Gastrointestinal Dysfunction in Parkinson's Disease and its Impact on OFF Periods Video Transcript

Indication

• INBRIJA^® is indicated for intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa.

Selected Important Safety Information

• INBRIJA^® is contraindicated in patients taking or who have recently taken (within 2 weeks) nonselective monoamine oxidase (MAO) inhibitors (e.g., phenelzine and tranylcypromine) due to risk of hypertension. Discontinue use of nonselective MAO inhibitors at least 2 weeks prior to initiating INBRIJA.
• INBRIJA is not recommended in patients with asthma, COPD, or other chronic underlying lung disease because of the risk of bronchospasm.

Gastrointestinal Dysfunction in Parkinson's Disease and its Impact on OFF Periods
This video is brought to you by Acorda Therapeutics, Inc.

[Dr. Isaacson, Dr. Pfeiffer, and Dr. Pahwa seated at a table together, video headshots of Dr. Pfeiffer and Dr. Pahwa are shown, camera alternates focusing on Dr. Isaacson speaking, Dr. Pfeiffer speaking, and Dr. Pahwa speaking]

Ronald F. Pfeiffer, MD
Rajesh Pahwa, MD

Hello. I'm Dr. Stuart Isaacson of the Parkinson's Disease and Movement Disorder Center of Boca Raton in Florida. I'd like to introduce my colleagues, Dr. Ronald Pfeiffer of the Parkinson's Center at Oregon Health and Science University in Portland, and Dr. Rajesh Pahwa at the Parkinson's Center at the University of Kansas. Ron, can you give us an introduction on the gastrointestinal problems, the dysfunction, the dysmotility, that's important in Parkinson's disease and why general neurologists should know about it and think about it, and think about it when they're treating patients with Parkinson's disease?

Ronald F. Pfeiffer, MD
Department of Neurology, Oregon Health and Science University, Portland, OR

Sure. Gastrointestinal dysfunction is tremendously common in people with Parkinson's disease and of particular importance, though, I think, is the issue of impaired gastric emptying that can be part of Parkinson's disease. That's important not only because it can cause GI symptoms of its own, but it also can cause unpredictable and ineffective responses to the patient's normal oral carbidopa/levodopa regimen. And because of that, patients with Parkinson's disease may have symptoms that are usually well-controlled but unpredictably, there may be no control, or they may not get a response to the medication.

Is this common, Raj? Is this something you see in your practice as well?

Prevalence data on GI dysfunction symptoms in Parkinson's disease vary from ~10% to ~80% depending on the study and the symptom. Parkinson's disease study populations sizes for these approximately 30 case-controlled studies varied from <10 to, in one study, >4500.

Yes, I mean, you see a lot of GI dysfunction symptoms that occur in Parkinson's, and depending on the study, you know, it may be over 80% of the patients have some GI issues. So if you start right from the mouth, people have excessive saliva, called sialorrhea, and the swallowing is affected. You can have dysphagia. Then, of course, the delayed gastric emptying is present. And then if you go to the small intestine, there's a small intestinal bacterial overgrowth, or SIBO. That can also affect the effectiveness of levodopa. And further down you have bowel dysfunction, so you pretty much have issues in Parkinson's all the way from the mouth to the other end of the body, so to speak.

['GI Dysfunction and Clinical Correlates in Patients with PD' slide is shown]

So it's clear that the GI dysfunction is common in Parkinson's disease patients. How do these GI issues impact the treatment with levodopa?

Rajesh Pahwa, MD
Department of Neurology, University of Kansas Medical Center, Kansas City, KS

So if you look at it, you know, early in the disease course, the patient has good response to medication. You know, they take it, they have stable levodopa levels. But what happens as the disease progresses, patients start having OFF periods. Now, what are OFF periods? OFF periods are return of Parkinson's symptoms or worsening of Parkinson's symptoms, even in patients who are compliant to their medications and take their medications on schedule. You know, we talk about the brain, but also the gut plays an important role in these OFF periods because the issue is the levodopa is not absorbed in the stomach, it's absorbed in the small intestine. And with all the problems that we have in the stomach, levodopa has to make it to the small intestine to be absorbed and start working.

You know, there was a very nice cross-sectional study done of 80 patients with mild to moderate Parkinson's disease, and it described or reported that fully 88% of those patients had delayed gastric emptying of solids. 38% had delayed gastric emptying of liquids, but only 35% of the patients actually experienced any GI symptoms that they were aware of, so it can happen even when people aren't aware of it.

