Objective: Evaluate the effects of amantadine formulations on the treatment of OFF and dyskinesia in Parkinson’s patients.

Background: There are currently three formulations of amantadine (AMT) available in the US: immediate release (IR) tablets, [1] immediate release/extended release (IR/ER) tablets [2] and delayed release/extended release (DR/ER) capsules. [3] The DR/ER formulation is the only FDA-approved and effective medication for Parkinson’s motor complications, decreasing both OFF time and dyskinesia compared to placebo. Clinical trials for other AMT IR and IR/ER formulations have demonstrated effects on dyskinesia in patients with Parkinson’s disease, however, no published trials have compared efficacy amongst all three.

Method: An indirect treatment comparison was performed. The literature studies of AMT IR in PD patients with OFF and dyskinesia were utilized, along with data from pivotal trials of AMT DR/ER and AMT IR/ER. For each trial, where available, the mean treatment differences (least squares mean or means) in diary states of OFF and ON with troublesome dyskinesia were obtained directly or calculated from the active and placebo arms, relative to baseline. The treatment effect magnitude was computed for each treatment option and reported as percentage. For AMT IR/ER, data for the two doses used in the phase 3 trials were pooled to increase the sample size using statistically weighted averages.

Results: AMT DR/ER (N=196) has shown statistically significant reductions in both OFF time, by 36% (P=.0006), and dyskinesia, by 30% (P<.0001). AMT IR and AMT IR/ER reduced dyskinesia by 19% (P=.033, N=61) and 13% (P=.005, N=194), respectively. Neither AMT IR nor AMT IR/ER demonstrated a significant change in OFF time (IR, -6.4% (P=.65, N=35); IR/ER, -1% (P= .87, N=194)). The main differentiators among the 3 AMT formulations are their PK profiles and dosage, with the bedtime-administered DR/ER formulation providing significantly higher AMT concentrations in the morning hours from 6am to 10am, than morning-administered IR/ER, or AMT IR 2 to 3 times/day.

Conclusion: Among the AMT formulations evaluated, only AMT DR/ER capsules reduced OFF time and provided meaningful improvement in dyskinesia. The improvements in OFF time seem to correlate with early morning AMT levels.

References: [1] Symmetrel (amantadine hydrochloride, USP) tablets and syrup (prescribing information). Chadds Ford, PA: Endo Pharmaceuticals, Inc.; 1/2009. [2] Osmolex ER (amantadine) extended-release tablets (prescribing information). Emeryville, CA: Adamas Pharmaceuticals, Inc.; 1/2020. [3] Gocovri (amantadine) extended release capsules (prescribing information). Emeryville, CA: Adamas Pharma, LLC; 1/2020.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/analysis-of-amantadine-formulations-for-off-and-dyskinesia-in-parkinson-disease/