amantadine (Rx)

>10%

Extended-release capsule (Gocovri)

• Hallucinations (21%)
• Dizziness (16%)
• Dry mouth (16%)
• Peripheral edema (16%)
• Constipation (13%)
• Fall (13%)
• Orthostatic hypotension (13%)

1-10%

Extended-release capsule (Gocovri)

• Urinary tract infection (10%)
• Nausea (8%)
• Anxiety (7%)
• Insomnia (7%)
• Livedo reticularis (6%)
• Contusion (6%)
• Depression/depressed mood (6%)
• Headache (6%)
• Benign prostate hyperplasia (6%)
• Decreased appetite (6%)
• Abnormal dreams (4%)
• Blurred vision (4%)
• Cough (3%)
• Pigmentation disorder (3%)
• Dystonia (3%)
• Confusional state (3%)
• Vomiting (3%)
• Gait disturbance (3%)
• Cataract (3%)
• Dry eye (3%)
• Joint swelling (3%)
• Muscle spasms (3%)

Immediate-release tablet/capsule or syrup

• 5-10%

  • Nausea
  • Dizziness/lightheadedness
  • Insomnia

• 1-5%

  • Depression
  • Anxiety and irritability
  • Hallucinations
  • Confusion
  • Anorexia
  • Dry mouth
  • Constipation
  • Ataxia
  • Livedo reticularis
  • Peripheral edema
  • Orthostatic hypotension
  • Headache
  • Somnolence
  • Nervousness
  • Dream abnormality
  • Agitation
  • Dry nose
  • Diarrhea
  • Fatigue

<1%

Immediate-release tablet/capsule or syrup

• Congestive heart failure
• Psychosis
• Urinary retention
• Dyspnea
• Skin rash
• Vomiting
• Weakness
• Slurred speech
• Euphoria
• Thinking abnormality
• Amnesia
• Hyperkinesia
• Hypertension
• Decreased libido
• Visual disturbance
• Corneal edema
• Decreased visual acuity
• Sensitivity to light
• Optic nerve palsy
• Convulsion
• Leukopenia
• Neutropenia
• Eczematoid dermatitis
• Suicide/ suicide ideation

Postmarketing Reports

Extended-release capsule (Gocovri)

• Seizures

Contraindications

Tablet, syrup, capsule

• Hypersensitivity to amantadine, rimantadine
• Untreated narrow-angle glaucoma
• Breastfeeding

Extended-release capsule or tablet

• End-stage renal disease (CrCl<15 mL/min/1.73m²)

Cautions

Reports of falling asleep while engaged in activities of daily living (eg, operation of motor vehicles); patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event; advise patients of the potential to develop drowsiness

Avoid abrupt withdrawal; abrupt discontinuation of amantadine may cause an increase in symptoms of Parkinson disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech

In clinical trials, suicidal ideation, depression, and/or depressed mood were reported; monitor for depression, including suicidal ideation or behavior

Tablet, syrup, capsule

• Since 2008-09 influenza season, Centers for Disease Control and Prevention (CDC) advises against use for treatment or prophylaxis of influenza in US
• Reports of congestive heart failure (CHF), peripheral edema, and hypotension with amantadine; monitor patients with history of CHF, peripheral edema, and/or orthostatic hypotension
• Amantadine may accumulate in the plasma and body when renal function declines; see Dosing Considerations
• Rare instances of reversible elevation of liver enzymes have been reported in patients receiving amantadine, though the mechanism is unknown
• History of seizures, eczematoid rash, severe psychosis or psychoneurosis
• Consider reducing anticholinergic dosages before initiating amantadine therapy
• Risk of neuroleptic malignant syndrome (NMS) with dosage reduction or withdrawal; management of NMS should include intensive symptomatic treatment, medical monitoring, and treatment of any concomitant serious medical problems for which specific treatments are available
• Possibility of reduced effectiveness after several months; may regain efficacy if dosage is increased

Extended-release capsule or tablet

• Patients with a major psychotic disorder should ordinarily not be treated with amantadine because of the risk of exacerbating psychosis; observe patients for the occurrence of hallucinations throughout treatment, especially at initiation and after dose increases
• In controlled clinical trials, patients experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness or hypotension; monitor patients for dizziness and orthostatic hypotension, especially after starting amantadine extended-release or increasing the dose

Parkinson patients

• Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and inability to control these urges while taking one or more of the medications, including amantadine, that increase central dopaminergic tone
• May be linked to higher melanoma risk; monitor for melanomas frequently and on a regular basis when using amantadine for any indication; periodic skin examinations should be performed by appropriately qualified individuals

