Symmetrel

Adamantane Antivirals
Anti-Parkinson Agents, NMDA Receptor Antagonists

Immediate-release capsules or tablets (e.g., Symmetrel):
May be administered without regard to meals.
 
Extended-release capsules (e.g., Gocovri):
Not interchangeable with other extended-release amantadine products.
Can be taken with or without food.
Patients should swallow the extended-release capsules whole. They should not crush, chew, or divide capsules.
If needed, may be administered by carefully opening and sprinkling the entire contents of capsule on a small amount (teaspoonful) of soft food, such as cool applesauce. The drug/food mixture should be swallowed immediately without chewing. Do not store mixture for future use.
Missed dose: If a dose is missed, it is recommended to skip the missed dose. The next dose should be taken as scheduled.
 
Extended-release tablets (e.g., Osmolex ER):
May be administered without regard to meals.
Swallow tablets whole; do not chew, crush, or divide tablets.
Osmolex ER has a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell is eliminated from the body; patients should not be concerned if they occasionally notice the tablet shell in their stool.

Oral solution:
Administer using a calibrated measuring device to ensure accurate dosing.

suicidal ideation / Delayed / 0-3.0
heart failure / Delayed / 0.1-1.0
corneal opacification / Delayed / 0.1-1.0
visual impairment / Early / 0.1-1.0
seizures / Delayed / 0-0.1
coma / Early / Incidence not known
cardiac arrest / Early / Incidence not known
pulmonary edema / Early / Incidence not known
arrhythmia exacerbation / Early / Incidence not known
keratitis / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
agranulocytosis / Delayed / Incidence not known
neuroleptic malignant syndrome / Delayed / Incidence not known

hallucinations / Early / 1.0-21.0
peripheral edema / Delayed / 1.0-16.0
orthostatic hypotension / Delayed / 1.0-13.0
constipation / Delayed / 1.0-13.0
depression / Delayed / 1.0-6.0
livedo reticularis / Delayed / 1.0-6.0
ataxia / Delayed / 1.0-5.0
confusion / Early / 1.0-5.0
blurred vision / Early / 0-4.0
dystonic reaction / Delayed / 0-3.0
cataracts / Delayed / 0-3.0
psychosis / Early / 0.1-1.0
amnesia / Delayed / 0.1-1.0
dysarthria / Delayed / 0.1-1.0
euphoria / Early / 0.1-1.0
dyspnea / Early / 0.1-1.0
hypertension / Early / 0.1-1.0
corneal edema / Early / 0.1-1.0
urinary retention / Early / 0.1-1.0
leukopenia / Delayed / 0-0.1
neutropenia / Delayed / 0-0.1
mania / Early / Incidence not known
hypertonia / Delayed / Incidence not known
delirium / Early / Incidence not known
dysphagia / Delayed / Incidence not known
impulse control symptoms / Delayed / Incidence not known
sudden sleep onset / Delayed / Incidence not known
tachypnea / Early / Incidence not known
sinus tachycardia / Rapid / Incidence not known
edema / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
withdrawal / Early / Incidence not known
antimicrobial resistance / Delayed / Incidence not known

dizziness / Early / 5.0-16.0
xerostomia / Early / 1.0-16.0
insomnia / Early / 5.0-10.0
nausea / Early / 5.0-10.0
infection / Delayed / 0-10.0
anxiety / Delayed / 1.0-7.0
headache / Early / 1.0-6.0
drowsiness / Early / 1.0-5.0
abnormal dreams / Early / 1.0-5.0
agitation / Early / 1.0-5.0
irritability / Delayed / 1.0-5.0
fatigue / Early / 1.0-5.0
diarrhea / Early / 1.0-5.0
anorexia / Delayed / 1.0-5.0
paranoia / Early / 0-3.0
cough / Delayed / 0-3.0
vomiting / Early / 0.1-3.0
xerophthalmia / Early / 0-3.0
arthralgia / Delayed / 0-3.0
muscle cramps / Delayed / 0-3.0
hyperkinesis / Delayed / 0.1-1.0
weakness / Early / 0.1-1.0
photosensitivity / Delayed / 0.1-1.0
rash / Early / 0.1-1.0
libido decrease / Delayed / 0.1-1.0
tremor / Early / Incidence not known
paresthesias / Delayed / Incidence not known
libido increase / Delayed / Incidence not known
mydriasis / Early / Incidence not known
skin hyperpigmentation / Delayed / Incidence not known
fever / Early / Incidence not known
diaphoresis / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
leukocytosis / Delayed / Incidence not known

