Amantadine


Article Author:
Carol Chang


Article Editor:
Kamleshun Ramphul


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Patrick Le
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Saad Nazir
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Muhammad Hashmi
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Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
12/5/2018 9:10:47 PM

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 levels of resistance have emerged recently, initially from Asia and now to North America. As of 2011, the CDC does not recommend treatment or prophylaxis of influenza A due to the high levels of resistance.[1][2][3]

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

Besides, the 2 FDA-approved usages of amantadine; there are a few other diseases that can benefit from amantadine. Clinical trials have conflicting results for 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. 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 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. [4]

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.

Administration

FDA Approved

Amantadine is typically administered orally once daily or in divided doses depending on the indication. There is also amantadine syrup available. For the treatment of influenza A, amantadine 200 mg daily or 100 mg twice daily should be administered within 24 to 48 hours after onset of symptoms. It 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, amantadine is also given orally 100 mg twice daily and increased to 200 mg twice daily as needed. For patients taking other parkinsonian drugs, dosing should begin at 100 mg once daily.

Non-FDA Approved

Huntington chorea: 100 mg oral 3 to 4 times daily

Multiple sclerosis-related fatigue: 100 mg oral twice daily, increasing to 200 mg twice daily as needed

Restless leg syndrome: 100 mg oral daily, increasing to 300 mg per day as needed

Traumatic brain injury: 100 mg oral 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. Reduce the dose by half for one week before discontinuing.

Clearance of amantadine is greatly reduced in elderly patients and patients with renal impairment. Dose modification should be considered in such cases.

Adverse Effects

The main advantage to 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 should be monitored especially with the elderly. Patients should be cautioned 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 needed in 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 has a renal excretion, so the extended release formula is contraindicated in patients with the end-stage renal disease. Due to the possible anticholinergic side effects, patients with glaucoma or prostate hypertrophy should use with caution.

Amantadine is drug category C for pregnancy. Teratogenic events have been observed in humans and multiple animal reproduction studies. Another antiparkinsonian agent should be used for patients with Parkinson disease. 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 benefits of the drug to the mother before starting the drug.

Monitoring

When administering amantadine, renal monitor function, mental status, such as depression/suicidality and psychosis, and blood pressure. Those with seizure disorders should be monitored for seizure activity. Patients with heart failure should be watched for increase water retention and lower leg edema. Liver enzymes should be monitored in patients with liver disease as an irreversible elevation in transaminases has been reported.[5][6]

  • Renal function: Elevation in Cr 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 with Parkinson disease and 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 important to know patient's history of mental illness and seizures before proceeding with therapy. 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.

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 or primary care providers who prescribe this agent should closely monitor the patient for adverse effects. In addition, the patient's renal function and mental status must be monitored. Amantadine can increase the risk of depression and lower the threshold for seizures. Irreversible changes in the liver have been reported and hence liver enzymes need to be monitored at the same time.


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Amantadine - Questions

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A 55-year old male with new-onset Parkinson disease is started on a drug and comes back a few weeks later with ataxia, slurred speech, hallucinations, and dizziness. He wants to know if this is a side effect of the drug or a worsening of Parkinson disease. The symptoms are most likely a result of which of the following?



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Which of the following drugs is frequently associated with livedo reticularis?



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A 77 year old female with Parkinson disease has had a progression of symptoms. Her tremor has become particularly debilitating. Amantadine has been added to the medication regimen. Which of the following is not a side effect of amantadine?



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What is the mechanism of action of amantadine?



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Which of the following medications blocks the penetration and uncoating of influenza A virus?



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Amantadine - References

References

Naderi S,Faghih H,Aqamolaei A,Mortazavi SH,Mortezaei A,Sahebolzamani E,Rezaei F,Akhondzadeh S, Amantadine as adjuvant therapy in the treatment of moderate to severe OCD: a double blind randomized trial with placebo control. Psychiatry and clinical neurosciences. 2018 Nov 28     [PubMed]
Dragašević-Mišković N,Petrović I,Stanković I,Kostić VS, Chemical management of levodopa-induced dyskinesia in Parkinson's disease patients. Expert opinion on pharmacotherapy. 2018 Nov 9     [PubMed]
Machado-Alba JE,Calvo-Torres LF,Gaviria-Mendoza A,Castrillón-Spitia JD, [Prescribing patterns of antiparkinson drugs in a group of Colombian patients, 2015]. Biomedica : revista del Instituto Nacional de Salud. 2018 Sep 1     [PubMed]
Okigbo AA,Helkowski MS,Royes BJ,Bleimeister IH,Lam TR,Bao GC,Cheng JP,Bondi CO,Kline AE, Dose-dependent neurorestorative effects of amantadine after cortical impact injury. Neuroscience letters. 2018 Nov 22     [PubMed]
Sreedharan M,Devadathan K,Pathan HK,Chalipat S,Mohammed KPA, Amantadine for the Treatment of Refractory Absence Seizures in Children. Journal of pediatric neurosciences. 2018 Apr-Jun     [PubMed]
Isaacson SH,Fahn S,Pahwa R,Tanner CM,Espay AJ,Trenkwalder C,Adler CH,Patni R,Johnson R, Parkinson's Patients with Dyskinesia Switched from Immediate Release Amantadine to Open-label ADS-5102. Movement disorders clinical practice. 2018 Mar-Apr     [PubMed]

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