Amantadine

Introduction Overview

Generic Name

amantadine

Brand Name

Gocovri

Dosage Form

Extended-release capsule

Drug Class

Dopaminergic antiparkinsonism agents

Pharmacokinetics

Absorption:
Gocovri is administered orally as an extended-release capsule formulation that allows for a controlled and sustained release of amantadine throughout the day. After oral administration, amantadine is rapidly and almost completely absorbed from the gastrointestinal tract, with peak plasma concentrations achieved approximately 12 to 24 hours post-dose due to its extended-release design. Food intake does not significantly affect the bioavailability of amantadine from Gocovri, and the medication can be taken with or without food. The extended-release formulation ensures steady plasma levels, reducing peak-trough fluctuations observed with immediate-release amantadine formulations.

Distribution:
Amantadine exhibits a large volume of distribution, indicative of extensive tissue penetration including crossing the blood-brain barrier to exert central nervous system effects. It is moderately bound to plasma proteins, approximately 67 to 70%, which facilitates its penetration into various tissues. Given its lipophilic properties, amantadine distributes well into brain tissue, which is essential for its antiparkinsonian activity. The distribution phase is influenced by patient factors such as age and renal function, with altered tissue concentrations observed in the elderly or in patients with renal impairment.

Metabolism:
Amantadine undergoes minimal hepatic metabolism; the drug is primarily excreted unchanged. The lack of significant metabolism decreases the likelihood of hepatic drug interactions and reduces variability caused by liver function differences. Some minor metabolic pathways may exist, but they do not play a clinically significant role in its elimination. This property contributes to the predictable pharmacokinetic profile of Gocovri in adult patients, including those with hepatic impairment where dose adjustments are generally not required.

Elimination:
The primary route of elimination of amantadine is renal excretion via glomerular filtration and tubular secretion. The elimination half-life ranges from 10 to 15 hours in individuals with normal renal function, allowing for once-daily dosing. Renal clearance is significantly impacted in patients with impaired kidney function, resulting in higher plasma concentrations and prolonged elimination half-life, necessitating dosing adjustments to mitigate toxicity. Severe renal impairment and end-stage renal disease are contraindications for Gocovri use due to accumulation risk. In patients with moderate renal impairment, initial dosing is reduced with careful titration based on clinical response and tolerability.

Dosage Forms

Available Dosage Forms:
Gocovri is available as extended-release capsules formulated specifically for once-daily oral administration at bedtime. The capsules are designed to release amantadine slowly to maintain therapeutic plasma levels over 24 hours.

The dosing strengths and forms are:
- Extended-release capsules 137 mg
- Extended-release capsules 274 mg

Dosages for Adults and Adolescents:
The recommended initial dose in adults with Parkinson’s disease is 137 mg taken orally once daily at bedtime for one week, to be increased to the maintenance dose of 274 mg once daily at bedtime thereafter. This titration enhances tolerability by reducing initial side effects. The capsules should be swallowed whole; if swallowing is difficult, the contents may be sprinkled onto a small amount of applesauce and ingested immediately without chewing or crushing the pellets.

Renal Dose Adjustments:
- Mild renal impairment (Creatinine Clearance 60-89 mL/min/1.73 m^2): No dosage adjustment necessary.
- Moderate renal impairment (CrCl 30-59 mL/min/1.73 m^2): Start at 68.5 mg once daily at bedtime, may increase to 137 mg daily after one week if tolerated.
- Severe renal impairment (CrCl 15-29 mL/min/1.73 m^2): Limit dose to 68.5 mg once daily at bedtime.
- End-stage renal disease (CrCl <15 mL/min/1.73 m^2): Use contraindicated.

Specific Patient Populations:
Elderly patients may be more susceptible to side effects such as dizziness and confusion; careful dose titration is advised. Gocovri is not recommended for use in pediatric populations due to lack of established safety and efficacy. Pregnant or breastfeeding women should avoid Gocovri due to unknown effects; consultation with a healthcare provider is essential.

Mechanism Of Action

Gocovri contains amantadine, a unique antiparkinsonian agent with a multifaceted mechanism of action, primarily exerting its therapeutic effects via modulation of dopaminergic neurotransmission in the central nervous system. Amantadine facilitates the release of dopamine from presynaptic neurons and inhibits dopamine reuptake, thereby increasing extracellular dopamine levels in areas such as the basal ganglia, which are critical in the pathophysiology of Parkinson's disease. This dopaminergic enhancement mitigates the motor symptoms associated with dopamine deficiency.

