Amantadine - an antiviral drug for Parkinson disease.

Amantadine is an antiviral drug used for the treatment and prophylaxis of influenza A infections. It is not currently recommended because of resistance to the drug. It is also used to treat the following disorders:

  • Treatment of drug-induced extrapyramidal symptoms.
  • Treatment of Parkinson disease with or without concomitant dopaminergic medications.

Off-Label Uses Of Amantadine in Adults include: 

 

  • Chorea of Huntington disease
  • Fatigue related to multiple sclerosis
  • Restless legs syndrome;
  • Traumatic brain injury

 

Treatment & prophylaxis of Influenza A:

  • Note: Currently not recommended for the treatment or prophylaxis of influenza A infection because of resistance to it.

Treatment of Influenza A (manufacturer's labeling):

  • Immediate release:
    • 200 mg once a day or 100 mg twice a day.
    • Amantadine therapy should be initiated within 24 to 48 hours of the onset of symptoms and continued for a day or two after the resolution of symptoms.
    • Therapy is generally recommended for a total of five days.

Prophylaxis of Influenza A infection:

  • Immediate release:
    • 200 mg once daily or 100 mg twice daily.
    • It should be continued for 14 days following vaccination.

Drug-induced extrapyramidal symptoms:

  • Extended-release tablet:
    • 129 mg once daily
    • Increase the dose at weekly intervals to a maximum dose of 322 mg/day.
  • Immediate-release:
    • 100 mg twice daily which may be increased to 300 mg/day if required.

Parkinson disease:

  • Extended-release formulations:
    • Capsule
      • 137 mg once daily. Increase the dose after 1 week to the usual dose of 274 mg once daily.
    • Tablet
      • 129 mg once daily. Increase the dose at weekly intervals to a maximum dose of 322 mg per day.
  • Immediate release:
    • 100 mg twice daily as monotherapy
    • Increase the dose to 400 mg/day in divided doses.

Off-label use of Chorea of Huntington disease:

  • Immediate release:
    • 100 mg 3 to 4 times daily.

Off-label use in fatigue related to Multiple sclerosis:

  • Immediate release:
    • 100 mg twice daily.

Off-label use in Restless legs syndrome:

  • Immediate release:
    • 100 mg daily. Increase the dose by 100 mg every 3-5 days to a maximum daily dose of 300 mg per day in 1-3 divided doses.

Off-label use in Traumatic brain injury:

  • Immediate release:
    • 100 mg twice daily in the morning and afternoon. The dose may be increased by 100 mg weekly to a maximum daily dose of 200 mg twice daily.

Discontinuation of therapy: Amantadine should be slowly tapered off 

Dose in children:

Dose in Attention-deficit hyperactivity disorder (ADHD):

  • Children older than 5 years and Adolescents:
    • 50 mg/day.
    • Titrate the dose at 4 - 7 days intervals in 50 mg increments to the usual reported dose of 50  - 150/ day in 1-3 divided doses.
    • The doses should be divided into morning, noon and 4 pm dose.
  • The maximum daily dose of amantadine based on the weight is:
    • 30 kgs or less: 100 mg/day
    • more than 30 kgs: 150 mg/day

Amantadine dose in Autism (hyperactivity, irritability):

  • Children older than 5 years and Adolescents:
    • 2.5 mg/kg/dose once a day for 1 week, then increase to 2.5 mg/kg/dose twice daily to a maximum daily dose of 200 mg/day

Treatment & prophylaxis of Influenza A:

Note: Amantadine is not currently recommended by the ACIP for the treatment and prophylaxis of influenza A infection.

  • Treatment of Influenza A:

    • Children aged 1-9 years:
      • 5 mg/kg/day in 2 divided doses to a maximum daily dose of 150 mg/day.
    • Children older than 10 years and less than 40 kgs:
      • 5 mg/kg/day in 2 divided doses
    • Children older than 10 years and more than 40 kgs:
      • 100 mg twice daily.

Note: The usual duration of treatment is 3-5 days. Therapy should be initiated within 48 hours of symptoms and continued for 48 hours after the resolution of symptoms. When used for prophylaxis in high-risk patients, it should be continued for 2 weeks after vaccination (until immunity has developed).


