Dopamine Agonist Delivery Systems for OFF Episodes

EP: 1.Overview of OFF Episodes in Parkinson Disease

EP: 2.Challenges of Identifying OFF Episodes in Parkinson Disease

EP: 3.Recognizing Triggers for OFF Episodes in Parkinson Disease

EP: 4.Clinical Burden of OFF Episodes in Parkinson Disease

EP: 5.Impact of Levodopa Absorption on OFF Episodes in Parkinson Disease

EP: 6.On-Demand Therapies to Manage OFF Episodes in Parkinson Disease

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EP: 7.Dopamine Agonist Delivery Systems for OFF Episodes

EP: 8.Using Apomorphine Infusion for OFF Episodes in Parkinson Disease

EP: 9.Apomorphine Formulation Efficacy for OFF Episode Management in Parkinson Disease

EP: 10.Role of Patient Education for SubQ and Pen-Based OFF Episode Therapies

EP: 11.Unmet Needs and Advice for the Management of OFF Episodes in Parkinson Disease

Laxman Bahroo, DO: We should talk about the delivery systems of the different products. We have 2 approved products for apomorphine. We have the subcutaneous and the sublingual, and while it’s the same chemical entity, the delivery makes the dosing different. And of course, at the same time, the effectiveness is different in that sense. They’re both medications that I call PRN as needed therapies. The term people use is on demand. I tell my patients it’s on demand or as needed for OFF episodes. That’s how I’ve always written prescriptions, as needed for OFF episodes. But their dosing is different. Subcutaneous apomorphine comes out in 0.1, 0.2, 0.3 mL, the dosing ranges from 0.2 to 0.6 mL. There might be some room for 0.1 mL dosing as well in individuals who are more sensitive or maybe more nauseous. That may be what I call a stepping-stone dose. On the other hand, the sublingual comes in 10 mg all way up to 30 mg, and individuals will titrate those doses as well. This administration changes that. My personal feeling with the subcutaneous injectable is that it kicks in as early as 7 to 10 minutes. You can see data out there that show it kicks in within 10 minutes, and then by 20 minutes, it’s fully ON. And usually, it lasts about 60 to 90 minutes. The sublingual comes on a little more slowly, kicking in at about 15, 20 minutes. By 30 minutes you’re getting that meaningful end point difference that was studied in the trial. Then you still see an improvement at up to 60 minutes. It comes on more slowly and lasts a little longer. That’s what makes a difference of whether I go with an injectable vs a sublingual in that sense.

Regarding adverse effects, it’s similar with one exception. With the sublingual, you must know it could cause oral irritation. If you look at the trials, it has a bunch of different oral adverse effects, but I usually will tell folks, if they get irritation of the oral mucosa, oral ulcers, the tongue feels thicker or swollen, then they must discontinue it. That was the safety recommendation from the FDA, that if somebody has this, you’d have to discontinue the medication and find an alternate option. The formulation makes it easier in administration on one end, but then the efficacy is different for the sublingual vs the subcutaneous. But at the same time, the adverse effect profile for the most part it’s similar, nausea, orthostasis. We do have to be mindful and warn individuals about it. About a third of the patients will develop some sort of oral irritation. It’s not uncommon, and it does seem to be occur with longer duration use. It’s important that once a patient is successfully titrated, I’ll reinforce that they should be mindful of this, and if they don’t get irritation, they don’t worry about it. But if they get it, then they should notify us.

Sanjay Iyer, MD: With the sublingual, I will counsel my patients that after the 3-minute mark, once it should have been fully absorbed, I ask them to clean their mouth out, rinse it out, make sure they’re getting that residue out to try to avoid the oral irritation, although it can still happen as we know. I think about the reliability of the on-demand therapy, and when you look at the inhaled product vs the sublingual product vs the injectable, there’s a lot more variability in the success with the inhaled product and the sublingual, just by virtue of how you’re doing it. When you’re trying to inhale it, you may cough it out, you’re losing some of the dose, or you didn’t get a full inhalation, or some of it is stuck in the back of your throat. With the sublingual product, it’s challenging. If you ask somebody to put something and stick it to the bottom of their tongue, and hold it there for 3 minutes without doing anything, it can be challenging to do that. And saliva is pooling, you’re swallowing, some people are challenged with that. But with a simple injectable that’s going to deliver the full dose every time you do it, the reliability speaks for itself.