Additionally, amantadine acts as a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor involved in excitatory neurotransmission. By inhibiting NMDA receptor-mediated excitatory signals, amantadine reduces glutamatergic excitotoxicity that may contribute to motor complications such as dyskinesia in Parkinson’s disease. This NMDA receptor antagonism plays an important role in diminishing levodopa-induced dyskinesias, the involuntary movements commonly seen in patients under long-term levodopa therapy.

Amantadine also exhibits anticholinergic and antiviral properties, although these are less relevant to its antiparkinsonian effects. Compared to other dopaminergic agents and NMDA antagonists, amantadine presents a balanced profile that not only addresses motor impairment but also reduces dyskinetic movements, improving overall motor function and quality of life.

Clinical studies have demonstrated that Gocovri’s extended-release formulation maintains therapeutic plasma concentrations aligned with near-sleep pharmacokinetics, promoting symptom control during waking hours and reducing off-time episodes. Research indicates that through sustained dopaminergic stimulation and NMDA receptor blockade, Gocovri effectively attenuates motor fluctuations and levodopa-induced dyskinesia with a favorable safety profile compared to immediate-release preparations.

Pharmacological Actions

Enhances dopamine release and inhibits dopamine reuptake to increase dopaminergic neurotransmission.
Non-competitive antagonism of NMDA glutamate receptors reducing excitotoxicity and dyskinesia.
Modulates basal ganglia motor control pathways to improve Parkinson’s disease motor symptoms.
Mitigates levodopa-induced dyskinesia by balancing dopaminergic and glutamatergic signaling.
Acts as a neuroprotective agent by inhibiting excessive glutamate-mediated neuronal excitation.
Exhibits mild anticholinergic activity contributing to modulation of extrapyramidal symptoms.
Oral extended-release delivery provides sustained plasma drug levels for 24-hour symptom control.
Reduces “off” episodes experienced by Parkinson’s patients treated with levodopa-carbidopa.
Potentially modulates other neurotransmitter systems indirectly via dopamine-glutamate interaction.
Improves motor fluctuations without significantly increasing dopaminergic side effects.

Therapeutic Or Clinical Uses

Treatment of levodopa-induced dyskinesia in patients with Parkinson’s disease.
Adjunct therapy with levodopa/carbidopa in Parkinson’s patients experiencing motor "off" episodes.
Management of motor fluctuations associated with dopaminergic therapy in Parkinson’s disease.
Reduction of involuntary, sudden uncontrolled movements in Parkinson’s disease.
Improvement of quality of life by enhancing motor function and reducing motor complications.
Used in adult patients with Parkinson’s disease receiving levodopa-based therapy.
Dose titration allows for individualized management of dyskinesia severity.
Utilized as a once daily bedtime medication to optimize daytime symptom control.
Off-label uses may include management of other movement disorders associated with dopamine dysregulation.

Side Or Adverse Effects

Dizziness and increased risk of falls, especially in elderly patients.
Dry mouth, leading to discomfort and potential dental issues.
Peripheral edema presenting as swelling in legs and feet.
Nausea and constipation affecting gastrointestinal comfort.
Sleep disturbances including insomnia and sudden daytime somnolence.
Severe nervous system reactions such as neuroleptic malignant syndrome-like symptoms with rigidity and high fever.
Hallucinations, agitation, and behavioral changes including depression and suicidal ideation.
Orthostatic hypotension causing light-headedness or fainting upon standing.
Urinary retention or painful urination indicating possible autonomic involvement.
Potential for increased impulsive behaviors such as compulsive gambling or sexual urges.
Allergic reactions including hives and facial swelling requiring immediate medical attention.
Confusion and agitation more likely in patients with pre-existing cognitive impairment.
Seizures reported rarely, necessitating caution in patients with seizure history.
Severe headache and auditory disturbances (e.g. ringing in the ears) in overdose scenarios.
Potential exacerbation of underlying psychiatric conditions.

Precautions

Avoid use in patients with history of severe kidney disease or impaired renal function.
Monitor for development of skin malignancies as Parkinson’s patients are at higher risk of melanoma.
Use cautiously in patients with a history of cardiac disease such as congestive heart failure.
Assess risk in patients with glaucoma and other ocular conditions before use.
Exercise caution in patients with history of seizures or predisposition to convulsive disorders.
Avoid abrupt discontinuation to prevent worsening of Parkinsonian symptoms and withdrawal syndromes.
Alcohol consumption is contraindicated due to increased risk of adverse CNS effects and dose dumping.
Avoid concomitant use with stimulants or diet pills which may exacerbate side effects.
Carefully evaluate use in patients with psychotic disorders, including schizophrenia or severe depression.
Regular renal function monitoring is advised to adjust dosing appropriately.
Patient counseling to recognize signs of dizziness and orthostatic hypotension to prevent falls.
Advise against driving or operating machinery until individual response to medication is known.
Discuss risks of unusual urges and behavioral changes, including impulse-control disorders.
Use caution in elderly due to increased susceptibility to side effects and altered pharmacodynamics.
Pregnancy and lactation: safety not established, avoid use or consult healthcare provider.

