Amantadine - Uses, Dosage, Side Effects, and More

Overview:

Amantadine belongs to a class of medications referred to as adamantanes. It is used to treat the following conditions:

• Parkinson’s disease.

• Respiratory infections caused by the influenza A virus.

Amantadine is available in a variety of dosage forms, including:

• Tablet.

• Tablet, extended-release.

• Capsule.

• Capsule, extended-release.

• Capsule, liquid-filled.

• Solution.

• Syrup.

How Does Amantadine Work?

• Amantadine works to control movement problems associated with Parkinson’s disease by increasing the amounts of dopamine in some parts of the body.

• The antiviral action of Amantadine works through the inhibition of influenza A virus replication.

Uses of Amantadine:

• Parkinson’s Disease: Amantadine may be given alone or in combination with other drugs like Levodopa or Carbidopa for episodes of Parkinson’s disease. It is also indicated for extrapyramidal reactions caused by anti-Parkinsonian drugs.

Extrapyramidal reactions are side effects of antipsychotic medications. They typically occur as symptoms such as involuntary muscle contractions, involuntary facial movements, tremors, muscle stiffness, and jerky movements.

• Respiratory Diseases: Respiratory illnesses caused by influenza A virus may be treated and controlled by Amantadine. It is also used as prophylaxis (a preventive measure) against influenza A virus symptoms. However, reports of high resistance levels to Amantadine have resulted in the infrequent use of this drug since 2011.

Dosage Restrictions:

• Route of Administration: Oral.

• Dosage Forms:

• Tablet: Triangular-shaped, light orange, convex-curved.

• Capsule, Extended-Release: White opaque size #2 or light blue opaque size #0.

• Syrup: Clear, colorless.

• Tablet, Extended-Release.

• Capsule.

• Capsule, Liquid-Filled.

• Solution.

• Available Strengths:

• Tablets:

• 100 mg tablets.

• Capsule, Extended-Release:

• 68.5 mg capsules.

• 137 mg capsules.

• Syrup:

• 480 ml (16 oz) bottles with 50 mg Amantadine in every 5 ml of the syrup.

• Recommended Dosage:

• Dosage for Parkinson’s Disease:

Initial Dose:100 mg daily.

Increase in Dosage:

Time to Increase: 1 to a few weeks after the initial dose.

Increase To:

• 200 mg daily [100 mg twice daily (if used alone)].

• 400 mg daily (divided doses) in patients who do not respond even to 200 mg daily.

• Concomitant Therapy:

Concomitant use of Amantadine with anticholinergic anti-Parkinson drugs may provide better results than solo therapy with either of the two. Amantadine dosage may either be 100 mg daily or twice daily, while the dosage of drugs like Levodopa may be increased until an optimal concentration is obtained, with good results.

• Dosage for Drug-Induced Extrapyramidal Reactions:

• 100 mg twice daily.

• 300 mg daily (divided doses) for patients who do not respond to 200 mg daily.

• Dosage for Respiratory Illnesses (Influenza A Virus):

• Adults:

• 200 mg daily (two 100 mg tablets or four teaspoons of syrup) as a single dose or as a split-dosage schedule twice a day.

• Children:

• 1 - 9 Years: 2 to 4 mg/lb/day (4.4 to 8.8 mg/kg/day). No more than 150 mg per day.

• 9 - 12 Years: 200 mg daily in divided doses (100 mg tablet twice daily or two teaspoons of syrup twice a day).

Special Considerations:

Dosage Adjustment:The following patients may require a reduction in drug dosage:

• Patients with impaired renal function (kidney function).

• Patients suffering from congestive heart failure (chronic heart condition characterized by inadequate pumping of the blood by the heart).

• Patients with peripheral edema (swelling of the limbs, specifically the hands and lower legs).

• Patients with a history of orthostatic hypotension (drop in blood pressure that occurs when a person stands after sitting or lying down).

Drug Safety Concerns:

• Pregnancy: Amantadine may cause harm to the fetus.

• Infants: Safety and efficacy data on Amantadine in children below one year of age is unavailable.

