AMANTADINE

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) 1-Adamantanamine
2) 1-Aminoadamantane
3) 1-Aminodiamantane
4) CAS 768-94-5

Available Forms Sources

1) Amantadine is available as 100 mg tablets, 100 mg capsules, and as a 50 mg/5 mL syrup (Prod Info amantadine hcl oral capsules, 2006; Prod Info SYMMETREL(R) oral tablet, syrup, 2003).

1) Amantadine is indicated for the prophylaxis and treatment of influenza A viral infections, treatment of drug-induced extrapyramidal reactions, and treatment of Parkinson's disease (Prod Info amantadine hcl oral capsules, 2006; Wilcox, 1985). Amantadine has also been used in the management of herpes zoster (S Sweetman , 2000).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Amantadine is used in the treatment of Parkinson's disease, as prophylaxis for parkinsonian side effects for patients on neuroleptic drugs, and as an antiviral agent.
B) PHARMACOLOGY: Amantadine is a weak dopamine agonist, with some antimuscarinic activity, and a N-methyl-D-aspartate receptor antagonist. Amantadine inhibits the presynaptic reuptake of catecholamines and increases dopamine release. It may also directly stimulate the dopamine receptor to make the postsynaptic dopamine system more sensitive to the presence of dopamine. Amantadine exerts antiviral activity by inhibiting the replication of the influenza A virus.
C) TOXICOLOGY: Works at antimuscarinic receptors leading to anticholinergic effects. It also inhibits the presynaptic reuptake of catecholamines and can cause increased dopaminergic and sympathomimetic postsynaptic stimulation.
D) EPIDEMIOLOGY: Amantadine exposures are uncommon; most patients will not have significant symptoms. There are isolated reports of seizures, dysrhythmias, and psychiatric symptoms following large exposures.
E) WITH THERAPEUTIC USE

1) Anticholinergic symptoms of dry mouth, tachycardia, and difficulty in focusing are seen even with therapeutic administration. Other common adverse effects that may occur include nausea, dizziness, insomnia, agitation, anxiety, hallucinations, peripheral edema, headache, and orthostatic hypotension. Dose reduction or abrupt withdrawal of amantadine therapy may result in the development of manifestations of neuroleptic malignant syndrome, such as hyperthermia, rigidity, and autonomic instability.

F) WITH POISONING/EXPOSURE

1) MILD TO MODERATE OVERDOSE: Anticholinergic effects of dry mouth, mydriasis, tachycardia, and urinary retention have been reported with acute overdose ingestions of amantadine. Nausea, dizziness, insomnia, agitation, anxiety, headache, and dystonic reactions may also develop.
2) SEVERE OVERDOSE: May cause ventricular dysrhythmias, torsades de pointes, hyperthermia, QRS widening, prolonged QTc, hallucinations, psychosis, hypotension, acute lung injury, hypokalemia, lethargy, ataxia, and seizures. Patients with renal insufficiency may have increased risk of toxicity. Serotonin syndrome may develop when amantadine is taken concomitantly with other serotonergic agents.

0.2.20)

A) Amantadine is classified as FDA pregnancy category C. Amantadine has been shown to have teratogenic effects in humans and teratogenic and embryonic lethality effects in animal rats. It is excreted into breast milk in low concentrations and has been shown to have impaired effects on fertility in humans and rats.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Care is symptomatic and supportive. Treat dystonic reactions with benzodiazepines or diphenhydramine. Treat anxiety and agitation with benzodiazepines.

B) MANAGEMENT OF SEVERE TOXICITY

1) Care is symptomatic and supportive. Treat hallucinations and psychosis with benzodiazepines. Treat seizures with benzodiazepines as needed; if refractory, consider phenobarbital or propofol. Treat hypotension with intravenous fluids; add vasopressors if necessary. Treat torsades de pointes with magnesium, overdrive pacing. Correct electrolyte abnormalities. Treat QRS widening with sodium bicarbonate. Treat serotonin syndrome with benzodiazepines and cyproheptadine if symptoms persist. Severe cases may require neuromuscular paralysis and mechanical ventilation.

C) DECONTAMINATION

1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and seizures.
2) HOSPITAL: Consider administration of activated charcoal in patients with a recent ingestion who are awake and able to protect their airway. It is most effective when administered within one hour of ingestion. Do not administer in patients who are at risk for abrupt onset of seizure or mental status depression unless airway is protected. Consider gastric lavage only in recent large overdose (2 g) as overdose is rarely life-threatening.

D) AIRWAY MANAGEMENT

1) Endotracheal intubation should be performed in patients with persistent seizures, mental status depression, or an inability to protect their airway.