Warnings

Do not use Gocovri if patient has received a live nasal influenza vaccine (FluMist) within the past 14 days.
Avoid nasal flu vaccination during treatment with Gocovri and for at least 48 hours after the last dose due to risk of systemic reactions.
Contraindicated in patients with end-stage renal disease due to risk of drug accumulation and toxicity.
Sudden sleep episodes have been reported; patients should be warned about performing activities requiring alertness.
Risk of neuroleptic malignant syndrome-like reactions upon abrupt cessation; dose tapering is essential.
Potential for severe allergic reactions including angioedema and anaphylaxis.
Use caution in patients with pre-existing psychiatric disorders due to risk of hallucinations, agitation, and suicidal ideation.
Concomitant use with alcohol or CNS depressants may enhance sedative effects and increase risk of respiratory depression.
Patients should be monitored closely for signs of orthostatic hypotension which can lead to falls or syncope.
Dose-dumping may occur if capsules are crushed or chewed, leading to increased side effects.
Not interchangeable with other amantadine products due to differing extended-release profiles.
Overdose can be fatal with symptoms including severe agitation, hallucinations, seizures, and respiratory compromise.
Avoid use in individuals with hypersensitivity to amantadine or its components.
Use with caution in patients prone to low blood pressure or fainting episodes.

Contraindication

Hypersensitivity to amantadine or any component of Gocovri formulation.
Severe renal impairment or end-stage renal disease (CrCl <15 mL/min/1.73 m^2).
Recent administration (within 14 days) of a live attenuated nasal influenza vaccine (FluMist).
Known history of hypersensitivity or allergic reactions to amantadine including hives or anaphylaxis.
Patients with a history of neuroleptic malignant syndrome triggered by dopamine antagonists or withdrawal.
Conditions where anticholinergic properties may be contraindicated, such as narrow-angle glaucoma if uncontrolled.
Use in combination with other amantadine-containing products due to risk of toxicity.
Presence of severe congestive heart failure without close medical supervision.

Drug Interactions

Concomitant use with other CNS depressants or sedatives (e.g., opioids, benzodiazepines) may potentiate sedation and respiratory depression.
Glaucoma medications may interact, requiring monitoring for increased intraocular pressure.
Sodium bicarbonate-containing medicines can alkalinize urine, reducing renal clearance of amantadine, increasing toxicity risk.
Anticholinergic drugs may potentiate additive side effects including dry mouth, urinary retention, and confusion.
Stimulants such as caffeine or ADHD medications may exacerbate side effects or increase risk of agitation.
Concurrent use with levodopa/carbidopa is common but requires monitoring for enhanced dopaminergic side effects.
Alcohol increases risk of CNS adverse effects including sudden sleep episodes and dizziness.
Drugs that affect renal function or compete for renal tubular secretion may alter amantadine clearance.
Other dopaminergic agents may have additive effects increasing risk for hallucinations and dyskinesias.
Use with sodium bicarbonate may require dose adjustment due to changes in renal elimination.
Potential interaction with medications that prolong QT interval has not been extensively studied; caution advised.
No significant hepatic metabolism reduces likelihood of cytochrome P450 mediated drug interactions.
Use caution when co-administering with antipsychotics or drugs with central anticholinergic activity.

Preparations Of The Drug

Gocovri extended-release capsules containing amantadine hydrochloride, available in 137 mg and 274 mg strengths.
Capsules formulated for once-daily oral administration at bedtime to optimize therapeutic effects.
Capsules designed with sustained-release beads to ensure controlled 24-hour drug release and plasma concentration.
No immediate-release amantadine formulations are interchangeable with Gocovri due to differing pharmacokinetics.
Packaging includes child-resistant bottles with clear dosing instructions to prevent accidental ingestion.
Storage recommendation: Keep at room temperature, protected from moisture, heat, and light.
Capsules should be swallowed whole or the contents sprinkled on a small amount of applesauce for patients with swallowing difficulties.
Not recommended for crushing, chewing, or dividing to prevent dose dumping and adverse effects.
No oral liquids or injectable forms available under the Gocovri brand for Parkinson’s disease treatment.
Prescribed only by healthcare professionals experienced in Parkinson’s disease management.