AMANTADINE HYDROCHLORIDE
Clinical safety rating: caution
Amantadine hydrochloride is an antiviral agent primarily used for prophylaxis and treatment of influenza A, though its use is limited by resistance. It also serves as an antiparkinsonian agent to manage drug-induced extrapyramidal symptoms and Parkinson's disease, and is used off-label for fatigue in multiple sclerosis.
Amantadine hydrochloride is an antiviral and antiparkinsonian agent. Its antiviral mechanism involves inhibition of the M2 ion channel of influenza A virus, preventing viral uncoating and replication. In Parkinson's disease, it increases dopamine release and inhibits dopamine reuptake, and also acts as an NMDA glutamate receptor antagonist, reducing excitotoxicity.
| Metabolism | Amantadine is primarily excreted unchanged in urine via glomerular filtration and tubular secretion. It undergoes minimal hepatic metabolism, with no major cytochrome P450 involvement. |
| Excretion | Renal: 90% unchanged drug via glomerular filtration and tubular secretion; minor fecal (<5%) and biliary elimination. |
| Half-life | Terminal elimination half-life: 10-14 hours in young adults; up to 34 hours in elderly (due to age-related decline in renal function); prolonged in renal impairment (up to 7 days in anuria). |
| Protein binding | Approximately 67% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | 3-10 L/kg, indicating extensive tissue distribution (e.g., brain, lungs, erythrocytes). |
| Bioavailability | Oral bioavailability: 86-90% after immediate-release formulation; steady-state achieved within 4-7 days. |
| Onset of Action | Oral: 48-72 hours for antiparkinsonian effects; intravenous: within minutes for antiviral effect (not typical). |
| Duration of Action | Antiparkinsonian effects persist for 24-36 hours after single dose; requires twice-daily dosing for steady state. |
For parkinsonism/drug-induced extrapyramidal symptoms: initial 100 mg twice daily; may increase to 300-400 mg/day in divided doses if needed. For influenza A treatment/prophylaxis in adults: 200 mg once daily or 100 mg twice daily; initiate prophylaxis as early as possible and continue for at least 10 days post-exposure.
| Dosage form | CAPSULE |
| Renal impairment | CrCl 30-50 mL/min: 200 mg on day 1, then 100 mg once daily. CrCl 15-29 mL/min: 200 mg on day 1, then 100 mg every other day. CrCl <15 mL/min or on hemodialysis: 200 mg every 7 days. Adjust based on clinical response and tolerability. |
| Liver impairment | No specific dosage adjustment required in hepatic impairment, but use with caution due to potential central nervous system effects. |
| Pediatric use | Influenza A treatment/prophylaxis: children 1-9 years: 4.4-8.8 mg/kg/day (max 150 mg/day) in 1-2 divided doses; 9-12 years: 100 mg twice daily; ≥12 years: adult dosing. Not routinely recommended due to widespread resistance. |
| Geriatric use | Initiate at 100 mg once daily or lower, considering age-related decline in renal function; titrate slowly with careful monitoring for adverse CNS effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies have shown teratogenic and embryotoxic effects at high doses, but well-controlled human studies are lacking. Consider alternative therapies if feasible.
| FDA category | Animal |
| Placental transfer | Amantadine crosses the placenta; fetal concentrations may approach maternal levels. The clinical significance of this transfer is not fully understood. |
| Breastfeeding |
■ FDA Black Box Warning
None
| Common Effects | Nausea, Dizziness, Insomnia, Anxiety, Hallucinations, Confusion, Livedo reticularis, Peripheral edema, Dry mouth, Constipation, Orthostatic hypotension |
| Serious Effects | Neuroleptic malignant syndrome, suicidal ideation/behavior, severe hallucinations/psychosis, seizures, heart failure exacerbation, serotonin syndrome (when combined with serotonergic agents), and severe skin reactions. |
["Hypersensitivity to amantadine or any component of the formulation","Severe uncontrolled psychiatric disorder (relative)"]
| Precautions | ["Risk of suicidality, especially in patients with a history of psychiatric disorders","May exacerbate seizure disorder; use with caution in epilepsy","Can cause orthostatic hypotension, dizziness, and blurred vision, impairing ability to drive or operate machinery","Neuroleptic malignant syndrome (NMS) has been reported with dose reduction or discontinuation","Renal function impairment requires dose adjustment; accumulation can cause toxicity","Elderly patients are more susceptible to CNS effects"] |
Loading safety data…
| Amantadine is excreted into breast milk; milk-to-plasma ratio (M/P) approximately 0.7-1.0 (based on single case, M/P 1.0 at 200 mg/day). Infant serum concentrations up to 6% of maternal therapeutic levels reported. Potential for anticholinergic effects and extrapyramidal symptoms in nursing infant. AAP recommends caution; weight benefits vs. risks. |
| Teratogenic Risk | First trimester: Human data limited; animal studies (rat, rabbit) at doses 2-3 times human therapeutic dose showed increased fetal malformations (cardiovascular, skeletal). Second and third trimesters: No controlled data; case reports of preeclampsia, premature labor, and fetal distress with use near term. FDA Pregnancy Category C. |
| Fetal Monitoring | Maternal: Liver function tests (LFTs) and renal function at baseline and periodically; ECG for QT prolongation risk; psychiatric and neurologic status (dyskinesias, confusion, hallucinations). Fetal/neonatal: For third trimester use, monitor for preterm labor, fetal distress via non-stress test (NST) or biophysical profile (BPP); neonatal observation for extrapyramidal symptoms, lethargy, and respiratory depression. |
| Fertility Effects | Based on animal studies, no significant impairment of fertility in rats or rabbits at human therapeutic doses. Human data insufficient; no reports of decreased fertility in women or men. Theoretical concern for anticholinergic effects on cervical mucus or ejaculatory function, but not documented. |
| Food/Dietary | Avoid alcohol and caffeine; alcohol may increase CNS depression, caffeine may exacerbate insomnia and nervousness. No specific food restrictions. |
| Clinical Pearls | For Parkinson's disease, start at 100 mg twice daily; increase gradually to 100 mg TID or QID if needed. In elderly or renal impairment, reduce dose. Avoid abrupt discontinuation to prevent neuroleptic malignant syndrome. Monitor for orthostatic hypotension, livedo reticularis, and peripheral edema. Can worsen psychosis in patients with dementia. For influenza A, start within 48 hours of symptoms; not a substitute for vaccination. Use with caution in patients with seizure disorders or heart failure. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly without consulting your doctor. · May cause dizziness or blurred vision; avoid driving until you know how this medicine affects you. · Avoid alcohol as it may increase side effects like dizziness. · Notify your doctor if you experience swelling in your legs or ankles, a lacy purple skin rash, or confusion. · If you miss a dose, take it as soon as you remember unless it is close to your next dose; do not double up. · Wear sunscreen and protective clothing; amantadine may make your skin more sensitive to sunlight. · Do not take this medicine for influenza unless directed by a doctor; it is not a substitute for the flu vaccine. |