GOCOVRI, Osmolex ER, Symmetrel

Rx

Synthetic antiviral agent with dopamine agonist properties
Used primarily for motor symptoms of Parkinson's disease (PD) or drug-induced EPS; an extended-release product can be used as an adjunct to carbidopa-levodopa in PD patients experiencing 'off' episodes
Not recommended by CDC for treatment or prophylaxis of influenza A infection due to resistant strains

137 mg PO once daily at bedtime, initially. After 1 week, increase to the recommended dose of 274 mg PO once daily at bedtime. Cautious dosing based on renal function is recommended in geriatric patients. SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE AMANTADINE PRODUCTS: Gocovri is not interchangeable with other products. DISCONTINUATION: Rapid dose reduction or withdrawal may cause adverse reactions. If discontinuing after more than 4 weeks of use, the dose should be reduced by half for the final week of dosing, if possible.

100 mg PO twice daily for monotherapy in younger adults. For geriatric adults, patients with serious medical illness, or those receiving other antiparkinsonian drugs: 100 mg PO once daily for 1 to several weeks, then increase to the usual dose of 100 mg PO twice daily. If loss of effectiveness occurs, benefit may be regained by increasing the dose to 300 mg/day in divided doses. Alternatively, a drug holiday period of several weeks may be helpful; then dosing may be reinitiated with improved effectiveness. Max: Rarely, a patient may require up to 400 mg/day PO in divided doses, but closely monitor.

Initially, 129 mg PO once daily in the morning. May increase dose at weekly intervals as needed. Max: 322 mg/day PO (administered as a 129 mg and 193 mg ER tablet given once daily in the morning). SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Osmolex ER is not interchangeable with other products. For patients unable to tolerate more than 100 mg/day of immediate-release amantadine, there is no equivalent dose/regimen of amantadine ER tablets. DISCONTINUATION: Do not discontinue abruptly. Reduce the dose gradually from higher doses to 129 mg/day for 1 to 2 weeks before discontinuing.

137 mg PO once daily at bedtime, initially. After 1 week, increase to the recommended dose of 274 mg PO once daily at bedtime. Cautious dosing based on renal function is recommended in geriatric patients. SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Gocovri is not interchangeable with other products. DISCONTINUATION: Rapid dose reduction or withdrawal may cause adverse reactions. If discontinuing after more than 4 weeks of use, the dose should typically be reduced by half for the final week of dosing, if possible.

100 mg PO twice daily. Occasionally, patients with drug-induced EPS may require up to 300 mg/day PO in divided doses, but patients receiving more than 200 mg/day should be monitored closely.

100 mg PO once daily, initially. May titrate to 100 mg PO twice daily. Occasionally, patients with drug-induced EPS may require up to 300 mg/day PO in divided doses, but patients receiving more than 200 mg/day should be monitored closely.

129 mg PO once daily in the morning, initially. May increase at weekly intervals as needed. Max: 322 mg/day PO (administered as a 129 mg and 193 mg ER tablet given once daily in the morning). SWITCHING FROM IMMEDIATE- OR EXTENDED-RELEASE (ER) AMANTADINE PRODUCTS: Osmolex ER is not interchangeable with other products. For patients unable to tolerate more than 100 mg/day of immediate-release amantadine, there is no equivalent dose/regimen of amantadine ER tablets. DISCONTINUATION: Do not discontinue abruptly. Reduce the dose gradually from higher doses to 129 mg/day for 1 to 2 weeks before discontinuing.

200 mg/day PO, given as a single dose or in 2 divided doses. Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve. Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

100 mg PO once daily. Start treatment as soon as possible and continue for 24 to 48 hours after the disappearance of signs and symptoms. Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

100 mg PO twice daily. Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve. Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

4.4 to 8.8 mg/kg/day PO, given in 2 divided doses (Max: 150 mg/day). Start treatment as soon as possible and continue for 24 to 48 hours after the symptoms resolve. Initiation of treatment within 48 hours of illness onset confers the greatest benefit; however, antiviral therapy started after 48 hours may still be beneficial in severe, complicated, progressive illness or hospitalized patients. The CDC recommends against use due to resistance.

