Many adverse reactions associated with amantadine involve the central nervous system (CNS). Two of the most frequent (5% to 10%) adverse events reported during clinical trials of immediate-release amantadine were dizziness and insomnia. Instruct patients to avoid arising suddenly from a seated or lying position and to inform their prescribing physician if dizziness or lightheadedness occurs. Less frequent (1% to 5%) CNS adverse events observed in clinical trials of immediate-release amantadine included anxiety, ataxia, agitation, confusion, depression, drowsiness or fatigue, hallucinations, headache, irritability, nervousness, and abnormal dreams. Cases of abnormal thinking, amnesia, dysarthria or slurred speech, euphoria, hyperkinesis, psychosis, and weakness were reported in 0.1% to 1% of patients. Rare (less than 0.1%) but potentially serious CNS adverse events included oculogyric episodes, suicidal ideation, suicide attempts, and completed suicides. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following CNS or related effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: dizziness (16%), headache (6%), dystonic reaction (3%), hallucinations (21%), anxiety (7%), insomnia (7%), depression (6%), abnormal dreams (4%), confusion (3%), gait disturbance (3%), falls (13%), and contusion (6%). Less than 3% of patients experienced somnolence, fatigue, suicidal ideation or attempt, apathy, delusions, illusions, and paranoia. Many of these events occurred in patients receiving short courses and in patients with and without prior history of psychiatric illness. The following adverse effects led to treatment discontinuation in more patients receiving amantadine than placebo: hallucinations (8%), abnormal dreams (2%), dysphagia (2%), and gait disturbance (2%). The following events were reported more frequently in patients 65 years and older than adults younger than 65 years: hallucinations (31% vs. 10%) and falls (17% vs. 8%). Women experienced abnormal dreams more frequently than men (9% vs. 0%) while men experienced dizziness (20% vs. 11%), anxiety (11% vs. 2%), and gait disturbance (6% vs. 0%) more frequently than women. Rarely (less than 0.1%), seizures have occurred with amantadine use. The threshold for seizure activity may be decreased in patients with a history of epilepsy; therefore caution is advised when administering amantadine to these individuals. Other CNS adverse events occurring during postmarketing use of immediate-release amantadine include aggression, coma, delirium, delusions, dysphagia, EEG changes, gait abnormalities, hypertonia, hypokinesia, involuntary muscle contractions, mania, paranoia, paresthesias, stupor, and tremor. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established. Additionally, abrupt discontinuation of amantadine has been associated with adverse CNS events and may precipitate delirium, agitation, delusions, hallucinations, paranoia, stupor, anxiety, depressed state, and slurred speech.[28049] [46061] [62262] [62273] [62887]

Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. In postmarketing use of amantadine, pathologic gambling, libido increase including hypersexuality, and other impulse control symptoms have been reported. Causality due to dopaminergic agents has not been established; however, in some cases, the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving amantadine. Likewise, patients should be instructed to report such changes while receiving amantadine. Dose reduction or discontinuation should be considered in those who experience these effects.[28049] [46061] [62262] [62273] [62887]

Some patients treated with amantadine have reported sudden sleep onset. Some incidents have occurred while the patient was driving or performing other potentially hazardous activities. In some cases excessive drowsiness has resulted in auto accidents or other harmful events in the course of daily living. Sudden sleep onset has occurred as late as 1 year after the initiation of treatment, and the relation to the medication is not entirely clear. Prior to initiating treatment with amantadine, patients should be advised of the potential to develop somnolence and specifically asked about factors that may increase the risk of experiencing such an event such as concomitant use of sedating medications (coadministration with other CNS depressants), ethanol ingestion, and the presence of sleep disorders (e.g., narcolepsy, sleep apnea). Reassessment for drowsiness or oversedation is necessary throughout amantadine therapy because patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), amantadine should generally be discontinued. If a decision is made to continue the drug, patients should be advised against driving or operating heavy machinery or engaging in other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.[28049] [46061] [62273] [62262] [62887]

