Amantadine: Side effects
Amantadine is a symmetrical C10 tricyclic amine with an unusual structure (1-adamantanamine hydrochloride). It interferes with virus uncoating by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate the uncoating process. Most consistent antiviral activity has been observed against influenza A virus, but amantadine has little or no activity against influenza B virus. However, influenza A virus can become rapidly resistant to amantadine in vitro. Amantadine also promotes the release of dopamine from nerve endings, but may also delay its reuptake into synaptic vesicles.
Doses of 100-200 mg/day are often used and are usually well tolerated. The best-documented adverse reactions are nausea, psychotic episodes (mania, hallucinations, agitation, confusion), restless legs, and convulsions. Minor adverse reactions often resemble those caused by anticholinergic agents, for example blurred vision, dryness of the mouth, insomnia, lethargy, and rash. In rare cases, photosensitization has been described. Oral or aerosol administration can be accompanied by gastrointestinal or minor neurological symptoms, such as insomnia, light-headedness, concentration difficulties, nervousness, dizziness, and headache in individuals taking 200 mg/day. These symptoms disappear on withdrawal. More severe but rare complications include convulsions and coma. Local nasal adverse effects of the aerosolized form can mimic the symptoms of upper respiratory tract infection. In Parkinson’s disease, in which doses of 200 mg/day or more have been used, minor adverse effects resembling those caused by anticholinergic agents (for example blurred vision, dry mouth, as well as livedo reticularis, rash, and photosensitization, can occur.
Organs and Systems
Cardiovascular
Reversible congestive cardiac failure has been attributed to amantadine.
Nervous system
Insomnia is common with amantadine. Myoclonus, especially vocal, can occur.
A 48-year-old woman with a 17-year history of Parkinson’s disease developed a sensorimotor peripheral neuropathy after taking amantadine 300 mg/day for 8 years. She had livedo reticularis after only 1 year of treatment and this had become increasingly extensive. Attempts to withdraw the drug resulted in worsening Parkinsonian symptoms. However, after the neuropathy had been diagnosed, amantadine was withdrawn, with improvement of the neurological symptoms within 6 weeks and complete resolution after 6 months. However, the livedo reticularis was still present 18 months after withdrawal.
This is the first description of peripheral neuropathy in these circumstances, but it suggests that chronic livedo reticularis may be a forerunner of more severe problems.
Three Japanese women aged 78-87 years who had taken amantadine 100-200 mg/day for 1 month to 5 years, in two cases together with co-careldopa, developed multifocal myoclonus and two were confused. Amantadine concentrations were high in the two patients in whom they were measured, at over 3000 µg/ml; a concentration over 1000 µg/ml is regarded as toxic. Amantadine was withdrawn and the myoclonus disappeared within 1-2 weeks and did not recur. Cortical myoclonus has also been described with levo-dopa and bromocriptine, but the mechanism is not known.
Sensory systems
Rarely, amantadine causes visual impairment due to corneal abrasions, local edema, and superficial keratitis.
Psychological, psychiatric
The risk of mental complications seems to increase substantially if doses of 200 mg or more are given. Amantadine can cause mania and is contraindicated in patients with bipolar affective disorder.
- While taking amantadine, an elderly man developed the Othello syndrome, a severe delusion of marital infidelity, as described in Shakespeare’s plays Othello and A Winter’s Tale; it abated with drug withdrawal.
- Amantadine and phenylpropanolamine may have caused intense recurrent deja vu experiences in a healthy 39-year-old within 24 hours of starting both drugs for influenza.
Fluid balance
Resistant edema of the ankles in the absence of cardiac disease has repeatedly been described and well documented by rechallenge.
Skin
Livedo reticularis has been stated to occur in as many as 90% of patients; it is very common in female patients especially those with antiphospholipid antibodies.
Long-Term Effects
Drug withdrawal
On withdrawal of amantadine after long-term therapy, acute delirium with confusion, disorientation, agitation, and paranoia occurred in three patients. Reintroduction of the drug returned the patients to the baseline status.
In four patients, amantadine withdrawal was associated with delirium and confusion. The patients, three of them women, were aged 70-83 years and all but one were considered to have early dementia. Amantadine exposure was 1-5 years and the symptoms occurred within a week of drug withdrawal. In all cases they were reversed by reintroduction. The mechanism of the withdrawal reaction is unknown, but it should obviously be borne in mind, especially in elderly patients with long exposure to the drug and with already impaired cognitive function.
