Navigating Challenges in Hepatic Encephalopathy Treatment

Pharmacy Times interviewed Jennifer Marsh, PharmD, BCCCP, assistant professor, University of South Florida Taneja College of Pharmacy, on challenges associated with the treatment of patients with hepatic encephalopathy (HE). Marsh also discusses the medication options available for HE, as well as considerations during treatment, emphasizing the pharmacist's vital role in patient care and medication management.

Pharmacy Times: What is the current standard of care for the treatment of HE?

Jennifer Marsh, PharmD, BCCCP: There are 2 major medications that we think of when it comes to the treatment of hepatic encephalopathy. Starting first with lactulose, this is an orally taken disaccharide that's not absorbable. It works in a few different ways, but overall is thought to help reduce the amount of ammonia produced in the gastrointestinal system and then absorbed into the gastrointestinal tract. This medication is a little bit unique in that it's titrated actually to maintaining 2 to 3 soft bowel movements per day.

Then the next medication, which is typically an add on to lactulose, is called rifaximin (Xifaxan; Salix Pharmaceuticals), which is a non-absorbable antibiotic. It's thought to change the gut microbiome in a way that helps to reduce that ammonia production as well.

So these 2 medications are typically taken in conjunction with other supportive care measures, like maintaining good nutritional status, as well as then the identification and treatment of any precipitating factors, so things like infection or gastrointestinal bleeding.

Pharmacy Times: What are some of the challenges associated with the treatment of HE?

Marsh: There are a few challenges associated with treatment, including mainly prescription drug coverage. So especially rifaximin can be quite costly for patients, particularly those that don't have prescription drug coverage. In addition to that, sometimes maintaining effective dosing of lactulose can be a challenge, both with maintaining adherence to the medication as well as making sure that it's being dosed effectively.

Then the last thing that comes to mind is that with these patients, sometimes with the altered mentation, there might be enough agitation that poses risks to the patient or others. In those cases, when we think about using agents to control that agitation, we have to be mindful of the underlying liver dysfunction, and identifying agents that might be less sedating or are not going to accumulate as much in that liver dysfunction.

Pharmacy Times: What are challenges associated with treating HE in the transition of care?

Marsh: As I mentioned, prescription drug coverage can be a challenge. So sometimes we get these patients started on therapy on the inpatient side, and they might be well maintained and optimized. But that doesn't do much good for the patient if they're not able to continue therapy at discharge. So, we want to make sure that we're being proactive in identifying any barriers to coverage, helping to navigate the prior authorization process, really making sure that we're maintaining good documentation to support the indication for the medication.

Then secondarily, once we have patients on a regimen and they're going to be able to continue at a discharge, we want to make sure that we're also identifying someone in addition to the patient for education on the medications. By nature of this disease state, there might come a time in the future that the patient has some sort of altered mentation. So, we want to make sure that there's someone else in their life, whether that's a caregiver or a family member, that's able to be educated on the purpose of the medications, how to take them effectively, and when to then contact the health care team in the future if the patient status changes.

Pharmacy Times: How can lack of outpatient access to rifaximin impact treatment?

Marsh: The lack of access to rifaximin can be a big impediment when it comes to effective treatment of hepatic encephalopathy. So, when we have patients that are maintained on an effective regimen, we of course want them to be able to continue that to prevent any future recurrences. Without the ability to access the medication, that patient is then at risk for recurrence, and then associated readmissions, as well as then some of the complications that can occur in patients with altered mentation. So, things like falls are also possible in the future if patients can't maintain that prescription drug.

Pharmacy Times: What are some of the challenges associated with lactulose acceptance and proper titration in the treatment of HE?

Marsh: Lactulose is unique compared to some other medication formulations for adults in that it is traditionally given as a liquid. So right off the bat, there's going to be some barriers for patients that would prefer not to take a liquid. In fact, patients are likely going to be expected to take it multiple times per day. So, if that's already an uncomfortable process for them, then that might reduce the likelihood that they're going to be able to maintain adherence to the medication.

