AHFS Class:

• Central Nervous System Agents, Miscellaneous 28:92

Generic Name(s):

• Memantine Hydrochloride

Chemical Name:

• 3,5-Dimethyl-1-adamantanamine₂₁

Molecular Formula:

• C₁₂HN

Memantine hydrochloride is an N -methyl-d-aspartate (NMDA) receptor antagonist.1,2,3,4,5,6,7,8,9,10,11,12,13

Alzheimer's Disease

Memantine hydrochloride is used for the management of moderate to severe dementia of the Alzheimer's type (Alzheimer's disease).1,2,17,18

Short-term use of memantine in patients with moderate to severe Alzheimer's disease has been associated with improvements in cognitive function, behavior, and activities of daily living; however, the benefits have been modest.26,27,28,29,30 Because memantine may provide some beneficial effects and has a favorable safety profile, experts state that the drug may be considered (alone or in combination with a cholinesterase inhibitor) in patients with moderate to severe Alzheimer's disease.26,27,30 Although memantine also has been used in patients with mild Alzheimer's disease†, clinical trials have shown that the drug is no more effective than placebo when used for milder forms of the disease.26,27,30 The long-term efficacy of memantine (e.g., beyond 6 months) has not been established, and additional studies are needed to determine whether benefits of the drug are sustained.27,30

Efficacy of conventional preparations of memantine hydrochloride (tablets and oral solution) has been established in 2 short-term (24 or 28 weeks), randomized, controlled clinical studies in adults (50-93 years of age) with moderate to severe Alzheimer's disease.1,2 In both studies, patients treated with memantine hydrochloride received an initial dosage of 5 mg once daily, with weekly increases in increments of 5 mg daily until a dosage of 10 mg twice daily was reached.1,2,5 Patients enrolled in the 24-week study were receiving donepezil hydrochloride (a cholinesterase inhibitor) at a stable dosage prior to randomization and continued to receive such therapy in addition to either memantine or placebo during the study period.1,2 In both studies, changes from baseline in cognitive performance were assessed using the Severe Impairment Battery (SIB) scale.1,2,5 Changes from baseline in overall daily function and overall clinical effects (including information from caregivers) were assessed using the modified Alzheimer's disease Cooperative Study Activities of Daily Living inventory (ADCS-ADL) and the Clinician's Interview Based Impression of Change (CIBIC plus) scales, respectively.1,2,5 In both studies, patients receiving memantine experienced less deterioration in cognitive and daily function than patients receiving placebo.1,2,5 In the 24-week study, patients receiving memantine experienced less decline in CIBIC plus scores than patients receiving placebo;2 however, while improvements in CIBIC plus scores were observed in patients receiving memantine in the 28-week study, the difference from placebo (intent-to-treat analysis) was not statistically significant.5,8,10 In an unpublished 24-week, open-label extension of the 28-week trial, improvement relative to the projected rate of continued decline in cognition, daily function, and overall clinical impression of change was observed in patients who were switched from placebo to memantine.3,4,8,9,14

A third randomized, controlled clinical study of 12 weeks' duration was conducted in nursing home patients with severe dementia (Alzheimer's disease or vascular dementia) using conventional preparations of memantine (e.g., Namenda^®).1,4 In this study, memantine hydrochloride was initiated at a dosage of 5 mg once daily and increased to 10 mg once daily after 1 week.1 Daily function was assessed using the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP), and overall clinical effects were assessed using the Clinical Global Impression of Change scale (CGI-C); cognitive function was not evaluated.1,4 In a subset of patients diagnosed as having Alzheimer's disease, memantine was more effective than placebo, as assessed by changes from baseline in both the BGP and CGI-C scales.1,4

Efficacy of memantine hydrochloride extended-release capsules (e.g., Namenda XR^®) has been established in a randomized, double-blind study in patients with moderate to severe Alzheimer's disease receiving a cholinesterase inhibitor (e.g., donepezil, galantamine, rivastigmine).18 Patients were randomized to receive add-on therapy with memantine hydrochloride extended-release capsules (28 mg once daily) or placebo.18 At 24 weeks, patients who received memantine had statistically significant improvements in cognitive function (as assessed by the SIB scale) and overall clinical effect (as assessed by the CIBIC plus scale).18 However, a wide range of responses was observed in the cognitive performance measure.18