Neuroleptic malignant syndrome can occur on withdrawal of amantadine.
Susceptibility Factors
Renal disease
In a case of end-stage renal insufficiency, amantadine caused coma, though drug plasma concentrations were not greatly increased.
Amantadine Hydrochloride: Cautions
Amantadine generally is well tolerated, although serious adverse effects have been reported rarely.
The incidence of adverse effects associated with amantadine therapy appears to be dose related.
The most frequently reported adverse effects with amantadine are similar to those observed with rimantadine and include adverse CNS and GI effects; however, amantadine is associated with more frequent and/or severe nervous system effects than rimantadine, including in geriatric adults. Adverse effects associated with amantadine usually are mild and are reversible upon discontinuance of the drug. In some patients, adverse effects subside after the first week of therapy with the drug.
Nervous System Effects
Dizziness (lightheadedness), insomnia, nervousness, anxiety, and impaired concentration are among the most frequent adverse effects of amantadine and have been reported in up to 5-10% of healthy, young adults receiving the usual dosage of the drug (200 mg daily). However, limited data suggest that the incidence of adverse CNS effects may be lower in adults receiving a lower dosage of the drug.
These adverse effects are usually mild, but may be more disturbing for geriatric patients than for younger patients.
Adverse CNS effects are more common with usual dosages of amantadine than of rimantadine, probably in part because of differences in pharmacokinetics of the drugs In a 6-week study of daily 200-mg prophylactic doses of amantadine or rimantadine in healthy adults, about 13 or 6% of patients receiving the respective drug discontinued therapy because of adverse CNS effects versus about 4% of those receiving placebo.
Irritability, depression, ataxia, confusion, somnolence, abnormal dreams, agitation, fatigue, headache, and hallucinations have been reported in 1-5% and psychosis, abnormal thinking, amnesia, hyperkinesia, euphoria, weakness, and slurred speech have been reported in 1% or less of patients receiving amantadine. In addition, forgetfulness, a sense of drunkenness or detachment, drowsiness, coma, stupor, delirium, hypokinesia, hypertonia, delusions, aggressive behavior, paranoid reaction, manic reaction, involuntary muscle contractions, gait abnormalities, paresthesia, EEG changes, tremor, and, rarely, lingual facial dyskinesia or seizures have been reported.
Patients at Risk for CNS Effects
Patients with active seizure disorders appear to be at risk of an increased frequency of seizures during amantadine therapy; seizures also have been reported in patients with renal impairment and in geriatric individuals. Patients with a history of mental or behavioral disorders and those receiving concomitant anticholinergic drug therapy also may be at increased risk of adverse CNS effects of the drug. The more serious CNS effects (e.g., marked behavioral changes, delirium, agitation, hallucinations, seizures) of amantadine or rimantadine have been associated with high plasma concentrations of the drugs and have been observed most often among patients with renal impairment, seizure disorders, or certain psychiatric disorders and among geriatric patients who received prophylactic 200-mg doses daily. Clinical studies and experience indicate that lower dosages of amantadine in at-risk patients reduces the incidence and severity of these serious adverse effects.
Suicide Risk
Suicide attempts (resulting in death in some patients) have been reported rarely in patients receiving amantadine, many of whom received short courses of the drug for influenza prophylaxis or treatment. The manufacturer states that the incidence and pathophysiology of these suicide attempts are not known. Suicide ideation or attempts have been reported in patients with or without a prior history of psychiatric disorders. Amantadine can exacerbate mental status in patients with a history of psychiatric disorders or substance abuse. Patients with suicidal tendencies may exhibit abnormal mental states including disorientation, confusion, depression, personality changes, agitation, aggressive behavior, hallucinations, paranoia, other psychotic reactions, somnolence, or insomnia. Because of the possibility of serious adverse effects, amantadine should be administered with caution to patients receiving drugs with CNS activity and in those in whom potential risks outweigh benefits of therapy with the drug. Since intentional overdosage with amantadine has been reported in some patients, the least amount of drug feasible should be prescribed.
Neuroleptic Malignant Syndrome
Possible neuroleptic malignant syndrome (NMS) has been reported in patients receiving amantadine and was associated with dosage reduction or withdrawal of the drug. NMS is potentially fatal and requires immediate initiation of intensive symptomatic and supportive care. Patients should be observed closely when the dosage of amantadine is reduced or the drug is discontinued; this precaution is especially important in patients receiving concomitant therapy with an antipsychotic agent.
