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  • CLASSES

    Anti-Alzheimer Combination Products
    Anti-Alzheimer Drugs, NMDA Receptor Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antagonist at N-methyl-D-aspartate (NMDA) receptors; partially blocks excitatory glutamate activation; indicated for the treatment of moderate to severe Alzheimer's disease.

    COMMON BRAND NAMES

    Namenda, Namenda XR

    HOW SUPPLIED

    Memantine/Namenda Oral Sol: 5mL, 10mg
    Memantine/Namenda Oral Tab: 5mg, 10mg, 5-10mg
    Namenda XR Oral Cap ER: 7mg, 14mg, 21mg, 28mg, 7-14-21-28mg

    DOSAGE & INDICATIONS

    For the treatment of symptoms of moderate to severe Alzheimer's disease.
    Oral dosage (immediate-release tablets or oral solution)
    Adults and the Geriatric

    Initially, 5 mg PO once daily. The initial dosage is titrated slowly over 3 weeks. Increase the dose by 5 mg/week over a 3-week period to a target dose of 10 mg PO twice daily at week 4. It takes roughly 15 days to reach steady state plasma concentrations. Periodic evaluation after initiation and during continuation of therapy may be helpful to the clinician in deciding treatment duration (i.e., continue treatment if improvement or stability in functional, cognitive or behavioral status continues). In a US Phase III trial for moderate to severe AD, the dosage was 10 mg PO twice daily during the 6 month trial. Treated patients showed significantly slower declines in cognition and ability to perform daily self-care activities than placebo-treated patients. The Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus), a primary outcome measure to determine clinical applicability of test results, was found to be significant (p = 0.03) when analyzed with the observed cases (72% of patients), but only approached significance in the intent-to-treat analysis with last observation carried forward (p = 0.06).

    Oral dosage (extended-release capsules)
    Adults and Geriatric patients

    Initially, 7 mg PO once daily. The dose should be increased in 7 mg increments at minimum intervals of 1 week up to the recommended target dose of 28 mg once daily. During the titration phase, ensure that the previously established dose is well tolerated before increasing to the next dosage level. The maximum daily dose is 28 mg/day. When switching from the immediate-release (IR) tablets to the extended-release (ER) capsules, the following conversion is recommended: 10 mg twice daily of the IR tablets should be converted to 28 mg once daily of the ER capsules beginning the day after the last dose of the IR tablet. It should be noted that there are no data on the comparative efficacy of these 2 regimens. Patients with severe renal impairment receiving 5 mg twice daily of the IR tablets may be converted to the ER capsules at a dose of 14 mg once daily beginning the day after the last dose of the IR tablet.

    For the treatment of symptoms of mild to moderate vascular dementia†.
    Oral dosage
    Adults

    In one study, patients with mild to moderate vascular dementia receiving memantine 20 mg/day PO had less cognitive deterioration at 28 weeks but this effect was not clinically discernible. Further study is needed to determine the potential benefit of memantine in the treatment of vascular dementia.

    For the symptomatic treatment of acquired pendular nystagmus†.
    Oral dosage
    Adults

    Limited data suggest 10 mg PO once daily titrated to 40 mg/day (administered as 10 mg 4 times daily) may be effective in reducing median eye speed and/or improving visual acuity. Study duration was 7 to 14 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    20 mg/day PO immediate-release formulations; 28 mg/day PO extended-release formulation.

    Elderly

    20 mg/day PO immediate-release formulations; 28 mg/day PO extended-release formulation.

    Adolescents

    Use not indicated.

    Children

    Use not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are required for patients with mild to moderate hepatic impairment. Memantine should be administered with caution to patients with severe hepatic impairment.

    Renal Impairment

    CrCl >= 30 ml/min: No dosage adjustment is recommended for patients with mild to moderate renal impairment.
    CrCl 5—29 ml/min: After calculating estimated CrCl based on Cockroft-Gault equation, a target dose of 5 mg PO twice daily of immediate-release formulations is recommended (see adult dosage titration recommendations). A target dose of 14 mg/day of the extended-release capsule is recommended.
    CrCl < 5 ml/min: No quantitative recommendation available; no specific information with respect to hemodialysis is available.

    ADMINISTRATION

    Oral Administration

    If a patient misses a single dose, that patient should not double up on the next dose. The next dose should be taken as scheduled. If a patient fails to take memantine for several days, dosing may need to be resumed at lower doses and re-titrated.

    Oral Solid Formulations

    Immediate-release tablets:
    May administer with or without food.
     
