In February 2018, the FDA approved amantadine (Osmolex ER, Osmotica Pharmaceuticals) for the treatment of Parkinson disease and drug-induced extrapyramidal reactions in adults.1

Parkinson disease is a neurological disorder where patients have a lack of dopaminergic neurons in the substantia nigra. The affected population is estimated to extend toward 10 million worldwide.2 Drug-induced extrapyramidal reactions, mainly caused by antipsychotics, has led to many problematic symptoms such as dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia. Anticholinergics, such as amantadine have been used to treat extrapyramidal symptoms caused by antipsychotics for many years now.3        

Dosage and Administration

Amantadine is taken in a dose of 129 mg orally in the morning. The dose can be increased in weekly intervals, to 322 mg (129-mg and 193-mg tablet) in the morning. Do not interchange amantadine with other amantadine products. Amantadine is an extended-release product and should be swallowed whole (do not chew, crush, split tablets), and can be taken with or without food.4

Titration interval and dosing frequency will need to be adjusted in patients with moderate to severe renal impairment.
 
Table 1. Renal Dose Adjustments
Estimated GFR (ml/min/1.73m2) Minimum Titration Interval Frequency of Dosing Regimen
60-89 (Mild renal impairment) Increase every week (no change) Every 24 hours (no change)
30-59 (Moderate renal impairment) Increase every 3 weeks Every 48 hours
15-29 (Severe renal impairment) Increase every 4 weeks Every 96 hours
<15 (End-stage renal impairment) Contraindicated

Pharmacology

The exact mechanism of amantadine is unknown. Amantadine is a weak N-methyl-D-aspartate uncompetitive antagonist and exhibits dopaminergic effects.4
 
Table 2. Method of Supply4
Dosing Administration/Packaging NDC Information
129 mg tablets
  • Unit-dose cards of 10 tablets
  • Bottles of 30 tablets
  • Bottles of 90 tablets
 
  • 68025-0075-11
  • 68025-0075-30
  • 68025-0075-90
193 mg tablets
  • Unit-dose cards of 10 tablets
  • Bottles of 30 tablets
  • Bottles of 90 tablets
   
  • 68025-0076-11
  • 68025-0076-30
  • 68025-0076-90
258 mg tablets
  • Unit-dose cards of 10 tablets
  • Bottles of 30 tablets
  • Bottles of 90 tablets
 
  • 68025-0077-11
  • 68025-0077-30
  • 68025-0077-90
NDC indicates National Drug Code.

Storage

Amantadine is stored at room temperature at 20°C to 25°C (68°F-77°F) with permitted excursions between 15°C to 30C (59°F-86°F) in a tight container.4

Drug Interactions and Contraindications

Other drugs that have anticholinergic effects (Benadryl, antipsychotics) can worsen the anticholinergic adverse effects (AEs) of amantadine. Doses may need to be reduced if anticholinergic AEs occur (drowsiness, dry mouth, dizziness, urinary retention).4

Amantadine has an excretion rate related to the acidity of the urine. Any drug, change in diet, or patient state that influences urine pH (carbonic anhydrase inhibitors, sodium bicarbonate, urinary tract infection) may alter the elimination or accumulation of amantadine and will need to be monitored.

Alcohol increases sedation and orthostatic hypotension and should not be taken with amantadine. Live influenza vaccines are also not recommended as amantadine may interfere with the efficacy of the vaccine.

Amantadine is contraindicated in patients with end-stage renal disease (creatinine clearance less than 15 ml/min/1.73m2).

Warnings and Precaution

Somnolence and excessive drowsiness have been seen in patients taking amantadine. Patients should be advised not to drive and to avoid other dangerous activities if they become sleepy. Dizziness and orthostatic hypotension can also occur with amantadine, especially with alcohol use. Advise patients to not use alcohol while taking amantadine.4

Suicide and/or suicidal attempts have also been reported in patients taking amantadine. Patients need to be monitored for depression and suicidal ideations. Amantadine can also exacerbate psychosis and cause aggressive behavior, hallucinations, and paranoia. Other compulsive behaviors that can occur include gambling urges, sexual urges, and binge eating.

Amantadine should not be abruptly discontinued as it may lead to symptoms similar to neuroleptic malignant syndrome (NMS), categorized by elevated temperatures, rigid muscles, and altered consciousness. Slowly taper the drug before withdrawing.