Fatigue & lassitude associated with Multiple Sclerosis:

    • More than 10 years or weight less than 40 kgs:
      • 2.5 mg/kg/dose twice daily to a maximum daily dose of 150 mg per day.
    • More than 10 years and weight greater than 40 kg:
      • 100 mg twice daily to a maximum dose of 400 mg per day.

Traumatic brain injury:

  • Children older than 6 years and Adolescents less than 16 years:
    • 4-6 mg/kg/day in 2 divided doses to a maximum daily dose of:
      • 150 mg if less than 10 years or less than 40 kgs
      • 200 mg per day if older than 10 years or more than 40 kgs
  • Adolescents older than 16 years of age:
    • 100 mg twice daily for two weeks followed by 150 mg twice daily for 7 days and then 200 mg twice daily week-4 onwards.

Dose in Pregnancy & lactation:

Pregnancy Risk Factor C

In humans, adverse events have been reported in animal studies. Agents other than amantadine should not be used to treat Parkinson disease in pregnant patients.

Use of amantadine during breastfeeding

Amantadine can be found in breastmilk, and it may affect milk production. Manufacturers recommend weighing the risks to infant exposure against the benefits of breastfeeding/treatment of mother. 

Renal dose:

Extended-release capsule:

      • CrCl 60 mL/minute/1.73m2 or More
        • A patient who is taking a medication with a high dose of side effects does not need to adjust their dosage.
      • Patients with CrCl 30 to 59% mL/minute/1.73m2
        • 68.5 mg daily. After one week, increase the dose to 137mg
      • Patients with CrCl 15-29 mL/minute/1.73m2
        • 68.5 mg daily
      • CrCl 15 mL/minute/1.73m (ESRD) (includes patients on hemodialysis).
        • Contraindicated

      Extended-release tablet

      • CrCl >=60mL/minute/1.73m2
        • A patient who is taking a medication with a high dose of side effects does not need to adjust their dosage.
      • CrCl 30 to 59% mL/minute/1.73m2
        • Each day, 129 mg. You can increase the dosage to 3 weeks, to 322 mg once a day.
      • CrCl 15 to 29, mL/minute/1.73m2
        • Dose: 129 mg once every 96 hours. You should not increase the dose more often than once every four weeks, to a maximum of 322 mg every hour
      • CrCl 15 mg/minute/1.73m (ESRD), for patients on hemodialysis
        • Contraindicated

      Tablets for immediate release:

      • CrCl 30-50 mL/minute
        • 200 mg per day on Day 1, and then 100 mg each day
      • CrCl 15 to 29, mL/minute
        • 200 mg on Day 1, 100 mg on Days 2 and 3.
      • CrCl 15mL/minute
        • 200 mg per week
      • Hemodialysis
        • 200 mg per week
      • Peritoneal dialysis
        • Supplemental doses are not necessary
      • Continuous renal replacement therapy
        • 100 mg daily, or alternate days

Dose in Liver disease:

 The manufacturer has not recommended any dose adjustment in patients with liver disease. It should be used with caution. 

Side effects:

Common Side Effects:

  • Cardiovascular:
    • Orthostatic hypotension
    • presyncope
    • syncope
    • peripheral edema
  • Central nervous system:
    • Dizziness
    • delusions
    • hallucination
    • illusion
    • paranoia
    • falling
  • Gastrointestinal:
    • Xerostomia
    • constipation

Less common side effects:

  • Cardiovascular:
    • Livedo reticularis
  • Central nervous system:
    • Insomnia
    • anxiety
    • depression
    • headache
    • abnormal dreams
    • agitation
    • ataxia
    • confusion
    • drowsiness
    • fatigue
    • irritability
    • nervousness
    • dyschromia
    • dystonia
    • apathy
    • suicidal ideation
  • Gastrointestinal:
    • Nausea
    • decreased appetite
    • anorexia
    • diarrhea
    • vomiting
  • Genitourinary:
    • Urinary tract infection
    • benign prostatic hypertrophy
  • Hematologic & oncologic:
    • Bruises
  • Neuromuscular & skeletal:
    • Joint swelling
    • muscle spasm
  • Ophthalmic:
    • Blurred vision
    • cataract
    • xerophthalmia
  • Respiratory:
    • Dry nose
    • cough

 

Contraindication to amantadine include:

  • A severe allergy to amantadine and any component of this formulation
  • End-stage renal disease (extended only).