    Extended-release capsules:
    May administer with or without food.
    Do not chew, crush, or divide the capsule.
    May have patient swallow whole or the capsule may be opened and the entire contents sprinkled on applesauce before swallowing. The entire contents of the capsule should be consumed; the dose should not be divided.

    Oral Liquid Formulations

    Oral solution:
    The oral solution is administered with a dosing device that comes with the drug and consists of a syringe, syringe adaptor cap, tubing and other supplies needed to administer the drug. Instruct the patient or caregiver on the correct use of the oral dosing syringe.
    Do not mix the oral solution with any other liquid.
    May administer with or without food.
    Withdraw the correct volume of oral solution for the dose into the supplied syringe, and then slowly squirt the oral solution into the corner of the patient's mouth.

    STORAGE

    Namenda:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Namenda XR:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The use of memantine is contraindicated in any patient with a known memantine hypersensitivity, or any inactive ingredients or excipients contained within memantine.
    Caregivers of patients receiving memantine should be instructed on the escalating dose procedure for memantine.

    Renal disease, renal failure, renal impairment, urinary tract infection (UTI)

    Use memantine with caution in patients with renal disease; dosage adjustments of memantine are required in patients with severe renal impairment (CrCl < 30 ml/min). Data are not available for patients with renal failure on dialysis. Memantine is predominantly eliminated by the kidneys in part by tubular secretion. Conditions, drugs, and/or foods that raise urine pH may decrease urinary elimination of memantine and increase plasma concentrations, potentially increasing the risk of adverse effects, such as dizziness, headache or agitation. Use memantine with caution in patients with conditions that could affect urinary pH such as renal tubular acidosis, urinary tract infection (UTI), and renal failure. Coadministration of drugs that use the same cationic renal tubular secretion system for elimination could potentially result in altered plasma concentrations of memantine or the co-prescribed drug. Carefully monitor patients for response and adverse effects related to each agent.

    Hepatic disease

    Memantine undergoes partial hepatic metabolism, with about 48% of administered dose excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate (74%). According to the manufacturer, no dosage adjustments are needed in patients with mild to moderate hepatic impairment; however caution is advised when using the drug in those with severe hepatic disease.

    Pregnancy

    Memantine is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies in pregnant women. Memantine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Breast-feeding

    It is not known whether memantine is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered during breast-feeding.

    Children, infants

    Memantine is not indicated for use in infants, children, or adolescents. Memantine failed to demonstrate efficacy in two 12-week controlled trials (n = 578) of patients 6—12 years of age with autism spectrum disorders (ASD), including autism Asperger’s disorder and Pervasive Development Disorder Not Otherwise Specified (PDD-NOS). The dose of extended-release memantine was based upon weight as follows: < 20 kg (3 mg/day), 20—39 kg (6 mg/day), 40—59 kg (9 mg/day), and >= 60 kg (15 mg/day). The overall safety profile of memantine in pediatric patients was generally comparable to the safety profile in adults.

    Geriatric

    Memantine is eliminated primarily by the kidneys and dose adjustments are required in severe renal impairment. Geriatric patients may be at greater risk for renal impairment due to age-related changes in renal function, concomitant medications or other risk factors. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA guidelines, the continued use of memantine for the treatment of a cognitive disorder in residents of a LTCF should be re-evaluated as the underlying disorder progresses into advanced stages. Adverse effects of memantine include restlessness, distress, dizziness, somnolence, hypertension, headache, hallucinations, and increased confusion.

    Seizure disorder, seizures

    Memantine has not been formally evaluated in patients with seizure disorders; patients receiving memantine who have seizures or a history of a seizure disorder should be carefully monitored.

    ADVERSE REACTIONS

    Severe

    eczema vaccinatum / Delayed / 0.1-1.0
    atrial fibrillation / Early / 0.1-1.0
    pulmonary edema / Early / 0.1-1.0
    cardiac arrest / Early / 0.1-1.0
    myocardial infarction / Delayed / 0.1-1.0
    bradycardia / Rapid / 0.1-1.0
    apnea / Delayed / 0.1-1.0
    GI bleeding / Delayed / 0.1-1.0
    esophageal ulceration / Delayed / 0.1-1.0
    pulmonary embolism / Delayed / 0.1-1.0
    retinal detachment / Delayed / 0.1-1.0
    corneal opacification / Delayed / 0.1-1.0
    hearing loss / Delayed / 0.1-1.0
    retinal hemorrhage / Delayed / 0.1-1.0
    macular degeneration / Delayed / 0.1-1.0
    seizures / Delayed / 0.2-0.3
    stroke / Early / 1.0
    heart failure / Delayed / 1.0
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    coma / Early / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    AV block / Early / Incidence not known
    ileus / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    bone fractures / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known

