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MEMANTINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Memantine, an amantadine derivative, is an N-methyl-D-aspartate (NMDA) receptor antagonist.

Specific Substances

    1) 1-Amino-3,5-dimethyladamantane
    2) 3,5-Dimethyl-1-adamantylamine
    3) DMAA
    4) D-145
    5) CAS 19982-08-2 (memantine)
    6) CAS 41100-52-1 (memantine hydrochloride)
    1.2.1) MOLECULAR FORMULA
    1) C12H21N-HCl

Available Forms Sources

    A) FORMS
    1) Memantine is available in the United States as 5 mg and 10 mg film-coated tablets, 7 mg, 14 mg, 21 mg, and 28 mg extended-release capsules, and 2 mg/mL oral solution (Prod Info NAMENDA XR(R) extended release oral capsules, 2010; Prod Info Namenda(R) oral tablets, solution, 2007).
    B) USES
    1) Memantine is indicated in the treatment of moderate to severe dementia of the Alzheimer's type (Prod Info NAMENDA XR(R) extended release oral capsules, 2010; Prod Info Namenda(R) oral tablets, solution, 2007)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Memantine is indicated in the treatment of moderate to severe dementia of the Alzheimer's type.
    B) PHARMACOLOGY: Memantine hydrochloride is a low to moderate affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist which binds to NMDA receptor-operated cation channels. Memantine also blocks the 5-hydroxytryptamine-3 receptor (at a potency similar to the NMDA receptor) and nicotinic acetylcholine receptors (at one-sixth to one-tenth the potency). However, memantine has low to negligible affinity for gamma-aminobutyric acid, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors and for voltage-dependent calcium, sodium, or potassium channels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of memantine (less than 6%): Headache, diarrhea, dizziness, somnolence, fatigue, muscle weakness, akathisia, agitation, increased motor activity, insomnia, tachycardia, bradycardia, hypertension, constipation, seizures, and psychosis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE OVERDOSE: Effects can include agitation, bradycardia, confusion, dizziness, hypertension, lethargy, restlessness, unsteady gait, vertigo, vomiting and weakness.
    2) SEVERE OVERDOSE: Can cause nystagmus, hallucinations, psychosis, seizures, and coma.
    0.2.20) REPRODUCTIVE
    A) Memantine is classified as FDA pregnancy category B. The combination product of donepezil/memantine is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) ECG changes have rarely been reported with overdose. Obtain an ECG, and institute continuous cardiac monitoring.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe agitation with small doses of benzodiazepines. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Administer activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression or repeated seizures.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION PROCEDURE
    1) Hemodialysis or hemoperfusion are unlikely to be useful because of the large volume of distribution of memantine. Plasmapheresis was used in one patient and was associated with a decrease in memantine concentrations but it is not clear that it affected patient outcome.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for six hours to assess mental status. Patients who overdose with sustained release formulations should be monitored for at least 12 hours. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients should be admitted for severe agitation, CNS depression or seizures.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) Prolonged observation may be needed after overdose with sustained release formulations. When managing a suspected memantine overdose, the possibility of multidrug involvement should be considered.
    I) PHARMACOKINETICS
    1) Tmax: Oral (immediate-release): 3 to 7 hr; oral (extended-release): 9 to 12 hr. Absorption: Well absorbed following oral administration. Protein binding: 45%. Vd: 9 to 11 L/kg. Metabolism: A small amount of memantine is metabolized via the liver. Excretion: Approximately 48% excreted unchanged in the urine. Elimination half-life: Approximately 60 to 80 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause CNS depression or hypertension.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose of memantine has not been delineated. A 35-year-old woman developed headache, dizziness, double vision, coma, tachycardia, hypertension, respiratory alkalosis, and seizures after ingesting 2000 mg of memantine. She recovered followed supportive care, including 6 cycles of plasmapheresis. An overdose ingestion of up to 400 mg of memantine resulted in restlessness, psychosis, visual hallucinations, somnolence, stupor, and coma. The patient recovered without permanent neurologic sequelae. One patient developed elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count after ingesting 112 mg of memantine extended-release daily for 31 days.
    B) THERAPEUTIC DOSE: ADULT: IMMEDIATE-RELEASE: 5 to 20 mg orally once daily or in divided doses; MAX, 20 mg/day. EXTENDED-RELEASE: 7 to 28 mg orally daily; MAX, 28 mg/day. PEDIATRIC: The safety and efficacy of memantine in children have not been documented.