Warnings and Contraindications:

Contraindications:

• Renal Disease: Amantadine is contraindicated in patients with end-stage renal disease.

• Hypersensitivity: Amantadine should not be prescribed in patients with hypersensitivity to the drug itself or to components in the formulation.

Warnings and Precautions:

• Sleep: Patients may experience sedation while on Amantadine therapy and fall asleep while engaged in regular activities.

• Psychotic Changes: Patients with psychotic disorders may experience hallucinations.

• Depression, Suicidal Ideation: Depression and suicidal behavior may occur in patients taking Amantadine, so they must be monitored carefully.

• Orthostatic Hypotension: Patients taking Amantadine may start experiencing frequent episodes of dizziness and orthostatic hypotension.

• Compulsive Behaviors: Patients may begin experiencing impulse control and compulsive behaviors such as uncontrollable gambling and sexual urges, among others.

For Patients:

What Is Parkinson’s Disease?

Parkinson’s disease is a disorder of the central nervous system (specifically the brain) that affects movement. It causes uncontrollable movements in the form of tremors and is also characterized by shaking, imbalance and uncoordinated movements, and muscle stiffness. The symptoms usually worsen over time and can manifest as the inability to walk or talk properly. It occurs due to damage in the brain's nerve cells, which can cause dopamine levels to fall and lead to tremors, stiffness, and imbalance.

What Is Influenza A Respiratory Illness?

Influenza A is a virus that causes influenza (or the flu), a highly contagious viral illness. It can be especially concerning among vulnerable populations such as pregnant women, people with weak immune systems or chronic diseases, older populations, and young children. It is usually spread through airborne respiratory droplets from coughing, sneezing, saliva, and touching contaminated surfaces.

Why Is Amantadine Prescribed for Parkinsonism?

Amantadine has mild anti-Parkinsonian activity and decreases tremors, stiffness, and slowness of movement. Concurrent use of Amantadine with Levodopa allows for the conversion of Levodopa to Dopamine.

Why Is Amantadine Prescribed for Viral Illnesses Caused by Influenza A?

Amantadine is capable of decreasing not only the symptoms of influenza A illness but also reducing the severity of symptoms such as fever. However, high resistance levels demonstrated in cases from Asia and North America have led to a decline in the prescription of this drug for respiratory illnesses. The Centers for Disease Control (CDC) no longer recommends the use of Amantadine for prophylactic (preventive) or therapeutic (treatment) purposes in influenza A-origin respiratory illnesses.

How Should You Take Amantadine?

Amantadine is available in the following standard concentrations:

• Amantadine hydrochloride oral capsules and tablets:

• 100 mg.

• Amantadine hydrochloride oral capsule ER 24 hour:

• 68.5 mg.

• 137 mg.

• Amantadine hydrochloride oral syrup:

• 50 mg / 5 ml.

• Amantadine hydrochloride oral tablet ER 24 hour:

• 129 gm.

• 193 gm.

• 258 gm.

Influenza A:

• Within 24 to 48 hours of symptom onset, administer Amantadine 200 mg daily (or 100 mg twice daily).

• 24 to 48 hours after symptoms are resolved, continue the same dosage.

Prophylaxis: Continue the same dosage until influenza season is over.

Parkinson’s Disease:

• Initial Dose: 100 mg twice daily.

• Increase: Increase dosage to 200 mg twice daily if necessary.

• Concurrent Anti-Parkinsonian Drugs: For patients taking concurrent anti-Parkinsonian drugs, the dosage should be 100 mg once daily and only needs to be increased if deemed necessary by the physician.

What Should You Discuss With Your Doctor Before Beginning Treatment With Amantadine?

• Hypersensitivity Reactions: If you have previously demonstrated allergies to Amantadine or any other medication in the formulation, inform your doctor of the same.

• Pregnancy and Lactation: Tell your doctor if you are either pregnant or breastfeeding, as there is a possibility of harm to your baby in either case.

• Depression and Psychological Illnesses: If you have a history of depression, suicidal behavior, or other psychological illnesses, let your physician know.