200 mg/day PO, given as a single dose or 2 divided doses. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given. The CDC recommends against use due to resistance.

100 mg PO once daily. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given. The CDC recommends against use due to resistance.

100 mg PO twice daily. Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given. The CDC recommends against use due to resistance.

4.4 to 8.8 mg/kg/day PO, given in 2 divided doses (Max: 150 mg/day). Start prophylaxis in anticipation of an outbreak or before or after known exposure and continue for at least 10 days after a known exposure. If used with the influenza virus vaccine, continue for 2 to 4 weeks after the vaccine has been given. The CDC recommends against use due to resistance.

Dosage not FDA-approved. 300 to 400 mg/day PO, divided and given in 3 to 4 divided doses, has been studied. If needed, the dose may be slowly titrated over 3 to 4 days at initiation to minimize adverse effects. Amantadine was evaluated in 2 randomized, placebo-controlled crossover trials, each with 2 weeks of active treatment. One trial demonstrated that amantadine 300 mg/day (n = 24) improved coordination, balance, and mental alertness in 19 of 24 subjects (p = 0.006). After treatment, significant increases in quality of life scores occurred with amantadine (3.9 +/- 0.7) compared to placebo (2.95 +/- 0.7, p less than 0.001). Chorea severity of 6 body parts, judged blindly by investigators via video of subjects, did not change significantly. During the second trial, maximum chorea severity, as measured by the Unified Huntington's Disease Rating Scale, significantly decreased by 18% (p = 0.0007) among subjects who received amantadine 400 mg/day (n = 22). Wide variations in antichoreic effects were noted among subjects. The long-term efficacy of amantadine for the treatment of Huntington's chorea is unknown.

Dosage not established. 100 mg PO twice daily is the commonly used dosage from clinical trials. The results of trials with amantadine have been of varied design, have included low numbers of participants and have been of short study durations (3 and 6 weeks); patients have reported inconsistent improvements in fatigue, but documentation of positive impact on daily function and life-quality are lacking. Despite these limitations, amantadine is the only oral treatment that is recommended by clinical guidelines for MS-related fatigue.

Several case reports have documented marked improvements in symptoms associated with neuroleptic malignant syndrome (NMS). Amantadine 100 mg PO twice daily has been used for as long as 3 weeks.

†Indicates off-label use

Amantadine is primarily excreted in the urine unchanged. Dosage adjustments do not appear to be necessary for immediate-release products. Recommendations for the extended-release capsules or tablets are not available.

Immediate-release capsules, oral solution, or tablets in adults (e.g., Symmetrel):
CrCl greater than 50 mL/minute: No dosage adjustment needed.
CrCl 30 to 50 mL/minute: 200 mg PO for 1st day, then reduce dose to 100 mg PO daily.
CrCl 15 to 29 mL/minute: 200 mg PO for 1st day, then reduce dose to 100 mg PO on alternate days.
CrCl less than 15 mL/minute: 200 mg every 7 days.
 
Extended-release capsules in adults (e.g., Gocovri):
CrCl 60 mL/minute or greater: No dosage adjustment needed.
CrCl 30 to 59 mL/minute: 68.5 mg PO once daily at bedtime. Increase if needed after 1 week to a maximum of 137 mg once daily at bedtime.
CrCl 15 to 29 mL/minute: 68.5 mg PO once daily at bedtime.
CrCl less than 15 mL/minute: Use is contraindicated.
 
Extended-release tablets in adults (e.g., Osmolex ER):
CrCl 60 mL/minute or greater: No dosage adjustment needed.
CrCl 30 to 59 mL/minute: 129 mg PO once every 48 hours initially. May increase every 3 weeks up to a maximum of 322 mg once every 48 hours.
CrCl 15 to 29 mL/minute: 129 mg PO once every 96 hours initially. May increase every 4 weeks up to a maximum of 322 mg once every 96 hours.
CrCl less than 15 mL/minute: Use is contraindicated.
 