Warnings and Precautions

  • Depression in the CNS:
    • CNS depression can be caused by Amantadine, which may impair mental or physical abilities. Before initiating therapy, patients who use heavy machinery should be notified.
    • Some patients may fall asleep completely without warning signs. Patients taking the drug to treat Parkinson disease or those with a sleep disorder may experience this effect.
  • Disorders of impulse control:
    • It has been linked to pathological gambling, increased libido and urges for money. Some patients may benefit from dose reduction, but not all.
  • Melanoma
    • Periodic skin examination is recommended as studies have shown that it can be associated with the development melanoma.
  • Psychosis
    • Monitor patients for visual and auditory hallucinations and delusions, illusions, paranoia, and other symptoms, particularly after adjustment of doses and in patients suffering from psychotic disorders.
  • Suicidal ideation and depression:
    • Patients with a history of mental illness have been shown to be at greater risk for suicidal ideation/attempt, especially if they are taking Amantadine.
  • Cardiovascular disease
    • Patients with heart failure should be cautious. Dosage reduction may be necessary if there is a possibility of dizziness, orthostatic hypotension or peripheral edema.
  • Eczema:
    • Patients who have a history of recurrent or eczematoid skin dermatitis should not use this drug.
  • Glaucoma
    • Patients with untreated angle closing glaucoma should be avoided
  • Hepatic impairment
    • It has been shown to cause liver enzyme elevations that can be reversed.
  • Influenza A:
    • The current ACIP guidelines don't recommend the use of amantadine and rimantadine for treatment or prevention of influenza A infection.
  • Renal impairment
    • Patients with ESRD should avoid extended-release formulations. Patients with kidney failure should not take Amantadine.
  • Seizure disorder
    • Patients who have had seizure disorders in the past should not use this drug.

 

Amantadine: Drug Interaction

Note: Drug Interaction Categories:

  • Risk Factor C: Monitor When Using Combination
  • Risk Factor D: Consider Treatment Modification
  • Risk Factor X: Avoid Concomitant Use
    •  

    Risk Factor C (Monitor therapy).

    Agents for Alkalinizing May increase serum Amantadine concentrations.
    Anticholinergic Agents Anticholinergic agents may have an anticholinergic effect that Amantadine can enhance.
    Bromopride Might decrease the therapeutic effects of Anti-Parkinson Agents. (Dopamine Agonist).
    BuPROPion Anti-Parkinson Agents (Dopamine Agonists) can increase the toxic/adverse effects of BuPROPion.
    Inhibitors of carbonic anhydrase May increase serum Amantadine concentrations.
    Glycopyrrolate Systemic Amantadine might increase the anticholinergic effects of Glycopyrrolate.
    Memantine Memantine's toxic/adverse effects may be exacerbated by NMDA Receptor Antagonists.
    Methylphenidate May increase the toxic/adverse effects of Anti-Parkinson Agents. (Dopamine Agonist).
    Metoclopramide Might decrease the therapeutic effects of Anti-Parkinson Agents. (Dopamine Agonist).
    Propiverine May increase the harmful/toxic effects of Amantadine.
    Solriamfetol Anti-Parkinson Agents (Dopamine Agonists) can increase the hypertensive effects of Solriamfetol.
    Trimethoprim Amantadine may have an adverse/toxic effect. In particular, there may be an increase in the risk of myoclonus or delirium. Amantadine can increase serum Trimethoprim concentrations. Trimethoprim could increase Amantadine's serum concentration.
    Urinary acidifying agents May lower the serum level of Amantadine.

    Risk Factor D (Think about therapy modification)

     
    Antipsychotic Agents, First Generation (Typical) AntiParkinson Agents (Dopamine Agonist) may have a decreased therapeutic effect. Anti-Parkinson Agents, Dopamine Agonist, may decrease the therapeutic effect Antipsychotic Agents First Generation [Typical]. If possible, avoid concomitant therapy and watch for decreased effects of both agents if they cannot be avoided. Antipsychotics other than clozapine or quetiapine, may not be as effective in reducing the anti-Parkinson effects.
    Antipsychotic Agents, Second Generation (Atypical) AntiParkinson Agents (Dopamine Agonist) may have a less therapeutic effect. Treatment: If possible, consider using another antipsychotic agent in Parkinson's patients. Clozapine and quetiapine may be used if an atypical antipsychotic is required. These drugs have the lowest interaction risks.
    Influenza Virus Vaccine (Live/Attenuated). Antiviral Agents (Influenza B and A) can reduce the therapeutic effects of Influenza Virus Vaccine Live/Attenuated. Management: Do not use antiinfluenza agents during the 48-hour period preceding and ending two weeks after live vaccine administration.
    Tafenoquine Increased serum concentrations of OCT2 Substrates. Management: Do not use OCT2 Substrates with tafenoquine. If the combination is impossible to avoid, then monitor for signs of toxic effects and consider taking a lower dose of OCT2 Substrates according to the labeling.
     