Clinical Effects

Summary Of Exposure

    A) USES: Memantine is indicated in the treatment of moderate to severe dementia of the Alzheimer's type.
    B) PHARMACOLOGY: Memantine hydrochloride is a low to moderate affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist which binds to NMDA receptor-operated cation channels. Memantine also blocks the 5-hydroxytryptamine-3 receptor (at a potency similar to the NMDA receptor) and nicotinic acetylcholine receptors (at one-sixth to one-tenth the potency). However, memantine has low to negligible affinity for gamma-aminobutyric acid, benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors and for voltage-dependent calcium, sodium, or potassium channels.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) The following adverse effects have been reported following therapeutic use of memantine (less than 6%): Headache, diarrhea, dizziness, somnolence, fatigue, muscle weakness, akathisia, agitation, increased motor activity, insomnia, tachycardia, bradycardia, hypertension, constipation, seizures, and psychosis.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE OVERDOSE: Effects can include agitation, bradycardia, confusion, dizziness, hypertension, lethargy, restlessness, unsteady gait, vertigo, vomiting and weakness.
    2) SEVERE OVERDOSE: Can cause nystagmus, hallucinations, psychosis, seizures, and coma.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In double-blind, placebo-controlled trials of patients with moderate to severe Alzheimer's type dementia, hypertension was reported in 4% of patients who received memantine hydrochloride extended-release 28 mg/day (n=341) compared with 2% of patients who received placebo (n=335) for a treatment period up to 24 weeks (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    b) Hypertension was reported in 4% of patients (n=940) who received memantine during a clinical trial (Prod Info Namenda(R) oral tablets, solution, 2007).
    2) WITH POISONING/EXPOSURE
    a) Hypertension has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    b) CASE REPORT: Tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg) developed in a 35-year-old woman who also developed headache, dizziness, double vision, coma, respiratory alkalosis, and seizures after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. Her condition did not improve despite supportive care. She underwent 6 cycles of plasmapheresis which decreased blood memantine concentration. She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).
    B) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance, tachycardia has been reported in patients treated with memantine hydrochloride (Prod Info Namenda(R) oral tablets, solution, 2007).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg) developed in a 35-year-old woman who also developed headache, dizziness, double vision, coma, respiratory alkalosis, and seizures after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. Her condition did not improve despite supportive care. She underwent 6 cycles of plasmapheresis which decreased blood memantine concentration. She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).
    b) Bradycardia has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    C) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) Based on clinical experience from double-blind and open-label trials (n=750), bradycardia was associated with the use of extended-release memantine hydrochloride (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    2) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) ECG changes has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH POISONING/EXPOSURE
    a) Coma has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    b) CASE REPORT: A 35-year-old woman presented with headache, dizziness, double vision, loss of consciousness 12 hours after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. During physical examination, she was unconscious (Glasgow Coma Scale of 6), and had mydriasis, horizontal nystagmus, temperature of 37.5 degrees C, tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg). She experienced seizures which responded to IV diazepam. Laboratory results revealed respiratory alkalosis (PaO2 82.6 mmHg; PaCO2 23.3 mmHg; pH 7.55; O2 saturation 91.7%; HCO3 29.9 mmol/L; lactate 16 mg/dL). Her condition did not improve despite supportive care. She underwent 6 cycles of plasmapheresis which decreased blood memantine concentration. She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) In postmarketing surveillance, grand mal convulsions have been reported in patients treated with memantine hydrochloride (Prod Info Namenda(R) oral tablets, solution, 2007).
    b) CASE REPORT: A 72-year-old woman with no seizure history had a single tonic-clonic seizure 3 weeks after starting memantine. Her dose was increased 2 days prior to the seizure. Using the Naranjo scoring system, memantine was rated as a probable cause (Peltz et al, 2005).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Seizures developed in a 35-year-old woman who also developed headache, dizziness, double vision, coma, tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg), and respiratory alkalosis after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. Her condition did not improve despite supportive care. She underwent 6 cycles of plasmapheresis which decreased blood memantine concentration. She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence, fatigue, and muscle weakness have been rarely reported following therapeutic administration of memantine (Prod Info Namenda(R) oral tablets, solution, 2007; Starck et al, 1997; Gortelmeyer & Erbler, 1992).
    2) WITH POISONING/EXPOSURE
    a) Drowsiness, somnolence, and lethargy have been reported with overdose (Cekmen et al, 2011; Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    b) Somnolence, stupor, and loss of consciousness were reported in a patient who ingested up to 400 mg of memantine. The patient recovered without permanent neurologic sequelae (Prod Info Namenda(R) oral tablets, solution, 2007).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches were reported in several patients following therapeutic administration of memantine (Prod Info Namenda(R) oral tablets, solution, 2007; Gortelmeyer & Erbler, 1992; Ditzler, 1991).