Memantine may be used in combination with a cholinesterase inhibitor.25,26,27,28,30 A fixed-combination preparation containing memantine hydrochloride and donepezil hydrochloride (Namzaric^®) is commercially available for the treatment of moderate to severe dementia of the Alzheimer's type in patients receiving a stable donepezil hydrochloride dosage of 10 mg once daily.25 There is some evidence indicating that the addition of memantine to established therapy with a cholinesterase inhibitor may result in less clinical deterioration than therapy with a cholinesterase inhibitor alone in patients with moderate to severe Alzheimer's disease, but the effect size appears to be small and of uncertain clinical importance.27,30

Autism Spectrum Disorders

Because glutamatergic neurotransmission has been implicated in the pathophysiology of autism spectrum disorders (ASD)†, drugs that modulate glutamate such as memantine have been investigated as potential treatments.1,20,21,22,23 However, efficacy of memantine has not been established for this use, and clinical studies generally have found no difference with the drug compared with placebo on primary efficacy measures in patients with autism.1,21,22 In 2 randomized controlled studies in children 6-12 years of age with ASD, no statistically significant difference in scores on the Social Responsiveness Scale (SRS), a rating instrument evaluating core symptoms of autism (i.e., social awareness, information processing, capacity for reciprocal response, anxiety/avoidance, and autistic preoccupations and traits), was observed in patients receiving memantine and those receiving placebo.1,21 In these studies, memantine hydrochloride was administered as extended-release capsules in dosages ranging from 3-15 mg daily based on weight.1,21

Administration

Memantine hydrochloride is administered orally (as tablets, extended-release capsules, or oral solution) without regard to meals.1,16,17,18,19 Memantine hydrochloride tablets and oral solution are equivalent on a mg-per-mg basis.15,17

The oral solution should be administered using the oral dosing syringe provided by the manufacturer, referring to the accompanying patient information for instructions.1 Memantine hydrochloride oral solution should not be mixed with any other liquid.1

The extended-release capsules should be swallowed intact and not divided, chewed, or crushed; alternatively, the capsules may be opened, sprinkled on applesauce, and swallowed without chewing.18

The fixed-combination preparation containing memantine hydrochloride and donepezil hydrochloride (Namzaric^®) may be used in patients currently receiving a stable dosage of donepezil hydrochloride 10 mg daily.25 The fixed-combination capsules should be swallowed intact (and not divided, chewed, or crushed); alternatively, the capsules may be opened, sprinkled on applesauce, and swallowed without chewing.25 The entire contents of each capsule should be consumed; the dose should not be divided.25

If a dose of memantine is missed, the next dose should be taken as scheduled; the dose should not be doubled to make up for a missed dose.1,17,18,25 If treatment is interrupted for several days, the drug may need to be restarted with a lower dosage and retitrated.1,17,18

Dosage

Memantine is commercially available as memantine hydrochloride; dosage is expressed in terms of the hydrochloride salt.1,17,18

Tablets and Oral Solution

The recommended initial adult dosage of memantine hydrochloride (as tablets or oral solution) for the treatment of moderate to severe dementia of the Alzheimer's type is 5 mg once daily.1,17 Dosage should be increased to the recommended maintenance dosage of 10 mg twice daily (effective dosage in clinical trials) in increments of 5 mg daily at minimum intervals of 1 week.1 The manufacturer states that dosage should be increased as follows: first to 10 mg daily (5 mg twice daily), then to 15 mg daily (5 mg and 10 mg as separate doses), and then to 20 mg daily (10 mg twice daily).1

Extended-release Capsules

The recommended initial adult dosage of memantine hydrochloride (as extended-release capsules) for the treatment of moderate to severe dementia of the Alzheimer's type is 7 mg once daily.18 If the drug is well tolerated, dosage should be increased to the recommended maintenance dosage of 28 mg once daily (effective dosage in clinical trials) by increments of 7 mg daily at minimum intervals of 1 week.18

Patients currently receiving memantine hydrochloride conventional tablets or oral solution at a dosage of 10 mg twice daily may be switched to the extended-release capsules at a dosage of 28 mg once daily; the transition should occur on the day following the last dose of the conventional preparation.18

Fixed Combination of Memantine and Donepezil (Namzaric®)

Patients receiving a stable donepezil hydrochloride dosage of 10 mg daily and not currently receiving memantine who are switching to the fixed-combination preparation: The recommended initial dosage of the fixed-combination preparation is 7 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening.25 Dosage may be increased in increments of 7 mg of the memantine hydrochloride component at minimum intervals of at least 1 week up to the maximum recommended maintenance dosage of 28 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening.25

Patients who are switching from separate memantine and donepezil preparations (i.e., donepezil hydrochloride 10 mg daily; memantine hydrochloride 10 mg twice daily or 28 mg once daily as the extended-release preparation) to the fixed-combination preparation: Initial dosage of the fixed-combination preparation is 28 mg of memantine hydrochloride and 10 mg of donepezil hydrochloride once daily in the evening.25 Therapy with the fixed-combination preparation should be initiated on the day following the last dose of the individual preparations.25

