Amantadine

Dosage for Amantadine is highly individualized and depends on the specific condition being treated, as well as the patient's age and kidney function.

• Parkinson’s Disease: The standard dose for immediate-release Amantadine is 100 mg twice daily when used as monotherapy. If a patient is already taking other antiparkinsonian drugs, the starting dose is usually 100 mg once daily, which may be increased to 100 mg twice daily after one to several weeks. Some patients may require up to 400 mg daily in divided doses, though toxicity risk increases significantly above 200 mg.
• Drug-Induced Extrapyramidal Reactions: The usual dose is 100 mg twice daily. Patients with particularly severe symptoms may require 300 mg daily in divided doses.
• Influenza A: For treatment or prophylaxis, the standard dose is 200 mg daily, either as a single dose or 100 mg twice daily.
• Extended-Release (Gocovri): For dyskinesia, the initial dose is 68.5 mg once daily at bedtime, increasing to 137 mg once daily after one week.

Amantadine is FDA-approved for use in children for the treatment of Influenza A, though it is rarely used for this purpose today due to viral resistance.

• Children (1 to 9 years): The dose is calculated by weight, typically 4.4 to 8.8 mg/kg per day, not to exceed 150 mg per day. This is usually divided into two doses.
• Children (9 to 12 years): 100 mg twice daily.
• Movement Disorders: Amantadine is not generally approved for Parkinson's-like symptoms in pediatric populations, and its safety in children for non-antiviral indications has not been established.

Renal Impairment

Because Amantadine is cleared by the kidneys, dosage adjustments are mandatory for anyone with a reduced Glomerular Filtration Rate (GFR).

• Creatinine Clearance (CrCl) 30-50 mL/min: Dose may be reduced to 100 mg daily.
• CrCl 15-29 mL/min: Dose may be reduced to 100 mg every other day.
• CrCl <15 mL/min (End-stage renal disease): 100 mg every 7 days.

Failure to adjust the dose in these patients can lead to severe neurotoxicity, including seizures and coma.

Hepatic Impairment

No specific dosage adjustments are typically required for patients with liver disease, as the drug is not significantly metabolized by the liver. However, caution is advised as these patients may have secondary renal issues.

Elderly Patients

Patients over the age of 65 are at a higher risk of side effects due to age-related declines in kidney function. Healthcare providers usually start elderly patients at the lowest possible dose (100 mg once daily) and monitor closely for confusion or hallucinations.

To ensure the best results and minimize side effects, follow these guidelines:

• Consistency: Take the medication at the same time(s) each day. If taking it twice daily, space the doses evenly (e.g., morning and mid-afternoon).
• Food: You may take Amantadine with or without food. If the medication causes an upset stomach, taking it with a meal or a glass of milk may help.
• Sleep Interference: Because Amantadine can cause insomnia, the last dose of the day should generally be taken in the late afternoon rather than right before bed (unless using the Gocovri extended-release brand, which is specifically designed for bedtime dosing).
• Swallowing: Immediate-release tablets and capsules should be swallowed whole. Do not crush or chew extended-release formulations (Osmolex ER or Gocovri) as this can cause the entire dose to be released at once, increasing the risk of toxicity.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Never double the dose to catch up, as this significantly increases the risk of adverse neurological effects.

Amantadine overdose is a medical emergency and can be fatal. Signs of overdose include:

• Severe confusion or agitation
• Hallucinations and psychosis
• Seizures (convulsions)
• Cardiac arrhythmias (irregular heartbeat)
• Acute respiratory distress

In the event of a suspected overdose, call 911 or your local emergency services immediately. Treatment typically involves supportive care, intravenous fluids, and sometimes the administration of physostigmine to reverse central nervous system toxicity. Hemodialysis is not effective in removing Amantadine from the system.

> Important: Follow your healthcare provider's dosing instructions precisely. Do not adjust your dose or stop taking the medication without medical guidance, as sudden discontinuation can lead to a worsening of symptoms or a withdrawal syndrome.

