Continuing Education Activity

Amantadine is an antiviral agent with mild antiparkinsonian activity. Amantadine was used in the early 2000s for Influenza A treatment. However, high levels of resistance have emerged recently, initially from Asia and now in North America. As of 2011, the CDC does not recommend treatment or prophylaxis of influenza A due to the high levels of resistance. Amantadine is now used mostly for Parkinson disease. This activity outlines the indications, contraindications, activity, adverse drug reactions, warning, precautions, toxicity, and limitations of amantadine in the clinical setting as relates to the essential points necessary for members of an interprofessional team managing the care of patients with Parkinson disease.

Objectives:

• Identify the proper indications for amantadine therapy.
• Describe the mechanism of action of amantadine.
• Review the potential adverse effects of amantadine.
• Outline the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care when dosing amantadine to improve patient outcomes for Parkinson patients.

Indications

Amantadine is an antiviral agent with mild antiparkinsonian activity. Amantadine was used in the early 2000s for Influenza A treatment. A 2006 meta-analysis showed that the drug decreased influenza symptoms by one day and decreased the severity of fever and other symptoms. However, high resistance levels have emerged recently, initially from Asia and now in North America. As of 2011, the CDC does not recommend treatment or prophylaxis of influenza A due to the high resistance levels.[1] 

Amantadine is now used mostly for Parkinson disease. Clinical trials have shown that amantadine decreases bradykinesia, rigidity, and tremor symptoms. There is a combined synergistic effect with added levodopa, which is converted to dopamine by striatal enzymes in the CNS. There can be a transient benefit to the drug, so short-term therapy for patients with the mild disease is best.[2][3]

Besides the two FDA-approved usages of amantadine, a few other diseases can benefit from amantadine. Clinical trials have conflicting results for the reduction of chorea in Huntington disease. The 2012 American Academy of Neurology guidelines suggests amantadine is likely effective in decreasing chorea, although the degree of effect is unknown.[4] Amantadine is a first-line agent for fatigue in multiple sclerosis. Amantadine may be useful in restless leg syndrome. However, data is limited to a small clinical trial. Amantadine has also been used in traumatic brain injuries. Initial studies had suggested that it may promote functional recovery. A clinical trial in 2012 concluded amantadine accelerated the pace of functional recovery in patients with severe traumatic brain injuries. However, there were no significant differences in overall improvement compared with the placebo group.

FDA-labeled Indications

• Parkinson disease: Drug-induced extrapyramidal reactions
• Influenza A: Prophylaxis and treatment

Non-FDA Approved Indications

• Huntington disease: Chorea
• Multiple sclerosis: Fatigue
• Restless leg syndrome
• Traumatic brain injuries

Mechanism of Action

The mechanism of action of amantadine is uncertain. Antiviral activity primarily interferes with viral replication. Amantadine disrupts the transmembrane domain of the viral M2 protein, which prevents infectious viral nucleic acid entry into the host cell. It may also inhibit the assembly of influenza A virus isolates from each of the subtypes (H1N1, H2N2, and H3N2) during replication. Influenza B has a structurally different M2 protein, which makes amantadine ineffective.[5]

In the treatment of Parkinson disease, studies have shown amantadine acts on dopamine neurons. Amantadine is a weak, non-competitive antagonist of the NMDA receptor, which increases dopamine release and prevents dopamine reuptake. Although amantadine does not have anticholinergic activity, there may be anticholinergic side effects such as dry mouth, urinary retention, and constipation clinically.[6][7]

Administration

Dosage Formulation

• Amantadine hydrochloride oral capsules and oral tablets: 100 mg
• Amantadine hydrochloride oral capsule ER 24 Hour: 68.5 mg, 137 mg
• Amantadine hydrochloride oral syrup: 50 mg / 5 mL
• Amantadine hydrochloride oral tablet ER 24 Hour: 129 gm, 193 mg, 258 gm

FDA Approved

Amantadine is typically administered orally once daily or in divided doses depending on the indication. 

• For the treatment of influenza A, amantadine 200 mg daily or 100 mg twice daily should be administered within 24 to 48 hours after the onset of symptoms and should be continued for 24 to 48 hours after the symptoms have resolved. For prophylaxis, patients should continue treatment for the entirety of the influenza season.

• For the treatment of Parkinson disease, amantadine is also given orally at 100 mg twice daily and increased to 200 mg twice daily as needed. Dosing should begin at 100 mg once daily for patients taking other parkinsonian drugs.

Non-FDA Approved

• Huntington chorea: 100 mg orally three to four times daily.

• Multiple sclerosis-related fatigues: 100 mg orally twice daily, increasing to 200 mg twice daily as needed.

• Restless leg syndrome: 100 mg orally daily, increasing to 300 mg per day as needed.

• Traumatic brain injury: 100 mg orally twice daily, increasing to 200 mg twice daily as needed.

Discontinuation of Therapy

It is important not to discontinue amantadine abruptly as it can cause neuroleptic malignant syndrome-like symptoms, such as high fever, tachycardia, muscle rigidity, and altered mental status. Instead, reduce the dose by half for one week before discontinuing.