E) ANTIDOTE

1) None

F) VENTRICULAR DYSRHYTHMIA

1) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Because amantadine can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution. Consider lidocaine for stable monomorphic ventricular tachycardia. Sodium bicarbonate may be effective for ventricular dysrhythmias, particularly in association with QRS widening. Administer sodium bicarbonate 1 to 2 milliequivalents/kilogram intravenously. Repeat as needed to achieve an arterial pH of 7.4 to 7.5. Unstable rhythms require immediate cardioversion.

G) TORSADES DE POINTES

1) Electrical cardioversion if hemodynamically unstable. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present. Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics.

H) RHABDOMYOLYSIS

1) IV 0.9% NS to maintain urine output of 2 to 3 mL/kg/h.

I) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) Control agitation and muscle activity with benzodiazepines. Enhance evaporative cooling by keeping skin damp with water/ice packs and using cooling fans.

J) ENHANCED ELIMINATION

1) These procedures have not been shown to be effective because the volume of distribution is large. Since the serum half-life is very long in patients with renal failure, dialysis may be necessary in patients with poor renal function.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic adults with inadvertent ingestions of an extra dose and asymptomatic children with inadvertent ingestions of a single pill can be managed at home.
2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions, and children ingesting more than a pill should be referred to a healthcare facility. Monitor asymptomatic patients with significant exposures for at least 8 to 12 hours after ingestion.
3) ADMISSION CRITERIA: All patients with more than mild symptoms should be admitted to the hospital.
4) CONSULT CRITERIA: Consult a medical toxicologist or poison center for assistance with patients with significant toxicity or in whom the diagnosis is not clear.

L) PITFALLS

1) When managing a suspected amantadine overdose, the possibility of multidrug involvement should be considered. Ventricular dysrhythmias and acute lung changes may be delayed in onset; reliable follow-up is imperative.

M) PHARMACOKINETICS

1) Peak blood levels are reached 1 to 4 hours after an oral dose. 60% to 70% protein bound. Volume of distribution is 4 to 8 liters/kg. Primarily excreted unchanged in the urine; 5% to 15% undergoes hepatic acetylation. Elimination half-life is 9 to 20 hours. Relatively long half-lives of 20 hours and 28.9 hours were reported in elderly patients, and 45 hours was reported in a child with renal dysfunction.

N) DIFFERENTIAL DIAGNOSIS

1) Include other anticholinergic agents and agents that may cause QT prolongation and torsades de pointes.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH POISONING/EXPOSURE

1) HYPERTHERMIA has been reported following an overdose (Farrell et al, 1995).
2) CASE REPORT: A 37-year-old woman developed a temperature of 42 degrees C on the day following an ingestion of 120 capsules of amantadine 100 mg in a suicide attempt. The hyperthermia persisted for several days and was resistant to treatment with Pavulon(R) and dantrolene (Brown et al, 1987).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Mild dilated pupils have been reported (Claudet & Marechal, 2009; Yang & Deng, 1997; Farrell et al, 1995; Armbruster et al, 1974; Fahn et al, 1971). Pupils were moderately dilated in a child for 20 hours post-ingestion (Berkowitz, 1979).

3.4.6)

A) WITH POISONING/EXPOSURE

1) DRY MOUTH has been reported (Yang & Deng, 1997; Armbruster et al, 1974; Fahn et al, 1971).

Cardiovascular

3.5.2)

A) VENTRICULAR ARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 37-year-old woman presented with tachycardia which progressed quickly to bradycardia with prolonged QT (0.56) and malignant ventricular ectopy following an ingestion of 120 100-mg capsules of amantadine in a suicide attempt (Brown et al, 1987).
b) CASE REPORT: A 17-year-old girl developed frequent multifocal premature ventricular contractions associated with an ingestion of 1.3 grams of amantadine (Pimentel & Hughes, 1991).

B) TORSADES DE POINTES

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Torsade de pointes, ventricular fibrillation, and cardiopulmonary arrest were reported after ingestion of 2.5 g (Sartori et al, 1984). Cardiac effects persisted for up to 36 hours after ingestion.

C) RIGHT HEART FAILURE

1) WITH THERAPEUTIC USE

a) Congestive heart failure has been seen with long term use (Vale & MacLean, 1977). Congestive heart failure may also develop in those with a history of congestive heart failure or peripheral edema (Prod Info amantadine hcl oral capsules, 2006).

D) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Hypotension has occurred with cardiac dysrhythmias following overdose (Schwartz et al, 2008; Sartori et al, 1984).

