Parkinson’s disease, a neurodegenerative disorder, affects approximately 1 million individuals in the United States, and 60,000 new cases are diagnosed annually.1 Characterized by low dopamine concentrations and progressive brain-cell destruction, Parkinson’s disease affects the body’s motor system, including neurotransmitters.2,3 Accurately diagnosing Parkinson’s disease can be challenging and generally requires a medical history, neurologic examination, and laboratory tests to rule out other disorders.1
The symptoms of Parkinson’s disease include trembling or tremor, limb rigidity, bradykinesia (slowness of movement), and impaired balance and coordination.1 The disease can also cause difficulty speaking, swallowing, and performing everyday activities. Overall, Parkinson’s disease can have a considerable impact on the patient’s quality of life.2
When the symptoms of Parkinson’s disease are being controlled, the episode is referred to as “on” time.2 Conversely, when symptoms are not responding to treatment, the episode is called an “off” time.2 Treatments for Parkinson’s disease include levodopa plus carbidopa, dopamine agonists, monoamine oxidase (MAO)-B inhibitors, catechol-O-methyltransferase (COMT) inhibitors, anticholinergic drugs, and amantadine.3
Levodopa continues to be the mainstay treatment for Parkinson’s disease.2,4 However, long-term treatment with levodopa often leads to dyskinesia, a movement disorder characterized by involuntary muscle movements, which can further complicate the patient’s well-being and activities of daily living.2,5,6
FDA Approves Gocovri for Dyskinesia Associated with Parkinson’s Disease
On August 24, 2017, the US Food and Drug Administration (FDA) approved amantadine (Gocovri; Adamas Pharmaceuticals), an oral, extended-release drug for the treatment of dyskinesia in patients with Parkinson’s disease who receive levodopa-based therapy, with or without concomitant dopaminergic medications.7,8 Amantadine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the first drug to receive FDA approval specifically for this indication.7
In 2015, the FDA granted amantadine orphan drug status for levodopa-induced dyskinesia.7,9 Formerly used as an antiviral agent for influenza (flu), amantadine is not currently recommended for flu in the United States, because certain flu viruses are resistant to or do not respond to treatment with the drug.10
“Gocovri’s approval is an important advancement for the treatment of Parkinson’s disease, as it is the first FDA-approved medicine for the treatment of dyskinesia in Parkinson’s disease patients,” said Rajesh Pahwa, MD, Laverne & Joyce Rider Professor of Neurology, Kansas Medical Center, and Director, Parkinson’s Disease and Movement Disorder Center, University of Kansas Health System.7
Mechanism of Action
Amantadine is a weak, uncompetitive antagonist of the NMDA receptor that contains the active ingredient amantadine hydrochloride. Although its exact mechanism of action in treating dyskinesia in Parkinson’s disease is unknown, amantadine exhibits anticholinergic activity in animal studies, but is also associated with dopaminergiclike side effects (eg, dry mouth, constipation), and it may exert a direct or indirect effect on dopamine neurons, resulting in dopamine reuptake.8
Dosing and Administration
The initial daily dosage of amantadine is 137 mg, administered orally once daily at bedtime; after 1 week, the dose should be increased to the recommended dose of 274 mg daily.8
Amantadine capsules should be swallowed whole and should not be crushed, chewed, or divided. If necessary, the capsule can be carefully opened, and the contents can be sprinkled over a small amount of soft food, such as a teaspoonful of applesauce. The drug–food mixture should be swallowed immediately without chewing; the mixture should not be stored for future use.8
Amantadine can be taken with or without food, and should not be used with alcohol. The dose should be reduced for patients with moderate or severe renal impairment, as recommended in the prescribing information.8
Amantadine is available as an extended-release formulation in 68.5-mg or 137-mg capsules.8
Clinical Trials
The safety and efficacy of amantadine were evaluated in 2 phase 3 randomized, double-blind, placebo-controlled clinical trials—Study 1 and Study 2—in patients with Parkinson’s disease associated with dyskinesia.5,6,8 Eligible patients had to have at least 1 hour of troublesome dyskinesia time during the day and at least mild functional impact as a result of dyskinesia. The patients’ mean age in both studies was 55 years (range, 29-75 years).8
The primary efficacy end point in both studies was change in the total score of the Unified Dyskinesia Rating Scale from baseline to week 12. In Study 1, the treatment duration was up to 25 weeks. In Study 2, the treatment duration was 13 weeks.8
Treatment with amantadine in Study 1 and in Study 2 demonstrated a significant reduction in the Unified Dyskinesia Rating Scale total score at week 12 compared with placebo (Table).5,6,8
Regarding the key secondary end points, in both studies amantadine demonstrated a significant increase in “on” time, without troublesome dyskinesia, and a significant reduction in “off” time from baseline to week 12 compared with placebo (Table).5,6,8