    Moderate

    confusion / Early / 6.0-6.0
    constipation / Delayed / 3.0-5.0
    hypertension / Early / 4.0-4.0
    hallucinations / Early / 3.0-3.0
    hypotension / Rapid / 0.1-2.0
    dyspnea / Early / 2.0-2.0
    peripheral edema / Delayed / 0-2.0
    urinary incontinence / Early / 2.0-2.0
    skin ulcer / Delayed / 0.1-1.0
    amnesia / Delayed / 0.1-1.0
    aphasia / Delayed / 0.1-1.0
    psychosis / Early / 0.1-1.0
    delirium / Early / 0.1-1.0
    hypertonia / Delayed / 0.1-1.0
    peripheral neuropathy / Delayed / 0.1-1.0
    angina / Early / 0.1-1.0
    hemoptysis / Delayed / 0.1-1.0
    melena / Delayed / 0.1-1.0
    dysuria / Early / 0.1-1.0
    hematuria / Delayed / 0.1-1.0
    urinary retention / Early / 0.1-1.0
    anemia / Delayed / 0-1.0
    leukopenia / Delayed / 0.1-1.0
    diabetes mellitus / Delayed / 0.1-1.0
    hyponatremia / Delayed / 0.1-1.0
    phlebitis / Rapid / 0.1-1.0
    myopia / Delayed / 0.1-1.0
    blurred vision / Early / 0.1-1.0
    blepharitis / Early / 0.1-1.0
    depression / Delayed / 2.0
    ataxia / Delayed / 1.0
    cataracts / Delayed / 1.0
    conjunctivitis / Delayed / 1.0
    dyskinesia / Delayed / Incidence not known
    pseudoparkinsonism / Delayed / Incidence not known
    hyperlipidemia / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known
    encephalopathy / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    fecal incontinence / Early / Incidence not known
    colitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    dysphagia / Delayed / Incidence not known
    myoclonia / Delayed / Incidence not known
    dehydration / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known

