Continuing Education Activity

Memantine acts as an antagonist for the N-methyl-D-aspartate (NMDA) receptor subtype of the glutamate receptor. Memantine slows the neurotoxicity involved in Alzheimer disease and other neurodegenerative diseases. Memantine is an uncompetitive, low-affinity, open-channel blocker that blocks the extrasynaptic NMDA receptor (NMDAR) that selectively enters the receptor-associated ion channel during its open state. As a result, the drug prevents the disruption of normal synaptic transmission, safeguarding against further damage caused by excitotoxicity-induced neuronal cell death. This is why memantine is commonly used in combination with acetylcholinesterase inhibitors for the treatment of Alzheimer dementia, which is approved by the United States Food and Drug Administration (FDA).

Memantine blocks the NMDAR subtype of glutamate receptors, preventing the overactivation of glutamine receptors and facilitating normal activity. The drug's antagonistic effects counteract an excessively active glutaminergic system in the central nervous system, believed to contribute to the neurotoxicity observed in Alzheimer disease. This activity reviews the pharmacology, indications, adverse effects, drug interactions, and contraindications of memantine, highlighting the collaborative efforts of interprofessional healthcare teams in treating patients with dementia.

Objectives:

• Identify appropriate candidates for memantine therapy based on the diagnosis of moderate to severe Alzheimer dementia and in accordance with FDA-approved indications.

• Screen patients for contraindications and potential risks associated with memantine, considering factors such as comorbidities and medication interactions.

• Select suitable combinations of memantine with acetylcholinesterase inhibitors, recognizing the synergistic effects in the treatment of Alzheimer dementia.

• Coordinate with the interprofessional healthcare team to develop and implement a holistic care plan, considering both pharmacological and non-pharmacological approaches to Alzheimer management.

Indications

Memantine is an antagonist of the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate receptor. Memantine is used to slow the neurotoxicity involved in Alzheimer disease and other neurodegenerative diseases.[1] Glutamate is a major excitatory neurotransmitter in the brain. Among the receptors activated by glutamate is the NMDAR, which is crucial for processes such as learning and memory. Excessive activation of NMDARs is associated with neuronal loss or damage, contributing to acute and chronic neurological disorders, including dementia. However, maintaining physiological NMDAR activity is essential for normal neuronal function. Agents that completely block NMDAR activity would result in undesirable clinical adverse effects.

Memantine blocks the NMDAR subtype of glutamate receptors, preventing the overactivation of glutamine receptors and facilitating normal activity. The drug's antagonistic effects counteract an excessively active glutaminergic system in the central nervous system, believed to contribute to the neurotoxicity observed in Alzheimer disease.[2][3]

Pharmacologic Class

NMDAR antagonist

Description

Chemical name: 1-amino-3,5-dimethyladamantane hydrochloride

Molecular formula: C₁₂H₂₁N•HCl

Molecular weight: 215.76 g

FDA-Approved Indication

Memantine is approved by the United States Food and Drug Administration (FDA) for the treatment of moderate-to-severe Alzheimer dementia.[4]

Off-Label Uses

Memantine may be utilized off-label for conditions such as mild-to-moderate Alzheimer dementia and vascular dementia, chronic pain, psychiatric disorders, and mild cognitive impairment, as well as in cases of brain metastases in patients with a favorable prognosis undergoing whole brain radiation therapy (WBRT) or hippocampal avoidance WBRT, as recommended by the American Society for Radiation Oncology.[5]

Diagnosis of Alzheimer Disease

The DSM-5 criteria for diagnosis include the following characteristics:

• Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains: complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition.
• The cognitive deficits interfere with independence in everyday activities.
• The cognitive deficits do not occur only in the context of delirium.
• Another mental disorder does not better explain the cognitive deficits.
• The onset is an insidious and gradual progression of impairment in at least 2 cognitive domains:
  • Evidence of a causative Alzheimer disease genetic mutation from family history or genetic testing.
  • All 3 of the following: Clear evidence of a decline in memory and learning and one or more other domains; steadily progressive, gradual decline in cognition, without extended plateaus; and no evidence of mixed etiology due to other neurodegenerative disorders or cerebrovascular disease.

