Side Effects of Amantadine
Amantadine causes CNS side effects in approximately 13% of patients at standard dosing (200 mg/day), which is significantly higher than placebo (4%) and includes nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness. 1
Common Side Effects (5-10% incidence)
The most frequently reported adverse reactions at recommended doses include: 2
- Nausea
- Dizziness (lightheadedness)
- Insomnia
Less Common Side Effects (1-5% incidence)
- Depression, anxiety, and irritability
- Hallucinations and confusion
- Anorexia and dry mouth
- Constipation
- Ataxia
- Livedo reticularis
- Peripheral edema
- Orthostatic hypotension
- Headache and somnolence
- Nervousness and dream abnormalities
- Agitation
- Dry nose and diarrhea
- Fatigue
Gastrointestinal Effects
Gastrointestinal side effects (nausea and anorexia) occur in approximately 1-3% of persons taking amantadine, which is comparable to placebo rates of 1%. 1
Serious Side Effects and High-Risk Populations
Serious CNS toxicity can occur, particularly in high-risk patients, and includes marked behavioral changes, delirium, hallucinations, agitation, and seizures. 1
High-Risk Populations for Severe Side Effects:
These severe reactions are associated with high plasma drug concentrations and occur most often in: 1
- Patients with renal insufficiency (90% of amantadine is excreted unchanged in urine) 3
- Patients with seizure disorders
- Patients with certain psychiatric disorders
- Older persons taking 200 mg/day for prophylaxis
Dosage reduction in these populations significantly reduces the incidence and severity of side effects. 1
Cardiovascular and Respiratory Toxicity
In acute overdosage, serious complications include: 2
- Cardiac arrest and arrhythmias (including malignant arrhythmias)
- Tachycardia and hypertension
- Acute respiratory failure and pulmonary edema
- Adult respiratory distress syndrome (ARDS)
Anticholinergic Effects
Amantadine has anticholinergic effects and can cause mydriasis; it should not be used in patients with untreated angle-closure glaucoma. 1
Other anticholinergic manifestations include: 2
- Urinary retention
- Visual disturbances (punctate subepithelial corneal opacity, corneal edema, decreased visual acuity, light sensitivity, optic nerve palsy)
Rare but Serious Effects (<0.1-1% incidence)
- Convulsions
- Leukopenia and neutropenia
- Suicidal ideation, suicide attempts, and completed suicide
- Neuroleptic malignant syndrome
- Psychosis and oculogyric episodes
- Congestive heart failure
Time Course and Reversibility
Most side effects are mild and cease soon after discontinuing the drug; they can also diminish or disappear after the first week despite continued use. 1
However, abrupt discontinuation may precipitate: 2
- Delirium, agitation, and delusions
- Hallucinations and paranoid reactions
- Stupor, anxiety, and depression
- Slurred speech
Clinical Pitfalls and Monitoring
A critical pitfall is failing to adjust dosing in renal insufficiency—amantadine toxicity can occur at drug levels usually not associated with severe presentations when renal function is impaired. 3
Key monitoring considerations:
- Assess renal function before initiating therapy 3
- Monitor for early CNS symptoms (nervousness, insomnia, difficulty concentrating) 4
- Be aware that subtle cognitive effects (decreased performance on sustained attention tasks) may occur even without gross symptoms 4
- Consider that visual hallucinations may indicate toxicity, especially with concurrent renal impairment 5
Drug Interactions
Anticholinergic agents (such as diphenhydramine) may exacerbate amantadine's CNS effects and should be used cautiously in combination. 6