PAMORAs in OIC: Observations on Safety/Efficacy & Administration
Considerations for the safety/efficacy profile of peripherally acting mu-opioid receptor antagonists, particularly given their administration route.
David Wang, MD: I’ll just go back to what you were saying about how amazing it was to have an oral formulation of this. In my practice, I’ve historically most been familiar with using methylnaltrexone (Relistor) subcutaneously, which in the inpatient setting has just been wonderful. I use it with a high degree of confidence. But a lot of our patients want to avoid getting that point. They want to prevent this from becoming a lifestyle-affecting issue for them. The other oral agent, oral methylnaltrexone, is also a very effective peripherally acting mu-opioid receptor antagonist (PAMORA). Rick, would you mind telling us a little about the study data and efficacy and safety of that?
Richard Rauck, MD: You’re right, the subcutaneous came out long before the oral. There were some issues with just getting it into the right formulation for the oral formulation. They ended up using sodium lauryl sulfate, which turned out to be the magic sauce, it seems, that made the oral work that way. The trials that came out then were designed a little differently from some of the others that subsequently came along. That was in part because the Food and Drug Administration was trying to define what we talked about earlier, end points and how to look at opioid-induced constipation.
As it turned out, the phase III trial with Relistor oral was something that looked at that quantitative measure. That is, you had at least 3 spontaneous bowel movements and at least an increase in 1 spontaneous bowel movement per week in 3 of 4 weeks that it was under double-blind conditions. The trial had a 4-week double-blind phase in which everybody took it once a day and then there was actually an 8-week open-label in which patients took it. Actually, I’m not sure that was open label in 8 weeks, but they took it as needed, so it was on a pro re nata dose, a little different from the other trials.
Then there was a safety trial, a safety component that was looked at as well that we published on. The efficacy did separate nicely and very robustly from placebo in the double-blind phase and as a primary end point. It also had some very nice separation on a lot of the secondary measures that were looked at.
I think the 1 that stuck out the most to me and was maybe the strongest, where they looked at rescue-free bowel movements within 4 hours after dosing. With Relistor compared with placebo—and this shouldn’t surprise you, David, because you used the injection a lot—we used to talk about how reliable and rapid the response was after subcutaneous injection. Similarly, with the oral formulation, within 4 hours, the percentage of patients who had a rescue-free bowel movement was strongly and statistically different from the placebo group in that setting.
The safety data were very promising, I think partly as Jeff and Brett both alluded to with the lack of interaction with CYPs. That certainly did not cause the problems. A little to your point, Jeff, on blood levels. It’s not always what maybe happens in the gut, but we know all these drugs can be prone, if there are increased blood levels, to reversing analgesia in the brain. That certainly was seen in a very nice dose response with naloxegol and a little less with naldemedine, but it certainly can be there. This drug didn’t seem to have that in the studies that they looked at from a safety standpoint. The first drug I ever studied in its class was alvimopan, which never made it to market because of a cardiac marker that people still aren’t sure about. Anyway, the cardiac safety profile with methylnaltrexone was very much the same as placebo, so no cardiac signal at all in the trial.
Stephen Anderson, MD, FACEP: You talked a tiny bit about onset of action. I work in an emergency department [ER]. It’s all about throughput. Sorry, that’s a bad pun. But I actually initially liked the subcutaneous formulation because I thought it worked quicker, but the truth of the matter is I’ve gone mostly to oral in the emergency department as long as nausea is not an issue, and I’ve been happy with the results.
Richard Rauck, MD: I think 1 point for all these drugs that we should probably mention, Steve, as you know, is that in patients in whom you suspect really a complete bowel obstruction and particularly if they’re in the ER, none of these drugs are indicated and in fact are contraindicated. They need a work-up and make sure that there’s not a bowel obstruction in that scenario.
Brett B. Snodgrass, FNP-C, CPE, FACPP, FAANP: I’ll add that, because it takes the acuity. It changes the acuity level when prescribing inpatient versus out.
Stephen Anderson, MD, FACEP: Correct.
Brett B. Snodgrass, FNP-C, CPE, FACPP, FAANP: Outpatients, they’re not vomiting. I feel pretty confident that we don’t have a bowel obstruction. Inpatient with oncology patients and other patients, you’re dealing with just a different population and again more of an acuity. So you really think, “What are we going to put them on? Is there any potential for obstruction because it’s a different population?” I also think the formulation matters as well inpatient. Somebody is going to give them the injection, and they’re getting other injections. Potentially they’re getting Lovenox (enoxaparin sodium) or something else. Therefore, injection is not an issue.
But outpatient, you mentioned them taking home a syringe. And they said, “I can’t do that” or “I don’t have anybody to give me that shot,” even though it’s easy. We all think it’s easy, but to a patient it’s daunting.
Therefore, yes, an oral formulation. I’ve had a lot of people very quickly say, “Well, clearly their constipation isn’t that bad.” I don’t know if that is better or worse, but again, it’s sometimes a daunting task to take a syringe home. Now others prefer that. With the syringe and injectable, you can take it to the bank with how quickly it’s going to work as opposed to the oral. There are pros and cons to both. It’s great to have 2 options.
David Wang, MD: Did you have anything to add to that, Theresa, in your practice?
Theresa Mallick-Searle, MS, NP-BC, ANP-BC: I completely agree with what my colleagues and panelists have been talking about. I was really excited when the oral formulation came out—very, very excited because I did feel a lot of resistance in my patient population in the outpatient setting to want to use the syringe. However, what I found in clinical practice is that the injectable formulation is a lot more predictable. Actually to the point about patients being fearful about wanting to go out, being anxious about when their bowel movement is going to start, they really enjoy the option of being able to know and get it over with and get on with their lives.
I really leave it up to the patient to decide, and I do the education that I need to do. If all else is equal in terms of insurance, then I’m very happy with whatever their decision is. In the hospital, my go-to is the injection formulation. I don’t even think we have the oral formulation on formulary. Again, it’s in the right patient situation. If I’m not worried about obstruction, I know that I’m going to be 100% effective. The injection formulation is really what I count on in the inpatient setting.
Brett B. Snodgrass, FNP-C, CPE, FACPP, FAANP: I would say also in the outpatient setting, oftentimes it’s driven by payer source. It is very likely you may have an option or have a choice or wish to use a different 1, but we’re oftentimes directed in the outpatient setting by what coverages.
Stephen Anderson, MD, FACEP: I think we’re going to talk about financials?
Brett B. Snodgrass, FNP-C, CPE, FACPP, FAANP: We’re going there, yes.
David Wang, MD: I would echo your experience, Theresa. I think keeping somebody around in the hospital and waiting for them to have a bowel movement is certainly an undignified way to spend their time.
Theresa Mallick-Searle, MS, NP-BC, ANP-BC: Oh, yes.
David Wang, MD: I also introduce the option early. I don’t sit on it too long. And after I’ve proceeded through my usual treatment workflow, I’d like to give them the chance to have a satisfying bowel movement. I do always warn them, though it can come very quickly.
Theresa Mallick-Searle, MS, NP-BC, ANP-BC: Yes.
David Wang, MD: Make sure we have a commode nearby.
Theresa Mallick-Searle, MS, NP-BC, ANP-BC: That’s the benefit, and then you can follow that up with a prescription for the oral formulation when they go home.