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Memantine and Donepezil

Pronunciation

(me MAN teen & doh NEP e zil)

Index Terms

  • Donepezil Hydrochloride and Memantine Hydrochloride
  • Memantine HCl/Donepezil HCl
  • Namzaric

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule ER 24 Hour Therapy Pack, Oral:

Namzaric: Memantine hydrochloride 7 mg and donepezil hydrochloride 10 mg (7s) & memantine hydrochloride 14 mg and donepezil hydrochloride 10 mg (7s) & memantine hydrochloride 21 mg and donepezil hydrochloride 10 mg (7s) & memantine hydrochloride 28 mg and donepezil hydrochloride 10 mg (7s) (28 ea) [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #6 (sunset yellow)]

Capsule Extended Release 24 Hour, Oral:

Namzaric: Memantine hydrochloride 14 mg and donepezil hydrochloride 10 mg, Memantine hydrochloride 28 mg and donepezil hydrochloride 10 mg [contains brilliant blue fcf (fd&c blue #1)]

Namzaric: Memantine hydrochloride 7 mg and donepezil hydrochloride 10 mg [contains brilliant blue fcf (fd&c blue #1), corn starch, fd&c yellow #6 (sunset yellow)]

Namzaric: Memantine hydrochloride 21 mg and donepezil hydrochloride 10 mg [contains corn starch, fd&c yellow #6 (sunset yellow)]

Brand Names: U.S.

  • Namzaric

Pharmacologic Category

  • Acetylcholinesterase Inhibitor (Central)
  • N-Methyl-D-Aspartate Receptor Antagonist

Pharmacology

Memantine: Glutamate, the primary excitatory amino acid in the CNS, may contribute to the pathogenesis of Alzheimer disease (AD) by overstimulating various glutamate receptors leading to excitotoxicity and neuronal cell death. Memantine is an uncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors, located ubiquitously throughout the brain. Under normal physiologic conditions, the (unstimulated) NMDA receptor ion channel is blocked by magnesium ions, which are displaced after agonist-induced depolarization. Pathologic or excessive receptor activation, as postulated to occur during AD, prevents magnesium from reentering and blocking the channel pore resulting in a chronically open state and excessive calcium influx. Memantine binds to the intra-pore magnesium site, but with longer dwell time, and thus functions as an effective receptor blocker only under conditions of excessive stimulation; memantine does not affect normal neurotransmission.

Donepezil: Alzheimer disease is characterized by cholinergic deficiency in the cortex and basal forebrain, which contributes to cognitive deficits. Donepezil reversibly and noncompetitively inhibits centrally-active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine. This appears to result in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system.

Use: Labeled Indications

Alzheimer disease (moderate to severe): Treatment of moderate to severe dementia of the Alzheimer type in patients stabilized on donepezil 10 mg once daily.

Contraindications

Hypersensitivity to memantine, donepezil, piperidine derivatives, or any component of the formulation

Documentation of allergenic cross-reactivity for cholinesterase inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Alzheimer dementia (moderate to severe): Oral:

Patients stabilized on donepezil 10 mg once daily and not currently on memantine: Initial: Memantine extended release (ER) 7 mg/donepezil 10 mg once daily in the evening. Increase dose in increments of memantine ER 7 mg at intervals of ≥1 week to maintenance dose of memantine ER 28 mg/donepezil 10 mg once daily based on patient response and tolerability. Maximum dose: memantine ER 28 mg/ donepezil 10 mg once daily.

Patients stabilized on memantine (10 mg twice daily or 28 mg ER once daily) and donepezil 10 mg: Initial: Memantine ER 28 mg/donepezil 10 mg once daily in the evening. Initiate combination therapy the day after the last dose of memantine and donepezil administered separately.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Mild to moderate impairment (CrCl 30 to 80 mL/minute): No dosage adjustment necessary.

Severe renal impairment (CrCl 5 to 29 mL/minute):

Patients stabilized on donepezil 10 mg once daily and not currently on memantine: Initial: Memantine ER 7 mg/donepezil 10 mg once daily in the evening. Increase dose in increments of memantine ER 7 mg at intervals of ≥1 week to maintenance dose of memantine ER 14 mg / donepezil 10 mg once daily.