    Risk Factor X (Avoid Combination)

    Alcohol (Ethyl). Amantadine may increase the CNS depressant effects. Dose-dumping may occur for at least one extended release amantadine product.
    Alizapride Might decrease the therapeutic effects of Anti-Parkinson Agents. (Dopamine Agonist).
    Amisulpride Anti-Parkinson Agents (Dopamine Agonist) may have a decreased therapeutic effect. Anti-Parkinson Agents, Dopamine Agonist, may decrease the therapeutic effects of Amisulpride.
    Sulpiride Might decrease the therapeutic effects of Anti-Parkinson Agents. (Dopamine Agonist).

Monitoring parameters:

Baseline and then periodic monitoring of the following parameter should be done:

  • Renal function
  • mental status including psychosis,
  • hallucinations,
  • depression and suicidality,
  • dizziness,
  • blood pressure
  • orthostasis

 

How to Administer:

Patients should be advised that extended-release capsules are taken.At bedtime, with or without food. You should swallow the drug whole, without chewing, crushing, or dividing it.

The Extended-release tablet is recommendedIn the morning, without food. You should swallow the tablets whole, without chewing or crushing them.

 

Mechanism of Action of Amantadine:

  • Antiviral Mechanism of Action:
    • Amantadine seems to block the release of viral nucleic acids into host cells by interfering in the transmembrane domains of the viral M2 proteins.
    • The exact mechanism of action is unknown. Amantadine can also be used to inhibit the replication of influenza A virus, but it has very little effect on influenza B virus.
  • Mechanism of action in Parkinson disease
    • Amantadine has been shown to be a weak and non-competitive NMDA antagonist.
    • It is unknown what the exact mechanism of amantadine's use in treating Parkinson disease or drug-induced extrapyramidal symptoms.
    • It also exhibits anticholinergic activities like dry mouth and urinary retention. However, studies on amantadine do not show that it has anticholinergic properties.

The Beginning of ActionIt is ready in 48 hours. It is easily absorbed and 67% protein bound. Bio-availabilityIs 86% to 94% Eliminating half-lifePatients with normal renal function have a time of 16 hours (9 to 31 hours), while patients with end-stage kidney disease take 8 days.

Time until plasma concentration peaksThe extended-release capsule lasts 12 hours, while the extended-release tablet takes 7.5 hours. The immediate-release tablet takes 2 to 4 hours. ExcretionIt is mostly via urine. 

 

International Brands:

  • Actison
  • Adamine
  • Amadin
  • Amanda
  • Amandin
  • Amandine
  • Amantadin
  • Amantan
  • Amantin
  • Amantine
  • Amantix
  • Amantril
  • Ampakine
  • Atadin
  • Atarin
  • Atenergine
  • Enzil
  • Hofcomant
  • Infex
  • Influ
  • Kinestrel
  • Lysovir
  • Mantadan
  • Mantadix
  • Mantidan
  • Mantra
  • Midantan
  • Neomidantan
  • Neomidantin
  • Parkadina
  • Parkintrel
  • PK Merz
  • PK-Merz
  • Prayanol
  • Symadin
  • Symmetrel
  • Tregor
  • Viergyt-K
  • Viregyt
  • Viregyt K
  • Viregyt-K
  • Virofral
  • Virosol
  • Zintergia
  • DOM-Amantadine HCl
  • MYLAN-Amantadine
  • PDP-Amantadine
  • PHL-Amantadine

 

Brands in Pakistan :

Amantadine (HCl) [Tabs 100 mg]

AMANTIN GENE-TECH LABORATORIES
PK MERZ BROOKES PHARMACEUTICAL LABORATORIES (PAK.) LTD.

 

Amantadine (HCl) [Caps 100 mg]

VIROFAL BIOCARE PHARMACEUTICAL
VIROFRAL ENGLISH PHARMACEUTICALS INDUSTRIES

 

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