Role of Memantine in Alzheimer Dementia

Alzheimer disease is a neurodegenerative disorder characterized by the presence of extracellular amyloid-beta protein, an intracellular neurofibrillary tangle composed of a hyperphosphorylated protein in the brain. There is a decrease in acetylcholine synthesis and impaired cortical cholinergic function in patients with Alzheimer dementia. Cholinesterase inhibitors (like donepezil, rivastigmine, and galantamine) in dementia provide symptomatic relief by inhibiting cholinesterase at the synaptic cleft and increasing cholinergic transmission. However, the mechanism of action of memantine is distinct from those of cholinergic agents and is neuroprotective.

Memantine is an uncompetitive, low-affinity, open-channel blocker that blocks the extrasynaptic NMDAR that selectively enters the receptor-associated ion channel during its open state. As a result, the drug prevents the disruption of normal synaptic transmission, safeguarding against further damage caused by excitotoxicity-induced neuronal cell death. This is why memantine is commonly used in combination with acetylcholinesterase inhibitors for the treatment of Alzheimer dementia.[2][6]

Mechanism of Action

Memantine is an uncompetitive antagonist of the NMDA subtype of glutamate receptors in the CNS. Alzheimer disease is believed to be caused by overstimulation of glutamate, the primary excitatory amino acid in the CNS, resulting in excitotoxicity and neuronal degeneration. The NMDAR is a voltage-gated cation channel blocked by magnesium ions in the physiologic unstimulated state. Stimulated magnesium is displaced, allowing calcium influx and activation. In Alzheimer disease, pathologic overstimulation of the receptor causes a chronically active state. Memantine counteracts the excessive stimulation.[1]

Memantine also exhibits antagonist activity at the serotonergic type 3 (5-HT3) and nicotinic acetylcholine receptors. Memantine has no activity at the gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.[1]

Pharmacokinetics

Memantine exhibits linear pharmacokinetics behavior over the therapeutic dose range.

Absorption: The Cmax and AUC0-24 values of memantine were 48% and 33% higher for the extended-release dosage regimen when comparing once daily 28 mg memantine hydrochloride extended-release capsules to twice 10 mg daily memantine hydrochloride. Memantine peak plasma concentration occurs around 9 to 12 hours post-dose after multiple doses of memantine hydrochloride extended-release capsules. Whether taken intact or sprinkled on applesauce, there is no difference in the absorption of memantine hydrochloride extended-release capsules.

Whether memantine hydrochloride extended-release capsules are taken with food or on an empty stomach, there is no difference in the Cmax or AUC. However, peak plasma concentrations are achieved about 18 hours and 25 hours after administration with food and on an empty stomach, respectively.

Distribution: The plasma protein binding of memantine is 45%. The average volume of distribution of memantine is 9 to 11 L/kg.

Metabolism: Memantine is partially metabolized in the liver. The hepatic microsomal enzyme system, specifically CYP450, does not significantly impact the breakdown of memantine.

Elimination: Most of the memantine is eliminated through urine without undergoing any changes. The elimination half-life is about 60 to 80 hours. Approximately 48% of the drug administered is eliminated unchanged in the urine. The remaining portion is transformed into 3 polar metabolites with minimal NMDAR antagonistic activity. These metabolites include the N-glucuronide conjugate, 6-hydroxy-memantine, and 1-nitroso-deaminated memantine. 74% of the administered dose is excreted as the sum of the parent drug and the N-glucuronide conjugate. Renal clearance involves active tubular secretion moderated by pH-dependent tubular reabsorption.

Administration

Available Dosage Forms and Strengths

Dosing parameters

• Starting dosage: 5 mg once daily
• Target dosage: 20 mg once daily
• Titration: Dosage increased by 5 mg daily in weekly intervals as tolerated
• Titration schedule
  • Week 1: 5 mg daily
  • Week 2: 10 mg daily (5 mg twice daily)
  • Week 3: 15 mg daily (5 mg one time and 10 mg one time daily)
  • Week 4: 20 mg daily (10 mg twice daily) 
• Switching from immediate-release (IR) to extended-release (ER): Start ER the day after the last dosage of IR; IR 10 mg twice daily should be switched to ER 28 mg daily.

