Amantadin

There is no specific antidote for an overdose of Amantadine. However, slowly administered intravenous physostigmine in 1 and 2 mg doses in an adult2 at 1- to 2-hour intervals and 0.5 mg doses in a child3 at 5- to 10-minute intervals up to a maximum of 2 mg/hour have been reported to be effective in the control of central nervous system toxicity caused by amantadine hydrochloride. For acute overdosing, general supportive measures should be employed along with immediate gastric lavage or induction of emesis. Fluids should be forced, and if necessary, given intravenously. The pH of the urine has been reported to influence the excretion rate of Amantadine. (L1744)

The anti-influenza A activities of amantadine and ribavirin were investigated seperately and in combination. In ferret tracheal ciliated epithelium, the combination of drugs synergistically delayed the virus-induced cytopathic effect.

Concurrent use /of alcohol/ with amantadine is not recommended since this may increase the potential for CNS effects such as dizziness, lightheadedness, orthostatic hypotension, or confusion.

Concurrent use /of anticholinergics, or other medications with anticholinergic activity; tricyclic antidepressants; other antidyskinetics; antihistamines; or phenothiazines/ with amantadine may potentiate the anticholinergic-like side effects, especially those of confusion, hallucinations, and nightmares; dosage adjustments of these medications or of amantadine may be necessary; also, patients should be advised to report occurrences of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy.

Concurrent use /of opioid- and anticholinergic-containing antidiarrheals/ with amantadine may potentiate the anticholinergic-like side effects; although significant interaction is unlikely with usual doses of opioid- and anticholinergic-containing antidiarrheals, significant interaction may occur if these medications are abused.

For more Interactions (Complete) data for AMANTADINE (10 total), please visit the HSDB record page.

Acute overdosage of amantadine has resulted in cardiac dysfunction (e.g., arrhythmia, tachycardia, hypertension); pulmonary edema and respiratory distress (including adult respiratory distress syndrome); renal dysfunction (e.g., increased BUN, decreased creatinine clearance, renal insufficiency); or CNS toxicity (e.g., insomnia, anxiety, psychotic reactions, lethargy, somnolence, coma). Hyperthermia also has occurred with amantadine overdosage. In addition, seizures may be exacerbated in patients with a history of a seizure disorder (A620).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 385(SRC), determined from a structure estimation method(2), indicates that amantadine is expected to have moderate mobility in soil(SRC). The pKa of amantadine is estimated as 10.45(SRC), using a method based on perturbed molecular orbital theory and linear free energy (LFER) methods(3). This pKa value indicates that amantadine will exist primarily in its protonated form in the environment and cations tend to adsorb to soils stronger than neutral molecules(4). Amantadine will not volatilize from moist soil surfaces since cations do not volatilize. Amantadine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 0.13 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2006).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 385(SRC), determined from a structure estimation method(2), indicates that amantadine is expected to adsorb to suspended solids and sediment(SRC). The pKa of amantadine is estimated as 10.45(SRC), using a method based on perturbed molecular orbital theory and linear free energy (LFER) methods(3). This pKa value indicates that amantadine will exist primarily in its protonated form in the environment and cations do not volatilize from water(4). According to a classification scheme(5), an estimated BCF of 15(SRC), from a log Kow of 2.44(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low (SRC). Biodegradation data were not available(SRC, 2006).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), amantadine, which has an estimated vapor pressure of 0.13 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase amantadine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 10 hours(SRC), calculated from its rate constant of 4.0X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3).

The main advantage of amantadine is that it has a low side effect profile. The primary adverse effects of amantadine may include orthostatic hypotension, syncope, peripheral edema, dizziness, delusions, hallucinations, falls, xerostomia, and constipation. Although livedo reticularis is a less common side effect, amantadine is one of the best-known drugs to cause it. This side effect is reversible with the withdrawal of medication. Serious adverse effects include neuroleptic malignant syndrome, psychosis, suicidal ideation, and CNS depression. Central nervous system (CNS) depression requires monitoring, especially in the elderly. Providers should caution patients against activities that require physical and mental alertness, such as driving and avoid combination with other CNS depressing agents, such as alcohol. Caution with usage and dosage adjustments may be necessary for those with heart disease, seizure disorder, hepatic impairment, and renal impairment.

There currently is no minimum toxicity dose listed. The limitation for increased doses beyond 400 mg per day is due to CNS effects. It is essential to know the patient's history of mental illness and seizures before proceeding with therapy. Toxicity may manifest as acute psychosis, cardiovascular toxicity, coma, and/or death. Although there is no antidote for amantadine, side effects resolve with discontinuation of usage. Some preparations of the drug may contain propylene glycol. Large amounts of propylene glycol can potentially be toxic and cause hyperosmolality, lactic acidosis, respiratory depression, and seizures. In addition, Amantadine toxicity is a concern in patients with severe renal impairment, as 90% of the dose administered orally is excreted unchanged in the urine.

The mechanism of its antiparkinsonic effect is not fully understood, but it appears to be releasing dopamine from the nerve endings of the brain cells, together with stimulation of norepinephrine response. It also has NMDA receptor antagonistic effects. The antiviral mechanism seems to be unrelated. The drug interferes with a viral protein, M2 (an ion channel), which is needed for the viral particle to become "uncoated" once it is taken inside the cell by endocytosis.

Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 2 grams. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including ARDS) have been reported. Renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucination, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.

Using a structure estimation method based on molecular connectivity indices(1), the Koc for amantadine can be estimated to be 385(SRC). According to a classification scheme(2), this estimated Koc value suggests that amantadine is expected to have moderate mobility in soil(SRC). The pKa of amantadine is estimated as 10.45(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(3). This estimated pKa indicates that amantadine will exist primarily in the protonated form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl amantadine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Amantadine hydrochloride/

MEDICATION (VET)

Used as a chemical intermediate for the synthesis of tromantadine.

Antiviral and treatment for Parkinson's disease

Analgesics, Non-Narcotic; Antiparkinson Agents; Antiviral Agents; Dopamine Agents

Prevent infection with various strains of influenza A virus.

Use (kg; approx.) in Germany (2009): >2500

Amantadine is brominated to 1-bromo compound, which is then reacted with acetonitrile in presence of sulfuric acid to produce n-(1-adamantanyl)acetamide. Alkaline hydrolysis liberates amantadine, which is reacted with hydrogen chloride in suitable solvent to yield official salt. /amantadine hydrochloride/

1-Bromoadamantane + acetonitrile (Ritter reaction)

Oral: Capsules, liquid-filled Tablets: 100 mg (available by nonpropriety name), 100 mg, Symmetrel, (Endo); Solution: 50 mg/5 mL, Symmetrel Syrup ( with parabens), (Endo).

Trade Names.Hydrochloride: Amazolon (Sawai), Mantadine (Du Pont), Mantadix (Du Pont, Rhône-Poulenc), Symmetrel (Ciba-Geigy), Virofral (Ferrosan). Sulfate: Contenton (SKD), PK-Merz (Merz).

administered PO, intranasal, SC, IP, or aerosol routes.

Tricyclo[3.3.1.13,7]decan-1-amine: ACTIVE

Available commercially as the free base or the hydrochloride, sulfate, or fumarate salts.