Infusion-Related Adverse Events

Transcript:

Ajai Chari, MD: Speaking to the infusion reaction, maybe you can tell us a little bit about what that looks like, when you see them, and what kinds of reactions have you seen?

Daniel Verina, NP: I think in the healthcare industry, we’ve been working with monoclonal antibodies for many years, over 25 years now. It’s a lot of anaphylaxis or hypersensitivity reactions. You’re going to see patients get nasal congestion, which I think is not as captured. Many patients may blame the nasal congestion on allergies or they feel like they’re coming on with a cold, but it was something that was really driven by the antibody. You’ll see them get chills, rigors, shortness of breath. Some people will complain of tingling of the throat or of the lips themselves.

One of the big adverse effects that was slightly different than with most antibodies that I have seen in my experience is that patients on the first infusion would complain about severe bone pain, whether it was in the long bones—the hip, the back, the chest—or they would have this diarrhea experience compared to other antibodies. Those are things they we’ll see. Usually about 30% to 40% of patients will have some type of adverse event or some type of adverse effect. But I will say after they’re exposed to the monoclonal antibody, to daratumumab, by the time they get to their second week, that second infusion, they will not have another adverse event. It drops down actually to 2%.

Ajai Chari, MD: To clarify, the usual adverse events that we see in oncology and myeloma from this initial dose issue, or the first few doses, we really try in clinical trials, they’re often described and categorized as infusion-related reaction, or IRR, to distinguish from other, say, adverse events, such as neutropenia, fevers, etcetera. So IRR, it’s a first few doses effect. For somebody who hasn’t given a lot of monoclonal antibodies, or perhaps may not be used to the nature of DARA [daratumumab], sometimes people do get a little concerned. If somebody does have a reaction, like bronchospasm or some shortness of breath, what do you do at the bedside?

Daniel Verina, NP: Those adverse effects, to go back, can happen within 5 minutes; typically we’ve been seeing the adverse effects occur within the first 90 minutes. And we’ll talk about how the infusion goes. Usually when the infusion rate changes from 50 cc to 100 cc, within 20 minutes you’ll see some adverse effects occur. But it can be up to 7 hours before the first reaction can occur. For your new exposure, your new healthcare provider who’s not seen monoclonal antibodies, you want to assure them that these are very typical adverse effects, they’re very common with monoclonal antibodies as a group. You want them to stop the infusion, you want to call your healthcare provider, and you want to give the appropriate medication, depending on the adverse effect that you’re dealing with.

If they’re feeling very short of breath, you may want to give them a little more steroid at that time to help mediate. You could also, if they feel very itchy or have a rash, some patients have developed rashes, you may want to give them some Benadryl to help, again, that particular adverse effects. We’ve used Demerol in the past for rigors or chills, too, which can help mitigate that, very small doses and the patients resolve very quickly.

The goal is at the time of adverse effect, you want to wait about a half hour to 40 minutes and see if the adverse effects resolves, and then reinitiate the medication, the daratumumab, but you want to start it at half the rate of when their reaction occurred. So, if it was at 100 cc an hour, you’re going to restart them back at 50 cc, wait an hour, and then escalate it.

Ajai Chari, MD: Perfect. I think you covered a lot of the bedside management issues with daratumumab. Some of the other things to be mindful of are, especially in somebody who is practicing perhaps in a community center, the infusion time may be quite limited. By the time somebody comes in, they often need laboratory tests, the drug has to be mixed, and then they give the premedications. These infusion-related reactions, if the median infusion time of the first dose is 6 to 8 hours, you can run into trouble. Some of the things people have done in the community are to do split dosing, so day 1 and day 2, so to mix half the bag the first day and then second half the next day.

That’s also important we learned in the inpatient setting because often, and we’ll talk more about this later in the discussion about the nursing implications, but often in an inpatient, if a nurse has a patient who has an allergic reaction and they’ve decided to pause and run it slowly, the stability of daratumumab is about 15 to 16 hours. It’s not like some of the other monoclonals, which can be run slowly over a day if they’re an inpatient. So I think 1 important bedside issue is time of infusion, and so sometimes people do split dosing.

And there are also some emerging data of rapid daratumumab, which is 90-minute infusion after they finish those first 3 doses, and that’s been published and done in a lot of settings. But it still again requires an IV [intravenous infusion] and has that 90-minute duration. I think the other important thing is in spite of all of this discussion about infusion-related reactions, I’m curious to see if Danny agrees. Even if patients have had significant reactions, I have never not been able to give daratumumab after getting through those initial few doses because of allergic issues or hypersensitivity. I think these infusion-related reactions are typically manageable, and eventually well tolerated, and we can resume standard dosing. Danny?

Daniel Verina, NP: Absolutely, I agree. I think sometimes you may have more than 1 reaction within the first infusion, depending on each reaction, but absolutely. Sometimes we’ve actually dose reduced it. So instead of being 16 mg/kg, what the indicated dose is, we’ve started patients at 4 mg/kg in fluid to see if they can almost desensitize them to the daratumumab to escalate it up, so that they can receive the drug at full dose. The other thing that we’ve done here, at Mount Sinai Health System too, is that we can concentrate the volume. Besides split dosing, which is a great option for the communities that do not have long infusion bed/chair time, this allows our patients who have severe renal insufficiency or congestive heart failure to still limit their fluids.

Ajai Chari, MD: Can you tell us a little bit more about that? Standard volume versus concentrated.

Daniel Verina, NP: The standard volume in healthy individuals is a liter for the first dose, and if they tolerate it well, then the fluid is decreased to 500 cc, so you double the concentration of the medication but the same dosage. And it stays at 500 mL throughout their entire time experiencing it. It’s given weekly for 8 weeks in a row, and then on the ninth week, it goes for every other week for another 8 doses, and then monthly, for our patients. So it’s 8 doses weekly, 8 doses every 2 weeks, and then monthly as long as they tolerate it or they don’t have progression of disease. But when we start talking about patients for concentrated volume, you’re really looking at the best dosage for the volume by their weight, and pharmacy will calculate by their weight to see if they get the right volume.

Transcript Edited for Clarity