Special Populations

No dosage adjustment is needed in patients with mild to moderate hepatic impairment.1 Memantine should be used with caution in patients with severe hepatic impairment.1

No dosage adjustment is needed in patients with mild to moderate renal impairment.1 In patients with severe renal impairment (i.e., creatinine clearance of 5-29 mL/minute), the recommended maintenance dosage of memantine hydrochloride is 5 mg twice daily (as conventional tablets or oral solution) or 14 mg once daily (as extended-release capsules).1,18

Contraindications

Known hypersensitivity to memantine hydrochloride or any ingredient in the formulation.1

Warnings/Precautions

General Precautions

Urinary Excretion

Conditions that increase urinary pH (e.g., dietary changes [e.g., from a high-protein to a vegetarian diet], concomitant use of drugs that alkalinize urine [e.g., carbonic anhydrase inhibitors, sodium bicarbonate], renal tubular acidosis, severe urinary tract infections) may decrease elimination of memantine, resulting in increased plasma memantine concentrations; the drug should be used with caution under such conditions.1,11

Specific Populations

Pregnancy

There are no adequate data to inform the developmental risks associated with the use of memantine in pregnant women.1 In animal reproduction studies, adverse developmental effects (e.g., decreased body weight, decreased skeletal ossification) were observed when the drug was administered to pregnant rats during the period of organogenesis or from late gestation throughout lactation to weaning at doses higher than those used clinically.1

Lactation

It is not known whether memantine is distributed into human milk or if the drug has any effects on the nursing infant or milk production.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for memantine and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of memantine have not been established in pediatric patients.1

Memantine has been evaluated in children 6-12 years of age with autism spectrum disorders (ASD)†; however, efficacy has not been demonstrated.1,20,21,22 (See Uses: Autism Spectrum Disorders.)

Geriatric Use

Clinical studies have been conducted principally in older patients since dementia of the Alzheimer's type occurs mainly in patients 65 years of age or older.1,2,5,7,15 Memantine pharmacokinetics were similar in elderly patients and younger adults.1

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), no change in exposure of memantine was observed compared with individuals with normal hepatic function; however, terminal half-life was increased by about 16% in patients with moderate hepatic impairment.1 No dosage adjustment is necessary in patients with mild or moderate hepatic impairment.1 Memantine has not been evaluated in patients with severe hepatic impairment and should be used with caution in such patients.1

Renal Impairment

The area under the plasma concentration-time curve (AUC) was increased by 4, 60, or 115% in individuals with mild (creatinine clearance exceeding 50-80 mL/minute), moderate (creatinine clearance 30-49 mL/minute), or severe (creatinine clearance 5-29 mL/minute) renal impairment, respectively.1 Terminal elimination half-life was increased by 18, 41, or 95% in those with mild, moderate, or severe renal impairment, respectively. 1 Dosage adjustment is recommended in patients with severe renal impairment, but not in those with mild or moderate renal impairment.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Common adverse effects reported with conventional preparations of memantine include dizziness, confusion, headache, and constipation.1,8,17

Common adverse effects reported with the extended-release capsule formulation of the drug include headache, diarrhea, and dizziness.18

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Memantine is minimally metabolized by cytochrome P-450 (CYP) isoenzymes.1 Drugs that inhibit or induce these enzymes are not likely to alter the pharmacokinetics of memantine.1,15

Memantine produces minimal inhibition of CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4 in vitro.1 No induction of CYP1A2, 2C9, 2E1, or 3A4/5 has been observed in vitro at concentrations exceeding those associated with therapeutic efficacy.1

Protein-bound Drugs

Because plasma protein binding of memantine is low (45%), a pharmacokinetic interaction with drugs that are highly protein bound (e.g., digoxin, warfarin) is unlikely.1

Drugs Secreted by Renal Tubular Cationic Transport

When memantine is used with drugs secreted by the same renal cationic system (e.g., cimetidine, hydrochlorothiazide, metformin, nicotine, quinidine, ranitidine, triamterene), altered plasma concentrations of the drugs are possible.1 However, concomitant use of memantine with a fixed combination of hydrochlorothiazide and triamterene did not affect bioavailability of either memantine or triamterene, and maximum plasma concentrations and area under the plasma concentration-time curve (AUC) of hydrochlorothiazide decreased by only 20%.1,10 In addition, concomitant use of memantine with a fixed combination of glyburide and metformin hydrochloride did not affect the pharmacokinetics of memantine, metformin, or glyburide, and the hypoglycemic effects of the glyburide-metformin combination were not affected.1