Laxman Bahroo, DO: I completely agree with that. That’s a great idea. Because in the beginning we were talking about ease of use, well, ease of use on the front end, if I lay out 3 cards for you and say, you can inject something, you can inhale something, and you put something under your tongue, people might say, well, these 2 options are better because I can do that. Most individuals will think of inhaled and they’ll think of an asthma inhaler, because we’ve all seen asthma inhalers, and it’s not that. It’s a device, it’s a pill that you must utilize, and it’s important for patients to be aware of it. I often will tell folks that this is the process of it. The inhaled option, which is helpful for many patients, it just needs more education for patients to learn how to use it, and to be able to inhale it, and to be able to take a full breath. Educate them on the cough issues of it. Similarly, for the sublingual, it makes sense to educate them about making sure they don’t swallow. Then after it’s absorbed, they should clean out their mouth, and those are steps they need to be aware of. And you’re right, the injectable may look like up front to not be a good option, because who wants to be injected or inject someone they care for? But at the end of the day, it’s a shot and you’re done, and there are no issues of, did I inhale enough, or did I clean out my mouth, or did it absorb, or did I swallow it? All those variables go away. You made an excellent point, Dr Iyer.

Sanjay Iyer, MD: A patient comes to mind, she’s a 47-year-old attorney. She does a lot of litigation and is in court a lot. She often has these unpredictable OFF episodes in the courtroom. It’s hard to put something in your mouth and keep it there for 3 minutes, or the inhaler obviously is not going to be easy to do. But she keeps the injectable in her purse, and she’ll just reach down, and she’ll stick it into her leg. She’ll inject it under the desk, she’s wearing a long skirt, nobody sees it, and she gets a very quick, reliable response. You think about the young people who are very active, who need immediate rescue, and often where people aren’t drawing attention to themselves, it can be a very good therapy.

Laxman Bahroo, DO: Absolutely. The important point is also, you mentioned an example of somebody who’s very active and young, and utilizes and sees the value of treating OFFs. I’ve had individuals who have chosen one of the other OFF options, such as the inhaled levodopa. And while it may work for them, it doesn’t work for some of their deeper OFFs. Then we go back to the drawing board and say, “Well, now you have these 2 options. I would strongly urge you to go toward the injectable.” And they say, “Well, no, not so fast. I want to try this.” OK, fine. And if it works great, but just because one of the other 2 options doesn’t work, it doesn’t mean none of them will work. In some ways, all paths may lead to, if they’re not getting a robust enough response with the inhaled or the sublingual, then I bring up the subcutaneous injectable apomorphine option for them. And I say, “Look, you understand the value of needing the treatment for this. You already know the importance of it. You’ve gone through 1 option, or maybe both options. Now, this may be the option that may ultimately be able to take care of this in a more definitive way.” And some folks will go from one to the other to the other.

I’ve had individuals who, because of the way the products came out, they may have been contemplating going on apomorphine subcutaneous, and then the inhaled levodopa came on, and they said, “Can I give this a try?” In my opinion, my policy is, there’s no problem with you trying it. What’s the worst? If you won’t like it, or don’t tolerate it, you go right back to the drawing board. We did, and they stayed there for some time. And when the sublingual came out, they migrated over to the sublingual, and some stayed back at the inhaled levodopa. Some went to the sublingual and stayed there. Some folks said, “I’m not getting the same response I wanted with either. I’m going to go back and consider the subcutaneous.” There are enough individuals with Parkinson disease who have these OFFs who can stratify themselves to an extent, and we can help stratify them based on their needs. We just find which product fits their needs based on their level of OFF, the severity of it, the need for the correction of this. And you’re absolutely right in terms of how reliable do they need that OFF reduction, and how much of a value does it add for them?

Sanjay Iyer, MD: One important consideration, as Parkinson disease progresses, for many people, their mouth will hang open, the lips are parsed, the excessive drooling that can occur. That’s something that must be factored in when you think about the delivery of these things. Not only would it be really clunky to be able to inhale the levodopa with all the saliva everywhere, but the strip under the tongue, not swallowing it, or if it’s coming out of your mouth, that can be a challenging thing.

Laxman Bahroo, DO: Absolutely. Those are very important points to consider. And it’s a very important point to consider in how we stratify this.

Transcript Edited for Clarity