• Medications: Tell your doctor about all the medicines and dietary and herbal supplements you may be taking so they may change the drug or alter the dose to prevent adverse drug reactions.

• Live Attenuated Influenza Vaccine: Tell your doctor if you have recently taken a live attenuated influenza vaccine or plan on doing so soon. The doctor may advise against it, change the medication, or recommend an inactivated influenza vaccine.

• Medical History: Give your doctor a detailed medical history, particularly if you have a history of the following conditions:

• Renal disease.

• Congestive heart failure.

• Peripheral edema.

• Orthostatic hypotension.

• Psychological illnesses.

What Side Effects Can You Expect With Amantadine?

The side effects of amantadine are limited. They include the following:

• Most Common Side Effects:

• Dizziness.

• Syncope (fainting).

• Orthostatic hypotension.

• Falls.

• Hallucinations.

• Delusions.

• Peripheral edema.

• Xerostomia (dry mouth).

• Constipation.

• Rare Side Effects:

• Livedo Reticularis: This side effect is rare but has occurred due to Amantadine. Livedo reticularis is a term used to describe mottled discoloration of the skin. This blanket finding may occur in several conditions due to blood vessel spasms or blood flow issues at the skin's surface.

• Serious Side Effects:

• Central Nervous System (CNS) Depression: Depression arising from the misuse or overuse of CNS depressant drugs such as Amantadine.

• Psychosis: A mental disorder characterized by dissociation from reality and occurring due to a combination of symptoms.

• Neuroleptic Malignant Syndrome (NMS): A potentially fatal reaction to antipsychotic medications that manifests as an alteration in the mental state of the patient, muscle stiffness and rigidity, fever, and nerve dysfunction.

• Suicidal Behavior.

Can You Stop Taking Amantadine Without Your Doctor’s Approval?

Never attempt to discontinue the use of the drug yourself. Discontinuation of Amantadine has been known to cause high fever and confusion in patients. The symptoms are similar to those in neuroleptic malignant syndrome (NMS) and usually occur following sudden withdrawal or rapid dose reduction. This condition is referred to as withdrawal-emergent hyperpyrexia (high fever) and confusion.

Can You Stop Taking Amantadine Without Your Doctor’s Approval?

• Parkinson’s Disease: Symptoms such as compulsive behaviors, addictions (gambling, sexual addiction), and depression may occur on long-term use of Amantadine.

• Respiratory Illnesses: Amantadine is not indicated for long-term use in respiratory illnesses caused by the influenza A virus as the possibility of developing drug resistance is relatively high.

How Should You Take Amantadine?

• Amantadine should be swallowed whole. It should not be chewed, crushed, or divided.

• The contents may be sprinkled over soft food items and consumed immediately. However, the drug-food mixture must not be allowed to sit for a long time.

• The drug may be taken either with or without food.

Are There Any Dietary Restrictions to Consider When Taking Amantadine?

No dietary restrictions exist in relation to Amantadine consumption except for alcohol restrictions. The consumption of alcohol is not recommended when taking Amantadine as it contributes to increased CNS effects like orthostatic hypotension, dizziness, and confusion.

How Should You Store and Dispose of Amantadine?

• Storage: Store Amantadine at 20°C to 25°C (68°F to 77°F). Keep the drug away from conditions of extreme heat and moisture.

• Disposal: Dispose of Amantadine by contacting your local medicine take-back program if available. If not, contact a pharmacy to find out more about the options available to you (such as flushing or disposing of the drug in the trash).

What Can You Do In Case of Overdose?

• An overdose of Amantadine can be quite concerning and may result in death.

• If you overdose on Amantadine, contact your doctor or visit the emergency room immediately. Alternatively, contact your local poison control room.

What Should You Do if You Miss a Dose?

• If you miss a dose of Amantadine capsule, tablet, or syrup, take the dose as soon as you remember. If it is time for the next dose, do not attempt to make up for it by double-dosing. Instead, take the next dose and continue as per usual.

• If you are taking the extended-release tablet or capsule, simply wait until it is time for the next dose.

