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  • CLASSES

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

    DEA CLASS

    Rx

    DESCRIPTION

    Oral N-methyl-D-aspartate (NMDA) receptor antagonist
    For use in moderate to severe Alzheimer's disease both as monotherapy and in combination with donepezil
    Concurrent medical conditions, drugs, or foods that raise urine pH may decrease urinary elimination of memantine and increase exposure, potentially increasing the risk of adverse effects

    COMMON BRAND NAMES

    Namenda, Namenda XR

    HOW SUPPLIED

    Memantine/Namenda Oral Sol: 5mL, 10mg
    Memantine/Namenda Oral Tab: 5mg, 10mg, 5-10mg
    Memantine/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

    Initially, 5 mg PO once daily. Then, titrate 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. Periodic evaluation may be helpful to determine treatment duration (i.e., continue treatment if improvement or stability in functional, cognitive or behavioral status continues).

    Oral dosage (extended-release capsules)
    Adults

    Initially, 7 mg PO once daily. Titrate in 7-mg increments at no sooner than 1 week intervals up to the recommended target dose of 28 mg PO once daily. During titration , ensure that the previously established dose is well-tolerated before increasing to the next dosage level. Max: 28 mg/day PO. CONVERSION FROM IMMEDIATE-RELEASE (IR): Convert 10 mg twice daily of the IR forms to 28 mg PO once daily of the ER capsules, beginning the day after the last dose of the IR dose form. There are no data on the comparative efficacy of these 2 regimens.

    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.

    Geriatric

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

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    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/minute or more: No dosage adjustment is needed.
    CrCl 5 to 29 mL/minute: A target dose of 5 mg PO twice daily of immediate-release (IR) formulations is recommended. A target dose of 14 mg PO once daily of the extended-release (XR) form is recommended. If switching from the IR forms to XR, switch to memantine XR 14 mg PO once daily the day following the last dose of 5 mg memantine IR.
    CrCl less than 5 mL/minute: No dosage recommendation is available; no specific hemodialysis information is available.

    ADMINISTRATION

    Oral Administration

    Inform caregivers of the needed dose titration schedule.
    If a patient misses a single dose, the dose should be skipped and the next dose should be taken as scheduled. The patient should not take double or extra doses.
    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 controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    The use of memantine is contraindicated in any patient with a known memantine hypersensitivity or hypersensitivity to any inactive ingredients or excipients contained within the products.

    Renal failure, renal impairment, renal tubular acidosis (RTA), urinary tract infection (UTI)

    Memantine is predominantly eliminated by the kidneys in part by tubular secretion. Dosage adjustments of memantine are required in patients with severe renal impairment (CrCl less than 30 mL/minute). No data are available for use of memantine in patients with renal failure on dialysis. Use memantine with caution in patients with conditions that could affect urinary pH such as renal tubular acidosis (RTA), severe urinary tract infection (UTI), and renal failure. 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. The concurrent use 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. Caution is advised when using memantine in those with severe hepatic disease as specific studies of the drug in these patients are not available and the elimination half-life may be prolonged. No dosage adjustments are required in patients with mild to moderate hepatic impairment.

    Geriatric

    The majority of people with Alzheimer's disease are 65 years and older; during clinical trials in patients with Alzheimer's dementia, there was no noted differences in adverse effects reported among geriatric patients and those younger than 65 years of age. Geriatric patients may be at greater risk for renal impairment due to age-related changes in renal function, concomitant medications or other risk factors that may influence dosage. 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.

    Pregnancy

    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. In animal studies in rats and rabbits, memantine was not teratogenic during the period of organogenesis up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6- and 21-times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at 18 mg/kg/day orally in a rat study from pre-mating through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in rats treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 basis.

    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 less than 18 years of age. Memantine failed to demonstrate efficacy in two 12-week controlled trials (n = 578) of pediatric patients 6 to 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: weight less than 20 kg (3 mg/day), weight 20 to 39 kg (6 mg/day), weight 40 to 59 kg (9 mg/day), and weight 60 kg or more (15 mg/day). The overall safety profile of memantine in pediatric patients was generally comparable to the safety profile in adults.

    ADVERSE REACTIONS

    Severe

    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / 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
    depression / Delayed / 3.0-3.0
    hypotension / Rapid / 2.0-2.0
    dyspnea / Early / 2.0-2.0
    urinary incontinence / Early / 2.0-2.0
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    headache / Early / 6.0-8.0
    dizziness / Early / 5.0-7.0
    diarrhea / Early / 5.0-5.0
    anxiety / Delayed / 4.0-4.0
    cough / Delayed / 4.0-4.0
    influenza / Delayed / 4.0-4.0
    drowsiness / Early / 3.0-3.0
    vomiting / Early / 2.0-3.0
    weight gain / Delayed / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    fatigue / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    rash / Early / Incidence not known
    agitation / Early / Incidence not known
    irritability / Delayed / Incidence not known
    pharyngitis / Delayed / Incidence not known
    fever / Early / Incidence not known
    rhinorrhea / Early / 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.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (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.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    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.
    Ertugliflozin; 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.
    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.
    Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    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 Bicarbonate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Chloride: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    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.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    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. In animal studies in rats and rabbits, memantine was not teratogenic during the period of organogenesis up to the highest doses tested (18 mg/kg/day in rats and 30 mg/kg/day in rabbits, which are 6- and 21-times, respectively, the maximum recommended human dose [MRHD] on a mg/m2 basis). Slight maternal toxicity, decreased pup weights and an increased incidence of non-ossified cervical vertebrae were seen at 18 mg/kg/day orally in a rat study from pre-mating through the postpartum period. Slight maternal toxicity and decreased pup weights were also seen at this dose in rats treated from day 15 of gestation through the post-partum period. The no-effect dose for these effects was 6 mg/kg, which is 2 times the MRHD on a mg/m2 basis.

    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

    Memantine is an antagonist at N-methyl-D-aspartate (NMDA) receptors with a low to moderate binding affinity. Persistent activation of central nervous system NMDA receptors by the excitatory amino acid glutamate has been theorized to contribute to the symptoms of Alzheimer's disease. Memantine is thought to exert its therapeutic effect by binding to the NMDA receptor-operated cation channels. There is no evidence that memantine slows or prevents neurodegenerative processes in Alzheimer's disease. High affinity NMDA antagonists, such as ketamine and dextromethorphan, are associated with excessive psychomimetic effects at dosages needed for dementia treatment and are therefore not practical alternatives. Memantine has negligible affinity for gamma-amino-butyric-acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, and glycine receptors, and for voltage-dependent calcium, sodium, or potassium channels. Memantine appears to have antagonist activity at the 5-HT3 receptor, with similar potency to that of the NMDA receptor and partial affinity for nicotinic acetylcholine receptors with one-sixth to one-tenth the potency.

    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 to 0.5 microM) are similar between patients with dementia and healthy controls. Memantine undergoes partial hepatic metabolism; however, the hepatic CYP450 system does not play a significant role in the metabolism of the drug. Renal clearance involves active tubular secretion moderated by pH dependent tubular reabsorption. 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. Alternatively, acidification of the urine may increase the elimination of memantine. Memantine has an elimination half-life of 60 to 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%).
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: MATE1
    In vitro data suggest that MATE1 has a role in the renal secretion of memantine. When in vitro cells were exposed to cimetidine, a MATE1 inhibitor, MATE1 memantine excretion was abolished.

    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 to 7 hours and 9to 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.