Most patients taking Amantadine will experience some mild to moderate side effects as their body adjusts to the medication. These often diminish over time but should be monitored.

• Nausea and Anorexia: A feeling of sickness in the stomach or a loss of appetite. This is usually most prominent during the first two weeks of therapy.
• Dizziness and Lightheadedness: Often caused by orthostatic hypotension (a drop in blood pressure when standing up). Patients should rise slowly from a sitting or lying position.
• Insomnia: Difficulty falling or staying asleep. This is due to the drug's mildly stimulatory effect on the central nervous system.
• Livedo Reticularis: This is a very specific side effect of Amantadine. It appears as a reddish or purplish 'net-like' mottling of the skin, usually on the legs. While it looks concerning, it is typically harmless and reverses once the drug is discontinued.

• Dry Mouth (Xerostomia): A decrease in saliva production which can lead to dental issues if not managed.
• Constipation: Slowing of the digestive tract, which may require increased fiber or fluid intake.
• Peripheral Edema: Swelling of the ankles or feet due to fluid retention.
• Blurred Vision: Difficulty focusing, which may affect the ability to drive or operate machinery.
• Agitation and Nervousness: A feeling of 'jitteriness' or anxiety.

• Urinary Retention: Difficulty starting urination or fully emptying the bladder, particularly in men with enlarged prostates.
• Ocular Changes: Corneal edema or decreased visual acuity. Any change in vision requires an immediate ophthalmic evaluation.
• Skin Rash: Eczematoid dermatitis or photosensitivity (increased sensitivity to sunlight).
• Leukopenia: A decrease in white blood cell count, which may slightly increase the risk of infection.

> Warning: Stop taking Amantadine and call your doctor immediately if you experience any of these serious reactions.

• Hallucinations and Psychosis: Seeing or hearing things that are not there, or experiencing severe confusion and paranoia. This is more common in elderly patients or those with pre-existing psychiatric conditions.
• Suicidal Ideation: New or worsening thoughts of self-harm or suicide. Amantadine has been associated with mood changes that require urgent intervention.
• Seizures: Amantadine can lower the 'seizure threshold,' making a seizure more likely, especially in those with a history of epilepsy.
• Congestive Heart Failure (CHF): Symptoms include sudden weight gain, shortness of breath (especially when lying down), and significant swelling in the legs.
• Neuroleptic Malignant Syndrome (NMS): Although rare, if Amantadine is stopped abruptly, patients may develop high fever, muscle rigidity, and altered mental status. This is a life-threatening emergency.
• Impulse Control Disorders: Some patients experience intense urges to gamble, increased sexual urges, or uncontrollable spending. These are 'reward-seeking' behaviors triggered by the drug's effect on dopamine.

Prolonged use of Amantadine may lead to certain 'wearing off' effects where the drug becomes less effective for Parkinson's symptoms. Additionally, the skin mottling (livedo reticularis) may become more pronounced over years of use. There is also a risk of developing corneal deposits or chronic edema in the eyes, necessitating regular eye exams for long-term users.

No FDA black box warnings currently exist for Amantadine. However, the FDA does require prominent warnings regarding the risk of suicide, CNS depression, and the dangers of abrupt discontinuation.

Report any unusual symptoms or changes in behavior to your healthcare provider immediately. Side effects can often be managed by adjusting the dose rather than stopping the medication entirely.

Amantadine is a potent medication that affects the central nervous system. Patients must be aware that its benefits come with significant responsibilities regarding monitoring and safety. It is not suitable for everyone, particularly those with certain underlying psychiatric or renal conditions. Patients should never share this medication with others, even if they have similar symptoms.

At this time, there are no FDA black box warnings for Amantadine. However, this does not mean the drug is without risk. Clinicians treat the warnings for suicidality and CNS toxicity with the highest level of clinical priority.

