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Memantine (Ebixa®, Axura®, Namenda®, Akatinol®) is a moderate-affinity, uncompetitive, voltage-dependent, NMDA-receptor antagonist with fast on/off kinetics that inhibits excessive calcium influx induced by chronic overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer’s type.
In well designed clinical trials, oral memantine, as monotherapy or in addition to a stable dose of acetylcholinesterase inhibitors, was well tolerated during the treatment of mild to severe Alzheimer’s disease for up to 52 weeks. Memantine generally modified the progressive symptomatic decline in global status, cognition, function and behaviour exhibited by patients with moderate to severe Alzheimer’s disease in four 12- to 28-week trials. In patients with mild to moderate Alzheimer’s disease, data from three 24-week trials are equivocal, although meta-analyses indicate beneficial effects on global status and cognition. Memantine is an effective pharmacotherapeutic agent, and currently the only approved option, for the treatment of moderate to severe Alzheimer’s disease.
Memantine is an uncompetitive antagonist that blocks the NMDA channel with higher affinity, but less voltage-dependency, than magnesium. It moderately inhibits excitatory activity while preserving learning behaviours in vivo when compared with more potent NMDA receptor channel blockers. During pathological activation of the NMDA receptor, memantine blocks excessive calcium entry through the channel and is neuroprotective in in vitro and in vivo models.
Oral memantine is completely absorbed with an absolute bioavailability of ≈100%. Steady-state plasma concentrations, achieved after about 2 weeks of memantine 20 mg/day, range from 70 to 150 gmg/L, while the steady-state area under the plasma concentration-time curve from time 0 to 24 hours is ≈1800 gmg · h/L after 4 weeks of treatment.
Memantine is excreted in urine mostly as unchanged parent drug with the remainder being metabolised by glucuronidation, hydroxylation and N-oxidation to form NMDA-inactive metabolites. Memantine and its metabolites are primarily eliminated by the kidneys with a terminal elimination half-life of 60–100 hours. Total renal clearance in healthy volunteers is 170 mL/min/1.73m2.
The efficasy of memantine 20 mg/day has been examined in seven randomised, double-blind, placebo-controlled, multicentre trials of 12–28 weeks’ duration in patients with mild to severe Alzheimer’s disease.
In two of four trials in patients with moderate to severe Alzheimer’s disease, intent-to-treat analyses indicated that global status was significantly better with memantine than with placebo, either as monotherapy or in addition to a stable dose of donepezil. In a third trial, while global status did not differ significantly based on intent-to-treat analysis, observed-case analysis favoured memantine over placebo. However, preliminary data from a fourth trial indicate numerical differences between memantine and placebo treatment groups that were not significant.
In patients with moderate to severe Alzheimer’s disease, memantine or donepezil plus memantine also maintained superior cognitive performance and function with respect to placebo or placebo plus donepezil in two of the three trials in which they were assessed, and superior behaviour in two of the four trials.
In one published trial in patients with mild to moderate Alzheimer’s disease, memantine monotherapy significantly attenuated the decline in global status and cognition observed in placebo recipients; however, in preliminary data from another monotherapy trial, significantly greater effects with memantine seen at 12 and 18 weeks were lost at trial end, apparently as a result of an improvement in global status and cognition in placebo recipients in the last weeks of the trial. Initial results of a third study in this patient population, with memantine or placebo added to a stable dose of an acetylcholinesterase inhibitor, indicate a numerical difference that was not significant.
Meta-analyses indicate significant effects of memantine on global status, cognition and function in patients with mild to severe Alzheimer’s disease, and on global status, cognition, function and behaviour in patients with moderate to severe Alzheimer’s disease.
Memantine was generally well tolerated with a good safety profile during clinical trials, most adverse events being of mild or moderate severity. Adverse events were reported by 70% of patients receiving either memantine or placebo, but most were not considered drug related. In pooled analyses, memantine was associated with a higher incidence of dizziness, headache, constipation and somnolence than placebo. Serious adverse events occurred in 12.7% of memantine and 13.8% of placebo recipients.