Additionally, the way it's dosed, we want to titrate the medication to be able to achieve 2 to 3 soft bowel movements per day. And it can be very tricky to not under or overdose the medication in a fashion that's going to place them at risk for potentially either not achieving our therapeutic effect if we underdose the medication, or also in the case of being too aggressive, then we might put patients at risk for things like abdominal cramping, diarrhea, and some of the downstream effects of that can even be water losses to the point of developing hypernatremia. So, we definitely want to be careful of making sure that we're selecting an appropriate initial dose, but also being very mindful to adjust that dose to be able to achieve our therapeutic targets.

This honestly can be a challenge even on the inpatient side and how we actually address these orders. So placing orders that are going to achieve that effect, as well as then maintain compliance with regulatory standards with regards to as needed orders versus standing orders versus instructions to hold the medications. So oftentimes, I recommend using a combination, where we start a scheduled dosing for patients, and then we add potentially some as needed doses on top if we need to give more in a day to be able to achieve our targets.

Pharmacy Times: What can cause the inappropriate use of ammonia levels when guiding treatment, and how can pharmacists address this?

Marsh: Ammonia levels can be somewhat controversial when it comes to their utility in hepatic encephalopathy. So starting out, there may be complicated patients that have multiple potential causes for their brain dysfunction. In some cases, it may be useful to use an ammonia level to help better distinguish. Sor example, having an elevated ammonia level may help to support the diagnosis of hepatic encephalopathy. But even in the absence of that elevated level, we know that providers will still make the clinical decision to initiate therapy and continue therapy for hepatic encephalopathy. So, we do want to make sure that we're being mindful of what we're going to do with the level if it's a lab that we're going to check in patients.

In practice, both initiation and titration aren’t based on ammonia levels. So, it's not like we're going to be chasing a specific number once we’re starting therapy. This is even included in the choosing wisely initiative. So, we want to make sure that we're treating and then targeting therapy that's really looking at clinical improvement in symptoms, rather than a specific lab.

Pharmacy Times: Your institution recently evaluated an alternative rifaximin dosing strategy as a potential cost savings initiative. What were the results of this investigation?

Marsh: We want to think about the fact that there's a few dosing strategies that have been investigated for the use of rifaximin and hepatic encephalopathy. So, there's even some literature using lower doses, like rifaximin 550 milligrams once a day or rifaximin 400 milligrams twice a day, and there's a limited amount of literature supporting that those may be appropriate dosing strategies. However, we were really looking at our standard dosing right now which is rifaximin 550 milligrams twice daily and considering the use instead of rifaximin 400 milligrams 3 times per day.

So, with any formulary decision, we first want to look at the comparative efficacy of our options, and then consider things like cost or operations. Our decision was to continue using our current dosing of rifaximin 550 milligrams twice a day, mainly because of some of those operational considerations. Considering the way that the drug was supplied, we would have to change it to unit dosing. We also had concerns about increasing from a twice daily dosing to 3 times daily dosing. Just like on the outpatient side where we want to think about how well patients are going to be able to maintain 3 times a day dosing, we have similar concerns with our nurses and the workload and the potential for missed doses as we increase the frequency of our medications.

Pharmacy Times: Any closing thoughts on the treatment challenges associated with HE and pharmacist’s role in patient care?

Marsh: One thing that comes to mind is that we do want to think about duration of therapy. So, for some patients that may be listed for transplant and undergo a solid organ transplant, we want to make sure that we're going back to that patient educating them on which therapies are no longer indicated, in addition to education on their new regimens. There also might be patients that after some time with clinical improvement may be addressing precipitating factors. There may be joint decision by a prescriber and patient to discontinue secondary prophylaxis of hepatic encephalopathy. So, in those cases, we want to make sure that we're doing interdisciplinary discussions, notifying anyone that needs to be made aware, for example, of discontinuing outpatient prescriptions, so that they're no longer going to be filled, and then that'll help minimize errors and reconciliation.

The last thing that comes to mind is that for patients, especially with a new diagnosis, is the pharmacist is well poised to look at their existing medications, whether that's things that they're taking previously from home or any new medication and making sure that we're evaluating how it could be contributing to changes in mentation. So, this might be a good time to look at deprescribing opportunities, maybe exchanging for alternative therapies, or just notifying the patient and team that there are other agents that might be contributing to those changes.