During clinical trial evaluation of immediate-release amantadine, the following cardiopulmonary adverse events were reported in 1% to 5% of amantadine-treated patients: peripheral edema and orthostatic hypotension. Dyspnea, hypertension, and heart failure were reported in 0.1% to 1% of amantadine-treated patients. During clinical trial evaluation of 274 mg/day of the extended-release amantadine capsules (e.g., Gocovri), the following cardiopulmonary effects were reported in at least 3% of amantadine-treated patients: peripheral edema (16%), orthostatic hypotension (13%), and cough (3%). The following adverse effects led to treatment discontinuation in more patients receiving amantadine than placebo: peripheral edema (3%) and postural syncope (2%). Orthostatic hypotension was reported more frequently in patients 65 years and older than adults younger than 65 years (8% vs. 2%). Men experienced the following effects more frequently than women: peripheral edema (19% vs. 11%) and orthostatic hypotension (7% vs. 2%). Cardiopulmonary adverse events reported during postmarketing use of immediate-release amantadine include cardiac arrest, arrhythmia exacerbation (including malignant arrhythmias), hypotension, sinus tachycardia, acute respiratory failure, pulmonary edema, and tachypnea. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[46060] [46061] [62262] [62887]

During clinical trial evaluation of immediate-release amantadine, nausea was reported in 5% to 10% of amantadine-treated patients. Adverse gastrointestinal (GI) effects reported in 1% to 5% of amantadine-treated patients included anorexia, xerostomia, constipation, dry nose, and diarrhea. Vomiting occurred infrequently (0.1% to 1%). During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following GI effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: xerostomia (16%), constipation (13%), nausea (8%), vomiting (3%), and appetite decrease (6%). Xerostomia led to treatment discontinuation in more patients receiving amantadine than placebo (3%). Women experienced nausea (13% vs. 4%) and xerostomia (22% vs. 11%) more frequently than men. Some of these events may be due to amantadine-related anticholinergic effects. Amantadine associated anticholinergic effects are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. A dose reduction may alleviate these effects in some patients. Deaths have been reported from overdose with amantadine; the lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to anticholinergic effects.[46060] [46061] [62262] [62887]

Livedo reticularis, a reticulated vascular pattern that appears as a purple lace-like skin discoloration, may occur with amantadine therapy. During clinical trial evaluation of immediate-release amantadine, livedo reticularis was reported in 1% to 5% of amantadine-treated patients. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), livedo reticularis was reported in 6% of patients treated with 274 mg/day of extended-release amantadine. Women experienced livedo reticularis more frequently than men (13% vs. 0%). Livedo reticularis can appear 1 month to 1 year from initiation of therapy, and can be an exacerbation of a preexisting condition. Livedo reticularis is believed to be caused by abnormal capillary permeability associated with peripheral vasoconstriction which results in decreased skin temperature and peripheral blood flow. Patients with peripheral edema should be closely monitored since the edema may be indicative of livedo reticularis. Dosage reduction or amantadine discontinuation may be necessary.[28049] [46061] [62262] [62273] [62887]

During clinical trial evaluation of immediate-release amantadine, diffuse, white, subendothelial or other corneal opacification was reported in 0.1% to 1% of amantadine-treated patients. After discontinuation the opacities will usually resolve within a few weeks. Other types of visual impairment experienced by 0.1% to 1% of patients in clinical trials of immediate-release amantadine included corneal edema, decreased visual acuity, photosensitivity, and optic nerve palsy. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following ophthalmic effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: blurred vision (4%), cataracts (3%), and xerophthalmia (3%). Women experienced cataracts more frequently than men (7% vs. 0%). Blurred vision (3%) led to treatment discontinuation in more patients receiving amantadine than placebo. Cases of keratitis and mydriasis have been noted during postmarketing use of immediate-release amantadine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established. Some of these events may be due to the anticholinergic effects associated with amantadine, which are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. Because of the anticholinergic side effects and the potential for mydriasis, avoid prescribing amantadine to patients with untreated angle closure glaucoma.[28049] [46061] [62262] [62273] [62887]