• Missed dosage: If a single dose is missed, do not double up on the next dose; if several dosages are missed, resume at a lower dose and titrate as tolerated.

Adult Dosage

Dosage forms:[3]

• Capsule, extended-release, 24-hour, oral, as hydrochloride - generic: 7 mg, 14 mg, 21 mg, 28 mg

• Solution, oral, as hydrochloride - generic: 2 mg/mL (360 mL)

• Tablet, oral, as hydrochloride -generic: 5 mg, 10 mg 

Administration:

• Any formulation: With or without food, do not chew, crush, or divide

• Extended-release capsules: The entire contents of the capsule may be swallowed and sprinkled on food and swallowed immediately.

• Oral solution: Do not mix with any other liquid; administer with the provided dosing device supplied with a syringe, syringe adaptor cap, tubing, and other needed supplies; slowly squirt into the corner of the mouth.

Storage:

• Room temperature between 20°C to 25°C (68°F to 77°F)

Specific Patient Populations

Hepatic impairment: Pharmacokinetics of memantine was studied after administration of 20 mg single dose of memantine hydrochloride in 8 patients with moderate hepatic impairment (Child-Pugh Class B score of 7 to 9), and 8 healthy volunteers matched as closely as possible by weight, age, and gender. Compared to healthy volunteers, there was no change in Cmax and AUC of memantine exposure in patients with moderate hepatic impairment. In subjects with moderate hepatic impairment, the terminal elimination half-life increased by approximately 16% compared to healthy volunteers.

Renal impairment: Pharmacokinetics of memantine was studied after administration of 20 mg single dose of memantine hydrochloride in 7 patients with severe renal impairment (5 to 29 mL/min creatinine clearance), 8 patients with moderate renal impairment (30 to 49 mL/min creatinine clearance), 8 patients with mild renal impairment (>50 to 80 mL/min creatinine clearance), and 8 healthy volunteers (>80 mL/min creatinine clearance) matched closely by weight, age, and gender. Compared to healthy subjects, average AUC increased by 115%, 60%, and 4% in subjects with severe, moderate, and mild renal impairment, respectively. Similarly, the terminal elimination half-life increased by 95%, 41%, and 18% in subjects with severe, moderate, and mild renal impairment, respectively.[7]

Pregnant considerations: Memantine is considered a pregnancy category B drug. There is insufficient data on using memantine hydrochloride extended-release capsules and associated developmental risks in pregnant women. Some adverse developmental effects (decreased body weight and skeletal ossification) were observed in the offspring of rats when memantine was administered during pregnancy at doses associated with minimal maternal toxicity. Typically, these doses are higher than the maximum recommended daily dose in humans. The risk of major congenital abnormalities and miscarriage is unknown.

Breastfeeding considerations: Whether the administered memantine is excreted in human milk, affects breastfed infants, or affects milk production is unknown. The recommendation is to consider the developmental and health benefits of breastfeeding along with the clinical needs of the mother.

Pediatric patients: The safety and effectiveness of memantine hydrochloride have not been established in pediatric patients.

Older patients: No dose adjustment of memantine is needed as the pharmacokinetics in adults and older patients are similar.

Gender: After administering multiple doses of memantine hydrochloride 20 mg daily, female patients had about 45% higher exposure than males. However, there was no difference in exposure when body weight was considered.

Adverse Effects

The most common adverse effects of memantine in clinical trials include dizziness, headache, confusion, diarrhea, and constipation.[8][9] Additional adverse effects include fatigue, pain, hypertension, weight gain, hallucination, confusion, aggressive behavior, vomiting, abdominal pain, and urinary incontinence.[10]

Uncommon (post-marketing surveillance, clinical trials, or case reports) adverse effects are listed below. 