    2) WITH POISONING/EXPOSURE
    a) Headache has been reported with overdose (Cekmen et al, 2011).
    E) AKATHISIA
    1) WITH THERAPEUTIC USE
    a) Akathisia, consisting of severe anxiety and uncontrollable restlessness, occurred in approximately 20 of 45 patients who received memantine therapeutically during a randomized, placebo-controlled clinical trial, and necessitated the discontinuation of memantine treatment in one patient (Gortelmeyer & Erbler, 1992).
    F) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) Agitation and increased motor activity have been frequently reported following therapeutic administration of memantine (Orgogozo et al, 2002; Gortelmeyer & Erbler, 1992; Ditzler, 1991), and may be partially due to a too rapid increase of the memantine dose.
    b) Agitation occurred in 23 of 126 patients (18%) who received memantine, 20 mg daily for 28 weeks, during a randomized placebo-controlled clinical trial, and was the most common reason for discontinuation of therapy (5% of patients) (Reisberg et al, 2003).
    2) WITH POISONING/EXPOSURE
    a) Agitation and restlessness have been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    b) A patient experienced restlessness following an overdose ingestion of up to 400 mg of memantine (Prod Info Namenda(R) oral tablets, solution, 2007).
    G) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia has frequently occurred with memantine therapy (Reisberg et al, 2003; Gortelmeyer & Erbler, 1992; Ditzler, 1991), and may be partially due to a too rapid increase of the memantine dose.
    H) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness may commonly occur with memantine therapy (Prod Info Namenda(R) oral tablets, solution, 2007; Orgogozo et al, 2002; Wilcock et al, 2002; Starck et al, 1997).
    2) WITH POISONING/EXPOSURE
    a) Dizziness and vertigo have been reported with overdose (Cekmen et al, 2011; Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    I) UNSTEADY GAIT
    1) WITH POISONING/EXPOSURE
    a) Unsteady gait has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    J) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) Asthenia has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    K) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has frequently occurred in patients receiving memantine therapeutically (Prod Info NAMENDA XR(R) extended release oral capsules, 2010; Wilcock et al, 2002).
    B) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Vomiting has been reported with overdose (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has been reported with therapeutic use of memantine (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ALKALINE PHOSPHATASE RAISED
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One patient developed elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count after ingesting 112 mg of memantine extended-release daily for 31 days (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) RESPIRATORY ALKALOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 35-year-old woman presented with headache, dizziness, double vision, loss of consciousness 12 hours after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. During physical examination, she was unconscious (Glasgow Coma Scale of 6), and had mydriasis, horizontal nystagmus, temperature of 37.5 degrees C, tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg). She experienced multiple seizures which responded to IV diazepam. Laboratory results revealed respiratory alkalosis (PaO2 82.6 mmHg; PaCO2 23.3 mmHg; pH 7.55; O2 saturation 91.7%; HCO3 29.9 mmol/L; lactate 16 mg/dL). Her condition did not improve despite supportive carel. She underwent 6 cycles of plasmapheresis which decreased blood memantine concentration. She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) CONTUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 80-year-old woman developed extensive bruising after initiating memantine therapy. Her medication list prior to starting memantine 5 mg/day included aspirin, digoxin, periazine, and temazepam. The day following her first dose of memantine, she experienced extensive bruising over scalp and forehead. This bruising extended after her second dose to her face, neck, upper and lower limbs. She had no trauma or history of bruising. Labs (hemoglobin, platelet count, clotting profile) were all within normal limits. Memantine and aspirin therapy were discontinued and the bruising resolved over a period of three weeks. It is not clear whether memantine was the cause of the bruising (Scharf et al, 2005).
    B) PLATELET COUNT ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One patient developed elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count after ingesting 112 mg of memantine extended-release daily for 31 days (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) SYNDROME OF INAPPROPRIATE VASOPRESSIN SECRETION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An 84-year-old man with a 6-year history of Alzheimer's disease, who had been taking memantine 30 mg/day instead of the prescribed dose of 10 mg/day of donepezil and memantine for a month, presented with a 2-day history of delirium, lethargy, and visual hallucinations. Laboratory results revealed a low blood sodium level (116 mmol/L) and a diagnosis of syndrome of inappropriate antidiuretic hormone (SIADH) secretion was made. Other abnormal laboratory results included a decrease in blood osmolarity (243 mOsm/kg; normal less than 275 mOsm/kg), an increase in sodium output in the urine (83 mmol/L; normal less than 20 mmol/L), a BUN of 5 mg/dL (reference range, 8 to 23 mg/dL), and plasma uric acid of 2.9 mg/dL (reference range, 3.4 to 7 mg/dL). Following the discontinuation of memantine and treatment with IV saline with water restriction, his condition resolved within 1 week. All risk factors and etiologies were analyzed and it was determined that memantine was considered to be the cause of SIADH (Oncel et al, 2015).

