Drug Safety

, Volume 31, Issue 7, pp 577–585

Memantine for the Treatment of Alzheimer’s Disease

Tolerability and Safety Data from Clinical Trials
  • Martin R. Farlow
  • Stephen M. Graham
  • Gustavo Alva
Short Communication

Abstract

Background: Memantine, a moderate-affinity, uncompetitive antagonist of N- methyl-D-aspartate (NMDA) receptors, is the first non-cholinergic agent approved for the treatment of Alzheimer’s disease (AD), and the first medication approved in the US and Europe for the treatment of moderate to severe stages of the disease. The objective of this study was to analyse safety and tolerability data from phase III memantine trials and from the open-label extensions of those trials.

Method: We conducted an analysis of the pooled data for tolerability and safety from six double-blind, placebo-controlled, memantine trials with a minimum duration of 24 weeks (three trials in mild to moderate AD and three in moderate to severe AD; 20 mg/day; 2311 patients) and four open-label extensions of those trials (two in mild to moderate AD and two in moderate to severe AD; 20 mg/day, 1405 patients), for a total treatment period of up to 2 years.

Results: The analysis revealed that adverse events occurring during both short-and long-term memantine treatment were minimal, and similar in type and frequency to those reported for placebo-treated patients. The most frequently reported adverse events in placebo-controlled trials included agitation (7.5% memantine vs 12.0% placebo), falls (6.8% vs 7.1%), dizziness (6.3% vs 5.7%), accidental injury (6.0% vs 7.2%), influenza-like symptoms (6.0% vs 5.8%), headache (5.2% vs 3.7%) and diarrhoea (5.0% vs 5.6%). Discontinuations due to adverse events were similar in memantine-and placebo-treated groups (8.9% vs 9.8%, respectively).

Conclusion: Consistent with the favourable tolerability profile of memantine observed in clinical use, this analysis of pooled safety data indicates that both short-and long-term memantine treatment of patients with AD is safe and well tolerated, with an adverse event profile similar to that of placebo.