• Neurologic: abnormal gait, cerebral infarction, cerebrovascular accident, intracranial hemorrhage, seizure, somnolence, tardive dyskinesia, neuroleptic malignant syndrome

• Cardiovascular: bradyarrhythmia, heart failure, myocardial infarction, peripheral edema, syncope, tachycardia

• Endocrine: weight change

• Gastrointestinal: loss of appetite, nausea

• Hematologic: anemia

• Hepatic: hepatitis, liver failure[11]

• Renal: acute renal failure, urinary tract infection

• Respiratory: bronchitis, pneumonia, upper respiratory infection

• Dermatologic: rash, Stevens-Johnson syndrome

• Musculoskeletal: arthralgia

• Others: falling injury, influenza-like symptoms, neuroleptic malignant syndrome

Drug-Drug Interactions

Drugs causing alkaline urine: Alkaline urine conditions with a pH of 8 can reduce the clearance of memantine by approximately 80%, leading to an accumulation of the drug and potentially increasing the risk of adverse effects. Hence, carbonic anhydrase inhibitors and sodium bicarbonate should be used cautiously due to the risk of adverse effects.[12]

NMDA antagonists: Combining memantine with other NMDA antagonists, including amantadine, ketamine, and dextromethorphan, can increase neuropsychiatric adverse effects. However, a recent study concluded that memantine can be administered with amantadine or dextromethorphan. Use with caution.[13]

Contraindications

Box Warnings

Patients with hypersensitivity to memantine hydrochloride or any agents used in the formulation.[14]

Warning and Precautions

Genitourinary conditions: Conditions that raise urine pH, like renal tubular acidosis, may decrease the urinary elimination of memantine.

Cardiovascular disease: Increased incidence of cardiac failure, angina, and hypertension occurred in clinical trials. 

Hepatic impairment: Precaution use in severe hepatic impairment; effects of impairment on pharmacokinetics have not been established. [8]

Monitoring

No routine monitoring is required for toxicity.

Monitoring Efficacy: Memantine may take months for any noticeable improvement.

• Activities of daily living

• Cognitive functioning improvements 

• Slowing in the progression of decline in cognitive function and memory impairment

• Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) [15]

Toxicity

Memantine overdose can result in several signs and symptoms. These may include agitation, asthenia, confusion, visual hallucinations, vertigo, coma, slowed movement, somnolence, dizziness, lethargy, loss of consciousness, ECG changes, bradycardia, increased blood pressure, psychosis, restlessness, stupor, unsteady gait, vomiting, and weakness. Clinicians must be aware of these potential effects when using memantine alone or in combination with other drugs and/or alcohol.[16]

According to the literature, known adverse effects when co-ingested with antidiabetic drugs include coma, diplopia, and agitation—prolonged usage results in elevated levels of serum uric acid, serum alkaline phosphatase, and a low platelet count.

There are very few reports of fatal outcomes associated with memantine, and it is unclear if memantine was the cause. The recommendation is to contact a poison control center to stay updated on the latest overdose management strategies. General supportive measures are recommended, and treatment should address the symptoms. The elimination of memantine can be increased by acidifying urine.

Enhancing Healthcare Team Outcomes

Currently, the cure for Alzheimer disease does not exist, and the limited available drugs are primarily targeted at mild cognitive impairment. Unfortunately, the prognosis for patients with Alzheimer remains unfavorable.

An interprofessional team should manage patients with Alzheimer disease, as well as the medications they receive. Prescribers of memantine should be aware that the drug can worsen the symptoms of dementia. Therefore, these patients should be closely monitored by the interprofessional healthcare team, including physicians, advanced practice practitioners, nursing staff, pharmacists, mental health nurses, a neurologist, a psychiatrist, and social workers, reporting complications to the rest of the team, so shared decision making can guide the next steps in managing the case.

Pharmacists should ensure appropriate dosing, perform medication reconciliation, and counsel patient caregivers and family members regarding potential adverse medication events. Nurses provide valuable counseling and monitoring and must consult with the prescriber if they note any concerns with memantine therapy. The response to memantine is mild, and most patients do not show immense benefit.[17][18][19]