Amantadine (amantadine HCl)

Dosage of amantadine hydrochloride conventional tablets, capsules, and oral solution is expressed in terms of amantadine hydrochloride; dosage of amantadine hydrochloride extended-release capsules is expressed in terms of amantadine.

Amantadine hydrochloride is administered orally. Adverse effects (e.g., CNS effects) may be minimized if the daily dosage is given in 2 equally divided doses.

Amantadine hydrochloride is commercially available as tablets or liquid-filled capsules containing 100 mg of the drug and as an oral solution containing 50 mg/5 mL.

Amantadine hydrochloride is administered orally as conventional (i.e., immediate-release) tablets, conventional capsules, extended-release capsules,or a conventional oral solution.

In vitro studies indicate that amantadine does not significantly inhibit the enzyme activity of drug metabolizing cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, 2E1, 3A4, and 3A5.

Amantadine has negligible or no inhibitory activity against cellular transporters (P-gp, BCRP, MATE2-K, OAT1, OAT3, OATP1B1, and OATP1B3) at clinically relevant plasma concentrations.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Antiviral Agents/Influenza Virus Vaccine Live

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Amantadine,(1) oseltamivir,(2) rimantadine,(3) zanamivir,(4) and baloxavir,(5) may inactivate the intranasal live influenza virus vaccine, preventing the body from developing an immune response.

CLINICAL EFFECTS: Administration of amantadine,(1) oseltamivir,(2) rimantadine,(3) zanamivir,(4) and baloxavir,(5) may render the intranasal live influenza virus vaccine ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of amantadine,(1) oseltamivir,(2) rimantadine,(3) zanamivir(4), baloxavir(5), and the intranasal live influenza virus vaccine(6) state that these agents should not be initiated within 2 weeks of the administration of the intranasal live influenza virus vaccine and that the vaccine should not be administered within 48 hours of the discontinuation of these agents. Inactivated influenza vaccine may be used at any time.(1)

DISCUSSION: Because antiviral drugs such as amantadine,(1) oseltamivir,(2) rimantadine,(3) zanamivir,(4) and baloxavir (5) inhibit the replication of live viruses, these agents may interfere with the efficacy of the intranasal live influenza virus vaccine.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

N-Methyl-D-Aspartate (Nmda) Antagonists/Memantine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine.(1,2)

CLINICAL EFFECTS: Concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The UK manufacturer of memantine states that the concurrent use of memantine with N-methyl-D-aspartate (NMDA) antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2)

DISCUSSION: Because N-methyl-D-aspartate (NMDA) antagonists act at the same receptor system as does memantine, concurrent use may result in more frequent and more pronounced side effects, especially CNS-related effects. Therefore, the UK manufacturer of memantine states that the concurrent use of memantine with NMDA antagonists such as amantadine or ketamine should be avoided.(1) The US manufacturer of memantine states that concurrent use should be approached with caution.(2) In a study in 52 healthy subjects, concurrent memantine (20 mg daily) and dextromethorphan/quinidine (30/30 mg daily) resulted in no changes in dextromethorphan or memantine levels. There was a slight increase in dizziness as measured by the dizziness visual analog scale (VAS) when compared to memantine alone but not the combination of dextromethorphan/quinidine alone. For other pharmacodynamic assessments, there was either no effect or improvement on some subscales.(3)

Selected Dopaminergic Agents/Slt Antipsychotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Selected dopaminergic agents are used to treat neurologic conditions such as Parkinson Disease (PD) or restless legs syndrome, and endocrine disorders such as hyperprolactinemia by directly or indirectly increasing dopamine concentrations at D2 receptors in the central nervous system (CNS). Antipsychotic agents counteract this effect by blocking dopamine activity at CNS D2 receptors.(1-5)

CLINICAL EFFECTS: The efficacy of either agent may be decreased, leading to exacerbation of the disease being treated. In patients with Parkinson disease motor symptoms may worsen, increasing the risk for falls, dysphagia or aspiration.(4,7) Compared with Parkinson patients not receiving antipsychotic therapy, Parkinson patients receiving antipsychotics appear to have an increased mortality risk.(6) Patients with other conditions such as restless legs syndrome or a psychotic disorder may also experience symptom exacerbation due to this combination.