E) ELECTROCARDIOGRAM ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A prolonged QTc interval (533 ms) and QRS (124 msec) were reported in a 24-year-old man following an amantadine overdose ingestion of an unknown amount. The patient's initial serum amantadine level was 27,000 ng/mL. The patient recovered following treatment with an intravenous sodium bicarbonate drip (Farrell et al, 1995).
b) CASE REPORT: A 33-year-old woman presented to the emergency department approximately 60 minutes after intentionally ingesting 10 g amantadine (166 mg/kg) and 4 alprazolam tablets of unknown strength. An ECG demonstrated sinus tachycardia with QRS widening (113 msec) and QTc interval prolongation (526 msec). Laboratory analysis revealed hypokalemia (potassium 3 mEq/L). With supportive care, including potassium repletion, her hypokalemia resolved approximately 10 hours postingestion, and her ECG abnormalities normalized 14 hours postingestion (Schwartz et al, 2008).

F) TACHYARRHYTHMIA

1) WITH THERAPEUTIC USE

a) CASE REPORT: Tachycardia was reported in a 31-year-old heroin addict following ingestion of amantadine for treatment of an upper respiratory tract infection (Yang & Deng, 1997).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: A 2-year-old child developed sinus tachycardia (129 bpm) following an amantadine overdose ingestion of 0.8 to 1.5 grams (Claudet & Marechal, 2009).

G) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 47-year-old woman experienced pulseless cardiac arrest following presentation to the emergency department 30 minutes after intentionally ingesting 10 g amantadine (150 mg/kg) and 250 mg diphenhydramine. An ECG indicated ventricular tachycardia and the patient was successfully electrically cardioverted . Laboratory analysis indicated severe hypokalemia (potassium 1 mEq/L), and a repeat ECG revealed QRS widening (200 msec) and QTc interval prolongation (534 msec). An initial serum amantadine concentration, obtained approximately 2.5 hours postingestion, was 29 mcg/mL. With intensive supportive therapy, the patient gradually recovered with resolution of her ECG abnormalities and hypokalemia. A repeat serum amantadine concentration, obtained approximately 51 hours postingestion, had decreased to 0.92 mcg/mL (Schwartz et al, 2008).

3.5.3)

A) ANIMAL STUDIES

1) HEART DISORDER

a) Animal studies have shown negative inotropic effects (Sartori et al, 1984).

Respiratory

3.6.2)

A) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORTS: Adult respiratory distress syndrome (ARDS) was reported in two adults who died and in one patient who survived following ingestion of a large amount (Farrell et al, 1995; Brown et al, 1987; Sartori et al, 1984).

B) PULMONARY HEMORRHAGE

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Sudden apnea, about 48 hours postingestion, secondary to pulmonary edema and hemorrhage, resulted in death in an adult who ingested 2 grams (Simpson et al, 1988).

Neurologic

3.7.2)

A) CENTRAL NERVOUS SYSTEM DEFICIT

1) WITH THERAPEUTIC USE

a) CASE REPORT: Drowsiness, weakness, tremulousness, confusion, jitteriness, hallucinations, nightmares and apprehension were reported (Armbruster et al, 1974).

2) WITH POISONING/EXPOSURE

a) Initially, central nervous system depression is seen, followed by central nervous system stimulation after overdose (Sartori et al, 1984).
b) CASE REPORT: Ataxia and lethargy were reported in a 37-year-old who ingested 120 100-mg capsules of amantadine in a suicide attempt (Brown et al, 1987).

B) COMA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 37-year-old man with multiple sclerosis and end-stage renal disease developed mental status changes, anxiety, disorientation, and agitation that rapidly progressed to a comatose state following overdose administration of amantadine, 100 mg twice daily for 3 days. The prescribed dose was 100 mg per week. The EEG revealed diffuse slowing and a laboratory analysis showed that the serum amantadine level was 1600 ng/mL. The patient gradually recovered following charcoal hemoperfusion and supportive care (Macchio et al, 1993).

C) CENTRAL STIMULANT ADVERSE REACTION

1) WITH THERAPEUTIC USE

a) Amantadine has been shown to have a stimulating effect following CNS depression due to ketamine anesthesia and ethanol intoxication (Messiha, 1977; Domenichini et al, 1972) .
b) CNS toxicity has been associated with amantadine plasma concentrations of 1000 nanograms/mL (Aoki & Sitar, 1988; Ing et al, 1979; Armbruster et al, 1974).
c) Therapeutic dose will produce CNS stimulation in 13% to 33% of adults with normal renal function (Aoki & Sitar, 1988; Bryson et al, 1982).
d) A study of elderly patients receiving antiviral treatment revealed a higher incidence of adverse effects related to the CNS in patients receiving amantadine compared with rimantadine. Adverse effects associated with amantadine therapy included agitation, confusion, hallucinations, lethargy, seizures and tremors (Keyser et al, 2000).
e) CASE REPORT: A 27-year-old renal transplant patient with acute renal insufficiency presented with confusion, visual hallucinations and a 4-month history of tremors. She had been taking several medications including amantadine (dose increased 5 days before admission) and acyclovir (the presumed cause of her renal insufficiency). On examination, she had ataxia, agitation, and aggressive behavior. On admission, her initial serum amantadine concentration was 4115 ng/mL (serum concentrations greater than 1000 ng/mL have been associated with toxicity) which decreased to 955 ng/mL 5 days after amantadine was discontinued. She gradually improved and was discharged 7 days after admission (Michalski et al, 2009).

