Memantine

Pharmacologic Category

N-Methyl-D-Aspartate (NMDA) Receptor Antagonist

Dosing: Adult

Alzheimer disease, moderate to severe: Oral:

Immediate release: Initial: 5 mg daily; increase dose by 5 mg daily (if previous dose well tolerated) to a target dose of 20 mg daily; wait ≥1 week between dosage changes. Doses >5 mg daily should be given in 2 divided doses. Note: If treatment is interrupted for longer than several days, the treatment may need to be restarted at a lower dose and retitrated.

Suggested titration: 5 mg daily for ≥1 week; 5 mg twice daily for ≥1 week; 15 mg daily given in 5 mg and 10 mg separate doses for ≥1 week; then 10 mg twice daily

Extended release: Initial: 7 mg once daily, increase dose by 7 mg daily to a target maximum dose of 28 mg once daily; wait ≥1 week between dosage changes (if previous dose well tolerated)

Note: When switching from immediate release product to the extended release product, begin the extended release product the day after the last dose of the immediate release product. Patients on immediate release 10 mg twice daily should be switched to extended release 28 mg once daily.

Missed dose: If a single dose is missed, do not double up on the next dose; take the next dose as scheduled. If several days of dosing are missed, dosing may need to be resumed at lower doses and retitrated.

Vascular dementia, mild to moderate (off-label use): Oral: Immediate release: Initial: 5 mg once daily; titrate in increments of 5 mg daily each week to a target dose of 10 mg twice daily (Orgogozo, 2002; Wilcock 2002). Additional data may be necessary to further define the role of memantine in this condition.

* See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment: Adult

Note: Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.

Mild impairment: No dosage adjustment necessary.

Moderate impairment:

US labeling: No dosage adjustment necessary.

Canadian labeling: (CrCl 30 to 49 mL/minute): Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, titrate up to 5 mg twice daily; based on clinical response and tolerability, may further titrate dosage upward in weekly increments to 20 mg daily according to suggested titration schedule.

Severe impairment:

US labeling: CrCl 5 to 29 mL/minute: Immediate release: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may titrate up to a target dose of 5 mg twice daily; Extended release: Target dose of 14 mg once daily.

Note: When switching from immediate release product to the extended release product, begin the extended release product the day after the last dose of the immediate release product. Patients on immediate release 5 mg twice daily should be switched to extended release 14 mg once daily.

Canadian labeling: CrCl 15 to 29 mL/minute: Initial: 5 mg once daily; after at least 1 week of therapy and if tolerated, may titrate up to a target dose of 5 mg twice daily

Dosing: Hepatic Impairment: Adult

Mild-to-moderate impairment: No dosage adjustment necessary.

Severe impairment:

U.S. labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended.

Calculations

Use: Labeled Indications

Alzheimer disease: Treatment of moderate to severe dementia of the Alzheimer type.

* See Uses in AHFS Essentials for additional information.

Use: Off-Label: Adult

Vascular dementia (mild to moderate)Level of Evidence [C, G]

Data from two meta-analysis evaluating two randomized, double-blind, parallel-group, placebo controlled trials suggest that memantine may be beneficial for the treatment of mild to moderate vascular dementia based on a small, statistically significant effect on cognitive function. However, no significant difference was identified for clinical global ratings of change, suggesting cognitive improvements may not be clinically detectable. Additional data is necessary to further define the role of memantine in this condition.

Based on the American Psychiatric Association practice guidelines for the treatment of patients with Alzheimer Disease and other dementias, memantine given for vascular dementia is not supported by the evidence and further trials are needed. Access Full Off-Label Monograph

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Alzheimer's Disease and Other Dementias:

American Psychiatric Association, “Treatment of Patients with Alzheimer's Disease and Other Dementias, Second Edition,” October 2007

“EFNS 2010 Guidelines for the Diagnosis and Management of Alzheimer's Disease,” March 2010

Administration: Oral

Administer without regard to meals. Extended release capsules may be swallowed whole or entire contents of capsule may be sprinkled on applesauce and swallowed immediately; do not chew, crush, or divide. Withdraw and administer oral solution with provided dosing device; dose should be slowly squirted into the corner of the patient’s mouth. Do not mix oral solution with any other liquid. The Canadian labeling recommends tablets to be swallowed whole with water.

Storage/Stability

Capsule (extended release): Store between 20°C to 25°C (68°F to 77°F).

Tablet, oral solution: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to treat dementia in people with Alzheimer's disease.