Allergic Reactions / Anaphylaxis Risk

While rare, serious allergic reactions can occur. Symptoms include hives, difficulty breathing, and swelling of the face, lips, or throat. If these occur, seek emergency care immediately and do not take the medication again.

Psychiatric and CNS Risks

Amantadine can cause significant changes in mental status. Patients with a history of schizophrenia, bipolar disorder, or severe depression must be monitored closely. There is a documented risk of increased suicidality and the development of 'impulse control disorders,' where patients cannot resist the urge to gamble, spend money, or engage in other risky behaviors.

Seizure Disorders

Amantadine may increase the frequency or severity of seizures in patients with a history of epilepsy. Healthcare providers will weigh the benefits against the risks in these individuals.

Congestive Heart Failure (CHF)

Because Amantadine can cause fluid retention and peripheral edema, it may worsen pre-existing heart failure. Patients should report any sudden swelling or shortness of breath to their doctor immediately.

Glaucoma and Ocular Health

Amantadine has mild anticholinergic properties, which can increase intraocular pressure. Patients with narrow-angle glaucoma should use this medication with extreme caution.

To ensure safe use, your healthcare provider may require the following:

• Renal Function Tests: Baseline and periodic Blood Urea Nitrogen (BUN) and Creatinine tests to ensure the kidneys are clearing the drug effectively.
• Blood Pressure Monitoring: To check for orthostatic hypotension.
• Skin Exams: To monitor for the development of livedo reticularis.
• Mental Status Exams: Regular check-ins to screen for depression, hallucinations, or impulsive behaviors.

Amantadine can cause dizziness, blurred vision, and 'sleep attacks' (sudden onset of sleepiness). Do not drive, operate heavy machinery, or engage in dangerous activities until you know how this medication affects you. This is especially important when first starting the drug or after a dose increase.

Avoid alcohol while taking Amantadine. Alcohol can increase the central nervous system side effects of the drug, leading to extreme dizziness, confusion, and a higher risk of fainting or falls. In some cases, alcohol can trigger a toxic psychiatric reaction when combined with Amantadine.

Do not stop taking Amantadine suddenly. Abruptly stopping the medication can lead to a 'rebound' effect where Parkinson's symptoms become severely worse. More dangerously, it can trigger a condition similar to Neuroleptic Malignant Syndrome (NMS), characterized by high fever, rigid muscles, and mental confusion. If the drug needs to be stopped, your doctor will provide a tapering schedule to slowly reduce the dose.

> Important: Discuss all your medical conditions, especially kidney disease, seizure disorders, and mental health history, with your healthcare provider before starting Amantadine.

• Live Attenuated Influenza Vaccine (LAIV): Because Amantadine is an antiviral, it can interfere with the replication of the weakened virus in the live flu vaccine (nasal spray), making the vaccine ineffective. Amantadine should be stopped at least 48 hours before receiving the vaccine and should not be restarted for at least two weeks after vaccination.
• Potassium Chloride (Solid Oral Forms): Amantadine's mild anticholinergic effects can slow gut motility, increasing the time potassium tablets sit in the esophagus or stomach, which may cause severe irritation or ulcers.

• Anticholinergic Drugs (e.g., Benztropine, Oxybutynin, Trihexyphenidyl): Combining Amantadine with other anticholinergics can lead to 'anticholinergic toxicity.' Symptoms include severe confusion, hallucinations, dry mouth, constipation, and inability to urinate. This is particularly dangerous for elderly patients.
• Thiazide Diuretics (e.g., Hydrochlorothiazide): These can reduce the renal clearance of Amantadine, leading to higher blood levels and increased risk of toxicity.
• Carbonic Anhydrase Inhibitors (e.g., Acetazolamide): These drugs make the urine more alkaline, which reduces the kidneys' ability to excrete Amantadine, potentially leading to toxic accumulation.