Alkalinizing Agents

There is a potential for decreased memantine clearance with resulting increases in adverse effects when the drug is used concomitantly with agents that increase urine pH (e.g., carbonic anhydrase inhibitors, sodium bicarbonate).1 Caution is advised.1 Memantine clearance was decreased by approximately 80% at alkaline urine conditions (i.e., pH 8).1

Bupropion

Results of a pharmacokinetic study showed that memantine did not affect the pharmacokinetics of bupropion or its hydroxy-bupropion metabolite.1

Cholinesterase Inhibitors

Concomitant use of memantine with the cholinesterase inhibitor donepezil did not affect the pharmacokinetics of either drug or substantially alter acetylcholinesterase inhibition by donepezil.1,13 In a 24-week clinical study in patients with moderate to severe Alzheimer's disease, adverse effects observed with combination therapy with memantine and donepezil were similar to those observed with donepezil alone.1 In vitro and animal studies indicate that memantine does not affect the reversible inhibition of acetylcholinesterase produced by donepezil or galantamine.1,10

N -Methyl-d-aspartate (NMDA) Antagonists

Concomitant use of memantine with other NMDA antagonists (e.g., amantadine, ketamine, dextromethorphan) has not been systematically evaluated.1 Caution is advised if these drugs are used concomitantly.1

Warfarin

Memantine did not affect the pharmacokinetics or pharmacodynamics of warfarin (as assessed by the INR).1

Description

Memantine hydrochloride is a low- to moderate-affinity, noncompetitive N -methyl-d-aspartate (NMDA) receptor antagonist that binds preferentially to NMDA receptor-operated cation channels.1,3,4,5,6,7,8,9,10,11,12 The drug differs structurally and pharmacologically from other currently available agents used for the palliative treatment of Alzheimer's disease.1,2

Memantine is thought to act by blocking the actions of glutamate, the principal excitatory neurotransmitter in the CNS.1,2,3,6,9 The effects of glutamate are mediated by different receptor types, including NMDA receptors, which play a role in physiologic processes such as learning and memory formation.3,5,6 Persistent activation of NMDA receptors by glutamate has been implicated as a possible cause of neurodegeneration in various types of dementia, including dementia of the Alzheimer's type (Alzheimer's disease), and is thought to contribute to the symptomatology of Alzheimer's disease.1,3,5,6,12 In vitro studies have shown that β-amyloid, which accumulates to form amyloid plaques in patients with Alzheimer's disease, increases the release of glutamate upon neuronal depolarization, supporting a role for pathologic NMDA receptor activation in the disease.3,7 It has been postulated that low- to moderate-affinity NMDA receptor antagonists may prevent glutamate-induced neurotoxicity without interfering with the physiologic processes mediated by the activation of NMDA receptors.3,6,7,12 However, there currently is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer's disease.1

In addition to exhibiting antagonist activity at the NMDA receptor, memantine exhibits antagonist activity at the type 3 serotonergic (5-HT₃) receptor with a potency that appears to be similar to that at the NMDA receptor.1,10 Memantine also blocks the nicotinic acetylcholine receptor with a potency of about one-sixth to one-tenth that at the NMDA receptor.1,10 Memantine exhibits little or no affinity for γ-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.1,9,10

Memantine hydrochloride is well absorbed following oral administration of conventional preparations, with peak plasma concentrations achieved in about 3-7 hours.1,4 Following multiple-dose administration of extended-release capsules of the drug, peak plasma concentrations are achieved in about 9-12 hours.18 Memantine is eliminated principally in urine, with approximately 48% of an administered dose excreted as unchanged drug; the remainder of the dose is converted to metabolites that exhibit minimal NMDA receptor antagonist activity.1 The hepatic microsomal cytochrome P-450 (CYP) isoenzyme system does not play a substantial role in the metabolism of memantine.1 The terminal elimination half-life of memantine is approximately 60-80 hours.1

Advice to Patients

Importance of instructing patients and caregivers regarding proper dosing and administration of memantine.1

Importance of instructing patients and/or caregivers in proper use of the oral dosing syringe if the oral solution is used.1 Ensure that patients and/or caregivers are aware of the patient instruction sheet that is enclosed with the solution.1 Oral solution should not be mixed with any other liquids.1 Advise patients that questions about administration should be directed to their pharmacist or clinician.1

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Allergan USA, Inc. Namenda^® (memantine hydrochloride) tablets prescribing information. Madison, NJ; 2018 Nov.