• If you forget or cannot take Amantadine for several days, inform your doctor of the same.

What Else Should You Keep in Mind?

Amantadine can cause you to feel sleepy while actively engaging in daily activities. If you are prescribed Amantadine, wait several days to assess the emergence of these symptoms before performing tasks such as the operation of heavy machinery, or driving.

For Doctors:

Indications:

• Parkinson’s Disease: Amantadine is indicated for treating dyskinesia in patients with Parkinson’s disease receiving Levodopa, with or without the administration of concomitant dopaminergic medications.

• Respiratory Illnesses: Prophylaxis and treatment of the signs and symptoms of respiratory illnesses caused by the influenza A virus.

Limitations:

• Amantadine cannot be administered in patients with end-stage renal disease.

• Dosage must be cautiously evaluated in patients on anticholinergic drugs as Amantadine may potentiate anticholinergic effects or even cause symptoms such as dry mouth, constipation, and urinary retention.

Pharmacology:

Contents:

• Amantadine Tablets:

Active Ingredient:

• Amantadine hydrochloride 100 mg.

Inactive Ingredients:

• Hydroxypropyl methylcellulose.

• Magnesium stearate.

• Microcrystalline cellulose.

• Sodium starch glycolate.

• FD&C Yellow No. 6.

• Amantadine Syrup:

Active Ingredient:

• Amantadine hydrochloride (50 mg per 5 ml).

Inactive Ingredients:

• Artificial raspberry flavor.

• Citric acid.

• Methylparaben.

• Propylparaben.

• Sorbitol solution.

• Amantadine Capsules:

Active Ingredient:

• Amantadine hydrochloride 85 mg or 137 mg.

Inactive Ingredients:

• Copovidone.

• Ethylcellulose.

• Hypromellose.

• Magnesium stearate.

• Medium-chain triglycerides.

• Microcrystalline cellulose.

• Povidone.

• Talc.

Pharmacodynamics:

Mechanism of Action:

• Antiviral:

The antiviral mechanism of action of Amantadine is not entirely clear. However, it is understood that Amantadine inhibits or interrupts viral replication. The transmembrane domain of the viral M2 protein is interrupted by Amantadine, ensuring that viral nucleic acids are unable to enter the host cell. It also interferes with the assembly of influenza A virus isolates from the H1N1, H2N2, and H3N2 subtypes during virus replication.

• Anti-Parkinsonian:

The anti-Parkinsonian action of Amantadine relies on its effects on dopamine neurons. It is a weak antagonist of the NMDA (N-methyl-D-aspartate) receptor (a glutamate receptor and ion channel that regulates memory and brain aging). Its antagonistic activity increases the release of dopamine while also preventing its reuptake.

Pharmacokinetics:

• Absorption: Amantadine is well-absorbed orally.

• Maximum Plasma Concentration:

• Directly proportional to dose - up to 200 mg/day.

• Greater than proportional - doses over 200 mg/day.

• Maximum Plasma Concentration (Mean ± SD): 0.22 ± 0.03 µg/mL (range: 0.18 to 0.32 µg/mL).

• Time to Peak Concentration: 3.3 ± 1.5 hours (range: 1.5 to 8.0 hours).

• Oral Clearance: 0.28 ± 0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg).

• Half-life: 17 ± 4 hours (range: 10 to 25 hours).

• Plasma Protein Binding: 67 % (over a concentration range of 0.1 to 2.0 µg/mL).

• Excretion: Excreted unchanged in urine through glomerular filtration and tubular secretion.

Special Considerations:

• Gender: Mean total Amantadine clearance (adjusted for body weight in kilograms) is 1.2 times higher in males than females (95% CI: 1.1, 1.3, P=0.007). Dose adjustment by gender is not required.

• Renal Impairment: Adult patients with moderate to severe renal impairment may display lower renal clearance, increasing Amantadine accumulation in the plasma. Dose adjustment is necessary for patients with renal impairment.

Drug Interactions:

Drug Release:

• After 45 minutes: 52 % Amantadine release.

• After 2 hours: 95 % Amantadine release.