Livedo Reticularis
Livedo reticularis is a frequent adverse effect in patients receiving amantadine for the treatment of parkinsonian syndrome, and the possibility should be considered in patients receiving the drug for prolonged periods in the prevention of influenza A.
Livedo reticularis occurs mainly in the legs and diminishes when the legs are elevated. Livedo reticularis has been reported in 1-5% of patients, generally appears within 1 month to 1 year following initiation of amantadine therapy, and subsides within a few weeks to several months after discontinuance of the drug. In one study, livedo reticularis tended to fade or change into brown spots with prolonged amantadine therapy.
It has been suggested that, in many instances, this adverse effect is actually an accentuation of a preexisting, minor livedo reticularis and may result from abnormal capillary permeability associated with peripheral vasoconstriction accompanied by lowered skin temperature and decreased peripheral blood flow, and/or amantadine’s depletion of catecholamines in peripheral nerve endings.
Peripheral edema may precede or accompany livedo reticularis and may require dosage reduction or discontinuance of amantadine. The edema does not appear to be associated with an increase in total body water or sodium retention; it may result from increased vascular permeability in cutaneous tissues.
GI Effects
Nausea is one of the most frequent adverse effects of amantadine and has been reported in 5-10% of patients receiving the usual dosage of the drug. Anorexia, constipation, diarrhea, and dry mouth have been reported in 1-5% and vomiting has been reported in up to 1% of patients receiving amantadine. Abdominal discomfort or dysphagia also has been reported. The incidence of adverse GI effects is comparable for amantadine and rimantadine.
Cardiovascular Effects
Orthostatic hypotension and peripheral edema have been reported in 1-5% and congestive heart failure and hypertension in up to 1% of patients receiving amantadine. Cardiac arrest, arrhythmias including malignant arrhythmias, and tachycardia have occurred in patients receiving amantadine. • Ocular Effects Visual disturbance (e.g., punctate subepithelial or other corneal opacity), corneal edema, decreased visual acuity, ocular photosensitivity, or optic nerve palsy have been reported in up to 1% of patients receiving amantadine. Keratitis or mydriasis has occurred in patients receiving the drug. One patient experienced a sudden loss of visual acuity in both eyes, which gradually returned to normal several weeks after amantadine was discontinued.
Sensitivity and Dermatologic Effects
Allergic reactions, including anaphylactic reaction, rash, eczematoid dermatitis, photosensitization, pruritus, and diaphoresis, have occurred rarely in amantadine-treated patients.
Hematologic Effects
Hematologic effects reported in less than 0.1% of patients receiving amantadine include leukopenia, neutropenia, and leukocytosis.
Genitourinary Effects
Urinary retention and decreased libido have occurred in up to 1% of patients receiving amantadine.
Respiratory Effects
Dyspnea has been reported in up to 1% of amantadine-treated patients. Adverse respiratory effects reported rarely in amantadine-treated patients include acute respiratory failure, pulmonary edema, and tachypnea.
Other Adverse Effects
Fever or dry nose has occurred in patients receiving amantadine. Increased concentrations of creatine kinase (CK, creatine phosphokinase, CPK), BUN, serum creatinine, alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, Gamma-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP), ALT (SGPT), and AST (SGOT) have occurred in patients receiving amantadine.
Precautions and Contraindications
Amantadine should be administered with caution in patients with liver disease or a history of recurrent eczematoid dermatitis, uncontrolled psychosis or severe psychoneurosis, or seizure disorders, and in those receiving drugs with CNS activity. Patients with a history of seizure disorders should be observed closely for possible increased seizure activity. Because of possible CNS effects or visual disturbances, patients receiving amantadine should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.
Because amantadine may cause mydriasis, the drug should not be used in patients with untreated angle-closure glaucoma.
Because possible neuroleptic malignant syndrome was reported in patients receiving amantadine and was associated with a dosage reduction or withdrawal of the drug, patients, especially those receiving antipsychotic agents, should be observed closely when the dosage of amantadine is reduced or the drug is discontinued. Amantadine should be used with caution and dosage of the drug may need careful adjustment in patients with renal impairment, congestive heart failure, peripheral edema, or orthostatic hypotension. Dosage of the drug should be reduced in patients with active seizure disorders and in geriatric patients 65 years of age or older.