D) SEIZURE

1) WITH THERAPEUTIC USE

a) CASE REPORT: Agitation, confusion, and seizures were reported in a 31-year-old heroin addict following ingestion of amantadine for treatment of an upper respiratory tract infection (Yang & Deng, 1997).
b) CASE REPORT: Seizures, secondary to obstructive acute renal failure, were reported in a 69-year-old woman following amantadine therapy (Nakai et al, 2009).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Aggressive behavior and seizures were observed after a single 800 mg dose in an adult (Fahn et al, 1971).
b) CASE REPORT: Lethargy, seizures, and tremors of the extremities were reported in a 24-year-old man following an amantadine overdose ingestion of an unknown amount (Farrell et al, 1995).
c) CASE REPORT: 2-year-old child ingested 0.8 to 1.5 grams of amantadine and, 1 hour later, developed agitation, diaphoresis, and generalized seizures that progressed to status epilepticus. Over the next 7 hours, the patient continued to experience repeated generalized tonic-clonic or partial seizures refractory to intrarectal diazepam and an intravenous infusion of clonazepam. The seizures resolved, 10 hours later, after intravenous phenytoin administration. The patient made a complete recovery, without sequelae, and was discharged approximately 3 days post-ingestion (Claudet & Marechal, 2009).

E) NEUROLEPTIC MALIGNANT SYNDROME

1) WITH THERAPEUTIC USE

a) Several cases of NMS have been associated with the withdrawal of amantadine for neurologic reasons (Lazarus, 1985; Rosse & Ciolino, 1985).
b) CASE REPORT: A 61-year-old woman presented to her primary care physician with nausea, tremors, and diffuse flushing approximately 1 day after abruptly discontinuing amantadine therapy. The following day, the patient's symptoms progressed with increasing tremors and rigidity, low-grade fever, nausea, and flushing, consistent with a diagnosis of NMS. Her peak serum creatine phosphokinase concentration was 3322 International Units/L. With supportive care and after restarting amantadine therapy, the patient recovered (Brantley et al, 2009).

F) SEROTONIN SYNDROME

1) WITH THERAPEUTIC USE

a) GENERAL: Amantadine, a dopamine agonist, is considered a serotonergic drug. Theoretically, any drug or combination of drugs, that has the ability to increase serotonin activity can produce serotonin syndrome (Mills, 1995). At the time of this review, there are limited reports in the literature of this adverse event with amantadine.
b) CASE REPORT: A 76-year-old man with Parkinson's disease (treated with levodopa/carbidopa), NIDDM, and chronic depression (treated with sertraline), was started on amantadine. Within 3 days, the patient developed low grade fever, increasing confusion, diarrhea and frequent falls. Upon examination the patient was noted to have extreme rigidity in all limbs, agitation, and ongoing visual hallucinations. An EEG showed pronounced triphasic wave activity (not previously reported with serotonin syndrome) and diffuse slowing. Following supportive care, the patient's myoclonus resolved within 24 hours. The author suggested that the combination drug regimen, which included serotonin reuptake inhibitors and dopaminergic agents, increased the risk of developing serotonin syndrome (Dike, 1997).

G) DYSTONIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Dystonic posturing was seen in a 2.5-year-old child 2 hours after ingestion of 60 mg/kg. The dystonia responded to physostigmine (Berkowitz, 1979).

H) HALLUCINATIONS

1) WITH THERAPEUTIC USE

a) Delusional thinking and vivid hallucinations have been reported with the use of amantadine, especially in association with renal failure (Pimentel & Hughes, 1991; Wilcox, 1985; Borison, 1979).
b) Patients with reduced renal function are particularly at risk (Strong et al, 1991).

I) ATAXIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Ataxia was reported in a 37-year-old man with multiple sclerosis and end-stage renal disease following overdose administration of amantadine, 100 mg twice daily for three days (the prescribed dose was 100 mg per week). Upon admission, the patient was unable to ambulate more than 10 steps without assistance. Following an aggressive occupational and physical therapy program, 22 days later, the patient was able to ambulate 200 feet without devices (Macchio et al, 1993).

Gastrointestinal

3.8.2)

A) VOMITING

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Vomiting occurred in a 2-year-old child who ingested 0.8 to 1.5 grams of amantadine (Claudet & Marechal, 2009).

3.8.3)

A) ANIMAL STUDIES

1) VOMITING

a) Emesis and anorexia have been reported in animal studies (Vernier et al, 1969).

