Oral Therapy Adverse Events

Key opinion leaders discuss which characteristics of oral therapies need to be managed by pharmacists.

Alison Duffy, PharmD, BCOP: We talked a little bit about the efficacy and safety information. What characteristics of the oral therapies that we haven't mentioned before do you feel that you as a pharmacist, or all of us as pharmacists, need to manage? What drug interactions are on your radar with the BTK [Bruton tyrosine kinase] inhibitors?

Cody Steeves, PharmD, BCOP: Like we mentioned in the previous one, the characteristics of the therapies; venetoclax with food.

If a patient doesn't reliably eat every day at breakfast, I ask them, “Which meal do you eat the most reliably?” Most people have at least 1. “Take it with that meal, drink plenty of water, especially early on,” it's very important with venetoclax. It's important with ibrutinib, too, important with all of them, staying well hydrated. Especially at the initiation of therapy as we're going to see white cells die a lot faster. We want to make sure we're flushing everything through there.

Acalabrutinib being BID [taken twice a day], it's the only 1 of the 3 we have, and a lot of agents aren't designed to be taken twice a day these days. It's not something that is preferred by a lot of patients. You have to be at home with your pills every 12 hours, or have the wherewithal to take them with you. Things like that always need to be considered, too.

As far as the drug interactions, it is the pharmacist's wheelhouse, so to speak, helping and assisting the providers with these therapies. When I speak to patients on any of these BTK inhibitors, as well as, again, venetoclax, for this discussion, the things I think about are those antifungals, antiseizure medication, potentially, and potentially the cardiac medications, notably the non-DHP [dihydropyridine] calcium channel blockers.

All 3 of these therapies have their issues, but of the antifungals, fluconazole, is considered a moderate 3A4 inhibitor, and basically carries a 50% dose reduction for any of the agents with acalabrutinib changing to QD [every day] instead of twice a day. With ibrutinib it's like 1 step down, so 420 mg down to 280 mg, and then down to 140 mg, depending on the dosage appropriate for the patient. In that case, if those moderate inhibitors are used, that would be fluconazole, diltiazem, and verapamil.

When we get into the strong 3A4 inhibitors, the more potent antifungals, and the complication is a lot of these patients need to be on these drugs. Whether they have had chemotherapy in the past or if they have a high risk of fungal infection, they're actually pretty common agents in this patient population.

Then we have to consider pretty drastic reductions of the dosage, and some of them, acalabrutinib for example, the package insert recommends not to combine it at all. There's really no recommendation of dosing since there isn't even a smaller dosage form than the 100 mg. Venetoclax, we usually recommend a maximum of 70 mg daily in the patients needed to be on those, and ibrutinib, that's 70 to 140 mg daily, depending on how high the dose of posaconazole may be.

Then oftentimes, as we say, we treat the whole patient, we're not just treating their cancer, antifungal is not a negotiable therapy. If it's needed, it's needed. We need to be working with the providers to ensure the adequate dosing is used when patients need to take these. Then kind of the opposite of that would be the antiseizure therapy, which is going to induce 3A4 and potentially cause a reduction in the AUC [area under the concentration time curve] of these medications.

In this case with ibrutinib, venetoclax, there's actually no recommendation to use them together; it says please avoid therapy. Acalabrutinib, interestingly, has a package insert recommendation to double the dose to 200 mg twice a day in the setting that the 2 must be used together. I can say I haven't seen that in practice. I don't see a lot of patients on antiseizure therapy in general, but it is in the insert, and it's one of the few drugs we've seen that has that recommendation to increase the dose like that.

I would also say it's well outside my scope of practice, and typically the hematologists, too, to make any recommendations to change antiseizure prophylaxis, so I'm certainly not going to mess with that. A lot of doctors will go ahead and recommend we move forward with therapies because we're not going to give the patient a toxic level of drug. I'm not concerned for their safety, I'm just concerned, will this drug be fully effective?

Several months down the line, are we going to see the same response we would see out of the patients not taking this therapy? Then with acalabrutinib, specifically, as well, you mentioned it briefly, the acid-blocking therapy can reduce the concentrations of acalabrutinib, creating a less-acidic environment in the stomach. This can be relatively easy if it's something like calcium carbonate, a TUMS every now and then, with spacing by a couple hours.

Even the H2RAs [histamine₂-receptor agonists] we can space every 4 to 6 hours, although that gets pretty complicated when both drugs are taken twice a day and you're spacing everything out 4 to 6 hours, and trying to handle all that. But that is a better option than the PPIs [proton pump inhibitors], which are going to stay in our bodies for 24 hours. And really there's no recommendation on increasing acalabrutinib dosing; there's just a recommendation not to use them together.

We know that patients on PPI therapies can be any of a lot of things; they can be somebody who got heartburn a few weeks ago and they started taking omeprazole because they saw it at the pharmacy, and maybe they can try a trial without it. Versus a patient who has a history of bleeding ulcers, again similar to antifungal, it's not a negotiable therapy where they can stop it for a while and take a risk that they're going to have another ulcer here.

So a lot of factors to consider. We've said it many times, but it's all that patient-specific risk that we can handle with each patient, and decide which is the best agent for which patient.

Alison Duffy, PharmD, BCOP: I agree with you regarding all the challenges with drug interactions.

I've seen providers be appreciative of any interactions identified by pharmacists, whether it be in the specialty pharmacy retail setting, or in clinic, because there are so many things to think about with therapies, and so many different complicated interactions. I think as pharmacists we can help to identify the interactions, but also help to identify if there are any potential ways to minimize that. And it could just be making sure that it's on everybody's radar to monitor for toxicities more closely.

We've already talked about adherence, and I think pharmacists can be helpful with access, too. We can help understand all the intricacies of how to get that patient the drug at the right time. I think especially for CLL [chronic lymphocytic leukemia], in terms of the timeliness, it can be so important. However in our role as pharmacists we can facilitate that, I think we are in the driver's seat to help with that, as well.