Patients stabilized on memantine (5 mg twice daily or 14 mg ER once daily) and donepezil 10 mg: May switch patients to memantine ER 14 mg/donepezil 10 mg once daily.

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

Oral: Administer in the evening without regard to meals. Swallow capsule whole; do not divide, chew, or crush. May open capsule and sprinkle entire contents on applesauce; swallow immediately. Do not divide contents of capsule into separate doses.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F). Protect from light.

Drug Interactions

Alkalinizing Agents: May increase the serum concentration of Memantine. Monitor therapy

Anticholinergic Agents: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Monitor therapy

Antipsychotic Agents: Acetylcholinesterase Inhibitors (Central) may enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Benoxinate: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy

Benperidol: Memantine may diminish the therapeutic effect of Benperidol. Monitor therapy

Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May increase the serum concentration of Memantine. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Monitor therapy

Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy

NMDA Receptor Antagonists: May enhance the adverse/toxic effect of Memantine. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Succinylcholine: Acetylcholinesterase Inhibitors may increase the serum concentration of Succinylcholine. Management: Consider alternatives to this combination due to a risk of prolonged neuromuscular blockade. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Trimethoprim: May enhance the adverse/toxic effect of Memantine. Specifically, the risk of myoclonus and/or delirium may be increased. Trimethoprim may increase the serum concentration of Memantine. Memantine may increase the serum concentration of Trimethoprim. Monitor therapy

Adverse Reactions

See individual agents.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block with or without a history of cardiac disease; syncopal episodes have been associated with donepezil.

• GI effects: May cause dose-related diarrhea, nausea, and/or vomiting; usually resolves in 1 to 3 weeks.

• Neuroleptic malignant syndrome: Rare cases of neuroleptic malignant syndrome (NMS) have been reported (Matsumoto 2004; Warwick 2008). Discontinuation of donepezil therapy may be necessary in patients presenting with symptoms of NMS (eg, hyperthermia, irregular pulse or blood pressure, cardiac arrhythmia, diaphoresis, muscle rigidity, mental status changes, elevated creatine phosphokinase [CPK], unexplained high fever without additional symptoms).

• Rhabdomyolysis: Rare cases of rhabdomyolysis (including acute renal failure) have been reported after a few months of therapy (Sahin 2014) or in the days following therapy initiation and dose increase (Aricept Canadian product monograph 2014). Use with caution in patients with risk factors for rhabdomyolysis (eg, concomitant medications associated with rhabdomyolysis, history of muscular disorders, uncontrolled hypothyroidism, renal/hepatic impairment). Discontinuation of therapy may be necessary for marked elevation of CPK levels and/or symptoms (eg, muscle pain, tenderness or weakness, malaise, fever, dark urine) suggesting rhabdomyolysis.

Disease-related concerns:

• Cardiac conduction abnormalities: Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally active cholinesterase inhibitors (APA [Rabins 2007].

• Peptic ulcer disease: Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); cholinesterase inhibitors may increase gastric acid secretion. Monitor for symptoms of bleeding.

• Renal impairment: Use caution in patients with renal impairment; reduce dose in patients with severe renal impairment.

• Respiratory disease: Use with caution in patients with COPD and/or asthma.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; cholinomimetics may potentially cause generalized seizures, although seizure activity may also result from Alzheimer disease.

• Urinary tract obstruction: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms (APA [Rabins 2007]).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Urine pH: Clearance is significantly reduced by alkaline urine; use caution with medications, dietary changes, or patient conditions which may alter urine pH.

Monitoring Parameters

Mental status; general function (eg, activities of daily living); symptoms of active or occult GI bleeding; symptoms of GI intolerance

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. See individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, lack of appetite, muscle cramps, nausea, vomiting, loss of strength and energy, or insomnia. Have patient report immediately to prescriber black, tarry, or bloody stools; difficult urination; severe dizziness; passing out; chills; pharyngitis; difficulty breathing; seizures; severe headache; abdominal pain; heartburn; bradycardia; abnormal heartbeat; bruising; or vomiting blood (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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