Genitourinary

3.10.2)

A) RETENTION OF URINE

1) WITH POISONING/EXPOSURE

a) Urinary retention may occur with acute amantadine intoxication (Nakai et al, 2009; Halpern, 1985).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: A 31-year-old man developed protracted seizures and severe metabolic acidosis after therapeutic use of amantadine (Yang & Deng, 1997).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Primary respiratory alkalosis and mild metabolic acidosis has been reported following amantadine administration (Fahn et al, 1971).
b) CASE REPORT: High anion gap metabolic acidosis (pH 7.3, HCO3 18 mEq/L, anion gap 15 mEq/L) was reported in a 2-year-old child following an amantadine overdose ingestion of 0.8 to 1.5 grams; the acidosis was likely secondary to recurrent seizures (Claudet & Marechal, 2009).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH THERAPEUTIC USE

a) CASE REPORT: Rhabdomyolysis with a CPK of 150,600 International Units/L and anticholinergic syndrome (mydriasis, tachycardia, dry skin, agitation, confusion, and seizures) was reported in a 31-year-old heroin addict following ingestion of amantadine for treatment of an upper respiratory infection. The patient recovered with supportive care (Yang & Deng, 1997).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Rhabdomyolysis was reported in a 24-year-old man following an amantadine overdose ingestion of an unknown amount. The patient's initial serum amantadine level was 27,000 ng/mL (Farrell et al, 1995).

Reproductive

3.20.1)

3.20.2)

A) TETRALOGY OF FALLOT AND TIBIAL HEMIMELIA

1) Tetralogy of Fallot and tibial hemimelia (normal karyotype) were reported in an infant born exposed to oral amantadine 100 mg for 7 days during gestation weeks 6 and 7 (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

B) CARDIOVASCULAR MALDEVELOPMENT

1) Cardiovascular maldevelopment (single ventricle with pulmonary atresia) was correlated with daily maternal amantadine 100 mg exposure during the first 2 weeks of pregnancy (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

C) ANIMAL STUDIES

1) RATS: Severe visceral and skeletal malformations were reported when female rats were administered oral 50 or 100 mg/kg doses (1.5 or 3 times the maximum recommended human dose, respectively, on a mg/m(2) basis) on gestation days 7 to 14 (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

3.20.3)

A) PREGNANCY CATEGORY

1) Amantadine is rated FDA pregnancy category C (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

B) ANIMAL STUDIES

1) RATS: Increased embryonic death was reported when female rats were administered oral 100 mg/kg doses (3 times the maximum recommended human dose, on a mg/m(2) basis) 5 days prior to mating to gestation day 6 or on gestation days 7 to 14 (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

3.20.4)

A) BREAST MILK

1) Amantadine is excreted into human breast milk (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012; Briggs et al, 1998).

3.20.5)

A) ANIMAL STUDIES

1) RATS: Slightly impaired fertility was observed in both male and female rats administered 32 mg/kg/day doses (equal to the maximum recommended human dose, on a mg/m(2) basis) (Prod Info amantadine HCl oral capsules, 2012; Prod Info amantadine HCl oral syrup, 2013; Prod Info amantadine HCl oral tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs, neurologic exam, and mental status.
B) Institute continuous cardiac monitoring, obtain an ECG, and monitor of electrolytes (including magnesium, potassium, and calcium), and renal function.
C) Specific amantadine concentrations are not readily available or useful to assist acute management.

4.1.2)

A) Monitor electrolytes (including magnesium, potassium, and calcium) and renal function tests after significant overdose.

4.1.4)

A) OTHER

1) ECG

a) Perform continuous cardiac monitoring and obtain an ECG.

2) MONITORING

a) Monitor vital signs, neurologic exam, and mental status.

Radiographic Studies

1) Chest x-rays should be obtained in significant ingestions. Death due to pulmonary edema, in the absence of preceding signs or symptoms, has been described (Simpson et al, 1988).

Methods

1) Amantadine can be identified by a specific gas chromatographic method (Bleidner et al, 1965).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) All patients with more than mild symptoms should be admitted to the hospital.
B) Since ventricular dysrhythmias and pulmonary changes can have an onset of up to 48 hours postingestion, cardiac and pulmonary monitoring is recommended for at least 48 hours in patients with significant ingestions (Sartori et al, 1984).
C) Patients with symptoms should not be discharged until they remain asymptomatic and dysrhythmia free for at least 24 hours. Ventricular dysrhythmias may recur (Sartori et al, 1984).

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic adults with inadvertent ingestions of an extra dose and asymptomatic children with inadvertent ingestions of a single pill can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a medical toxicologist or poison center for assistance with patients with significant toxicity or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Symptomatic patients, those with deliberate ingestions, and children ingesting more than a pill should be referred to a healthcare facility. Monitor asymptomatic patients with significant exposures for at least 8 to 12 hours after ingestion.