Inhibitory Activity:

Amantadine has no inhibitory activity against cellular transporters, including:

• P-gp.

• BCRP.

• MATE2-K.

• OAT1.

• OAT3.

• OATP1B1.

• OATP1B3.

Amantadine does not inhibit the enzyme activity of the drug-metabolizing cytochrome P450 isoforms, including:

• CYP1A2.

• 2B6.

• 2C19.

• 2C8.

• 2C9.

• 2D6.

• 2E1.

• 3A4.

• 3A5.

Substrate Activity:

Amantadine is not a substrate of the following:

• Anionic Transporters:

• OAT1.

• OAT3.

• Cationic Transporter:

• MATE2-K.

Amantadine is a poor substrate of the following:

• Cationic Transporters:

• OCT2.

• MATE1.

Clinical Trials:

Parkinson’s Disease:A study conducted in the United States and Canada evaluated the efficacy of Amantadine ER capsule in patients with dyskinesia associated with Parkinson’s disease.

Study Design:

• Type of Study: Randomized, double-blinded, placebo-controlled efficacy trial.

• Study Duration: 25 weeks.

• Methods: Patients [n= 121; modified Intention to Treat )mITT)] were randomized to two groups:

• Amantadine (274 mg): n=63.

• Placebo: n=58.

Patients were also given a stable dose of Levodopa. In addition, they were given dopamine agonists and/or MAO-B inhibitors.

• Primary Outcome Measure: Change in the total score of the Unified Dyskinesia Rating Scale (UDysRS) between baseline and Week 12.

• Secondary Outcome Measures: Changes from baseline to Week 12 in relation to ON time, with no history of troublesome dyskinesia or OFF time.

Baseline Scores:

• Mean UDysRS total score: 40.1 (range: 8-76).

• Mean ON time duration without troublesome dyskinesia: 8.4 hours (range: 0-15.3).

• Mean duration of OFF time: 2.8 hours (range: 0-9.5).

Results:

At Week 12:

• Significant decrease in mean UDysRS total score (reduction in dyskinesia) was noted (p=0.0009) in patients treated with Amantadine [-15.9 (1.62)] compared with placebo [-8.0 (1.64)].

• Significant increase in ON time (p<0.0001) without troublesome dyskinesia for Amantadine [3.6 (0.43)] compared to the placebo group [0.8 (0.43)].

• Significant decrease in OFF time (p=0.0171) from baseline to Week 12 for Amantadine [-0.6 (0.27)] as compared to placebo [0.3 (0.26)].

Other Off-Label Uses of Amantadine:

The use of Amantadine in diseases other than those explicitly approved by the FDA has been suggested. These non-FDA approved indications include:

• Huntington’s disease [for reducing chorea (involuntary movement disorder)].

• Restless leg syndrome.

• Fatigue in multiple sclerosis.

• Traumatic injury of the brain.

Patient Counseling Information:

• Advise the patient to read the information provided in the FDA-approved labeling.

• Advise patients on the best way to consume or administer Amantadine. The tablet must not be crushed, chewed, or split. The capsule contents may be carefully sprinkled over soft food if necessary but must be consumed immediately. The ideal way to consume Amantadine tablets or capsules is to swallow them whole, with or without food.

• Warn patients of the effects of Amantadine they must look out for. These include:

• Fatigue and sleepiness may cause patients to fall asleep while performing daily activities.

• Increased possibility of suicidal ideation and depression.

• The possibility of experiencing hallucinations, paranoia, compulsive behavior, psychosis, and impulse control disorders.

• Dizziness and orthostatic hypotension.

• Advise patients to avoid stopping the drug or changing the dose of their own accord. Any side effects must be reported to the physician, who may make an informed decision on how to proceed. In addition, patients must be forewarned of the withdrawal-emergent signs and symptoms if they stop taking the drug and asked to report these to the doctor immediately.

• Certain drugs may interfere with the action of Amantadine or react with it adversely. Patients should thus be encouraged to give their doctors a complete medical and drug history. Drug history should include all medications, dietary supplements, and herbal medicines and products.