KeywordsPlacebo Recipient Memantine Global Status Rivastigmine Galantamine
- 10.Forest Laboratories Inc. Prescribing information: Namenda™ tablets (memantine hydrochloride) [online]. Available from URL: http://www.frx.com/pi/namenda_pi.pdf [Accessed 2005 Feb 15]
- 11.McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev 2006. CD003154; 2 [online]. Available from URL: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003154/pdf_fs.html [Accessed 2006 Jun 6]
- 14.US Department of Health and Human Services. Memantine approval letter [online]. Oct 2003. Available from: http://www.fda.gov/cder/foi/appletter/2003/21487ltr.pdf [Accessed 2005 Mar].
- 15.European Medicines Agency. Ebixa. European Public Assessment Report. [online]. Jul 2002. Available from: http://www.emea.eu.int/humandocs/PDFs/EPAR/ebixa [Accessed 22 Feb 2005].
- 19.Chen H-SV, Wang YF, Rayudu PV, et al. Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 1998 Oct; 86(4): 1121–32PubMedCrossRefGoogle Scholar
- 22.Rammes G, Rupprecht R, Ferrari U, et al. The N-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT3 receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001 Jun 22; 306(1–2): 81–4PubMedCrossRefGoogle Scholar
- 30.Heim C, Sontag KH. Memantine prevents progressive functional neurodegeneration in rats. J Neural Transm 1995; 46 Suppl.: 117–30Google Scholar
- 33.Potkin SG, McDonald S, Gergel I, et al. Memantine monotherapy increases brain metabolism (PET) and effectively treats mild to moderate Alzheimer’s disease [abstract no. P02.292]. 24th Collegium Internationale Neuro-Psychopharmacologicum Congress; 2004 Jun 20–24; Paris. Int J Neuropsychopharmacol 2004; 7 (Suppl. 1): S380–1.Google Scholar
- 37.Dinse HR, Ragert P, Pleger B, et al. Pharmacological modulation of perceptual learning and associated cortical reorganization. Science 2003 Jul 4; 301(5629): 91–4. Plus supporting material [online]. Available from URL: http://www.sciencemag.org/cgi/data/301/5629/91/DC1/ [Accessed 2005 Feb 15]PubMedCrossRefGoogle Scholar
- 39.Tandon V. US Food and Drug Administration Center for Drug Evaluation and Research approval package for application number 21-487. Clinical pharmacology and biopharmaceutics review: memantine [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2003/21-487_Namenda.htm [Accessed 2005 Feb 18]
- 40.Wesemann W, Sturm G, Funfgeld EW. Distribution of metabolism of the potential anti-Parkinson drug memantine in the human. J Neural Transm Suppl 1980; (16): 143-8Google Scholar
- 46.Forest Laboratories Inc. Forest Laboratories Clinical Trials Registry: study no. MEM-MD-01 [online]. Available from URL: http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_MEM-MD-01_final.pdf [Accessed 2005 Jun 8]
- 48.Winblad B, Graham SM, Lee GS, et al. Efficacy and tolerability of memantine in nursing home patients with moderate-to-severe dementia of the Alzheimer’s type [poster no. 64]. 17th Annual Meeting of the American Association for Geriatric Psychiatry; 2004 Feb 21–24; Baltimore (MD)Google Scholar
- 50.Bakchine S, Pascual-Gangnant L, Loft H. Results of a randomised, placebo-controlled 6-month study in the treatment of mild-to-moderate Alzheimer’s Disease in Europe [poster no. P2087]. 9th Congress of the European Federation of Neurological Societies; 2005 Sep 17–20; AthensGoogle Scholar
- 51.Forest Laboratories Inc. Forest Laboratories Clinical Trials Registry: study no. MEM-MD-12 [online]. Available from URL: http://www.forestclinicaltrials.com/CTR/CTRController/CTRViewPdf?_file_id=scsr/SCSR_MEM-MD-12_final.pdf [Accessed 2005 Jun 8]
- 53.Doody RS, Tariot PN, Pfeiffer E, et al. Meta-analysis of 6-month memantine clinical trials in Alzheimer’s disease [poster no. 81]. New Clinical Drug Evaluation Unit 45th Annual Meeting; 2005 Jun 6–9; Boca Raton (FL)Google Scholar
- 55.Winblad B, Möbius HJ, Stöffler A. Glutamate receptors as a target for Alzheimer’s disease — are clinical results supporting the hope? J Neural Transm 2002; 62 Suppl.: 217–25Google Scholar
- 56.LU-99679 protocol, study report (data on file) Denmark: H. Lundbeck, A/S. 2005Google Scholar
- 57.Mani RB. US Food and Drug Administration Center for Drug Evaluation and Research approval package for application number 21-487. Medical reviews: memantine [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2003/21-487_Namenda.htm [Accessed 2005 Feb 18]