Monitoring

Oral Exposure

6.5.1)

A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and seizures.

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

6.5.3)

A) SUPPORT

1) Treatment should be directed at maintaining cardiovascular function and reducing CNS stimulation. Amantadine is somewhat like the cyclic antidepressants in that it may produce cardiac dysrhythmias for many hours after an ingestion.

B) MONITORING OF PATIENT

1) Monitor vital signs, neurologic exam, and mental status.
2) Institute continuous cardiac monitoring and obtain an ECG. Monitor electrolytes (including magnesium, potassium, and calcium), and renal function.
3) Specific amantadine concentrations are not readily available or useful to assist acute management.

C) VENTRICULAR ARRHYTHMIA

1) SUMMARY

a) Ventricular dysrhythmias may occur with amantadine (Pimentel & Hughes, 1991).
b) Institute continuous cardiac monitoring, obtain an ECG, and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders. Because amantadine can cause torsades de pointes and QTc prolongation, amiodarone should only be used with extreme caution. Consider lidocaine for stable monomorphic ventricular tachycardia. Sodium bicarbonate may be effective for ventricular dysrhythmias, particularly in association with QRS widening. Administer sodium bicarbonate 1 to 2 milliequivalents/kilogram intravenously. Repeat as needed to achieve an arterial pH of 7.4 to 7.5. Unstable rhythms require immediate cardioversion.

2) SODIUM BICARBONATE

a) May be effective for ventricular dysrhythmias, particularly in association with QRS widening. Administer sodium bicarbonate 1 to 2 milliequivalents/kilogram intravenously. Repeat as needed to achieve an arterial pH of 7.4 to 7.5. Monitor frequent blood gases and ECGs.

1) CASE REPORT: A 24-year-old man developed QRS widening (124 msec) and prolonged QTc (533 msec) after amantadine overdose. QTc prolongation improved after administration of intravenous sodium bicarbonate (Farrell et al, 1995).

3) HYPERTONIC SALINE

a) A 47-year-old woman developed pulseless ventricular tachycardia and profound hypokalemia (potassium 1 mmol/L) after ingesting 10 g amantadine. She was successfully defibrillated to sinus rhythm with a QRS of 236 mesc and a QTc of 567 mesc. She was treated with 300 mL of 3% sodium chloride IV over 10 minutes and 4 g magnesium sulfate, and 10 minutes later QRS widening and ECG abnormalities resolved. Potassium was repleted over the next 11 hours. There were no further dysrhythmias and she recovered (Schwartz et al, 2008).

4) LIDOCAINE

a) Lidocaine has been effective in treating the dysrhythmias (Pimentel & Hughes, 1991).
b) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).

c) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

d) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).

e) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

5) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).

D) TORSADES DE POINTES

1) SUMMARY

a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).

2) MAGNESIUM SULFATE

a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).

3) OVERDRIVE PACING

a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).

4) POTASSIUM REPLETION

a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).

5) ISOPROTERENOL

a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).

6) OTHER DRUGS

a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).

7) AVOID

a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

E) ACUTE LUNG INJURY

1) Pulmonary edema, delayed in onset for up to 48 hours, has been the primary cause of death after overdose (Brown et al, 1987; Sartori et al, 1984; Simpson et al, 1988).
2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).

F) HYPOTENSIVE EPISODE

1) Dopamine is theoretically a poor choice, as it appeared to exacerbate cardiac arrhythmias in one case (Sartori et al, 1984). Isoproterenol was similarly implicated.
2) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

G) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

H) PSYCHOMOTOR AGITATION

1) INDICATION

a) If patient is severely agitated, sedate with IV benzodiazepines.

2) DIAZEPAM DOSE

a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

3) LORAZEPAM DOSE

a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

4) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
5) CHLORPROMAZINE: It was used successfully in one case (Fahn et al, 1971). Care must be taken not to exacerbate amantadine's anticholinergic properties.

I) PHYSOSTIGMINE

1) SUMMARY: Physostigmine (1 mg/dose) was used to treat the bizarre behavior with success in one case (Casey, 1978), and dystonia and agitation in another case (Berkowitz, 1979). It should only be used in cases of severe, life-threatening, intractable anticholinergic effects.
2) PHYSOSTIGMINE/INDICATIONS

a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).

3) DOSE

a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

4) CAUTIONS

a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

5) ATROPINE FOR PHYSOSTIGMINE TOXICITY

a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).