Adverse Reactions
The most common (incidence >10% and greater than placebo) adverse reactions were hallucination (21%), dizziness (16%), dry mouth (16%), peripheral edema (16%), constipation (13%), fall (13%), and orthostatic hypotension (13%).8
Overall, 20% of patients who received amantadine discontinued treatment versus 8% of patients who received placebo.8 Adverse reactions that led to treatment discontinuation in at least 2% of patients who received amantadine were hallucinations (8%), dry mouth (3%), peripheral edema (3%), blurred vision (3%), postural dizziness and syncope (2%), abnormal dreams (2%), dysphagia (2%), and gait disturbance (2%).8
Contraindications
Amantadine is contraindicated in patients with end-stage renal disease.8
Drug Interactions
Drugs with anticholinergic properties may potentiate the anticholinergiclike side effects of amantadine; if patients exhibit atropinelike effects, the dose of the anticholinergic drug or the dose of amantadine should be reduced.8
Patients should be monitored for efficacy if their current diet or drugs increase the acidity or alkalinity of urine pH.8
Amantadine should not be used concomitantly with live attenuated influenza vaccines or with alcohol.8
Use in Specific Populations
Data are not available on the risk of amantadine to the breastfed infant. The mother’s need for amantadine and the benefits of breastfeeding should be weighed against any potential adverse effects on the infant.8
In clinical trials, hallucinations and falls occurred more frequently in patients aged ≥65 years than in younger patients. No dose adjustments are required because of the patient’s age, but dose selection is important, because elderly patients are at risk for diminished renal function.8
Warnings and Precautions
Before initiating treatment with amantadine, patients should be advised of the potential for drowsiness. Amantadine should be discontinued if the patient exhibits daytime sleepiness or falls asleep during activities that require full attention.8
Patients receiving amantadine should be monitored for depression, including suicidal ideation or behavior. For patients with a history of depression or suicidality, the benefits of amantadine treatment should be weighed against the associated risks.8
Patients with a major psychotic disorder should generally not receive amantadine. Patients should be monitored for hallucinations throughout the treatment duration, particularly at treatment initiation and dose increases.8
Patients should be monitored for dizziness and orthostatic hypotension, especially after amantadine initiation or a dose increase.8
Amantadine should not be discontinued suddenly; its abrupt discontinuation can increase the symptoms of Parkinson’s disease or result in delirium, agitation, anxiety, or other adverse effects.8
Conclusion
The FDA approval of amantadine, an oral, extendedrelease NMDA receptor antagonist, provides a new treatment option for dyskinesia in patients with Parkinson’s disease who receive levodopa-based therapy, with or without concomitant dopaminergic medications. In 2 clinical studies, treatment with amantadine demonstrated a significant reduction in dyskinesia, a significant improvement in “on” time without troublesome dyskinesia, and a significant decrease in “off” time in patients with Parkinson’s disease with dyskinesia.
References
1. National Institutes of Health. Parkinson’s disease: new research offers hope for better diagnosis and treatments. NIH MedlinePlus. 2016;10:24.
2. National Institutes of Health. Parkinson’s disease. Fact sheet. https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=109. Accessed January 10, 2018.
3. Mayo Clinic staff. Parkinson’s disease. www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062?p=1. Accessed January 10, 2018.
4. Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol. 2013;20:5-15.
5. Pahwa R, Tanner CM, Hauser RA, et al. ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson disease (EASE LID Study): a randomized clinical trial. JAMA Neurol. 2017;74:941-949.
6. Oertel W, Eggert K, Pahwa R, et al. Randomized, placebo-controlled trial of ADS-5102 (amantadine) extended-release capsules for levodopa-induced dyskinesia in Parkinson’s disease (EASE LID 3). Mov Disord. 2017;32:1701-1709.
7. Adamas Pharmaceuticals. Adamas announces FDA approval of GOCOVRI as first and only medication for the treatment of dyskinesia in Parkinson’s disease patients. Press release. August 24, 2017. http://ir.adamaspharma.com/releasedetail.cfm?releaseid=1038209. Accessed January 9, 2018.
8. Gocovri (amantadine) extended release capsules [prescribing information]. Emeryville, CA: Adamas Pharmaceuticals; August 2017.
9. Adamas Pharmaceuticals. Adamas Pharmaceuticals receives orphan drug designation for ADS-5102 for the treatment of levodopa-induced dyskinesia associated with Parkinson’s disease. Press release. April 10, 2015. http://ir.adamaspharma.com/releasedetail.cfm?releaseid=905919. Accessed January 10, 2018.
10. Centers for Disease Control and Prevention. Influenza antiviral drug resistance: questions & answers. www.cdc.gov/flu/about/qa/antiviralresistance.htm. Accessed January 10, 2018.