Intermittent hemodialysis
Amantadine is inefficiently removed by hemodialysis.
Immediate-release capsules, oral solution, or tablets (e.g., Symmetrel): 200 mg PO every 7 days in adults.
Extended-release capsules (e.g., Gocovri) or tablets (e.g., Osmolex ER): Use is contraindicated in patients with end-stage renal disease.

Acetaminophen; Aspirin, ASA; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Acetaminophen; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Acetaminophen; Caffeine; Pyrilamine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like amantadine, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
Amitriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Amoxapine: (Moderate) Medications with significant anticholinergic activity, like amoxapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Amphetamine; Dextroamphetamine Salts: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur.
Aspirin, ASA; Butalbital; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Aspirin, ASA; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. (Moderate) Additive anticholinergic effects and drowsiness may be seen when orphenadrine is used concomitantly with amantadine.
Atropine: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Atropine; Difenoxin: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. (Moderate) Concomitant administration of amantadine and diphenoxylate/difenoxin may cause an additive decrease in GI motility and should be used cautiously.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects.
Benzphetamine: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur.
Benztropine: (Moderate) Additive anticholinergic effects may be seen when benztropine is used concomitantly with other drugs that possess anticholinergic properties, such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of amantadine may produce additive effects.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of amantadine may produce additive effects.
Budesonide; Glycopyrrolate; Formoterol: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Bupropion: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution.
Bupropion; Naltrexone: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution.
Butalbital; Acetaminophen; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended. (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Caffeine; Sodium Benzoate: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Carbidopa; Levodopa: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
Carbidopa; Levodopa; Entacapone: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
Chlordiazepoxide; Amitriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Chlordiazepoxide; Clidinium: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as clidinium, may potentiate the anticholinergic effects of amantadine.
Chlorpromazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Clomipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Clozapine: (Moderate) Medications with significant anticholinergic activity, such as clozapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Codeine; Phenylephrine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Codeine; Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Cyclobenzaprine: (Moderate) Amantadine exhibits significant anticholinergic activity. Medications with significant anticholinergic activity, like cyclobenzaprine, may potentiate the anticholinergic effects of amantadine and may increase the risk of antimuscarinic-related side effects, including constipation and urinary retention.
Darifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with amantadine.
Desipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Dextromethorphan; Bupropion: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution.
Dextromethorphan; Quinidine: (Minor) Concomitant administration of quinidine with amantadine has been shown to decrease the renal clearance of amantadine. An in vivo study demonstrated that quinidine, a known organic cation transporter inhibitor, reduced amantadine clearance by approximately 33% in humans. The proposed mechanism is inhibition of the renal tubular secretion of amantadine, but the mechanism appears to be independent of OCT2 or other known renal drug transporters. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects.
Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when dicyclomine is used concomitantly with other drugs that possess anticholinergic properties, such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
Diethylpropion: (Moderate) Careful observation is required when amantadine is administered concurrently with central nervous system (CNS) stimulants. An increase in stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias may occur.
Diphenoxylate; Atropine: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. (Moderate) Concomitant administration of amantadine and diphenoxylate/difenoxin may cause an additive decrease in GI motility and should be used cautiously.
Disopyramide: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as disopyramide, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Donepezil: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine.
Donepezil; Memantine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events. (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine.
Doxepin: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Ergotamine; Caffeine: (Major) Amantadine used concomitantly with psychostimulants, such as caffeine, can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Ethanol: (Major) Advise patients to avoid alcohol while taking amantadine. Concomitant use with alcohol may increase the potential for CNS effects such as dizziness, confusion, lightheadedness, and orthostatic hypotension. In addition, if the patient is using amantadine extended-release (ER), alcohol use may result in amantadine dose-dumping and toxicity.
Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as amantadine may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
Flavoxate: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Fluphenazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Galantamine: (Moderate) The therapeutic benefits of cholinesterase inhibitors may be diminished when co-administered with drugs known to exhibit anticholinergic properties like amantadine.
Glycopyrrolate: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Glycopyrrolate; Formoterol: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Haloperidol: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since haloperidol is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy.
Homatropine; Hydrocodone: (Major) Significant systemic absorption has been reported in some cases with ocular homatropine. The anticholinergic effects of homatropine may be enhanced when combined with other drugs that possess antimuscarinic properties.
Hyoscyamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects.
Imipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Indacaterol; Glycopyrrolate: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Levodopa: (Minor) Amantadine can increase the efficiency of levodopa by its action on central nerve terminals.
Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer the intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 48 hours after administration of amantadine, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, amantadine may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with amantadine. Consult currently recommended guidance on the use of antiviral drugs against influenza.
Loxapine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since loxapine is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy.
Maprotiline: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as maprotiline, may potentiate the anticholinergic effects of amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
Memantine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
Methamphetamine: (Moderate) Amantadine used concomitantly with psychostimulants can result in increased stimulant effects, such as nervousness, irritability, or insomnia, and can lead to seizures or cardiac arrhythmias. Close monitoring of the patient is recommended.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects.
