BackgroundImmediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing. ObjectiveReport individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID. MethodsPD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale. ResultsOverall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were −5.5 [−9.8, −1.2], p = 0.012 and −5.2 [−9.5, −0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively). ConclusionsIR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

There are many different etiologies of blepharoptosis. Speculum-induced blepharoptosis can occur after intraocular surgery. A series of patients whose speculum-induced blepharoptosis was successfully treated with the recently U.S. Food and Drug Administration–approved drug Upneeq (oxymetazoline hydrochloride 0.1% ophthalmic solution, RVL Pharmaceuticals, Inc.) is presented.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

BackgroundAn extended-release formulation of amantadine (Osmolex ER™, Osmotica Pharmaceutical US LLC) was approved in February 2018 to treat Parkinson’s disease and drug-induced extrapyramidal reactions in adults.ObjectivesTo determine the pharmacokinetic profile of extended-release amantadine in subjects with varying degrees of renal impairment.MethodsAdults with normal renal function (creatinine clearance > 89 mL/min/1.73 m2), moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m2), or severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) received a single 129-mg dose (160 mg amantadine hydrochloride) of extended-release amantadine. Blood and urine samples for pharmacokinetic analysis were taken at scheduled intervals. A two-compartment pharmacokinetic population model was employed to determine optimum extended-release amantadine dosing in subjects with renal impairment.ResultsFollowing a single oral dose of the 129-mg extended-release amantadine tablet, amantadine plasma concentration increased slowly, reaching a peak at approximately 11 h. Amantadine elimination was reduced in subjects with renal impairment. Renal clearance decreased from 10,965 to 2618 mL/h in subjects with severe renal impairment compared to those with normal renal function. Pharmacokinetic modeling and simulation methods were used to recommend the oral administration of 129-mg extended-release amantadine tablets at intervals of 24, 48, 72, 96, 120, or 168 h depending on the degree of renal function.ConclusionsRenal impairment was associated with reduced amantadine clearance. Based on pharmacokinetic modeling and simulations, dose regimens were recommended for subjects with impaired renal function to provide systemic amantadine exposure similar to subjects with normal renal function taking a once-daily extended-release amantadine tablet.Electronic supplementary materialThe online version of this article (10.1007/s40263-019-00651-1) contains supplementary material, which is available to authorized users.

Anticholinergic medications are used to manage drug-induced extrapyramidal reactions (EPR), or movement disorders caused by antipsychotics and antidepressants. Long-term anticholinergic drug use is associated with increased cognitive impairment and dementia. An alternative to anticholinergics is amantadine hydrochloride, an N-methyl-D-aspartate antagonist receptor. This survey sought to gain psychiatrists’ insights on current therapeutic management of EPR, including amantadine immediate-release (IR) use, and the potential role of an amantadine extended-release (ER) formulation. This double-blind, quantitative survey of 98 US board-certified psychiatrists, mostly in private practice, who use amantadine IR to treat drug-induced EPR in adults was conducted between March and April 2018. Respondents were presented with amantadine ER pharmacokinetic data, reimbursement information, and a product profile. Respondents rated their views of amantadine IR in clinical use and their impression on the clinical utility of an amantadine ER formulation. Approximately 17% of patients treated by this group of psychiatrists experienced drug-induced EPR; patients with schizophrenia and schizoaffective disorder were most likely to be affected. Overall, 57% of patients who experience drug-induced EPR were treated with medication. Benztropine (44%) and amantadine (17%) were most commonly used to treat drug-induced EPR. Approximately 50% of patients started on amantadine IR experienced a benefit and remained on the therapy. When shown a product profile and attributes for amantadine ER, 93% of respondents anticipated prescribing the product. A majority of respondents would consider use of product in patients who could benefit from once daily dosing. Potential limitations of this survey include a limited number of respondents, underpowered for statistical significance, and a specific focus on amantadine-prescribing psychiatrists. The results of this survey reveal a majority of surveyed psychiatrists anticipate increased clinical utility of an amantadine ER formulation to treat drug-induced EPR. Of those who did not see clinical utility, cost was a common shared concern.