Reproductive

    3.20.1) SUMMARY
    A) Memantine is classified as FDA pregnancy category B. The combination product of donepezil/memantine is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Memantine was not teratogenic when given orally to pregnant rats and pregnant rabbits during organogenesis (at doses of 18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 9 and 30 times, respectively, the maximum recommended human dose on a mg/m(2) basis) (Prod Info Namenda(R) oral tablets, solution, 2007).
    2) Memantine was not teratogenic when given orally to pregnant rats and pregnant rabbits during organogenesis at doses of 18 mg/kg/day in rats and 30 mg/kg/day in rabbits ( 6 and 21 times, respectively, the maximum recommended human dose on a mg/m(2) basis) (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    3) An increase in non-ossified cervical vertebrae occurred in rats following maternal administration of oral memantine 19 mg/kg/day, given prior to mating and continued throughout postpartum (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Memantine is classified as FDA pregnancy category B (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    2) Donepezil/memantine is classified as FDA pregnancy category C (Prod Info NAMZARIC oral capsules, 2014).
    B) ANIMAL STUDIES
    1) RATS - Rats administered oral memantine 18 mg/kg/day prior to mating and continued throughout postpartum showed maternal toxicity and decreased pup weight. Maternal toxicity and decreased pup weight was also noted in rats administered memantine from day 15 of gestation throughout postpartum. The no-effect dose of memantine for these effects was 6 mg/kg (2 times the maximum recommended human dose on a mg/m(2) basis) (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is not known whether memantine is excreted in human breast milk (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS - In rats administered memantine in doses up to 18 mg/kg/day (6 times the the maximum recommended dose on a mg/m(2) basis) from 14 days prior to mating through gestation and lactation in females, or given for 60 days prior to mating in males, there was no fertility impairment or decrease in reproductive performance (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS19982-08-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS41100-52-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity when memantine was given orally to mice at doses up to 40 mg/kg/day for 113 weeks (10 times the maximum recommended human dose on a mg/m(2) basis). There was also no evidence of carcinogenicity in rats given memantine orally at doses up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day for 128 weeks (20 times and 10 times the maximum recommended human dose on a mg/m(2) basis, respectively) (Prod Info Namenda, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) ECG changes have rarely been reported with overdose. Obtain an ECG, and institute continuous cardiac monitoring.