J) BODY TEMPERATURE ABOVE REFERENCE RANGE

1) COOL COMPRESSES, sponging, hypothermic blankets, and acetaminophen may be indicated.
2) ICED BATHS may be indicated if hyperpyrexia is severe (temperature greater than 104 degrees F or 40 degrees C).
3) DIAZEPAM or pancuronium may be needed to control neuromuscular hyperactivity.
4) Monitor fluids and electrolytes closely.
5) Relieve hypothermia with appropriate covering.
6) BROMOCRIPTINE: Hyperthermia may be related to the dopamine blocking activity of amantadine, therefore oral bromocriptine may theoretically be useful, however there are no reports where this has been used alone successfully.

a) DOSE (ADULT): 5 milligrams 3 times a day. Bromocriptine was unsuccessful in one case (Lazarus, 1985).

7) DANTROLENE and Pavulon were reported to be unsuccessful in one case (Brown et al, 1987).

a) A combination of dantrolene and bromocriptine was effective in one case (Rosse & Ciolino, 1985).

K) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

L) SEROTONIN SYNDROME

1) SUMMARY

a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).

2) HYPERTHERMIA

a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
c) Non-depolarizing paralytics may be used in severe cases.

3) CYPROHEPTADINE

a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).

4) HYPERTENSION

a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.

5) HYPOTENSION

a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
c) NOREPINEPHRINE

1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
2) INITIAL DOSE

a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.

3) MAINTENANCE DOSE

a) 0.5 to 1 mL (2 to 4 mcg)/minute.

6) SEIZURES

a) DIAZEPAM

1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.

b) LORAZEPAM

1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2009; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).

c) RECURRING SEIZURES

1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.

d) PHENOBARBITAL

1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.

7) CHLORPROMAZINE

a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.

8) NOT RECOMMENDED

a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).

Enhanced Elimination

1) Hemodialysis does not remove significant amounts of amantadine (Prod Info amantadine hcl oral capsules, 2006).
2) A patient who was symptomatic on 4 micrograms/milliliter and receiving hemodialysis as therapy for kidney failure still had measurable serum levels 5 months after discontinuation of the amantadine (Armbruster et al, 1974).
3) Ing et al (1976) reported lowering of plasma amantadine levels by 36% following hemodialysis (2.8 micrograms/milliliter to 1.8 micrograms/milliliter) (Ing, 1976).

1) Despite a 40% reduction in amantadine blood levels, only 54 to 80 milligrams were removed during each dialysis procedure (Ing, 1976).

Abstracts

Case Reports

1) Overdose of amantadine (2.5 g) in a 37-year-old woman resulted in cardiopulmonary arrest that was treated successfully. However, during the arrest and over the next 40 hours, malignant tachyarrhythmias manifested by torsade de pointe and repeated ventricular fibrillation were observed.

a) Isoproterenol and dopamine exacerbated the arrhythmias, and the patient died of aspiration pneumonia and respiratory distress (Sartori et al, 1984).

2) A 37-year-old woman presented with CNS depression following a suicide attempt with ingestion of 120 of amantadine 100 mg capsules. Admission serum amantadine level was 23.4 mcg/mL (normal <0.8). Tachycardia on admission progressed quickly to sinus bradycardia with prolonged QT (0.56) and malignant ventricular ectopy. A single seizure and diffuse fasciculations were reported.

a) Some improvement in mental status was reported. The following day, she became rigid and had a temperature of 42 degrees C. Hyperthermia persisted for several days despite use of Pavulon and Dantrolene. The patient expired of ARDS (Brown et al, 1987).

1) A 2.5-year-old girl ingested 60 mg/kg of amantadine. She was given ipecac syrup 2 hours postingestion and progressively developed agitation, hallucinations, and dystonic posturing. Widely dilated pupils were noted and persisted for 20 hours postingestion. Symptoms were ameliorated with physostigmine 1 mg IV She was discharged 3 days postingestion with no sequelae (Berkowitz, 1979).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) DISEASE STATE

1) DRUG INDUCED EXTRAPYRAMIDAL RESPONSE: The usual dose is 100 mg twice daily. The dose may be increased as needed up to a maximum daily dose of 300 mg, administered in divided doses (Prod Info SYMMETREL(R) oral tablets, syrup, 2009; Wilcox, 1985).
2) PROPHYLAXIS AND TREATMENT OF INFLUENZA A: Daily dosage is 200 mg, given as a single dose or in two divided doses. Elderly, seizure-prone, or renally impaired patients may need to reduce their dose (Prod Info SYMMETREL(R) oral tablets, syrup, 2009; Anon, 1986).
3) PARKINSONISM: The usual dose is 100 mg twice a day. The dose may be increased as needed up to a maximum daily dose of 400 mg, administered in divided doses (Prod Info SYMMETREL(R) oral tablets, syrup, 2009).