Amantadine- and rimantadine-resistant strains of influenza A virus have been observed in some patients receiving the drug for the treatment of influenza A infection. Although most patients recover uneventfully even after resistant strains emerge, resistant strains are pathogenic and transmissible and can result in failures in drug prophylaxis in close contacts. The possibility of transmitting resistant strains should be considered when treating patients in close contact with other individuals at high risk for influenza A infection.
Individuals with influenza-like illness should be separated from and avoid contact with uninfected individuals as much as possible, regardless of whether they are receiving antiviral treatment. Clinicians should consider the possibility of primary or concomitant bacterial infection when making treatment decisions for patients with suspected influenza. Amantadine is contraindicated in patients with known hypersensitivity to adamantane derivatives (i.e., amantadine, rimantadine).
Pediatric Precautions
Safety and efficacy of amantadine in children younger than 1 year of age have not been established. When used in children, amantadine has caused CNS symptoms which resolved when the drug was discontinued. The incidence of adverse CNS-related effects appears to be higher in individuals receiving amantadine than in those receiving rimantadine. An increased incidence of seizures has been reported in children with an underlying seizure disorder receiving amantadine.
Geriatric Precautions
While safety and efficacy of amantadine in geriatric patients have not been established specifically, the drug has been used in many geriatric patients. The frequency and severity of adverse CNS effects reported in individuals older than 65 years of age receiving amantadine are higher than those reported in geriatric individuals receiving rimantadine. Geriatric adults may have decreased renal function and because individuals with renal impairment may be at increased risk of amantadine-induced toxicity, the dosage of amantadine hydrochloride for adults in this age group should not exceed 100 mg daily. This dosage may need to be reduced further in some geriatric patients.
Mutagenicity and Carcinogenicity
Amantadine was not mutagenic in the Ames microbial test using Salmonella typhimurium or a mammalian mutagen assay using Chinese hamster ovary cells when the tests were performed with or without metabolic activation. In addition, there was no evidence of chromosome damage in an in vitro test using freshly derived and stimulated human peripheral blood lymphocytes (with or without metabolic activation) or an in vivo mouse bone marrow micronucleus test (140-550 mg/kg; estimated human equivalent dosage of 11.7-45.8 mg/kg based on body surface area conversion). Long-term animal studies have not been performed to evaluate the carcinogenic potential of amantadine.
Pregnancy, Fertitlity and Lactation
Amantadine hydrochloride has been reported to be teratogenic in rats when administered in dosages of 50 mg/kg daily and embryotoxic when administered in dosages of 100 mg/kg daily (estimated human equivalent dosage of 7.1 and 14.2 mg/kg daily, respectively, based on body surface area conversion), but not when administered in dosages of 37 mg/kg daily (estimated human equivalent dosage of 5.3 mg/kg daily). There was no evidence of embryotoxic or teratogenic effects when amantadine hydrochloride was administered to rabbits in dosages of 32 mg/kg daily (estimated human equivalent dosage of 9.6 mg/kg daily).
One woman with a movement disorder similar to parkinsonian syndrome who may have been treated with amantadine hydrochloride (100 mg daily) during the first trimester of pregnancy delivered a child with a complex cardiovascular lesion (single ventricle and pulmonary atresia) which may have been caused by the drug.
Fallot and tibial hemimelia (normal karyotype) were reported in an infant exposed to amantadine hydrochloride during the first trimester of pregnancy (100 mg daily for 7 days during week 6 and 7 of gestation).
There are no adequate and well-controlled studies using amantadine in pregnant women, and the drug should be used during pregnancy only when the potential benefits outweigh the possible risks to the fetus. In a rat reproduction study involving 3 litters, fertility was slightly impaired when amantadine hydrochloride was administered in a dosage of 32 mg/kg daily (estimated human equivalent dosage of 4.5 mg/kg daily) to both males and females Fertility was not affected when the drug was given in a dosage of 10 mg/kg daily (estimated human equivalent dosage of 1.4 mg/kg daily); intermediate doses were not tested. In one instance, failure was reported during human in vitro fertilization (IVF) when the sperm donor ingested amantadine 2 weeks before and during the IVF cycle.
Amantadine is distributed into human milk. The manufacturer recommends that the drug not be used in nursing women.