    Mild

    cough / Delayed / 4.0-8.9
    headache / Early / 6.0-8.0
    influenza / Delayed / 2.0-7.1
    dizziness / Early / 5.0-7.0
    agitation / Early / 2.0-5.4
    diarrhea / Early / 2.0-5.0
    drowsiness / Early / 3.0-3.0
    vomiting / Early / 2.0-3.0
    back pain / Delayed / 3.0-3.0
    weight gain / Delayed / 3.0-3.0
    fatigue / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    anorexia / Delayed / 0-2.0
    alopecia / Delayed / 0.1-1.0
    pruritus / Rapid / 0.1-1.0
    hypothermia / Delayed / 0.1-1.0
    urticaria / Rapid / 0.1-1.0
    libido increase / Delayed / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    hypoesthesia / Delayed / 0.1-1.0
    syncope / Early / 0-1.0
    ptosis / Delayed / 0.1-1.0
    paresthesias / Delayed / 0.1-1.0
    appetite stimulation / Delayed / 0.1-1.0
    tremor / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    paranoia / Early / 0.1-1.0
    lacrimation / Early / 0.1-1.0
    tinnitus / Delayed / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    ocular pain / Early / 0.1-1.0
    diplopia / Early / 0.1-1.0
    rash (unspecified) / Early / 1.0
    anxiety / Delayed / 2.0
    vertigo / Early / 1.0
    insomnia / Early / 2.0
    infection / Delayed / 2.0
    nausea / Early / 2.0
    arthralgia / Delayed / 2.0
    weight loss / Delayed / 1.0
    increased urinary frequency / Early / 1.0
    restlessness / Early / Incidence not known
    irritability / Delayed / Incidence not known
    lethargy / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    fever / Early / Incidence not known
    rhinorrhea / Early / Incidence not known
    malaise / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known
    xerostomia / Early / Incidence not known
    carpal tunnel syndrome / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Abacavir; Lamivudine, 3TC: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetazolamide: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as memantine, may decrease adefovir elimination by competing for common renal tubular transport systems; therefore increasing serum concentrations of either adefovir and/or memantine may occur.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Alkalinizing Agents: (Moderate) Urinary alkalinizing agents may decrease the elimination of memantine, resulting in drug accumulation and potential toxicity. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Memantine should be used with caution with drugs known to increase urinary pH.
    Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Amantadine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Amiloride: (Minor) Cationic drugs that are eliminated by renal tubular secretion, such as amiloride, may decrease memantine elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of memantine and/or amiloride is recommended.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Cationic drugs that are eliminated by renal tubular secretion, such as amiloride, may decrease memantine elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of memantine and/or amiloride is recommended. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Anticholinergics: (Moderate) The adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Bromocriptine: (Moderate) The pharmacologic effects of dopaminergic agents, including the ergot derivative bromocriptine, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Carbonic anhydrase inhibitors: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Chlorpheniramine; Dextromethorphan: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Cimetidine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as cimetidine, could result in elevated serum concentrations of one or both drugs.
    Citric Acid; Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Clofarabine: (Moderate) Concomitant use of clofarabine and memantine may result in altered clofarabine levels because both agents are a substrate of OCT2. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OCT2 substrates.
    Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Promethazine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Quinidine: (Major) Cationic drugs that are eliminated by renal tubular secretion, such as quinidine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or quinidine is recommended to assess for needed dosage adjustments. In selected individuals, quinidine serum concentration monitoring may be appropriate. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Digoxin: (Moderate) Digoxin is eliminated by renal tubular secretion and may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or digoxin is recommended to assess for needed dosage adjustments. In selected individuals, digoxin serum concentration monitoring may be appropriate
    Dofetilide: (Major) Drugs that are actively secreted via cationic secretion (e.g., memantine) should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion. Competition for renal elimination may increase plasma concentrations of dofetilide and increase the risk of pro-arrhythmias.
    Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Entecavir: (Moderate) Entecavir is eliminated by active tubular secretion. In theory, coadministration of entecavir with other drugs that are eliminated by active tubular secretion, such as memantine, may increase the serum concentrations of entecavir or memantine due to competition for the drug elimination pathway.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Quinapril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as triamterene, could result in elevated serum concentrations of one or both drugs. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Ketamine: (Moderate) Ketamine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of ketamine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Lamivudine, 3TC: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Lamotrigine: (Minor) Coadministration of memantine and lamotrigine may decrease memantine clearance, resulting in increased plasma concentrations and the potential for adverse events, including vertigo and mental status changes. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and memantine is excreted via this route.
    Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Pioglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Rosiglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Methazolamide: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Midodrine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as midodrine, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or midodrine is recommended.
    Morphine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    Morphine; Naltrexone: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    Nicotine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, like nicotine, could result in elevated serum concentrations of one or both drugs.
    Pergolide: (Moderate) The pharmacologic effects of pergolide may be enhanced with use of memantine; dosage adjustments of pergolide may be required when memantine is coadministered.
    Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Salts: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Pramipexole: (Moderate) The pharmacologic effects of dopaminergic agents, including pramipexole, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    Procainamide: (Major) Cationic drugs that are eliminated by renal tubular secretion such as procainamide, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or procainamide is recommended to assess for needed dosage adjustments. In selected individuals, procainamide serum concentration monitoring may be appropriate.
    Quinidine: (Major) Cationic drugs that are eliminated by renal tubular secretion, such as quinidine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or quinidine is recommended to assess for needed dosage adjustments. In selected individuals, quinidine serum concentration monitoring may be appropriate.
    Quinine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as quinine, could result in elevated serum concentrations of one or both drugs.
    Ranitidine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as ranitidine, could result in elevated serum concentrations of one or both drugs.
    Ranolazine: (Moderate) Coadminister ranolazine and memantine with caution. Memantine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the memantine dose may be necessary.
    Ropinirole: (Moderate) The pharmacologic effects of dopaminergic agents, including dopamine agonists and certain ergot derivatives may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    Rotigotine: (Moderate) The pharmacologic effects of dopaminergic agents, including dopamine agonists such as rotigotine, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    Solifenacin: (Moderate) The adverse effects of solifenacin may be enhanced with use of memantine; dosage adjustments of the solifenacin may be required when memantine is coadministered.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    Triamterene: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as triamterene, could result in elevated serum concentrations of one or both drugs.
    Trimethoprim: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    Trospium: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as trospium, could result in elevated serum concentrations of one or both drugs.
    Vancomycin: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as vancomycin, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or vancomycin is recommended to assess for needed dosage adjustments. In selected individuals, vancomycin serum concentration monitoring may be appropriate.
    Vandetanib: (Minor) Use caution if coadministration of vandetanib with memantine is necessary, due to a possible increase in memantine-related adverse reactions, including vertigo and mental status changes. Memantine is an OCT2 substrate. Coadministration with vandetanib increased the Cmax and AUC of metformin, another OCT2 substrate, by 50% and 74%, respectively.