Adverse Reactions

The most common adverse reactions (≥5% of patients) at the recommended dosage of immediate-release amantadine were nausea, dizziness/lightheadedness, and insomnia.4

Pregnancy and Lactation

There is no data on the effect of amantadine in pregnant human patients. However, in rats and mice, there have been developmental toxicity resulting in embryo-lethality, reduced fetal body weights, and visceral and skeletal malformations.4

There is also no data on lactation. Potential adverse reactions to the infant and the benefits to the mother must be considered.

Clinical Studies

The efficacy and safety of this extended-release formulation is based on bioavailability studies to amantadine.4

Parkinson’s Disease Guidelines

According to the NICE guidelines for Parkinson disease, levodopa, dopamine agonists, monoamine oxidase B inhibitors, and catechol-o-methyl transferase inhibitors, all have some benefits in improving motor symptoms. Amantadine, (amantadine), is considered to not have benefits in motor symptoms benefits, off-time, and daily activities. Amantadine is only suggested for use in dyskinesia if modifying existing therapy did not help.5

Patient Counseling

Amantadine is a prescription drug used for the treatment of Parkinson disease and/or drug-induced extrapyramidal reactions in adult patients. Amantadine is taken at an initial dosage of 129 mg orally in the morning with or without food and can be increased weekly to a maximum dose of 322 mg daily. When taking amantadine, advise the patient to not chew, crush, or split the tablets. If a patient forgets to take a dose, they should just take the next dose at the next time scheduled. Amantadine should be stored at room temperature in a tight, closed container.4

Amantadine should not be discontinued abruptly as it may cause NMS symptoms and higher doses of amantadine need to be gradually tapered for 1 to 2 weeks before discontinuation. Overdoses have led to death with the lowest reported acute lethal dose of 0.8 grams amantadine. For acute overdose, supportive measures such as intravenous fluids can be given along with gastric decontamination if needed. Electrocardiographic monitoring should be done because arrhythmias have been reported after overdose. Increasing the acidity of urine may help increase the excretion rate of amantadine.

Patients should be warned of the sedative effects that amantadine can have and advise them to report any incidences of falling asleep while doing something in the daytime. Patients that have tendencies to fall asleep while on amantadine must be advised not to drive or operate machinery. Patients should also not take alcohol as that may cause increased sedative effects.  amantadine has also been shown to cause depression, suicide ideations, hallucinations, aggravate psychosis, and cause impulsive behavior such as gambling urges, sexual urges, and binge eating. Patients need to report any of these signs to the clinician. Dizziness and orthostatic hypotension have also been reported. Patients should stand up slowly after sitting or lying down for prolonged periods of time.

Adverse reactions that are frequently reported include nausea, lightheadedness, dizziness, and insomnia. Pregnant patients should be warned not to take amantadine as there have been reports of fetal harm from animal studies.

Patients who are taking both amantadine and other anticholinergic drugs or drugs that affect urinary pH should be monitored for additional side effects. Live influenza vaccines should not be given to the patient while on amantadine. Suggest an inactivated influenza vaccine instead.
REFERENCES
1. FDA approves Osmotica Pharmaceutical’s once-daily amantadine (amantadine) extended-release tablets for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults [news release]. Osmotica Pharmaceutical. www.osmolex.com/assets/doc/Osmotica_Press_Release.PDF. Updated February 19, 2018. Accessed September 10, 2018.
2. Causes and statistics. Parkinson’s Foundation. parkinson.org/understanding-parkinsons/causes-and-statistics. Accessed September 10, 2018.
3. Blair DT, Dauner A. Extrapyramidal symptoms are serious side-effects of antipsychotic and other drugs. Nurse Pract. 1992; 17(11):56,62-4,67.
4. amantadine [prescribing information]. Bridgewater, New Jersey: Vertical Pharmaceuticals; 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2?rel=0" 018/209410s000lbl.pdf Accessed September 10, 2018.
5. Parkinson’s disease in adults. National Institute for Health and Care Excellence. www.nice.org.uk/guidance/ng71/chapter/Recommendations#pharmacological-management-of-non-motor-symptoms. Updated July 2017. Accessed September 10, 2018.