Methscopolamine: (Major) Additive anticholinergic effects may be seen when methscopolamine is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Methylphenidate Derivatives: (Moderate) Use of amantadine with methylphenidate derivatives, which are CNS stimulants, requires careful observation. Coadministration may increase the risk of stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias.
Metoclopramide: (Major) Metoclopramide is a central dopamine antagonist and can antagonize the actions of dopamine agonists such as amantadine. In addition, metoclopramide may cause extrapyramidal reactions (e.g., acute dystonic reactions, pseudo-parkinsonism, akathisia, tardive dyskinesia), and rarely, neuroleptic malignant syndrome. The manufacturer of metoclopramide does not specifically contraindicate the use of metoclopramide and dopamine agonists; however, coadministration should be avoided if possible.
Modafinil: (Moderate) Use of amantadine with modafinil, a CNS stimulant, requires careful observation. Coadministration may increase the risk of stimulant effects, such as nervousness, irritability, insomnia, tremor, seizures, or cardiac arrhythmias.
Molindone: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since molindone is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy.
Neostigmine; Glycopyrrolate: (Major) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other drugs that possess antimuscarinic properties, such as amantadine.
Nortriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Olanzapine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
Olanzapine; Fluoxetine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
Olanzapine; Samidorphan: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as olanzapine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
Orphenadrine: (Moderate) Additive anticholinergic effects and drowsiness may be seen when orphenadrine is used concomitantly with amantadine.
Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when oxybutynin is used concomitantly with drugs with moderate to significant anticholinergic effects such as amantadine. Clinicians should note that anticholinergic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. With many of the listed agents, additive drowsiness may also occur when combined with oxybutynin.
Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving anticholinergic agents. Coadministration of pentazocine with amantadine may result in additive anticholinergic effects, such as urinary retention and constipation.
Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving anticholinergic agents. Coadministration of pentazocine with amantadine may result in additive anticholinergic effects, such as urinary retention and constipation.
Perphenazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Perphenazine; Amitriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine. (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs that possess antimuscarinic effects. (Major) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as atropine, may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects.
Phenothiazines: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Pimozide: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since pimozide is a dopamine antagonist, this drug should be avoided when possible in patients with Parkinson's disease who require amantadine therapy.
Prochlorperazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Promethazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Promethazine; Dextromethorphan: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Promethazine; Phenylephrine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Propantheline: (Major) Additive anticholinergic effects may be seen when propantheline is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Protriptyline: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Quinidine: (Minor) Concomitant administration of quinidine with amantadine has been shown to decrease the renal clearance of amantadine. An in vivo study demonstrated that quinidine, a known organic cation transporter inhibitor, reduced amantadine clearance by approximately 33% in humans. The proposed mechanism is inhibition of the renal tubular secretion of amantadine, but the mechanism appears to be independent of OCT2 or other known renal drug transporters. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects.
Rivastigmine: (Moderate) Concurrent use of amantadine and rivastigmine should be avoided if possible. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Amantadine may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of rivastigmine.
Scopolamine: (Major) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other antimuscarinics, such as amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
Sedating H1-blockers: (Moderate) Medications with significant anticholinergic activity may potentiate the anticholinergic effects of amantadine, and may increase the risk of antimuscarinic-related side effects. Additive drowsiness may also occur.
Solriamfetol: (Moderate) Monitor for dopamine-mediated effects including nausea, vomiting, dizziness, tremor, and changes in moods or behaviors if solriamfetol, a central dopamine and norepinephrine reuptake inhibitor, is administered with other dopaminergic drugs, such as amantadine. Caution is recommended since this combination has not been evaluated.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid concurrent use of amantadine and trimethoprim. A single case of toxic delirium has been reported after coadministration of trimethoprim and amantadine. Amantadine is an OCT2 substrate and trimethoprim is an OCT2 inhibitor.
Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.
Thioridazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Thiothixene: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since thiothixene is a dopamine antagonist, this drug is best avoided when possible in patients with Parkinson's disease who require amantadine therapy.
Tolterodine: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like tolterodine are used concomitantly with other drugs with moderate to significant anticholinergic effects such as amantadine. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Triamterene: (Minor) Use caution. Triamterene can reduce the renal clearance of amantadine, with subsequent increased amantadine serum concentrations. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects.
Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Use caution. Triamterene can reduce the renal clearance of amantadine, with subsequent increased amantadine serum concentrations. The clinical significance is not known. Monitor for possible side effects of amantadine, including dizziness, confusion, nausea/vomiting, xerostomia, and anticholinergic effects.
Tricyclic antidepressants: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Trifluoperazine: (Moderate) Although the mechanism of amantadine is not clear, it may potentiate the actions of dopamine. Since phenothiazines are dopamine antagonists, these drugs are best avoided when possible in patients with Parkinson's disease who require amantadine therapy. Also, the anticholinergic effects of phenothiazines can be additive to those of amantadine.
Trihexyphenidyl: (Moderate) Amantadine may exhibit anticholinergic activity, as may trihexyphenidyl. These drugs are not commonly used together. Both trihexyphenidyl and amantadine have significant anticholinergic activity and the combination may increase the risk of anticholinergic-related side effects. Clinicians should note that such effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation. Monitor for effects such as confusion, constipation, dizziness, difficulty with urination, dry mouth and eyes, and changes in vision.
Trimethoprim: (Major) Avoid concurrent use of amantadine and trimethoprim. A single case of toxic delirium has been reported after coadministration of trimethoprim and amantadine. Amantadine is an OCT2 substrate and trimethoprim is an OCT2 inhibitor.
Trimipramine: (Moderate) Additive anticholinergic effects and CNS effects may be seen when tricyclic antidepressants are used concomitantly with amantadine.
Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and amantadine are used concomitantly. In addition, some drugs which are actively secreted by the kidney, such as amantadine, may interact with trospium by competing for renal tubular secretion, further enhancing the possibility for anticholinergic side effects. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.