Frequently reported side effects of this drug

• Dizziness

• Headache

• Diarrhea

• Constipation

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Confusion

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to memantine or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Rare skin hypersensitivity reactions (eg, Stevens Johnson syndrome, erythema multiforme) have been reported; advise patients to report skin reactions immediately. Discontinue use with signs of hypersensitivity reaction.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease; although adverse cardiac events were infrequent in clinical trials, an increased incidence of cardiac failure, angina, bradycardia, and hypertension (compared with placebo) was observed.

• Hepatic impairment: Use with caution in patients with severe hepatic impairment. The Canadian labeling recommends avoiding use in severe impairment due to a lack of data in this population.

• Ophthalmic disease: Worsening of corneal condition has been observed in a clinical trial; periodic ophthalmic exams during use are recommended (Canadian labeling).

• Renal impairment: Use with caution in patients with severe renal impairment; dose adjustments for CrCl <30 mL/minute is required.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; may increase risk of seizures.

Other warnings/precautions:

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

* See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

In clinical trials, patients on memantine had less of a decline in cognitive function and activities of daily living (ADL) as compared to placebo. This was true for monotherapy with memantine, as well as combination therapy with donepezil, an acetylcholinesterase inhibitor. There is evidence showing memantine does not have a clinically significant impact on disruptive behaviors associated with Alzheimers disease (Ballard 2015; Fox 2012). Overall, observable clinical benefits from the use of memantine in Alzheimers dementia typically arise from the impact on functional outcomes. Therefore, the more severe the functional impairments, the more likely one is to see a clinically meaningful response to memantine (Di Santo 2013). Memantine should be dose adjusted for those with CrCl <30 mL/minute, and additional monitoring should be considered if patients are receiving medications which can alkalinize the urine.

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Breast-Feeding Considerations

It is not known if memantine is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Adverse Reactions

Adverse reactions similar in immediate and extended release formulations except as noted.

1% to 10%:

Cardiovascular: Hypertension (4%), hypotension (extended release: 2%)

Central nervous system: Dizziness (5% to 7%), confusion (6%), headache (6%), anxiety (extended release: 4%), depression (extended release: 3%), drowsiness (3%), hallucination (3%), pain (3%), aggressive behavior (2%), fatigue (2%)

Endocrine & metabolic: Weight gain (extended release: 3%)

Gastrointestinal: Diarrhea (5%), constipation (3% to 5%), vomiting (2% to 3%), abdominal pain (2%)

Genitourinary: Urinary incontinence (2%)

Infection: Influenza (4%)

Neuromuscular & skeletal: Back pain (3%)

Respiratory: Cough (4%), dyspnea (2%)

<1%, postmarketing, and/or case reports: Abnormal gait, abnormal hepatic function tests, acne vulgaris, agitation, agranulocytosis, anorexia, arthralgia, aspiration pneumonia, atrioventricular block, bone fracture, bradycardia, brain disease, bronchitis, cardiac failure, carpal tunnel syndrome, cerebral infarction, cerebrovascular accident, chest pain, cholelithiasis, claudication, colitis, coma, complete atrioventricular block, convulsions, decreased appetite, deep vein thrombosis, dehydration, delusions, dementia (Alzheimer type), disorientation, drug-induced Parkinson disease, dyskinesia, falling, fecal incontinence, fever, gastritis, gastroesophageal reflux disease, hepatic failure, hepatitis (including cytolytic and cholestatic), hyperglycemia, hyperlipidemia, hypoglycemia, impaired consciousness, impotence, increased INR, increased serum alkaline phosphatase, increased serum creatinine, insomnia, intracranial hemorrhage, irritability, lethargy, leukopenia, limb pain, loss of consciousness, malaise, myoclonus, nasopharyngitis, nausea, neuroleptic malignant syndrome, neutropenia, otitis media, pancreatitis, pancytopenia, peripheral edema, prolonged Q-T interval on ECG, psychotic reaction, renal failure, renal function test abnormality, renal insufficiency, restlessness, second degree atrioventricular block, sepsis, SIADH, Stevens-Johnson syndrome, suicidal ideation, suicidal tendencies, supraventricular tachycardia, tardive dyskinesia, thrombocytopenia, thrombotic thrombocytopenic purpura, tonic-clonic seizures, torsades de pointes, tremor, upper respiratory tract infection, urinary tract infection, weakness

* See Cautions in AHFS Essentials for additional information.