PREDISPOSING FACTORS: Patients with Parkinson or Diffuse Lewy Body (DLB) disease are particularly susceptible to adverse effects of dopamine blockade by antipsychotics.

PATIENT MANAGEMENT: Reassess the need for antipsychotic therapy. If psychosis or hallucinations are due to an antiparkinson agent, when possible consider reducing the dose or changing the antiparkinson agent before initiating antipsychotic therapy. In patients with PD and dementia, addition of a cholinesterase inhibitor (e.g. rivastigmine) may improve psychosis. If an antipsychotic is required, then an atypical antipsychotic should be used.(6,7) In patients with major psychotic disorders, consider reducing the dose, changing or stopping the dopaminergic agent. The US manufacturer of ropinirole recommends treatment with dopaminergic agents only if potential benefits outweigh risks.(1) The US manufacturer of entacapone states it should not ordinarily be used in patients with major psychotic disorders as entacapone may lead to an exacerbation of psychosis.(4)

DISCUSSION: An epidemiologic study evaluated 21,043 elderly patients with Parkinson disease to determine if recent initiation of a typical or atypical antipsychotic was associated with increased mortality. They found an adjusted odds ratio of 2.0 for death associated with atypical antipsychotics versus no antipsychotic They found an adjusted odds ratio of 2.4 for death associated with typical versus atypical antipsychotics. The authors noted the increased mortality found with typical antipsychotics supports current treatment recommendations to use atypical antipsychotic agents in patients with Parkinson disease.(6,7)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Amantadine; Foslevodopa; Levodopa/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Amantadine, levodopa, and bupropion have dopamine agonist effects. Toxicity may result from cumulative dopamine agonist effects.(1) Foslevodopa is a prodrug of levodopa.(2)

CLINICAL EFFECTS: Concurrent administration of amantadine/levodopa and bupropion may result in CNS toxicity, such as, restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use caution when amantadine/levodopa and bupropion are used concurrently. Monitor for signs of CNS toxicity, which may include restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.(1)

DISCUSSION: CNS toxicity has been reported with concurrent administration of amantadine and bupropion. Three out of six nursing home residents administered concurrent bupropion and amantadine developed confusion, restlessness, agitation, gross motor tremors, ataxia, gait disturbance, dizziness, and vertigo. Two patients had severe symptoms and were hospitalized.(3) In a case report, bupropion (75 mg twice daily) was added to amantadine, haloperidol, and benztropine. The patient became disoriented and agitated, developed visual and auditory hallucinations, impaired attention and memory, a fluctuating level of awareness, and unsteady gait.(4)

Memantine; Amantadine/Urinary Alkalinizers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Memantine and amantadine elimination is impaired by urinary alkalinization.(1,2)

CLINICAL EFFECTS: Potentiation of memantine or amantadine effects may be observed.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient for adverse reactions such as dizziness, headache, or confusion if a urinary alkalinizer is required. The memantine or amantadine dose may need to be adjusted when a urinary alkalinizer is started or stopped.(1,2)

DISCUSSION: The clearance of memantine was reduced by about 80% under alkaline urine conditions at pH 8. Urine alkalinization may lead to an accumulation of memantine with a possible increase in adverse effects. Urine pH is also altered by diet and clinical state of the patient (e.g., renal tubular acidosis or severe infections of the urinary tract). Hence, memantine should be used with caution under these conditions.(1) A study in rats showed that concomitant administration of sodium bicarbonate with amantadine caused a decrease in amantadine renal clearance (1.16 vs. 0.76). Amantadine's area-under-the-curve (AUC) was increased approximately 78%.(3) A study in 12 healthy subjects showed that plasma concentrations of memantine are dependent on urine pH. Alkaline urine pH caused a 79% reduction in renal clearance.(4)

*Patients with known hypersensitivity to amantadine hydrochloride or any ingredients in the formulations.

*Patients with known hypersensitivity to amantadine hydrochloride or any ingredients in the formulations.

There are no contraindication contraindications for this drug.

• Angle-closure glaucoma
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Drug abuse
• Psychotic disorder
• Suicidal ideation

• Orthostatic hypotension

The most common adverse effects (5-10%) of amantadine include nausea, dizziness, and insomnia.