2. Tariot PN, Farlow MR, Grossberg GT et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. JAMA . 2004; 291:317-24. [PubMed 14734594]

3. Doraiswamy PM. Non-cholinergic strategies for treating and preventing Alzheimer's disease. CNS Drugs . 2002; 16:811-24. [PubMed 12421115]

4. Jarvis B, Figgitt DP. Memantine. Drugs Aging . 2003; 20:465-76. [PubMed 12710865]

5. Reisberg B, Doody R, Stöffler A et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med . 2003; 348: 1333-41.

6. Scarpini E, Scheltens P, Feldman H. Treatment of Alzheimer's disease: current status and new perspectives. Lancet Neurol . 2003; 2:539-47. [PubMed 12941576]

7. Anon. Alzheimer's disease: emerging noncholinergic treatments. Geriatrics . 2003; 58 (Suppl):3-14, inside cover. [PubMed 12599937]

8. Anon. Memantine for Alzheimer's disease. Med Lett Drugs Ther . 2003; 45:73-4. [PubMed 12968123]

9. Feret B, Dicks R. Memantine. Formulary . 2004; 39:91-103.

10. Cada DJ, Levien T, Baker DE. Memantine. Hosp Pharm . 2004; 39:254-63.

11. Anon. Memantine for dementia?. Drug Ther Bull . 2003; 41:73-6. [PubMed 14593973]

12. Areosa SA, Sherriff F. Memantine for dementia. Cochrane Database Syst Rev . 2003; 3:CD003154.

13. Periclou AP, Ventura D, Sherman T et al. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother . 2004; 38:1389-94. [PubMed 15266045]

14. Reisberg B, Ferris S, Möbius HJ et al. Long-term treatment with the NDMA antagonist memantine: results of a 24-week, open-label extension study in moderately severe-to-severe Alzheimer's disease [abstract]. Neurobiol Aging . 2002; 23:S555, abst 2039.

15. Forest Laboratories, New York, NY. Personal communication.

16. Amneal Pharmaceuticals. Memantine hydrochloride film-coated tablets prescribing information. Bridgewater, NJ; 2019 Dec.

17. Apotex Corp. Memantine hydrochloride solution prescribing information. Weston, FL; 2017 Mar.

18. Allergan USA, Inc. Namenda XR^® (memantine hydrochloride) extended-release capsules prescribing information. Madison, NJ; 2019 Nov.

19. Mylan Pharmaceuticals. Memantine hydrochloride extended-release capsules prescribing information. Morgantown, WV; 2019 Feb.

20. Karahmadi M, Tarrahi MJ, Vatankhah Ardestani SS et al. Efficacy of Memantine as Adjunct Therapy for Autism Spectrum Disorder in Children Aged <14 Years. Adv Biomed Res . 2018; 7:131. [PubMedCentral][PubMed 30320040]

21. Aman MG, Findling RL, Hardan AY et al. Safety and Efficacy of Memantine in Children with Autism: Randomized, Placebo-Controlled Study and Open-Label Extension. J Child Adolesc Psychopharmacol . 2017; 27:403-412. [PubMedCentral][PubMed 26978327]

22. Hardan AY, Hendren RL, Aman MG et al. Efficacy and safety of memantine in children with autism spectrum disorder: Results from three phase 2 multicenter studies. Autism . 2019; 23:2096-2111. [PubMedCentral][PubMed 31027422]

23. Hyman SL, Levy SE, Myers SM et al. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics . 2020; 145 [PubMed 31843864]

25. Allergan. Namzaric^® (memantine and donepezil hydrochlorides) extended-release capsules prescribing information. Madison, NJ; 2019 Jan.

26. APA Work Group on Alzheimer's Disease and other Dementias., Rabins PV, Blacker D 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; 164:5-56. [PubMed 18340692]

27. Rabins PV, Rovner BW, Rummans T et al. Guideline Watch (October 2014): Practice Guideline for the Treatment of Patients With Alzheimer's Disease and Other Dementias. Focus (Am Psychiatr Publ) . 2017; 15:110-128. [PubMedCentral][PubMed 31997970]

28. Winslow BT, Onysko MK, Stob CM et al. Treatment of Alzheimer disease. Am Fam Physician . 2011; 83:1403-12. [PubMed 21671540]

29. American Geriatrics Society. A guide to dementia diagnosis and treatment. [Web]

30. McShane R, Westby MJ, Roberts E et al. Memantine for dementia. Cochrane Database Syst Rev . 2019; 3:CD003154. [PubMedCentral][PubMed 30891742]