Allergy and Idiosyncratic Reactions

Adamantane Derivative Allergy

Metabolism/Transport Effects

Substrate of OCT2

Drug Interactions Open Interactions

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

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

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

Erdafitinib: May increase the serum concentration of OCT2 Substrates. Risk C: Monitor therapy

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

Tafenoquine: May increase the serum concentration of OCT2 Substrates. Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification

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

Monitoring Parameters

Cognitive function; functional outcomes (eg, Activities of Daily Living [ADLs], Instrumental Activities of Daily Living [IADLs]); periodic ophthalmic exam (Canadian labeling)

Advanced Practitioners Physical Assessment/Monitoring

Monitor for hypertension, CNS changes, rash, and constipation on a regular basis throughout therapy.

Nursing Physical Assessment/Monitoring

Monitor for hypertension, CNS changes, rash, and constipation on a regular basis throughout therapy.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Namenda XR: 7 mg, 14 mg, 21 mg, 28 mg

Namenda XR Titration Pack: 7 mg (7s) and 14 mg (7s) and 21 mg (7s) and 28 mg (7s)

Generic: 7 mg, 14 mg, 21 mg, 28 mg

Solution, Oral, as hydrochloride:

Namenda: 10 mg/5 mL (360 mL [DSC]) [peppermint flavor]

Generic: 2 mg/mL (240 mL, 360 mL); 10 mg/5 mL (5 mL)

Tablet, Oral, as hydrochloride:

Namenda: 5 mg [contains fd&c blue #2 (indigotine), fd&c yellow #6 (sunset yellow)]

Namenda: 10 mg

Namenda Titration Pak: 5 mg (28s) and 10 mg (21s) [contains fd&c blue #2 (indigotine), fd&c yellow #6 (sunset yellow)]

Generic: 5 mg, 10 mg, 5 mg (28s) and 10 mg (21s)

Dosage Forms: Canada

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

Tablet, Oral, as hydrochloride:

Ebixa: 10 mg [contains polysorbate 80]

Generic: 5 mg, 10 mg

Anatomic Therapeutic Chemical (ATC) Classification

N06DX01

Generic Available (US)

Yes

Pricing: US

Capsule ER 24 Hour Therapy Pack (Memantine HCl ER Oral)

7 mg (per each): $15.26 - $15.28

14 mg (per each): $15.26 - $15.28

21 mg (per each): $15.26 - $15.28

28 mg (per each): $15.26 - $15.28

Capsule ER 24 Hour Therapy Pack (Namenda XR Oral)

7 mg (per each): $18.59

14 mg (per each): $18.59

21 mg (per each): $18.59

28 mg (per each): $18.59

Capsule ER 24 Hour Therapy Pack (Namenda XR Titration Pack Oral)

7 & 14 & 21 &28 mg (per each): $18.59

Solution (Memantine HCl Oral)

2 mg/mL (per mL): $1.76 - $2.67

Tablets (Memantine HCl Oral)

5 mg (per each): $6.09 - $6.10

10 mg (per each): $6.09 - $6.10

28 x 5 MG &21 x 10 MG (per each): $6.10

Tablets (Namenda Oral)

5 mg (per each): $8.90

10 mg (per each): $8.90

Tablets (Namenda Titration Pak Oral)

28 x 5 MG &21 x 10 MG (per each): $8.89

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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

Pharmacodynamics/Kinetics

Absorption: Well absorbed

Distribution: 9 to 11 L/kg

Protein binding: 45%

Metabolism: Partially hepatic, primarily independent of the CYP enzyme system; forms 3 metabolites (minimal activity)

Half-life elimination: Terminal: ~60 to 80 hours

Time to peak, serum: Immediate release: 3 to 7 hours; Extended release: 9 to 12 hours

Excretion: Urine (74%; ~48% of the total dose as unchanged drug; undergoes active tubular secretion moderated by pH-dependent tubular reabsorption; excretion reduced by alkaline urine pH)

Pharmacodynamics/Kinetics: Additional Considerations

Renal function impairment: Mean AUC_0-∞ increased by 4%, 60%, and 115% in patients with mild, moderate, and severe renal impairment, respectively. The terminal elimination half-life increased by 18%, 41%, and 95% in patients with mild, moderate, and severe renal impairment, respectively.

Hepatic function impairment: Terminal elimination half-life increased by ~16% in patients with moderate hepatic impairment.

Gender: Women had ~45% greater exposure than men; however, there was no difference in exposure when body weight was taken into account.

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

No significant effects or complications reported

Effects on Bleeding

No information available to require special precautions

Related Information

Oral Medications That Should Not Be Crushed or Altered

Index Terms

Memantine HCl; Memantine Hydrochloride

FDA Approval Date

October 16, 2003

References

Ballard C, Thomas A, Gerry S, et al. MAIN-AD investigators. A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in peoplewith Alzheimer's disease (MAIN-AD). J Am Med Dir Assoc. 2015;16(4):316-322.[PubMed 25523285]

Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer's disease. J Alzheimers Dis. 2013;35(2):349-361.[PubMed 23411693]

Ebixa (memantine) [product monograph]. Montreal, Quebec, Canada: Lundbeck Canada Inc; May 2015.

