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Challenges of current approaches to MANAGING dyskinesia

Medical Approaches

Dopaminergic manipulation1

  • Reduce dose
  • Fractionate
  • Reduced dose and add adjunctive therapy (eg, MAO-B inhibitor, dopamine agonist)

Dose reductions may increase OFF time and may result in suboptimal peak-dose effect3

Add non-dopaminergic therapy2,3

  • Amantadine IR (glutamate antagonist)
    • Not approved for dyskinesia
    • Low real-world use and persistency at high doses

Difficult to reach therapeutic plasma levels

Surgical Approach

Deep brain stimulation4

  • Established surgical option for dyskinesia in Parkinson's disease that can be effective for certain populations
  • Invasive
  • Complications possible

BID DOSING OF AMANTADINE IR DOES NOT ACHIEVE OPTIMAL PEAK PLASMA CONCENTRATIONS5

STEADY-STATE, 24-HR PHARMACOKINETIC PROFILE OF AMANTADINE IR

PK curve showing Amantadine IR BID dosing plasma concentrations
BID, twice daily; IR, instant release.

Amantadine IR2,5

  • Tmax ~2 hours
  • Half-life ~17 hours
  • In validated PD dyskinesia models in multiple species, an amantadine concentration of ~1400 ng/mL reduced dyskinesia by 50% (EC50)

Amantadine IR steady-state profile was simulated based on a model generated from steady-state data of amantadine IR BID (8 AM and 4 PM) and scaled based on reduced renal clearance seen in PD patients (70 mL/min/1.73 m2).5

PHARMACOKINETIC AND PRECLINICAL DATA DO NOT PROVIDE EVIDENCE OF CLINICAL SAFETY OR EFFICACY

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Important Safety Information

Indication

GOCOVRI™ (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

Contraindications

GOCOVRI™ (amantadine) is contraindicated in patients with creatinine clearance below 15 mL/min/1.73 m2.

Warnings and Precautions

Falling Asleep During Activities of Daily Living and Somnolence: Patients treated with Parkinson’s disease medications have reported falling asleep during activities of daily living. If a patient develops daytime sleepiness during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), GOCOVRI should ordinarily be discontinued or the patient should be advised to avoid potentially dangerous activities.

Suicidality and Depression: Monitor patients for depression, including suicidal ideation or behavior. Prescribers should consider whether the benefits outweigh the risks of treatment with GOCOVRI in patients with a history of suicidality or depression.

Hallucinations/Psychotic Behavior: Patients with a major psychotic disorder should ordinarily not be treated with GOCOVRI because of the risk of exacerbating psychosis. Observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases.

Dizziness and Orthostatic Hypotension: Monitor patients for dizziness and orthostatic hypotension, especially after starting GOCOVRI or increasing the dose.

Withdrawal-Emergent Hyperpyrexia and Confusion: Rapid dose reduction or abrupt discontinuation of GOCOVRI, may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech. Avoid sudden discontinuation of GOCOVRI.

Impulse Control/Compulsive Behaviors: Patients may experience urges (e.g. gambling, sexual, money spending, binge eating) and the inability to control them. It is important for prescribers to ask patients or their caregivers about the development of new or increased urges. Consider dose reduction or stopping medications.

Adverse Reactions

The most common adverse reactions (>10%) were hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

Drug Interactions

Other Anticholinergic Drugs: The dose of GOCOVRI should be reduced if atropine-like effects are observed.

Drugs Affecting Urinary pH: The pH of the urine has been reported to influence the excretion rate of amantadine. Monitor for efficacy or adverse reactions under conditions that alter the urine pH.

Alcohol: Concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension.

Indication

GOCOVRI™ (amantadine) extended release capsules is indicated for the treatment of dyskinesia in patients with Parkinson’s disease receiving levodopa-based therapy, with or without concomitant dopaminergic medications.

References: 1. Müller T, Woitalla D, Russ H, at al. Prevalence and treatment strategies of dyskinesia in patients with Parkinson’s disease. J Neural Transm. 2007;114:1023-1026. 2. Symmetrel (amantadine hydrochloride, USP) [Prescribing Information]. Chadds Ford, PA: Endo Pharmaceuticals Inc; 2009. 3. Navarro R, Whangbo A, Pahwa R, et al. An assessment of the persistence and medication possession ratio of adjunctive treatments to levodopa in patients with Parkinson’s disease. Poster presented at: 2017 ISPOR 22nd Annual International Meeting; May 20-24, 2017; Boston, MA. 4. Schermer M. Ethical issues in deep brain stimulation. Front Integr Neurosci. 2011; 5(17):1-5. doi:10.3389/fnint.2011.00017. 5. Data On File. Adamas Pharma LLC, Emeryville, CA.