Sublingual Film Well-Tolerated for Parkinson ‘Off’ Episodes
A majority of patients with Parkinson disease (PD) experiencing “off” episodes successfully tolerated titration to an effective and tolerable dose of sublingual apomorphine film (SL-apo; Kynmobi, Sunovion Pharmaceuticals) without the use of antiemetic medication, new research shows.
“The bottom line was that the majority of patients did not have dose-limiting nausea or vomiting,” co-investigator William Ondo, MD, from Houston Methodist Neurological Institute, Texas, told Medscape Medical News. “And although it really did not compare in a prospective, placebo-controlled manner use of [trimethobenzamide antiemetic]… versus not using [it], anecdotally and based on historic data, nausea really seemed to be about the same even without the antinausea medication.”
The findings were presented at the virtual International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2021.
This study was the dose-titration phase to determine the effective and tolerable dose of the drug as part of a longer study looking at safety and efficacy.
Only 13% of patients experienced nausea and/or vomiting, and of those, 74% cases were of mild severity and 26% were of moderate severity. These rates of nausea/vomiting were lower than those seen when trimethobenzamide (Tigan, Pfizer) was needed to be administered during the titration period, at the discretion of the investigator.
This multicenter, ongoing, open-label phase 3 study enrolled 176 patients (mean age, 64.4 years) who had had idiopathic PD for a mean of 8.0 years and had no prior exposure to SL-apo, with modified Hoehn and Yahr stage 1 to 3 disease (83% stage 2 or 2.5 during “on” time).
Study participants had Mini-Mental State Examination scores greater than 25, were receiving stable doses of levodopa/carbidopa, and had 1 or more (mean, 4.2) “off” episodes per day with a total daily “off” time of 2 hours or more. Patients with mouth cankers or sores within 30 days of screening were excluded.
Open-label dose titration occurred during sequential office visits while patients were “off,” with escalating doses of 10 to 35 mg in 5-mg increments to determine a tolerable dose leading to a full “on” period within 45 minutes. Patients self-administered this achieved dose of SL-apo for up to 5 “off” episodes per day with a minimum of 2 hours between doses for the full 48-week study period.
The study protocol prohibited antiemetic use except when clinically warranted at the investigator’s discretion. Of the 176 patients, 31 (18%) received the antiemetic trimethobenzamide and 145 (82%) did not.
Of the 176 patients, 76% received their effective and tolerated dose within the first 3 doses. Just over half (55%) received 10 mg or 15 mg. Only 24% received the highest doses of 25 mg or 30 mg.
Fifty-two percent of patients who received trimethobenzamide experienced treatment-related nausea and 13% experienced vomiting; in comparison, 13% not receiving trimethobenzamide had nausea and 1% had vomiting. Ten percent of patients in the former group and none in the latter discontinued the study because of nausea and/or vomiting.
| Variable | Patients Receiving Trimethobenzamide (n = 31) (%) | Patients Not Receiving Trimethobenzamide (n = 145) (%) |
|---|---|---|
| Nausea | 52 | 13 |
| Severitya | ||
| Mild | 63 | 74 |
| Moderate | 31 | 26 |
| Severe | 6 | 0 |
| Vomiting | 13 | 1 |
| Severitya | ||
| Mild | 25 | 100 |
| Moderate | 50 | 0 |
| Severe | 25 | 0 |
| Discontinued study because of nausea/vomiting | 10 | 0 |
|
aReflects the proportion of patients experiencing the adverse effect. |
The apomorphine sublingual film has “the advantage of ease of use compared to the injectable form,” Ondo said. “I think the injectable form, purely based on anecdotal experience, might start to work a minute or two faster than the sublingual form, but overall I would say efficacy as far as potency of turning ‘on’ and consistency of turning ‘on’ is comparable.”
In addition to the known adverse effects of nausea, vomiting, and hypotension with the use of any apomorphine, he said that long-term use of the sublingual form can lead to gingival irritation. Two recommendations are to place the film in a different site and to use a more basic toothpaste, such as one containing baking powder, because irritation may result from the acidity of the apomorphine.
Good News
Commenting on the study to Medscape Medical News, Ludy Shih, MD, MMSc, from Boston University School of Medicine in Massachusetts, vnoted that the drug label reports that “13 to 15% had oropharyngeal soft tissue swelling or pain… and 7% had oral ulcers and stomatitis.”
In addition, oral trimethobenzamide has been discontinued, although an injectable form is still available. This situation may present a problem, she said. “Most antinausea drugs block dopamine, so…I would say they’re contraindicated for treating people with Parkinson’s disease. But trimethobenzamide in particular is one that we often reach for…. But that appears to be constrained and may, in fact, be expensive for patients.”
Turning to the study findings, she said they suggest that “not everyone needs prophylactic use of trimethobenzamide before they take the apomorphine sublingual film, which is good news that helps doctors try to decide whether or not it’s reasonable to recommend people trying it without the trimethobenzamide.”
Although some patients did experience mild nausea, she said the fact that no needle is involved may attract some patients. Moreover, taking this medication may be easier than administering an injection during an “off” episode.
Dr Ondo is a consultant for Sunovion Pharmaceuticals, which sponsored the study. Dr Shih had no relevant disclosures.
International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2021. Abstract 394. Presented September 17-22, 2021.
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