    PREGNANCY AND LACTATION

    Pregnancy

    Memantine is classified as FDA pregnancy risk category B. There are no adequate and well-controlled studies in pregnant women. Memantine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    It is not known whether memantine is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when memantine is administered during breast-feeding.

    MECHANISM OF ACTION

    Mechanism of Action: Glutamate activation at the NMDA receptor is needed for learning and memory processes in the brain. There is evidence that the chronic excitatory activity of the neurotransmitter L-glutamate may play a role in the pathogenesis of Alzheimer's disease and other neurological disorders. Glutamate, the dominant excitatory amino acid in the brain, stimulates NMDA receptors, which in turn leads to increased intraneuronal concentrations of calcium (Ca2+). Excessive glutamate (and therefore Ca2+) in the CNS can lead to neuronal damage. For example, persistently elevated synaptic glutamate levels during hypoxia and ischemia can lead to cell death due to excess Ca2+ influx via NMDA receptor channels. Under normal resting conditions, NMDA receptor channels do not allow chronic Ca2+ influx because they are blocked by magnesium (Mg2+). Depolarization of the membrane allows the Ca2+ to bypass the Mg2+ blockade, and influx through the NMDA receptor channels.Memantine is an antagonist at (N-methyl-D-aspartate) NMDA receptors; memantine has a low to moderate affinity for the NMDA receptor. Blockade of NMDA receptors by memantine slows the intracellular calcium accumulation and helps to prevent further nerve damage. A low affinity antagonist to NMDA-type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. High affinity NMDA antagonists, such as ketamine and dextromethorphan, are associated with excessive psychotomimetic effects at dosages needed for dementia treatment.Memantine does not affect the release of dopamine or serotonin, nor does it alter monoamine oxidase (MAO-A or B) or adenylate cyclase activity. In-vitro studies demonstrate that memantine lacks affinity for most serotonin receptor subtypes (except 5HT3), muscarinic acetycholine, a and ß adrenergic, dopaminergic, histaminic, and glycine receptors. Memantine appears to have antagonist activity at the 5HT3 receptor, with similar potency to that of the NMDA receptor. Memantine also has partial affinity for nicotinic acetylcholine receptors, with one-sixth to one-tenth the potency (relative to the NMDA receptor).

    PHARMACOKINETICS

    Memantine is administered orally as an immediate-release tablet, extended-release capsule, and oral solution. Protein binding, roughly 45%, is not a clinical concern. It rapidly crosses the blood brain barrier and can be detected in the CSF within 30 minutes of an IV infusion. The volume of distribution is 9 to 11 L/kg suggesting extensive distribution into tissues. Steady-state therapeutic plasma concentrations (0.37—0.5 microM) are similar between patients with dementia and healthy controls.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    Memantine undergoes partial hepatic metabolism. In-vitro, memantine shows minimal inhibition of the cytochrome P450 (CYP) enzyme system and minimal substrate interactions. Renal clearance is 182 ml/min and substantially exceeds the glomerular filtration rate, indicating active renal secretion. Increases in urinary pH may decrease the elimination of memantine, resulting in drug accumulation and potential toxicity. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8 (see Drug Interactions). Alternatively, acidification of the urine may increase the elimination of memantine. Memantine has an elimination half-life of 60—80 hours. About 48% of the dose is excreted in urine as unchanged drug or as the sum of parent drug and the N-glucuronide conjugate (74%).

    Oral Route

    Memantine is rapidly and completely absorbed with 100% bioavailability. Food does not alter the extent of absorption of the immediate-release (IR) or extended-release (ER) formulation; therefore, the drug may be taken with or without food. There is no difference in the systemic exposure of extended-release memantine between swallowing the capsule intact or sprinkling the contents on applesauce. However, other methods of administration such as cutting, dividing, or chewing the capsules should be avoided. The pharmacokinetics of immediate-release memantine are linear in the range of 5—40 mg single oral doses. Peak concentrations of the IR and ER formulations occur in 3—7 hours and 9—12 hours, respectively. In a study comparing 28 mg/day of ER memantine to 10 mg twice daily of IR memantine, the extended-release memantine had a Cmax and AUC that were 48% and 33% higher, respectively. The serum concentration of memantine is roughly double that found in the cerebrospinal fluid (CSF).

    Intravenous Route

    Memantine can be detected in the CSF within 30 minutes of an IV infusion.