So this can be a big problem, this delayed gastric emptying and delayed onset. It almost seems that delayed onset of levodopa may be a symptom of gastroparesis in Parkinson's disease.

Definitely possible. And you know, our patients often ask us, how long should it take for my medicine to start working? And the thing is, everyone is different and the reason everyone is different because everyone's stomach is different on how long it takes for the medicine to make it in the small intestine to get absorbed.

And it's variable, gastric emptying. So sometimes just asking a patient, do some doses take longer than other doses to begin to work, may give a hint that this is a problem. How often do you see OFF periods in your patients? Is this something that they have every day or they have every week? Is this a common problem?

Sure, it's common, and it's partially dependent on how long they've had Parkinson's disease. I think, as Raj said earlier, if you're in the early stages of Parkinson's disease, you're not likely to notice end of dose wearing off, and in fact, you can miss doses and not notice anything. But as Parkinson's progresses, the tendency for the duration of benefit of a dose of levodopa to become shorter and shorter becomes more evident, and as that happens, I think gastric factors become increasingly important. And studies have shown a wide variability in both the time for absorption and the time to maximum peak levels of levodopa in patients with Parkinson's disease.

So Raj, how does the delayed gastric emptying influence the absorption of oral levodopa?

Rajesh Pahwa, MD
Department of Neurology, University of Kansas Medical Center, Kansas City, KS

Oral levodopa is not, as is commonly believed, absorbed in the stomach, but it is absorbed in the proximal small intestine. So the rate-limiting step in oral levodopa absorption is gastric emptying via the pyloric sphincter. Now, delayed gastric emptying can therefore cause variability in the onset of benefit of oral Parkinson's medicines and can also contribute to the production of OFF periods. As an example, here, we see a tablet in the stomach of a patient with Parkinson's disease still intact about one and a half hours after intake. So it kind of points such an important part of this because unless levodopa gets into the small intestine, it's not going to get absorbed.

[Slide shown with image of tablet in the stomach of a patient, with arrow pointing to tablet]

Photograph taken during gastroscopy. Arrow points to a tablet remaining in the stomach of a person with Parkinson's about 1.5 h after intake

Because that's where the transporter is...

Exactly.

Stuart H. Isaacson, MD
Parkinson's Disease and Movement Disorder Center of Boca Raton, Boca Raton, FL

...in the intestine, not in the stomach.

That's right.

So, that pill sitting in the stomach is sitting in the stomach and not being absorbed at all.

Right.

So, Ron, can you tell us a bit more about this variable absorption of oral levodopa in the GI tract?

['Oral CD/LD (25/100 mg) in PD Subjects*' graph is shown]

Sure. There's great variability in oral levodopa absorption, from patient to patient, and even within individual patients from one day to the next. Differing gastric emptying rates are an important factor that accounts for this variable absorption. In this graph, we can see evidence of patient to patient variability. It shows the levodopa plasma concentrations for 15 patients with Parkinson's disease, who each took an oral levodopa/carbidopa tablet at time zero. They had had no food for at least an hour before or an hour after the oral carbidopa/levodopa. And the time to maximum levodopa concentration in the plasma and maximum plasma concentrations are different for each patient, and considerably different. One patient has a peak levodopa concentration after only 15 minutes, whereas others take up to 120 minutes, or two hours, to reach their peak. This really nicely demonstrates the inherent variability in the gastrointestinal absorption of an oral dose of levodopa.

This study also nicely demonstrated that not only is the Tmax delayed, but the onset of entry of levodopa is delayed in many patients and is even, one of these curves had no entry of plasma levels for 90 minutes.

Which would clearly account for dose failure in a patient, which we all see.

Metabolization of levodopa by Enterococcal faecalis and Eggerthella lenta was determined by an in vitro study.

And, you know, the other additional thing to remember is that some bacteria such as Enterococcal faecalis and Eggerthella lenta, which are found in the gut also metabolized the levodopa.

This was a study.

That's right, there was a study about these, and these bacteria, by breaking down levodopa, reduce its bioavailability. And variability in these microbial activities can also be contributors to the heterogeneous response of the oral levodopa. So there are still other factors also involved with it.

We talked about a lot of things today. How would you put it all together and summarize it for a practicing clinician to sort of integrate all this information into their treatment strategies and their clinical days?