- 58.Tocco M, Olin JT, Feldman HH, for the MEM-MD-02 Study Group. Maintenance of response to memantine treatment in moderate to severe Alzheimer’s disease patients receiving stable donepezil treatment [poster no. 23]. 19th Annual Meeting of the American Association for Geriatric Psychiatry; 2006 Mar 10–13; San JuanGoogle Scholar
- 59.Feldman H, Schmitt FA, Doraiswamy PM, et al. Memantine and individual activities of daily living in moderate to severe Alzheimer’s disease [poster no. P02.092]. 57th Annual Meeting of the American Academy of Neurology; 2005 Apr 9–16; Miami Beach (FL)Google Scholar
- 60.Wilkinson D, Andersen HF. Prevention of worsening of clinical symptoms in moderate to severe Alzheimer’s disease in patients treated with memantine [poster]. 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy; 2006 April 19–22; GenevaGoogle Scholar
- 61.Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials [poster]. 9th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy; 2006 April 19–22; GenevaGoogle Scholar
- 68.American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th Ed. (DSM-IV). Washington, DC: American Psychiatric Association, 1994Google Scholar
- 71.National Institute for Clinical Excellence. Appraisal Consultation Document: Alzheimer’s disease — donepezil, rivastigmine, galantamine and memantine (review) [online]. Available from URL: http://www.nice.org.uk/page.aspx?o=245912 [Accessed 2005 Mar 1]
- 73.Loveman E, Green C, Kirby J, et al. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease. Health Technol Assess 2006 Jan; 10(1): 1–176Google Scholar
- 77.European Medicines Agency. European Public Assessment Report: procedural steps taken and scientific information after authorisation [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/ebixa/ebixa.htm [Accessed 2006 Jun 22]
- 78.European Medicines Agency. Ebixa. European Public Assessment Report: summary of product characteristics. [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/ebixa/ebixa.htm [Accessed 2006 Jul 25]
- 79.Merz Pharmaceuticals. Summary of product characteristics. Axura 10 mg film coated tablets [online]. Available from URL: http://download.merz.de/axura-info/pdf/memantine_product_characteristics.pdf#page=9 [Accessed 2006 May 1]
- 83.Johnson N, Davis T, Bosanquet N. The epidemic of Alzheimer’s disease. How can we manage the costs? Pharmacoeconomics 2000 Sep; 18(3): 215–23Google Scholar
- 85.Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 1997 Oct 22–29; 278(16): 1363–71PubMedCrossRefGoogle Scholar
- 89.Cummings JL, Frank JC, Cherry D, et al. Guidelines for managing Alzheimer’s disease: part I. Assessment. Am Fam Physician 2002 Jun 1; 65(11): 2263–72Google Scholar
- 90.Cummings JL, Frank JC, Cherry D, et al. Guidelines for managing Alzheimer’s disease: part II. Treatment. Am Fam Physician 2002 Jun 15; 65(12): 2525–34Google Scholar
- 91.Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998 May 11; 158(9): 1021–31Google Scholar
- 95.Windisch M, Hutter-Paier B, Schreiner E. Current drugs and future hopes in the treatment of Alzheimer’s disease. J Neural Transm 2002; 62 Suppl.: 149–64Google Scholar
- 97.Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. N Engl J Med 1997 Apr 24; 336(17): 1216–22Google Scholar
- 103.Pass MD, Shua-Haim JR, Patel P, et al. Safety, tolerability, and caregiver’s impressions of combination therapy with galantamine and memantine for the treatment of Alzheimer’s disease [abstract no. P1-392]. 9th International Conference on Alzheimer’s Disease and Related Disorders; 2004 Jul 17–22; Philadelphia (PA)Google Scholar
- 104.Shua-Haim JR, Pass MD, Patel S, et al. Safety, tolerability, and caregiver’s impressions of combination therapy with rivastigmine and memantine for the treatment of Alzheimer’s disease [abstract no. P1-377]. 9th International Conference on Alzheimer’s Disease and Related Disorders; 2004 Jul 17–22; Philadelphia (PA)Google Scholar
- 105.US National Institutes of Health. An evaluation of the safety and efficacy of memantine in agitated patients with moderate to severe Alzheimer’s disease [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00097916 [Accessed 2005 Mar 4]