The most common adverse effects (5-10%) of amantadine administered as conventional (immediate-release) preparations include nausea, dizziness, and insomnia.

The most common adverse effects (>10%) with extended-release amantadine capsules include hallucination, dizziness, dry mouth, peripheral edema, constipation, fall, and orthostatic hypotension.

More Frequent

• Accidental fall

Less Frequent

• Cataracts

Rare or Very Rare

• Agranulocytosis
• Chronic heart failure
• Corneal deposits
• Neutropenic disorder
• Oculogyric crisis
• Paranoid disorder
• Seizure disorder
• Sudden onset of sleep
• Suicidal
• Suicidal ideation

More Frequent

• Concentration difficulty
• Constipation
• Dizziness
• Hallucinations
• Insomnia
• Nervousness
• Orthostatic hypotension
• Peripheral edema
• Xerostomia

Less Frequent

• Acquired dystonia
• Acute cognitive impairment
• Anorexia
• Arthritis
• Benign prostatic hyperplasia
• Blurred vision
• Cough
• Depression
• Diarrhea
• Dream disorder
• Drowsy
• Dry eye
• Dyschromia
• Fatigue
• Gait abnormality
• Headache disorder
• Irritability
• Livedo reticularis
• Muscle spasm
• Nausea
• Nightmares
• Symptoms of anxiety
• Urinary tract infection
• Vomiting

Rare or Very Rare

• Allergic dermatitis
• Anticholinergic toxicity
• Corneal edema
• Delusional disorder
• Dry nose
• Dry throat
• Impulse control disorder
• Skin rash
• Urinary retention
• Visual changes

No enhanced messaging available.

Safety and efficacy of amantadine for the prevention or treatment of infections caused by influenza A viruses have not been established in neonates or children younger than 1 year of age.

Safety and efficacy of amantadine for the treatment of parkinson disease have not been established in pediatric patients; the majority of individuals with parkinson disease are 65 years of age or older. When used in children, amantadine has caused CNS symptoms, which resolved when the drug was discontinued. An increased incidence of seizures has been reported in children with an underlying seizure disorder receiving amantadine.

Amantadine has been reported to be embryotoxic/teratogenic in rats when administered in dosages of 50 and 100 mg/kg daily (1.5 and 3 times, respectively, the maximum recommended human dosage on a mg/m2 basis), but not when administered in a dosage of 37 mg/kg daily (the maximum recommended human dosage on a mg/m2 basis). 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) that may have been caused by the drug. Fallot and tibial hemimelia (normal karyotype) were reported in an infant exposed to oral 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.

Amantadine has been reported to be embryotoxic/teratogenic in rats when administered in dosages of 50 and 100 mg/kg daily (1.5 and 3 times, respectively, the maximum recommended human dosage on a mg/m2 basis), but not when administered in a dosage of 37 mg/kg daily (the maximum recommended human dosage on a mg/m2. 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) that may have been caused by the drug. 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.

Because amantadine is distributed into human milk, some manufacturers state that the drug should not be used in nursing women.

Because amantadine is distributed into human milk, some manufacturers state that the drug should not be used in nursing women.

The usual dosage of amantadine hydrochloride for the treatment or prophylaxis of influenza infection caused by susceptible influenza A viruses in adults 65 years of age or older without recognized renal disease is 100 mg daily.

Since renal function normally declines with age and amantadine-induced adverse effects have been reported more frequently in geriatric patients, some clinicians state that 100 mg daily should be the maximum dosage of amantadine hydrochloride for adults 65 years of age or older, and that dosage may need to be further reduced in some geriatric patients.

Dosage of amantadine conventional preparations should be reduced in geriatric patients 65 years of age or older. The manufacturer of the extended-release capsules states that no dosage adjustment is required based on age; however, because elderly patients are more likely to have decreased renal function, care should be taken to select dosage with caution and it may be useful to monitor renal function.

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.

The majority of individuals with parkinson disease are 65 years of age or older. Clearance of amantadine is reduced, plasma concentrations of the drug are increased, and elimination half-life may be prolonged in healthy geriatric adults compared with healthy young adults.

Reduced dosages may be needed in geriatric patients >=65 years of age because of renal decline in such patients.