During clinical trial evaluation of immediate-release amantadine, rash (unspecified) was reported in 0.1% to 1% of amantadine-treated patients. Eczematoid dermatitis occurred in less than 0.1% of patients. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), skin hyperpigmentation disorder (unspecified) was reported in 3% of patients treated with 274 mg/day of extended-release amantadine. Dermatologic adverse events reported with immediate-release amantadine include pruritus and diaphoresis. Anaphylactoid reactions, including fever and edema, have also been reported during postmarketing use of immediate-release amantadine. Similar effects should be anticipated with the extended-release formulations. Melanoma has been reported postmarketing, but due to the voluntary nature of these reports, neither a frequency nor a definitive causal relationship can be established; however, studies indicated that patients with Parkinson's disease have a 2- to 6- fold higher risk of developing melanoma than the general population. The cause for this increased risk, whether due to the drug or disease, is unknown. Despite the lack of data, health care providers are advised to perform frequent skin examinations on patients receiving amantadine for any indication.[28049] [46061] [62262] [62273] [62887]

During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following adverse musculoskeletal effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: arthralgia (joint swelling 3%) and muscle spasms (muscle cramps 3%). Involuntary muscle contractions have been reported in postmarketing use of immediate-release amantadine.[28049] [46061] [62262] [62273] [62887]

During clinical trial evaluation of immediate-release amantadine, leukopenia and neutropenia were reported in less than 0.1% of amantadine-treated patients. Agranulocytosis and leukocytosis have been noted during postmarketing use of immediate-release amantadine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[28049] [46061] [62262] [62273] [62887]

During clinical trial evaluation of immediate-release amantadine, adverse genitourinary (GU) effects including urinary retention and libido decrease were reported in 0.1% to 1% of amantadine-treated patients. The anticholinergic effects of amantadine may contribute to adverse reactions such as urinary retention and aggravation of prostatic hypertrophy. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), the following adverse GU effects were reported in at least 3% of patients treated with 274 mg/day of extended-release amantadine: urinary tract infection (10%) and benign prostatic hypertrophy (6% of male patients). Amantadine associated anticholinergic effects are more likely to occur in patients with increased plasma concentrations, such as those with renal dysfunction or in the elderly. Deaths have been reported from overdose with amantadine; the lowest reported acute lethal dose was 1 gram. Acute toxicity may be attributable to anticholinergic effects.[28049] [46061] [62262] [62273] [62887]

Laboratory abnormalities noted during postmarketing use of immediate-release amantadine include elevated hepatic enzymes (i.e., ALT and AST), hyperbilirubinemia, and elevations in other laboratory tests including blood urea nitrogen (BUN), serum creatinine, alkaline phosphatase, creatine phosphokinase (CPK), gamma-glutamyltransferase (GGT), and lactate dehydrogenase (LDH). Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.[28049] [46061] [62262] [62273] [62887]

Cases of neuroleptic malignant syndrome (NMS) have been associated with amantadine dose reduction or abrupt discontinuation or withdrawal from therapy. Characteristic symptoms of NMS include hyperthermia, muscle rigidity, involuntary movements, mental status change and altered consciousness, autonomic dysfunction, sinus tachycardia, tachypnea, hypertension, hypotension, elevated creatine phosphokinase, leukocytosis, myoglobinuria, and increased serum myoglobin. Observe patients carefully for NMS symptoms during amantadine dosage reductions or when therapy is stopped abruptly as early diagnosis is important. Treatment of NMS includes medical monitoring, intensive symptomatic therapy, and treatment of concomitant serious medical problems. Despite a lack of data from controlled trials, bromocriptine and dantrolene have been used in the treatment of NMS.[28049] [46061] [62262] [62273] [62887]

Antimicrobial resistance can occur during therapy with amantadine due to the development of viral mutations. Drug effectiveness may be diminished by resistance mutations or other factors such as viral virulence. Drug susceptibility patterns should be assessed when determining appropriateness of influenza A treatment with amantadine.[28049] [46061] [62273] [62262] [62887] Current information regarding viral resistance patterns can be obtained from the U.S. Centers for Disease Control (CDC).[62315]