References

  1. 1.
    Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 2003; 9(3): 275–308PubMedCrossRefGoogle Scholar
  2. 2.
    Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome: a double-blind, placebo controlled trial. Arzneimittelforschung 1991 Aug; 41(8): 773–80PubMedGoogle Scholar
  3. 3.
    Gortelmeyer R, Erbler H. Memantine in the treatment of mild to moderate dementia syndrome: a double-blind placebo-controlled study. Arzneimittelforschung 1992 Jul; 42(7): 904–13PubMedGoogle Scholar
  4. 4.
    Orgogozo JM, Rigaud AS, Stöffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002 Jul; 33(7): 1834–939PubMedCrossRefGoogle Scholar
  5. 5.
    Peskind ER, Potkin SG, Pomara N, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006 Aug; 14(8): 704–15PubMedCrossRefGoogle Scholar
  6. 6.
    Reisberg B, Doody R, Stöffler A, et al. Memantine in moderateto-severe Alzheimer’s disease. N Engl J Med 2003 Apr 3; 348(14): 1333–41PubMedCrossRefGoogle Scholar
  7. 7.
    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. JAMA 2004 Jan 21; 291(3): 317–24PubMedCrossRefGoogle Scholar
  8. 8.
    Wilcock G, Möbius HJ, Stöffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol 2002 Nov; 17(6): 297–305PubMedCrossRefGoogle Scholar
  9. 9.
    Winblad B, Poritis N. Memantine in severe dementia: results of the M-BEST Study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999 Feb; 14(2): 135–46PubMedCrossRefGoogle Scholar
  10. 10.
    FDA briefing document. Forest Laboratories, 2003. (Data on file)Google Scholar
  11. 11.
    Integrated summary of safety: 120-day update. Forest Laboratories, 2003. (Data on file)Google Scholar
  12. 12.
    Chen X, Zhang Z, Wang X, et al. A double-blind, randomised, placebo-controlled study of the efficacy and tolerability of memantine in Chinese patients with dementia of the Alzheimer’s type. Chin J Neurol (Zhonghua shen jing ke za zhi) 2007 Jun; 40(6): 364–8Google Scholar
  13. 13.
    Mount C, Downton C. Alzheimer disease: progress or profit? Nat Med 2006 Jul; 12(7): 780–4PubMedCrossRefGoogle Scholar
  14. 14.
    van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of memantine in patients with moderateto-severe Alzheimer disease. Alzheimer Dis Assoc Discord 2007 Apr/Jun; 21(2): 136–43CrossRefGoogle Scholar
  15. 15.
    Bakchine S, Loft H. Memantine treatment in patients with mild to moderate Alzheimer’s disease: results of a randomised, double-blind, placebo-controlled 6-month study. J Alzheimers Dis 2008 Feb; 13(1): 97–107PubMedGoogle Scholar
  16. 16.
    Porsteinsson AP, Grossberg GT, Mintzer J, et al. Memantine treatment in patients with mild to moderate alzheimer’s disease already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial. Curr Alzheimer Res 2008 Feb; 5(1): 83–9PubMedCrossRefGoogle Scholar
  17. 17.
    Reisberg B, Doody R, Stöffler A, et al. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol 2006 Jan; 63(1): 49–54PubMedCrossRefGoogle Scholar
  18. 18.
    MEM-MD-03: a long-term extension study evaluating the safety and tolerability of four memantine dosing regimens in patients with moderate to severe dementia of the Alzheimer’s type. Forest Laboratories, 2003. (Data on file)Google Scholar
  19. 19.
    Ott BR, Blake LM, Kagan E, et al. Open label, multicenter, 28-week extension study of the safety and tolerability of memantine in patients with mild to moderate Alzheimer’s disease. J Neurol 2007 Mar; 254(3): 351–8PubMedCrossRefGoogle Scholar
  20. 20.
    MEM-MD-11C: a long-term extension study evaluating the safety and tolerability of bid and qd administration of memantine in patients with mild to moderate dementia of the Alzheimer’s type, phase C. Forest Laboratories, 2005. (Data on file)Google Scholar
  21. 21.
    MEM-MD-12 AB: a long-term, open-label extension of a randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of memantine in patients with mild to moderate dementia of the Alzheimer’s type. Forest Laboratories, 2005. (Data on file)Google Scholar
  22. 22.
    McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev 2006; (2): CD003154Google Scholar
  23. 23.
    Doody RS, Tariot PN, Pfeiffer E, et al. Meta-analysis of six-month memantine trials in Alzheimer’s disease. Alzheimer’s Dement 2007 Jan; 3(1): 7–17CrossRefGoogle Scholar
  24. 24.
    Jones MW, McClean M, Parsons CG, et al. The in vivo relevance of the varied channel-blocking properties of uncompetitive NMDA antagonists: tests on spinal neurones. Neuropharmacology 2001 Jul; 41(1): 50–61PubMedCrossRefGoogle Scholar
  25. 25.
    Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist: a review of preclinical data. Neuropharmacology 1999 Jun; 38(6): 735–67PubMedCrossRefGoogle Scholar
  26. 26.
    Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 2006; (1): CD005593Google Scholar
  27. 27.
    Burns A, Gauthier S, Perdomo C. Efficacy and safety of donepezil over 3 years: an open-label, multicentre study in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2007 Aug; 22(8): 806–12PubMedCrossRefGoogle Scholar
  28. 28.
    Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000 Jun 27; 54(12): 2261–8PubMedCrossRefGoogle Scholar
  29. 29.
    Pirttila T, Wilcock G, Truyen L, et al. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicenter trial. Eur J Neurol 2004 Nov; 11(11): 734–41PubMedCrossRefGoogle Scholar
  30. 30.
    Farlow MR, Lilly ML, for the ENA713 B352 Study Group. Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer’s disease for up to 5 years [online]. Available from URL: http://www.biomedcentral.com/1471-2318/5/3 [Accessed 2008 May 14]
  31. 31.
    Periclou AP, Ventura D, Sherman T, et al. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother 2004 Sep; 38(9): 1389–94PubMedCrossRefGoogle Scholar
  32. 32.
    Dantoine T, Auriacombe S, Sarazin M, et al. Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer’s disease who failed to benefit from previous cholinesterase inhibitor treatment. Int J Clin Pract 2006 Jan; 60(1): 110–8PubMedCrossRefGoogle Scholar
  33. 33.
    Riepe MW, Adler G, Ibach B, et al. Adding memantine to rivastigmine therapy in patients with mild-to-moderate Alzheimer’s disease: results of a 12-week, open-label pilot study. Prim Care Companion J Clin Psychiatry 2006; 8(5): 258–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Martin R. Farlow
    • 1
  • Stephen M. Graham
    • 2
  • Gustavo Alva
    • 3
  1. 1.Department of NeurologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Forest Research InstituteJersey CityUSA
  3. 3.ATP Clinical ResearchCosta MesaUSA

Personalised recommendations