An extended-release formulation of amantadine received approval from the Food and Drug Administration on Aug. 24 for the treatment of dyskinesia in patients with Parkinson’s disease. The significant increase in functional time for Parkinson’s disease patients with dyskinesia who took extended-release amantadine was attributable both to a reduction in off-time and to a decrease in troublesome dyskinesia during on-time.
This is the first FDA approval for a drug to treat levodopa therapy-related dyskinesia in patients with Parkinson’s disease, according to an announcement from its manufacturer, Adamas Pharmaceuticals.
The approval of extended-release (ER) amantadine, which will be marketed under the brand name Gocovri, was based on two phase 3 clinical trials in this patient population; in the first study, patients who received extended-release (ER) amantadine had reductions in dyskinesia that were both statistically significant and clinically relevant, compared with patients who received placebo. Patients in the ER amantadine arm saw a 37% reduction on the Unified Dyskinesia Rating Scale (UDysRS) at 12 weeks, compared with a 12% reduction for the placebo group.
The second study also showed clinically relevant and statistically significant results, with a 46% reduction on the UDysRS for those taking ER amantadine, compared with a 16% reduction for those taking placebo.
The oral ER amantadine formulation delivers 274 mg of amantadine once daily at bedtime, allowing sustained high levels of the drug during waking hours, with peak levels delivered during the morning and throughout the day and a trough near bedtime.
When investigators of the two studies analyzed diaries that had been kept by Parkinson’s disease patients, they found that patients in the two studies who were taking ER amantadine experienced a placebo-adjusted reduction in off-time of about 1 hour per day.
Patients in the ER amantadine arm of the first study also had an increase of 3.6 hours per day of functional time, compared with a 0.8-hour increase for patients taking placebo. In the second study, functional time went up by 4.0 hours per day for patients in the ER amantadine arm, compared with an increase of 2.1 hours per day for those on placebo. Functional time was defined as on-time without troublesome dyskinesia.
Adverse reactions to ER amantadine that occurred in more than 10% of patients in the active arms of the study, and which occurred more frequently than in those taking placebo, included hallucinations, falls, orthostatic hypotension, dizziness, peripheral edema, dry mouth, and constipation.
The medication is contraindicated in those with creatinine clearance below 15 mL/min/1.73 m2. Prescribing information advises that amantadine ER be avoided or used with caution in patients with a history of suicidality and depression, hallucinations or psychotic behavior, and orthostatic hypotension or dizziness.
Patients taking ER amantadine may also experience impulsivity and sexual, spending, or gambling urges. Abrupt withdrawal or rapid dose reduction may result in withdrawal-emergent hyperpyrexia or confusion, including delirium, hallucinations, stupor, and slurred speech.
The clinical trials upon which the approval is based were funded by Adamas Pharmaceuticals.
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