Drug interactions overview

• Extended-release capsules or tablets

  • Products with anticholinergic properties may potentiate anticholinergic-like side effects of amantadine, reduce dose of anticholinergic drugs or of extended-release amantadine if atropine-like effects appear when these drugs are used concurrently
  • Since excretion rate of amantadine increases rapidly when urine is acidic, coadministration of urine acidifying drugs may increase elimination of amantadine from the body; alterations of urine pH towards the alkaline condition may lead to drug accumulation with a possible increase in adverse reactions; monitor for efficacy or adverse reactions under conditions that alter the urine pH to more acidic or alkaline, respectively
  • Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines; live vaccines are not recommended during treatment; inactivated influenza vaccines may be used, as appropriate
  • Concomitant use with alcohol is not recommended, as it may potentiate central nervous system effects (eg, somnolence, dizziness, confusion, lightheadedness, and orthostatic hypotension)

Pregnancy

No adequate data on developmental risk associated with amantadine use in pregnant women; animal studies suggest a potential risk for fetal harm with amantadine; in mice and rats, adverse developmental effects (embryo lethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals at clinically relevant doses

In mice, oral administration of amantadine (0, 10, or 40 mg/kg/day) to pregnant animals during organogenesis (gestation days 7-12) resulted in embryo lethality and reduced fetal body weight at highest dose tested, which was associated with maternal toxicity; the no-effect dose for developmental toxicity in mice (10 mg/kg/day) is less than the recommended human dose (RHD) of 274 mg/day, based on body surface area (mg/m²)

Lactation

Amantadine is excreted into human milk, but amounts have not been quantified; there is no information on the risk to a breastfed infant; amantadine may alter breast milk production or excretion

In published studies, amantadine reduced serum prolactin levels and symptoms of galactorrhea in patients taking neuroleptic drugs; the effect of amantadine on milk supply has not been evaluated in nursing mothers

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Antiviral

• The mechanism of antiviral activity is unknown; appears to primarily prevent the release of infectious viral nucleic acid into the host cell by interfering with transmembrane domain of viral M2 protein; amantadine is also known to prevent viral assembly during replication and inhibits replication of influenza A virus isolates from each of the subtypes (ie, H1N1, H2N2 and H3N2), but has very little or no activity against influenza B virus isolates

Parkinson disease

• The exact mechanism of amantadine in the treatment of Parkinson disease, drug-induced extrapyramidal reactions, dyskinesia associated with Parkinson disease is not known; amantadine is a weak, noncompetitive NMDA receptor antagonist
• Data from early animal studies suggest that amantadine may have direct and indirect effects on dopamine neurons; amantadine may have direct and indirect effects on dopamine neurons; it exerts dopaminergic-like side effects (eg, hallucinations and dizziness) in humans; although amantadine has not been shown to possess direct anticholinergic activity, clinically, it exhibits anticholinergic-like side effects (eg, dry mouth, urinary retention, and constipation)

Absorption

Bioavailability: 86-90%

Onset: Within 48 hr (antidyskinetic)

Peak plasma time: 2-4 hr (capsule, tablets, syrup); 12 hr (extended-release capsule)

Peak plasma concentration : 0.24 mcg/mL (100-mg single dose); 328 ng/mL (129-mg single extended-release tablet dose)

AUC : 20-30% higher (steady-state for single ER capsule dose); 8263 ng·hr/mL (129-mg single extended-release tablet dose)

Distribution

Protein bound: 67%

Vd: 1.5-6.1 L/kg (capsule, tablet, syrup); 3-8 L/kg (IV administration)

Metabolism

Not appreciably metabolized; small amounts of acetyl metabolite identified

Elimination

Half-life: 16 hr

Clearance: 0.2-0.3 L/hr/kg (capsule, tablet, syrup); 0.27 L/hr/kg (capsule, ER)

Excretion: Urine (80-90% unchanged) by glomerular filtration and tubular secretion

Excretion, extended-release tablets: Urine (85% [unchanged]; 0-15% (N-acetylated compound)

Metabolism accounts for 5-18% total clearance of amantadine

Urine pH reported to influence excretion rate of amantadine

Oral Administration

Administer daily dose in 2 divided doses to decrease adverse CNS effects

Administer 2nd dose several hours before bedtime to minimize insomnia

Amantadine immediate- or extended-release products are not interchangeable

Extended-release capsule

Administer with or without food

Swallow capsule whole; do not crush, chew, or divide capsules

Missed dose: Take next dose as scheduled

• Unable to swallow capsule

  • Administer by carefully opening and sprinkling the entire contents on small amount (teaspoonful) of soft food, such as applesauce; drug/food mixture should be swallowed immediately without chewing
  • Do not store mixture for future use

Extended-release tablet

• Swallow capsule whole
• Do not chew, crush, or divide tablets; administered without regard to food
• Missed dose: Take next dose as scheduled

Storage

All formulations: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)