• Trimethoprim/Sulfamethoxazole (Bactrim): This antibiotic can compete with Amantadine for secretion in the kidney tubules, potentially increasing Amantadine levels in the blood.
• Quinine/Quinidine: May decrease the renal clearance of Amantadine.
• Stimulants (e.g., Caffeine, ADHD medications): May increase the risk of nervousness, insomnia, and rapid heart rate when taken with Amantadine.

• Alcohol: As noted previously, alcohol significantly increases the risk of CNS side effects and should be strictly avoided.
• High-Protein Meals: While food generally doesn't stop Amantadine absorption, extremely high-protein meals can theoretically interfere with the transport of many dopaminergic drugs into the brain, though this is more significant for levodopa than for Amantadine.

• St. John’s Wort: May increase the risk of serotonin-related side effects or alter the metabolism of various drugs, though the direct interaction with Amantadine is considered low-risk compared to other antidepressants.
• Melatonin/Valerian Root: May increase the sedative effects if Amantadine is causing daytime sleepiness, but could also complicate the management of Amantadine-induced insomnia.

Amantadine is not known to interfere significantly with most common laboratory tests. However, it may rarely cause elevations in liver enzymes (AST/ALT) or bilirubin. Always inform the laboratory staff and your doctor that you are taking Amantadine before undergoing blood or urine tests.

Management Strategy

For each major interaction, the primary management strategy is dose adjustment or increased monitoring. If you must take a drug that interacts with Amantadine, your doctor may lower your Amantadine dose or schedule more frequent blood tests to check your kidney function.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. This includes over-the-counter cold medicines, which often contain antihistamines with anticholinergic properties.

Amantadine must NEVER be used in the following circumstances:

1. 1Known Hypersensitivity: If you have had a previous severe allergic reaction (anaphylaxis, Stevens-Johnson Syndrome) to amantadine hydrochloride or any of the inactive ingredients in the formulation.
2. 2End-Stage Renal Disease (ESRD): While not strictly 'never' used, it is contraindicated in patients who cannot be closely monitored for weekly dosing, as the drug is not cleared by dialysis and will rapidly reach lethal levels.
3. 3Untreated Narrow-Angle Glaucoma: Due to the risk of acutely increasing intraocular pressure, which can lead to permanent vision loss.

In these cases, a healthcare provider will perform a careful risk-benefit analysis:

• History of Seizures: Amantadine can lower the threshold for convulsions. It should be used with extreme caution in patients with epilepsy or those taking other medications that lower the seizure threshold.
• Congestive Heart Failure or Peripheral Edema: The drug's tendency to cause fluid retention can exacerbate these conditions.
• Active Psychosis or Severe Neurosis: Because Amantadine can induce hallucinations and agitation, it may worsen pre-existing psychiatric instability.
• Eczematoid Rash: Patients with a history of chronic skin conditions may find that Amantadine worsens their symptoms or triggers livedo reticularis.
• Gastric Ulcers: Use with caution in patients with a history of ulcers, especially when combined with other medications that slow gastric emptying.

There is a potential for cross-sensitivity with other adamantane derivatives, such as Rimantadine (another antiviral). If you have had an allergic reaction to Rimantadine, you should inform your doctor, as you are likely to be allergic to Amantadine as well.

> Important: Your healthcare provider will evaluate your complete medical history, including your kidney function and mental health status, before prescribing Amantadine. Always provide a full list of your current medical conditions.

Amantadine is classified as FDA Pregnancy Category C. This means that animal studies have shown evidence of teratogenicity (birth defects) at high doses, but there are no adequate, well-controlled studies in humans.

• Trimester Risks: In animal models, Amantadine has caused cardiovascular and skeletal malformations.
• Clinical Recommendation: Amantadine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women of childbearing age should discuss effective contraception with their doctor while taking this medication.

Amantadine is known to be excreted in human milk. Because it is a dopaminergic agent, it may also suppress prolactin secretion, potentially reducing the mother's milk supply. There is a risk of side effects in the nursing infant, such as vomiting, urinary retention, and skin rashes. Breastfeeding while taking Amantadine is generally not recommended. If the medication is essential for the mother's health, an alternative feeding method for the infant should be considered.

