temporary, and that there is no evidence to suggest that the dental infections are worse or more frequent on burosumab, but, to the contrary, there is evidence (already published) that dental health will improve on burosumab, rather than worsen.
I’m definitely in favor of patients having access to prescribing information (the labels), but we need those labels to be accurate for the layperson, not just the expert clinician who has read all the latest journal articles that might clarify the pros and cons of the treatment. In my experience as a patient, not a doctor, the burosumab label, as it exists now, lists more potential negatives than it should, which may be scaring prospective patients away from a treatment that would, in fact, be beneficial for them overall. It’s just one more barrier to access to effective treatment!
***
Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
If you’d prefer to read this blog as a newsletter, sent straight to your inbox, please sign up here.