Amantadine/Amantadine Hydrochloride/Symmetrel Oral Cap: 100mg
Amantadine/Amantadine Hydrochloride/Symmetrel Oral Sol: 5mL, 50mg
Amantadine/Amantadine Hydrochloride/Symmetrel Oral Tab: 100mg
GOCOVRI Oral Cap ER: 68.5mg, 137mg
Osmolex ER Oral Tab ER: 129mg, 193mg, 258mg

400 mg/day PO for immediate-release capsules, oral solution, or tablets; 274 mg/day PO for extended-release capsules; 322 mg/day PO for extended-release tablets.

400 mg/day PO for immediate-release capsules, oral solution, or tablets; 274 mg/day PO for extended-release capsules; 322 mg/day PO for extended-release tablets.

Immediate-release capsules, oral solution or tablets: 200 mg/day PO.
Extended-release capsules or tablets: Safety and efficacy have not been established.

9 years and older: 200 mg/day PO for immediate-release capsules, oral solution, or tablets. Safety and efficacy of extended-release capsules and tablets have not been established.
1 to 8 years: 8.8 mg/kg/day PO or 150 mg/day PO, whichever is less for immediate-release capsules, oral solution, or tablets. Safety and efficacy of extended-release capsules and tablets have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

The mechanism by which amantadine exerts an effect in the treatment of dyskinesia associated with Parkinson's disease or as an adjunct to carbidopa; levodopa in patients with Parkinson's disease experiencing 'off' episodes is unknown. Antiparkinsonian actions are unrelated to the antiviral effects. Amantadine is a weak, uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. In addition, the drug may have direct or indirect effects on dopamine neurons. It may release dopamine and norepinephrine from storage sites and inhibit the reuptake of dopamine and norepinephrine. Overall, amantadine is less effective than levodopa but can offer specific benefits such as in patients with levodopa-induced dyskinesia. Anticholinergic-like side effects have been reported and are usually more prominent in elderly patients.
 