Methods

    A) CHROMATOGRAPHY
    1) In one case report, standard liquid-liquid basic drug method following by gas chromatograph-mass spectrometer were used to determine postmortem blood and tissue concentrations of memantine (Bynum et al, 2007).
    2) Liquid chromatography with fluorescence detection was used for determination of memantine in human plasma. The limit of quantitation, using this method, was 3 ng/mL. There was no interference with the quantitation of memantine from administration of antidepressants, neuroleptics, or their respective metabolites (Suckow et al, 1999).
    3) Gas chromatography/negative ion chemical ionization mass spectrometry was used for determination of memantine in human plasma. The inter-assay precision, at the limit of quantitation, was 2.00% and the intra-assay variability was 3.22% (Leis et al, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients should be admitted for severe agitation, CNS depression or seizures.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored for six hours to assess mental status. Patients with overdose of a sustained release formulation should be monitored for at lease 12 hours. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor vital signs and mental status following significant overdose.
    C) ECG changes have rarely been reported with overdose. Obtain an ECG, and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor vital signs and mental status following significant overdose.
    3) ECG changes have been rarely reported with overdose. Obtain an ECG, and institute continuous cardiac monitoring.
    B) DELIRIUM
    1) Small doses of benzodiazepines may be useful in patients with severe agitation or delirium.
    C) HYPERTENSIVE EPISODE
    1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    3) SODIUM NITROPRUSSIDE/INDICATIONS
    a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    4) SODIUM NITROPRUSSIDE/DOSE
    a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    8) PHENTOLAMINE/INDICATIONS
    a) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    9) PHENTOLAMINE/ADULT DOSE
    a) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    b) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    10) PHENTOLAMINE/PEDIATRIC DOSE
    a) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    11) PHENTOLAMINE/ADVERSE EFFECTS
    a) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    12) CAUTION
    a) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    13) NITROGLYCERIN/INDICATIONS
    a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    14) NITROGLYCERIN/ADULT DOSE
    a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    15) NITROGLYCERIN/PEDIATRIC DOSE
    a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    D) 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, 2010; 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).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis or hemoperfusion are unlikely to be useful because of the large volume of distribution of memantine.
    B) PLASMAPHERESIS
    1) CASE REPORT: A 35-year-old woman presented with headache, dizziness, double vision, loss of consciousness 12 hours after ingesting 200 memantine tablets (10 mg each; total: 2000 mg). Her blood memantine concentration was 12,000 ng/mL. During physical examination, she was unconscious (Glasgow Coma Scale of 6), and had mydriasis, horizontal nystagmus, temperature of 37.5 degrees C, tachycardia (130 beats/min), and hypertension (BP 160/90 mmHg). She experienced seizures which responded to IV diazepam. Laboratory results revealed respiratory alkalosis (PaO2 82.6 mmHg; PaCO2 23.3 mmHg; pH 7.55; O2 saturation 91.7%; HCO3 29.9 mmol/L; lactate 16 mg/dL). Her condition did not improve despite supportive care. She underwent 6 cycles of plasmapheresis which was associated with improvement of her symptoms and decreased blood memantine concentration . She was discharged home after 40 days of hospitalization (Cekmen et al, 2011).

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose of memantine has not been delineated. A 35-year-old woman developed headache, dizziness, double vision, coma, tachycardia, hypertension, respiratory alkalosis, and seizures after ingesting 2000 mg of memantine. She recovered followed supportive care, including 6 cycles of plasmapheresis. An overdose ingestion of up to 400 mg of memantine resulted in restlessness, psychosis, visual hallucinations, somnolence, stupor, and coma. The patient recovered without permanent neurologic sequelae. One patient developed elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count after ingesting 112 mg of memantine extended-release daily for 31 days.
    B) THERAPEUTIC DOSE: ADULT: IMMEDIATE-RELEASE: 5 to 20 mg orally once daily or in divided doses; MAX, 20 mg/day. EXTENDED-RELEASE: 7 to 28 mg orally daily; MAX, 28 mg/day. PEDIATRIC: The safety and efficacy of memantine in children have not been documented.

Therapeutic Dose

    7.2.1) ADULT
    A) MEMANTINE
    1) EXTENDED-RELEASE CAPSULE: Initial, 7 mg orally once daily; titrate in 7-mg increments at intervals of at least 1 week as tolerated to a target dose of 28 mg once daily (MAX dose). Memantine hydrochloride extended-release capsules may be opened and sprinkled on applesauce. All of the contents of the capsule should be consumed and not be divided. Capsules not sprinkled on applesauce should be swallowed whole and not chewed, crushed, or divided (Prod Info NAMENDA XR(R) oral extended release capsules, 2014).
    2) IMMEDIATE-RELEASE ORAL SOLUTION: Initial, 5 mg (2.5 mL) orally once daily; titrate in 5-mg increments at intervals of at least 1 week to 10 mg/day (2.5 mL twice daily), 15 mg/day (2.5 mL and 5 mL taken separately), and 20 mg/day (5 mL twice daily); target daily dose is 20 mg/day (5 mL twice daily) (Prod Info NAMENDA oral solution, 2014; Prod Info NAMENDA oral tablets, oral solution, 2013).
    3) IMMEDIATE-RELEASE TABLET: Initial, 5 mg orally once daily; titrate in 5-mg increments at intervals of at least 1 week to 10 mg/day (5 mg twice daily), 15 mg/day (5 mg and 10 mg in separate doses), and 20 mg/day (10 mg twice daily); target daily dose is 20 mg/day (Prod Info NAMENDA oral tablets, oral solution, 2013).
    B) MEMANTINE AND DONEPEZIL
    1) EXTENDED RELEASE: The recommended dose is 28 mg memantine hydrochloride/10 mg donepezil hydrochloride orally once daily. The capsules may be swallowed whole, or opened and the contents sprinkled on applesauce and swallowed without chewing. The capsules should not be chewed, crushed, or divided (Prod Info NAMZARIC(R) oral extended-release capsules, 2016).
    7.2.2) PEDIATRIC
    A) The safety and efficacy of memantine in pediatrics and adolescents have not been established (Prod Info NAMZARIC(R) oral extended-release capsules, 2016; Prod Info NAMENDA XR(R) oral extended release capsules, 2014; Prod Info NAMENDA oral tablets, oral solution, 2013).