Amantadine is contraindicated in patients with a known amantadine hypersensitivity, rimantadine hypersensitivity, or hypersensitivity to any agent in the adamantine class.[28049] [46061] [62262]

Because amantadine is primarily excreted unchanged in the urine, patients with renal impairment require dosage adjustments. The use of the extended-release capsules (e.g., Gocovri) or extended-release tablets (e.g., Osmolex ER) is contraindicated in patients with end-stage renal disease (e.g., those with renal failure, on dialysis, or with CrCl less than 15 mL/minute). During use of the immediate-release products, dosage adjustments are required for patients with end-stage renal disease (renal failure), including those receiving dialysis. Deaths due to systemic drug accumulation have been reported in patients with renal impairment who were prescribed higher than recommended doses of amantadine for their level of renal function. Renal function should be monitored closely and the dose adjusted accordingly. Hemodialysis removes only a negligible amount of amantadine.[28049] [46061] [62262] [62273] [62887]

Patients should be monitored for dizziness and orthostatic hypotension, especially after starting amantadine or increasing the dose. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), more patients receiving amantadine experienced dizziness, syncope, orthostatic hypotension, presyncope, postural dizziness, or hypotension than patients receiving placebo. Patients with congestive heart failure or peripheral edema should also be cautiously treated with amantadine. Peripheral edema and congestive heart failure can be precipitated by amantadine, which is thought to induce a redistribution of fluid within the body rather than an increase in total body water. Peripheral edema can be preceded by or can accompany livedo reticularis and may require dose reduction or drug discontinuation.[28049] [46061] [62262] [62273] [62887]

Amantadine can increase seizure activity in patients with a seizure disorder. Patients with a history of seizures should be monitored closely when amantadine is initiated.[28049] [46061] [62273]

Patients should be monitored for depression, suicidal ideation or behavior, and hallucinations throughout treatment with amantadine. During clinical trial evaluation of the extended-release amantadine capsules (e.g., Gocovri), adverse effects including confusion, depression, depressed mood, suicidal ideation, suicide attempt, visual hallucination, auditory hallucination, delusions, illusions, and paranoia occurred in more patients receiving amantadine than placebo. Patients with a major psychotic disorder (e.g., schizophrenia, psychosis) should generally not be treated with amantadine because of the risk of exacerbating psychosis. Prescribers should consider whether the benefits outweigh the risks of treatment with amantadine in patients with a history of suicidality or depression. Suicide attempts and suicidal ideation have been reported in patients with and without a prior history of a psychiatric disorder. Because overdose has been lethal with an acute dose as low as 1 gram, amantadine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A benefit versus risk assessment should be considered in patients with a substance abuse disorder, since exacerbation of symptoms may occur.[28049] [46061] [62262] [62273] [62887]

Some patients receiving medications that increase dopaminergic tone have reported intense and uncontrollable urges to gamble, increased sexual urges, or other intense urges. Causality due to dopaminergic agents has not been established; however, in some cases the urges stopped after the dose was reduced or the drug was discontinued. Practitioners should inquire periodically about new or worsening impulse control symptoms in patients receiving amantadine. Likewise, patients should be instructed to report such changes while receiving amantadine. Dose reduction or discontinuation should be considered in those who experience these effects.[28049] [46061] [62262] [62273] [62887]

Patients treated for Parkinson's disease have reported sudden sleep onset, such as falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Prior to initiating treatment with amantadine, patients should be advised of the potential for somnolence and specifically asked about factors that may increase the risk of experiencing such an event such as coadministration with other CNS depressants, alcohol ingestion, or the presence of a sleep disorder (e.g., narcolepsy, sleep apnea). Assessment for somnolence is necessary throughout amantadine therapy. Patients should use caution in driving or operating machinery, or performing other potentially hazardous tasks. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), amantadine should generally be discontinued. If a decision is made to continue the drug, patients should be advised against driving or operating heavy machinery or engaging in other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. Manufacturers of amantadine products recommend against ethanol ingestion during treatment, as it may increase the potential for CNS and blood pressure effects such as hypotension, dizziness, confusion, lightheadedness, and orthostatic hypotension. With the extended-release capsule formula (e.g., Gocovri), ingestion of alcohol may result in dose-dumping.[28049] [46061] [62262] [62273] [62887]