So I think it's important to remember that GI issues can be common in patients with Parkinson's. Delayed gastric emptying is a significant contributing factor to OFF periods. Disturbances of the gut microbe, such as infections with levodopa metabolizing bacteria, may also be an important part of it. And quite apart from the impact of these conditions have on patients directly, the presence of some of these conditions, delayed gastric emptying in particular, can influence the efficiency of oral levodopa medications.

So for these reasons, it is important that we are aware of GI dysfunction that are experienced by our patients with Parkinson's disease. It can help us make better shared and informed treatment decisions to try to address the OFF periods that could occur in Parkinson's disease and that reflect both central and peripheral mechanisms. So, thank you for joining us today, and we hope this was informative.

Additional Important Safety Information

• Patients treated with levodopa, the active ingredient in INBRIJA, have reported falling asleep during activities of daily living, including operation of motor vehicles, which sometimes resulted in accidents. Many patients reported somnolence but some reported no warning signs (sleep attack). This may occur more than a year after initiating treatment. Reassess patients for drowsiness/sleepiness including occurrence during specific activities. Advise patients of potential for drowsiness and ask about factors that may increase this risk (e.g., sedating medications, sleep disorders).
  • Consider discontinuing INBRIJA in patients who report significant daytime sleepiness or falling asleep during activities that require active participation. If continuing INBRIJA, advise patients not to drive and to avoid activities that may result in harm. There is insufficient information that dose reduction will eliminate episodes of falling asleep during activities of daily living.
• Neuroleptic malignant syndrome-like symptoms (e.g., elevated temperature, muscular rigidity, altered consciousness, autonomic instability) have been reported with rapid dose reduction, withdrawal of, or changes in dopaminergic therapies.
• Hallucinations (with or without confusion, insomnia, and excessive dreaming) may occur and may respond to reducing levodopa therapy. Abnormal thinking and behavior may present with paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
• INBRIJA should ordinarily not be used in patients with major psychotic disorder due to risk of exacerbating psychosis. Dopamine antagonists used to treat psychosis may exacerbate symptoms of PD and decrease INBRIJA efficacy.
• Patients on medications that increase central dopaminergic tone such as INBRIJA can experience intense urges to gamble or spend money, increased sexual urges, binge eating and/or other intense urges, and inability to control them. In some cases, these urges stopped with dose reduction or medication discontinuation. Since some patients may not recognize these behaviors as abnormal, ask patients or their caregivers about development of new or increased urges and consider stopping INBRIJA if this occurs.
• INBRIJA may cause or exacerbate dyskinesias. If troublesome dyskinesias occur, consider stopping INBRIJA or adjusting other PD medications.
• Monitor patients with glaucoma for increased intraocular pressure.
• Abnormalities in laboratory tests may include elevations of liver function tests (e.g., alkaline phosphatase, AST, ALT, lactic dehydrogenase, bilirubin), blood urea nitrogen, hemolytic anemia, and positive direct antibody test. Increased levels of catecholamines and their metabolites in plasma and urine may result in false-positive results suggesting pheochromocytoma.
• The most common adverse reactions (≥ 5% and > placebo) were cough (15% vs 2%), upper respiratory tract infection (6% vs 3%), nausea (5% vs 3%), and sputum discolored (5% vs 0%).
• Use of selective MAO-B inhibitors with INBRIJA may be associated with orthostatic hypotension. Monitor patients taking these drugs concurrently.
• Dopamine D2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone, metoclopramide) and isoniazid may reduce levodopa efficacy; monitor for worsening symptoms.
• Iron salts or multivitamins with iron salts may reduce levodopa bioavailability.
• INBRIJA should be used during pregnancy/nursing only if potential benefit justifies potential risk. There are no adequate data on INBRIJA in pregnant women or breastfed infants. Animal data shows carbidopa/levodopa is developmentally toxic (including teratogenicity). Levodopa may affect milk production, interfering with lactation. Levodopa has been detected in human milk.
• Safety and effectiveness in pediatric patients have not been established.
• Geriatric patients (n=56) experienced more of the following adverse reactions than patients <65 (n=58): cough (25% vs 5%), upper respiratory tract infection (11% vs 2%), nausea (7% vs 3%), vomiting (4% vs 2%), pain in the extremities (4% vs 0%), and discolored nasal discharge (4% vs 0%).

Please see accompanying Full Prescribing Information at InbrijaFullPI.com

[Slides are shown with References]

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05/21 PD8450

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11/21 INB11536