Antiparkinsonian / antiviral (NMDA antagonist)
Amantadine is a medicine used in Parkinson disease, notably to treat dyskinesias (involuntary movements) in patients treated with levodopa and "off" episodes (return of symptoms between doses). It also has antiviral activity (influenza A), although current use focuses on Parkinson disease.
Also known as: Amantadina, Symmetrel
Memantine + amantadine: NMDA antagonists in combination — use with caution.
The FDA memantine label documents that the combination with other NMDA antagonists (amantadine, ketamine, dextromethorphan) should be avoided (section 7.1), given the risk of additive effects on the glutamatergic system. Memantine is a moderate-affinity NMDA antagonist used in Alzheimer disease; amantadine is a weak non-competitive NMDA antagonist used in Parkinson disease — the sum of the two may potentiate central adverse effects such as confusion, hallucinations, drowsiness and psychomotor impairment. The combination is possible in patients with overlapping dementia and Parkinson, but should be avoided or used with active monitoring. In the presence of signs of central toxicity, reduce or stop one of the drugs.
Memantine + amantadine: additive NMDA antagonism — avoid the combination (risk of central toxicity).
The FDA memantine label documents: "Use with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and such use should be approached with caution" (7.1). Amantadine, used in Parkinson disease, shares NMDA antagonism with memantine — possible additive CNS effects.
Monitor mental status changes and extrapyramidal effects.
Confusion, hallucinations or worsening of parkinsonian symptoms with the combination.
Use with caution; monitor confusion, hallucinations and CNS effects in the combination.
DailyMed/FDA (NIH/NLM) — approved Memantine label (section 7.1): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a3350f7d-2e51-4e1a-a6d0-c4f87ea99a56 ; approved Amantadine label (GOCOVRI): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bee0631-0028-1314-e063-6394a90aaaed
FDA label (GOCOVRI, 7.4): concomitant use with alcohol is not recommended, as it may increase the potential for CNS effects (dizziness, confusion, lightheadedness, orthostatic hypotension) and may result in dose-dumping (rapid release of the extended-release formulation).
Avoid alcohol during treatment with amantadine (extended-release).
DailyMed/FDA (NIH/NLM) — approved Amantadine label (GOCOVRI), section 7.4: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bee0631-0028-1314-e063-6394a90aaaed
FDA label (GOCOVRI, 4/8.6): contraindicated in end-stage renal disease (creatinine clearance < 15 mL/min/1.73 m²). Amantadine is excreted essentially unchanged in the urine — renal impairment accumulates the drug and increases the risk of toxicity.
Contraindicated in end-stage renal disease; in moderate/severe renal impairment (CrCl 15-59 mL/min), reduce the dose (68.5 mg/day in severe).
DailyMed/FDA (NIH/NLM) — approved Amantadine label (GOCOVRI), sections 4/8.6: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bee0631-0028-1314-e063-6394a90aaaed
FDA label (GOCOVRI, 8.1): no adequate data on the developmental risk in pregnant women; animal studies suggest a potential risk of fetal harm — adverse developmental effects (embryolethality, increased malformations, reduced fetal weight) at clinically relevant doses in rats and mice.
Potential risk of fetal harm based on animal data; use only if benefit justifies risk.
Amantadine is excreted into human milk (amounts not quantified) and may alter milk production or excretion (8.2).
Not specifically documented in the label (no 8.3 section with requirements).
DailyMed/FDA (NIH/NLM) — approved Amantadine label (GOCOVRI), section 8 Use in Specific Populations: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2bee0631-0028-1314-e063-6394a90aaaed ; Prontuário Terapêutico do INFARMED (11th ed., 2012) — Annex 2, Drugs and Breastfeeding: Toxicity has been reported in the infant; avoid.
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Antiparkinsonian/antidyskinetic: the efficacy in Parkinson disease dyskinesias and "off" episodes has no fully clarified mechanism; amantadine is a weak uncompetitive antagonist of the NMDA receptor, with no direct anticholinergic activity in animals, but with anticholinergic-like and dopaminergic-like side effects in humans (FDA label 12.1).
Weak uncompetitive antagonism of the NMDA receptor (glutamate); indirect effects on dopaminergic neurons. Inhibition of transporters (OCT2/MATE) explains the increased exposure to substrates such as metformin (see 173).
Extended-release form (GOCOVRI): median Tmax ~12 h (range 6-20 h) after bedtime dose; steady state by day 4; accumulation ratio 1.2-1.3. High-fat, high-calorie meal does not affect pharmacokinetics; no effect of sprinkling on applesauce (12.3).
Eight metabolites identified in urine; the quantified N-acetylated compound accounts for 0-15% of the administered dose; contribution to efficacy/toxicity is unknown (12.3).
Mean plasma half-life at steady state of approximately 16 hours; IV volume of distribution 3-8 L/kg; protein binding ~67% (0.1-2.0 µg/mL).