• Approved Use: Amantadine is approved for children aged 1 year and older for the treatment and prophylaxis of Influenza A.
• Movement Disorders: It is not approved for the treatment of Parkinson's disease or extrapyramidal symptoms in children.
• Safety: In children, the risk of central nervous system side effects (agitation, hallucinations) may be higher than in adults. Dosing must be strictly based on body weight.

Elderly patients (aged 65 and older) represent the largest group of Amantadine users, yet they are also at the highest risk for toxicity.

• Renal Clearance: Kidney function naturally declines with age. Since Amantadine is cleared by the kidneys, the half-life can double or triple in older adults.
• Fall Risk: Dizziness and orthostatic hypotension significantly increase the risk of falls and fractures in the elderly.
• Cognitive Effects: Older adults are much more susceptible to drug-induced confusion and hallucinations.
• Polypharmacy: Seniors are often on multiple medications (anticholinergics, diuretics) that interact with Amantadine.

This is the most critical special population for Amantadine. Dose adjustments are required for any CrCl below 50 mL/min.

• Monitoring: Frequent monitoring of serum creatinine is necessary.
• Toxicity: Signs of toxicity (confusion, twitching, seizures) in a patient with kidney disease should be treated as a medical emergency.

While the liver does not clear Amantadine, patients with severe liver disease (Child-Pugh Class C) often have 'hepatorenal syndrome' or other kidney issues. Caution is advised, and clinicians should monitor renal function closely in these patients.

> Important: Special populations require individualized medical assessment. Never start Amantadine if you are pregnant or breastfeeding without a detailed consultation with your specialist.

Amantadine's pharmacological profile is unique because it acts on multiple systems simultaneously.

1. 1Viral M2 Protein Inhibition: It binds to the transmembrane domain of the M2 protein ion channel of Influenza A. This prevents the hydrogen ion (H+) influx required for the virus to release its ribonucleoprotein complexes into the host cell cytoplasm.
2. 2NMDA Receptor Antagonism: Amantadine is a low-affinity, non-competitive antagonist of the NMDA-type glutamate receptors. By binding to these receptors, it reduces the excitatory effects of glutamate, which is overactive in the basal ganglia of Parkinson's patients. This is the primary mechanism for its anti-dyskinesia effect.
3. 3Dopaminergic Modulation: It increases the synthesis and release of dopamine while inhibiting its reuptake into presynaptic neurons. It may also increase the sensitivity of postsynaptic dopamine receptors.

• Onset of Action: For Parkinson's disease, the onset of therapeutic effect is typically seen within 48 to 72 hours. For antiviral effects, it must be started within 24-48 hours of symptom onset.
• Duration: The effects of a single dose last approximately 8 to 12 hours for immediate-release forms.
• Tolerance: Some patients may experience a 'diminishing return' after several months of therapy, where the drug's efficacy for motor symptoms decreases.

| Parameter | Value |

|---|---|

| Bioavailability | 86% - 94% |

| Protein Binding | ~67% |

| Half-life | 12 - 17 hours (Normal Renal Function) |

| Tmax | 2 - 4 hours (Immediate Release) |

| Metabolism | Minimal (<10% Acetylated) |

| Excretion | Renal 90% (Unchanged) |

• Molecular Formula: C10H17N·HCl
• Molecular Weight: 187.71 g/mol
• Solubility: Highly soluble in water and alcohol.
• Structure: A stable, symmetric tricyclic amine consisting of an adamantane backbone with an amino group at one of the bridgehead positions.

Amantadine is classified as an Influenza A M2 Protein Inhibitor and a Dopaminergic/Antiglutamatergic Agent. It is related to Rimantadine (antiviral) and Memantine (an NMDA antagonist used in Alzheimer's disease).