7.2.2)

A) DISEASE STATE

1) INFLUENZA

a) (1 to 9 years): 4.4 to 8.8 mg/kg/day to a maximum of 150 mg/day (Prod Info SYMMETREL(R) oral tablets, syrup, 2009).
b) (10 years and older): 200 mg/day in two divided doses (Prod Info SYMMETREL(R) oral tablets, syrup, 2009).

Minimum Lethal Exposure

1) In ADULTS, 1 to 3 grams of amantadine proved fatal. A 12 gram dose was also fatal.

1) ADULTS

a) Thirty-one mg/kg (2.5 g) caused fatal arrhythmias and cardiac arrest (Sartori et al, 1984).
b) Approximately 3000 mg of amantadine caused death within 24 hours in a 23-year-old physically healthy man with a diagnosis of chronic schizophrenia.
c) Amantadine was used for the treatment of extrapyramidal side effects of neuroleptic agents.
d) The plasma concentration reported was 4.8 mg% and no other drugs or alcohol were detected (Cook et al, 1986).
e) Ingestion of 12 g by a 37-year-old woman resulted in death (Brown et al, 1987).
f) Ingestion of 2 g resulted in death in a 34-year-old man (Simpson et al, 1988).
g) The lowest reported acute lethal dose of amantadine was 1 g (Prod Info SYMMETREL(R) oral tablets, syrup, 2009).

Maximum Tolerated Exposure

1) ADULTS

a) Ingestion of 2,800 mg was survived in a 61-year-old man (Fahn et al, 1971).
b) Ingestion of 100 mg every two hours for 24 hours (total dose 1,200 mg) in combination with diphenhydramine 25 mg four times a day, resulted in acute psychosis, with recovery over 48 hours with no specific treatment in a 35-year-old woman (Snoey & Bessen, 1990).
c) Two patients (a 47-year-old woman and a 33-year-old woman) developed ECG abnormalities and hypokalemia after intentional ingestion of 10 g amantadine. The 47-year-old woman developed pulseless ventricular tachycardia but was successfully resuscitated. Both patients recovered following supportive care (Schwartz et al, 2008).

2) PEDIATRIC

a) Ingestion of 600 mg (60 mg/kg) by a 2.5-year-old child resulted in hallucinations, agitation, and dystonic posturing with full recovery (Berkowitz, 1979).
b) Generalized seizures progressing to status epilepticus occurred in a 2-year-old child following an amantadine overdose ingestion of 0.8 to 1.5 g. The patient recovered, without sequelae, with supportive care (Claudet & Marechal, 2009).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) CASE REPORTS

a) FATAL CASES

1) The admission serum amantadine concentration in one fatal case was 23.4 mcg/mL (Brown et al, 1987). In another fatal case the postmortem plasma concentration was 48 mcg/mL (Cook et al, 1986).

b) NON-FATAL CASES

1) Plasma concentrations of 4.4 mcg/mL produced bizarre central nervous system symptoms of hallucinations, nightmares, and agitation (Armbruster et al, 1974).
2) CNS toxicity has been associated with amantadine plasma concentrations of 1000 nanograms/milliliter or greater (Macchio et al, 1993; Aoki & Sitar, 1988; Ing et al, 1979; Armbruster et al, 1974) plasma concentrations of 0.1 mg% to 0.5 mg% (Cook et al, 1986).
3) A 24-year-old man developed QRS and QTc interval prolongation, seizures, lethargy, dilated pupils, rhabdomyolysis, and ARDS following an amantadine overdose ingestion of an unknown amount. The patient's initial serum amantadine concentration was 27,000 nanograms/milliliter (Farrell et al, 1995).
4) A serum amantadine concentration of 4115 ng/mL was reported in a renal transplant patient who presented with confusion, visual hallucinations and a 4-month history of tremors. She had been taking numerous medications including amantadine (dose increased 5 days before admission) and acyclovir (the presumed cause of her renal insufficiency). On examination, she had ataxia, agitation, and aggressive behavior. Her serum amantadine concentration decreased to 955 ng/mL 5 days after amantadine was discontinued. She gradually improved and was discharged 7 days after admission (Michalski et al, 2009).
5) A 69-year-old woman developed seizures and obstructive acute renal failure following amantadine therapy, 100 mg twice daily, for treatment of the late effects of cerebral infarction. Her blood amantadine concentration peaked at 4.4 mcg/mL. Over the next 3 days, following urinary catheterization, her renal function improved and her blood amantadine concentration decreased to 0.47 mcg/mL (Nakai et al, 2009).

Toxicity Information

7.7.1)

A) Hydrochloride Salt

1) LD50- (ORAL)MOUSE:

a) 700 mg/kg

2) LD50- (ORAL)RAT:

a) 1275 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

Physicochemical

Physical Characteristics

Molecular Weight

Animal Toxicology

References

General Bibliography

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AMANTADINE

Classification | Detailed evidence-based information

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General Bibliography