Maximum Tolerated Exposure

    A) An overdose ingestion of up to 400 mg of memantine resulted in restlessness, psychosis, visual hallucinations, somnolence, stupor, and coma. The patient recovered without permanent neurologic sequelae (Prod Info Namenda, 2003).
    B) CASE REPORT: An 84-year-old man with a 6-year history of Alzheimer's disease, who had been taking memantine 30 mg/day instead of the prescribed dose of 10 mg/day of donepezil and memantine for a month, presented with a 2-day history of delirium, lethargy, and visual hallucinations. Laboratory results revealed a low blood sodium level (116 mmol/L) and a diagnosis of syndrome of inappropriate antidiuretic hormone (SIADH) secretion was made. Following the discontinuation of memantine and treatment with IV saline with water restriction, his condition resolved within 1 week. All risk factors and etiologies were analyzed and it was determined that memantine was considered to be the cause of SIADH (Oncel et al, 2015).
    C) CASE REPORT: A 35-year-old woman developed headache, dizziness, double vision, coma, tachycardia, hypertension, respiratory alkalosis, and seizures after ingesting 2000 mg of memantine. She recovered followed supportive care, including 6 cycles of plasmapheresis (Cekmen et al, 2011).
    D) CASE REPORT: One patient developed elevated serum uric acid, elevated serum alkaline phosphatase, and low platelet count after ingesting 112 mg of memantine extended-release daily for 31 days (Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 35-year-old woman developed headache, dizziness, double vision, coma, tachycardia, hypertension, respiratory alkalosis, and seizures after ingesting 2000 mg of memantine. Initially, her blood memantine concentration was 12,000 ng/mL. She recovered followed supportive care, including 6 cycles of plasmapheresis (Cekmen et al, 2011).

Workplace Standards

    A) ACGIH TLV Values for CAS19982-08-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS41100-52-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS19982-08-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS41100-52-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS19982-08-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS41100-52-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS19982-08-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS41100-52-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Memantine is a low-affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist (Prod Info Namenda(R) oral tablets, solution, 2007).
    B) Memantine appears to have a dual mechanism of action. At the receptor level, memantine exhibits rapid-binding kinetics and pronounced voltage-dependency, which result in modulation of the glutamatergic neurotransmission system. In a state of reduced glutamate release, memantine produces improved neurotransmission and activation of neurons. However, in situations of pathologically increased presynaptic release of glutamate, memantine inhibits the excitotoxic action of glutamate by blocking the NMDA receptor. This prevents exposure of the neuron to an excessive influx of calcium, which is thought to be one of the mechanisms responsible for neuronal death (Kornhuber & Weller, 1997; Gortelmeyer & Erbler, 1992).
    C) Memantine is thought to have a higher affinity to cerebellar than to frontal brain tissue (Schugens et al, 1997).

Physicochemical

Physical Characteristics

    A) Memantine is a fine white to off-white powder that is soluble in water (Prod Info Namenda(R) oral tablets, solution, 2007; Prod Info NAMENDA XR(R) extended release oral capsules, 2010).

Molecular Weight

    A) 215.76 (Prod Info Namenda(R) oral tablets, solution, 2007; Prod Info NAMENDA XR(R) extended release oral capsules, 2010)

References

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