Patients with Renal Impairment

The clearance of amantadine greatly diminishes in elderly patients and patients with renal impairment. Therefore, dose modification merits consideration in such cases. Depending upon Kidney function (creatinine clearance), the following dosage adjustments are recommended.

Creatinine clearance (mL/min/1.73m): Dose for Amantadine hydrochloride IR capsules

• If CrCL 30 to 50 mL/min: 200 mg on 1st day and followed by 100 mg each day after that.
• If CrCL 15 to 29mL/min: 200 mg 1st day and followed by 100 mg on alternate days.
• If CrCL 15 mL/min or lesser: 200 mg every seven days.
• If patients are on hemodialysis: 200 mg every seven days.

Patients with Hepatic Impairment

Exercise caution when amantadine is used in patients with liver diseases. There are rare reports on the reversible elevation of AST, ALT, and other liver enzymes in patients using amantadine. Although this relationship is not established, care needs to be taken when used in patients with pre-existing hepatic impairment.[8]

Pediatric Considerations

There is a lack of safety and efficacy data on amantadine in infants below the age of one year.

Geriatric Considerations

Amantadine is primarily excreted in the urine; it accumulates in the plasma and the body if renal function is declined. Hence the dose of amantadine should be decreased in individuals 65 years of age or older patients or patients with renal impairment. The dose of amantadine may need a reduction in patients with peripheral edema, congestive heart failure, or orthostatic hypotension.

Adverse Effects

The main advantage of amantadine is that it has a low side effect profile. The primary adverse effects of amantadine may include orthostatic hypotension, syncope, peripheral edema, dizziness, delusions, hallucinations, falls, xerostomia, and constipation. Although livedo reticularis is a less common side effect, amantadine is one of the best-known drugs to cause it. This side effect is reversible with the withdrawal of medication. Serious adverse effects include neuroleptic malignant syndrome, psychosis, suicidal ideation, and CNS depression. Central nervous system (CNS) depression requires monitoring, especially in the elderly. Providers should caution patients against activities that require physical and mental alertness, such as driving and avoid combination with other CNS depressing agents, such as alcohol. Caution with usage and dosage adjustments may be necessary for those with heart disease, seizure disorder, hepatic impairment, and renal impairment.[2]

Contraindications

Amantadine is contraindicated in patients with hypersensitivity to the drug or components of the formulation. The drug undergoes renal excretion, so the extended-release dosage form is contraindicated in patients with end-stage renal disease. Due to the possible anticholinergic side effects, patients with glaucoma or prostate hypertrophy should use with caution.

Amantadine is an FDA category C for pregnancy. Researchers have observed teratogenic events in multiple animal reproduction studies. Clinicians should select another antiparkinsonian agent for pregnant patients with Parkinson disease unless the benefits outweigh the risks. Amantadine is present in breast milk. It can influence the production and excretion of breast milk. Physicians should properly advise and weigh out the risk of infant exposure, the benefits of breastfeeding, and the benefits of the drug to the mother before starting the medication.[9]

Monitoring

When administering amantadine, monitor blood pressure, renal function, and mental statuses, such as depression/suicidality, and psychosis. Those with seizure disorders have to be monitored for seizure activity. Patients with heart failure require vigilance for increased water retention and lower leg edema. Clinicians also need to watch liver enzymes in patients with liver disease as an irreversible elevation in transaminases has been reported.[10][11]

• Renal function: Elevation in Creatinine and BUN, reduction in GFR
• Mental status: Hallucinations, delusions, depression, suicidality
• Blood pressure: Orthostatic hypotension
• LFT: Increase in AST and ALT

There is an association between Parkinson disease and the incidence of melanoma. Patients should be closely monitored and have periodic skin examinations.

Toxicity

There currently is no minimum toxicity dose listed. The limitation for increased doses beyond 400 mg per day is due to CNS effects. It is essential to know the patient's history of mental illness and seizures before proceeding with therapy. Toxicity may manifest as acute psychosis, cardiovascular toxicity, coma, and/or death. Although there is no antidote for amantadine, side effects resolve with discontinuation of usage. Some preparations of the drug may contain propylene glycol. Large amounts of propylene glycol can potentially be toxic and cause hyperosmolality, lactic acidosis, respiratory depression, and seizures. In addition, Amantadine toxicity is a concern in patients with severe renal impairment, as 90% of the dose administered orally is excreted unchanged in the urine.[12]

Enhancing Healthcare Team Outcomes

Amantadine was once widely prescribed for Parkinson disease and even influenza. However, there are many more effective drugs on the market, and the use of amantadine has declined. Nevertheless, nurse practitioners, physician assistants, or primary care providers who prescribe this agent should closely monitor the patient for adverse effects. Also, the patient's renal function and mental status require monitoring. Amantadine can increase the risk of depression and lower the threshold for seizures, so nurses should explicitly query and search for this information on patient intake. Irreversible changes in the liver can occur, and hence liver enzymes require monitoring at the same time. Pharmacists should examine the patient's medical record, look for drug interactions, verify dosing, and express any concerns to the prescriber. With an interprofessional team approach to healthcare, amantadine therapy can be most effective in those cases where it is still useful, and other agents can substitute for it with a collaborative assessment of the patient's needs and regimen. [Level V]