As an antiviral, amantadine can inhibit viral replication within viral-infected cells. Amantadine appears to block the uncoating of the virus particle and subsequent release of viral nucleic acid into the host cell. This process is thought to be caused by interference with fusion of the virion coat to vacuolar membranes. Amantadine also may interfere with penetration of the cell wall by adsorbed virus. To prevent a viral infection, the drug should be present before exposure to the virus, but, if given within 24 to 48 hours of onset of symptoms, the influenza may be less severe. However, the CDC recommends against using for influenza A due to resistance in circulating strains. As in recent past seasons, there continues to be high levels of resistance (more than 99%) to adamantane agents such as amantadine among influenza A viruses. Therefore, amantadine is not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses. Check for current information on the CDC website.

Amantadine is administered orally as immediate-release or extended-release formulations. The extended-release tablet (e.g., Osmolex ER) consists of an immediate-release outer layer and an extended-release core. The extended-release capsule (e.g., Gocovri) contains extended-release pellets within the capsule. Amantadine crosses the blood-brain barrier and distributes into tears, saliva, and nasal secretions. Protein binding is not clinically significant (about 67%). Some data suggest potential extravascular distribution. Amantadine is primarily excreted as the parent compound in the urine via glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for up to 15% of the administered dose in multiple studies. The contribution of this metabolite to the efficacy or toxicity of amantadine is not known. The average elimination half-life in adult patients with normal renal function is about 17 hours. Acidifying the urine increases the rate of excretion.
 
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: None

Amantadine is well absorbed orally. Bioavailability is 86% in the elderly and greater than 90% in young adults. Maximum plasma concentrations of the immediate-release formulation are directly related to doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum concentrations. The pharmacokinetics of the extended-release capsules and extended-release tablets are dose proportional with therapeutic dosing. The average time to peak plasma concentrations of the immediate-release formulation is about 3 hours (range: 1.5 to 8 hours). After a single bedtime dose of the extended-release capsule, the median time to maximum plasma concentrations is about 12 hours (range: 6 to 20 hours). Peak concentrations of the extended-release tablets occur in a median time of 7.5 hours (range: 5.5 to 12 hours). Steady-state concentrations of immediate-release amantadine following daily dosing are obtained in 2 to 4 days. Steady-state concentrations of the extended-release capsules are achieved 4 days after dose initiation. Administration with food does not alter the kinetics of amantadine; therefore, the various products may be administered without regard to meals.

There are no adequate data regarding the developmental risk associated with the use of amantadine during pregnancy. Based on available data, amantadine may have the potential to cause fetal harm; therefore, use during pregnancy should be avoided unless the potential benefits outweigh the possible risks to the fetus. Fetal malformations (Tetralogy of Fallot, tibial hemimelia, cardiovascular malformations) have been noted in 2 cases where normal doses of amantadine were used by the mother in the first trimester of human pregnancy. Published animal studies also suggest a potential risk for fetal harm with amantadine. In mice and rats, adverse developmental effects (embryolethality, increased incidence of malformations, and reduced fetal body weight) were observed when amantadine was administered to pregnant animals at clinically relevant doses.

Amantadine may potentially alter breast milk production or excretion, a factor which should be taken into account when considering the use of amantadine in breast-feeding mothers. Amantadine is excreted in human milk. Amantadine is a dopamine agonist and at usual prescribed doses may inhibit lactation. In published studies, amantadine reduced serum prolactin levels and the symptoms of galactorrhea in patients taking neuroleptic drugs. The effect of amantadine on milk supply has not been evaluated in nursing mothers. Manufacturers of immediate-release amantadine recommend against use of amantadine during breast-feeding. Consider the use of alternatives based on indication for use. Oseltamivir and zanamivir are preferred alternatives to amantadine for the prophylaxis or treatment of influenza A during breast-feeding, due to resistant strains and other clinical factors. However, patient factors, local susceptibility patterns, and specific microbial susceptibility should be assessed before choosing an alternative. The developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for amantadine and any potential adverse effects on the breast-fed infant from drug treatment or from the underlying maternal condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.