Fox C, Crugel M, Maidment I, et al. Efficacy of memantine for agitation in Alzheimer's dementia: a randomised double-blind placebo controlled trial. PLoS One. 2012;7(5):e35185.[PubMed 22567095]

Hort J, O'Brien JT, Gainotti G, et al, “EFNS Guidelines for the Diagnosis and Management of Alzheimer’s Disease,” Eur J Neurol, 2010, 17(10):1236-48.[PubMed 20831773]

Kavirajan H; Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol. 2007;6(9):782-792.[PubMed 17689146]

Lipton, SA, “Failures and Successes of NMDA Receptor Antagonists: Molecular Basis for the Use of Open-Channel Blockers like Memantine in the Treatment of Acute and Chronic Neurologic Insults,” NeuroRx, 2004, 1(1):101-10.[PubMed 15717010]

McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia.Cochrane Database Syst Rev. 2006;(2):CD003154.[PubMed 16625572]

Memantine [prescribing information]. Weston, FL: Apotex Corp; August 2017.

Namenda (memantine) [prescribing information]. Madison, NJ: Allergan USA Inc; November 2018.

Namenda XR (memantine) [prescribing information]. Madison, NJ: Allergan USA Inc; November 2019.

Namenda XR Titration Pack (memantine) [prescribing information]. Irvine, CA: Allergan USA, Inc; October 2016.

Orgogozo JM, Rigaud AS, Stoffler A, Möbius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002;33(7):1834-1839.[PubMed 12105362]

Rabins PV, Blacker D, Rovner BW, et al, “American Psychiatric Association Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Second Edition,” Am J Psychiatry, 2007, 164(12 Suppl):5-56.[PubMed 18340692]

Rabins PV, Rovner BW, Rummans T, Schneider LS, Tariot PN. Guideline watch (October 2014): Practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. American Psychiatric Association; 2014.

Reisberg B, Doody R, Stoffler A, et al, “Memantine in Moderate-to-Severe Alzheimer's Disease,” N Engl J Med, 2003, 348(14):1333-41.[PubMed 12672860]

Tariot PN, Farlow MR, Grossberg GT, et al, “Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil: A Randomized Controlled Trial. The Memantine Study Group,” JAMA, 2004, 291(3):317-24.[PubMed 14734594]

Wilcock G, Mobius HJ, Stoffler A; MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002;17(6):297-305.[PubMed 12409683]

Brand Names: International

Abixa (BD, ID, PH, UA); Admed (KR); Admenta (IN); Akatinol (CO, CR, CU, DO, GT, HN, NI, PA, PY, SV, UY); Albix (HK, KR); Alzema (LB); Amint-10 (PH); Axura (AT, BE, BG, CH, CZ, DE, DK, EE, ES, FI, FR, GB, GR, IE, IT, MT, NL, PL, PT, RO, RU, SE, SK, TR); Carrier (PY); Cerentia (EG); Cognitine (PH); Cordure (CO); Delmenda (EG); Dementa (BD); Denigma (PH, UA); Ebix (BR); Ebixa (AE, AR, AT, AU, BE, BG, BH, CH, CL, CN, CY, CZ, DE, DK, EE, EG, ES, FI, FR, GB, GR, HK, HR, HU, IE, IL, IS, IT, JO, KR, KW, LB, LT, LU, MT, MX, MY, NL, NO, NZ, PK, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW); Esmirtal (PE); Eutebrol (CR, DO, EC, GT, HN, NI, PA, PE, SV); Evy (TW); Exenta (LB); Foliant (LK); Limember (PE); Lindex (EC); Manotin (TW); Mantomed (NL); Marixino (AT, BE, CZ, IE, LV, MT, MY, NL, SG); Mema (UA); Memadem-10 (PH); Memanto (KR); Memanxa (AU); Memary (JP); Mementor (ZW); Memogen (BD); Memora (LB); Memoria (BH); Memoril (NZ); Memox (IL, UA); Memry (PH); Memxa (HK, MY, TH); Mentin (ZW); Mentra (PH); Nemdatine (AT, BE, CZ, IE, IL, LV, NL, SG); Neumantine (TH); Neuroplus (EC); Pentabixa (EG); Remem (TH); Remtin (BD); Tabixa (BH); Vilimen (TR); Witgen (TW); Ymana (HR); Zimerz (PH)

Last Updated 3/12/20

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