Caution is advisable when prescribing amantadine to patients with hepatic disease; although, no dosage adjustment is recommended. Rare cases of reversible elevated hepatic enzymes have been reported in patients receiving amantadine, although a causal relationship has not been established.[28049] [46061] [62273]

Use caution when administering amantadine to patients with a history of recurrent eczema. Eczematoid dermatitis occurred rarely during clinical trial evaluation of immediate-release amantadine.[28049] [46061] [62273]

Amantadine has anticholinergic effects and may cause mydriasis. Some manufacturers recommend against administering amantadine to patients with untreated closed-angle glaucoma.[28049] [46061] [62273]

Epidemiological studies have shown that patients with Parkinson's disease have a 2- to 6-fold higher risk of developing melanoma than the general population. It is unclear if this increased risk is disease-related or associated with other factors such as the medications used to treat Parkinson's disease. Therefore, it is recommended that a qualified practitioner (e.g., dermatologist) monitor for melanomas on a regular basis during amantadine use. In addition, patients should be instructed to regularly monitor for skin changes that may indicate the presence of melanoma and to promptly report these changes to their provider.[28049] [46061] [62273] The product labels for extended-release amantadine capsules and tablets do not carry a precaution for melanoma.[62262] [62887]

Avoid abrupt discontinuation of immediate-release or extended-release amantadine in patients with Parkinson's disease. A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. Abrupt discontinuation of amantadine in these patients may cause an increase in the symptoms of Parkinson’s disease or cause delirium, agitation, delusions, hallucinations, paranoid reaction, stupor, anxiety, depression, or slurred speech.[28049] [46061] [62262] [62273] When discontinuing amantadine extended-release tablets (e.g., Osmolex ER), the dose should be gradually reduced from higher doses to 129 mg daily for 1 to 2 weeks.[62887]

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.[28049] [46061] [62262] [62273] [62887]

Until more data become available on the effects of amantadine on fertility, caution is advisable when using amantadine in patients with infertility problems. In rat studies, amantadine given at a dose equal to 32 mg/kg/day (equal to the maximum recommended human dose) resulted in impaired fertility in both male and female rats. The no-effect dose for adverse effects on fertility (10 mg/kg/day) is less than the recommended human dose of 274 mg/day on a mg/m² basis. Failed human fertility has been reported when amantadine was used during in vitro fertilization; the male sperm donor had used amantadine 2 weeks prior to, and during the fertilization cycle.[28049] [46061] [62262] [62273] [62887]

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.[62262] 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.[28049] [46061] [62273] 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.[46966] [46967] 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.[62262] [62887] 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.

Because of an age-related decline in renal function, geriatric adults may experience amantadine drug accumulation with toxic effects; therefore, a dose reduction of immediate-release amantadine formulations is recommended in individuals who are 65 years of age or older.[28049] No dosage adjustments of the extended-release capsules (e.g., Gocovri) or extended-release tablets (e.g., Osmolex ER) are recommended in geriatric adults based on age alone. However, because geriatric patients are more likely to have decreased renal function, it may be useful to monitor renal function to guide dose selection.[62262] [62887] Deaths due to systemic drug accumulation have been reported in patients with renal impairment who were prescribed higher than recommended doses of amantadine for their level of renal function. Amantadine exhibits significant anticholinergic effects that can be problematic in the older adult and may be additive to the effects of other anticholinergic medications in any population.[28049] [62262]

Immediate-release amantadine is FDA-approved for children 1 year of age and older for the prophylaxis and treatment of uncomplicated influenza A. Safety and efficacy are not established in infants or neonates.[28049] [46061] [62273] The safety and efficacy of extended-release amantadine capsules (e.g., Gocovri) and extended-release amantadine tablets (e.g., Osmolex ER) have not been established in pediatric patients.[62262] [62887]