Is amantadine FDA (Food and Drug Administration) approved for TBI (traumatic brain injury)?

Is Amantadine FDA Approved for TBI?

No, amantadine is not FDA-approved for traumatic brain injury (TBI). Amantadine is FDA-approved only for influenza A prophylaxis and treatment, and for Parkinson's disease, but its use in TBI represents off-label prescribing despite widespread clinical utilization. 1, 2, 3

FDA-Approved Indications vs. TBI Use

• The FDA has approved amantadine exclusively for influenza A prevention and treatment in specific age groups, with detailed dosing recommendations for children aged 1-9 years (4.4-8.8 mg/kg/day, not exceeding 150 mg/day) and children ≥10 years (200 mg/day). 1
• No FDA approval exists for amantadine in any brain injury indication, including TBI, disorders of consciousness, or cognitive enhancement following neurological trauma. 2, 3
• The widespread clinical use of amantadine in TBI rehabilitation settings is based on "inferred belief systems" rather than regulatory approval or robust evidence. 4

Evidence Base for Off-Label TBI Use

Conflicting Research Findings

• A 2024 meta-analysis of 6 RCTs (426 patients) found amantadine improved Glasgow Coma Scale scores at day 7 (MD 1.50; 95% CI 0.08-2.92; p=0.038) and Mini Mental State Examination scores (MD 3.23; 95% CI 0.53-5.94; p=0.019), but showed no benefit for Disability Rating Scale, length of stay, or mechanical ventilation duration. 5
• Contradictory evidence from a 2018 multi-site RCT (119 patients with chronic TBI) demonstrated that amantadine 100 mg twice-daily did not improve cognition and may actually impede cognitive processing in the first 28 days (statistically significant differences favoring placebo for General Cognitive Index, p=0.002, and Learning Memory Index, p=0.001). 4
• A comprehensive 2020 review of 119 clinical studies concluded that most research supporting amantadine in brain injury involves very small populations with limited significance, small effect sizes, and inconsistent responses, with the "phenotype of responders remaining elusive." 2

Clinical Practice Guidelines

• The 2021 American Academy of Sleep Medicine guidelines suggest using armodafinil or modafinil (not amantadine) for hypersomnia secondary to TBI, with conditional recommendations based on moderate-quality evidence. 1
• Several clinical practice guidelines/recommendations have encouraged amantadine use in TBI, but these are based on limited evidence rather than FDA approval. 3

Critical Safety Considerations for Off-Label TBI Use

Dose-Dependent Toxicity in Vulnerable Populations

• The maximum daily dose for persons aged ≥65 years must not exceed 100 mg (not the standard 200 mg/day) due to dose-dependent CNS toxicity, with elderly women at particularly high risk due to smaller body size. 1, 6, 7
• Amantadine causes CNS side effects (nervousness, anxiety, insomnia, difficulty concentrating, lightheadedness) in approximately 13% of patients at 200 mg/day versus 4% with placebo. 1, 6
• Serious CNS toxicity—including marked behavioral changes, delirium, hallucinations, agitation, and seizures—occurs most often in patients with renal insufficiency, seizure disorders, psychiatric disorders, or elderly patients taking 200 mg/day. 1, 6

Renal Function Monitoring

• Approximately 90% of amantadine is excreted unchanged in urine; renal clearance is substantially reduced in renal insufficiency, requiring mandatory dose reduction when creatinine clearance is ≤50 mL/min/1.73m². 1, 6, 7
• Renal function declines with age, necessitating dose reduction in all elderly patients regardless of measured creatinine clearance. 1, 6, 7
• Hemodialysis contributes minimally to amantadine clearance, complicating management in dialysis patients. 1

Practical Algorithm for Off-Label TBI Use (If Considered)

Pre-Treatment Assessment

• Verify renal function (creatinine clearance) before initiating amantadine in any patient, especially those ≥65 years or with TBI-related complications. 6, 7
• Screen for contraindications: untreated angle-closure glaucoma (amantadine causes mydriasis), active seizure disorder without anticonvulsant coverage, severe psychiatric illness. 1, 6

Dosing Strategy

• Start at 100 mg/day maximum (not 200 mg/day) for elderly patients, those with any renal impairment, seizure history, or psychiatric history. 6, 7
• Consider further reduction below 100 mg/day for elderly women, patients with creatinine clearance 10-50 mL/min, or those with multiple risk factors. 1, 6, 7
• For patients with creatinine clearance <10 mL/min, consult package insert for specific dosing adjustments. 1

Monitoring Protocol

• Monitor closely for CNS toxicity (confusion, hallucinations, agitation) especially during the first week of treatment, as side effects may diminish after the first week despite continued use. 1, 6
• Observe patients with seizure disorders closely for increased seizure activity. 1, 6
• Reduce dose or discontinue immediately if serious side effects emerge; most adverse effects are mild and cease soon after discontinuation. 1, 6

Common Pitfalls to Avoid

• Do not use standard adult dosing (200 mg/day) in elderly TBI patients—this is the most common error leading to preventable CNS toxicity. 1, 6, 7
• Do not assume normal renal function in elderly or critically ill TBI patients without formal creatinine clearance calculation. 6, 7
• Do not expect consistent cognitive benefits based on the conflicting evidence; the 2018 RCT showed potential early cognitive impairment rather than improvement. 4
• Do not overlook the lack of FDA approval when obtaining informed consent or documenting off-label use. 2, 3
• Do not combine amantadine with other CNS-stimulating or anticholinergic drugs (e.g., bromocriptine) without recognizing additive toxicity risk. 6