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memantine (Auzura, Namenda, Exiba, Akatinol)

NMDA receptor antagonist. FDA approved 10/2003 Commercially available outside the US since 1982. Indications: 1) treatment of dementia a) including advanced Alzheimer's disease* - improves clinician's global impression [21] b) may be used in combination with cholinesterase inhibitor [12,16,19]; benefit of combination unclear [22] 2) night time neuropathic pain in diabetic patients * minimally effective; on list of drugs to avoid [26] Contraindications: - end-stage renal disease - not effective for mild Alzheimer's disease* * NICE does NOT recommend memantine except for clinical trials; - does NOT delay institutionalization & is NOT cost-effective; OK to continue if currently prescribed medication [18] Dosage: 1) start 5 mg PO QD 2) increase in 5 mg/day increments to 10 mg PO BID 3) divide dose BID 4) may be taken with or without food 5) maximum dose 20 mg TID 6) taper upon discontinuation to avoid potential psychiatric effects [23] 7) no evidence to guide decisions about discontinuing memantine [27] Tabs: 5 & 10 mg (Namenda) Extended release: 7, 14, 21, 28 mg. QD dosing [24] Solution: 10 mg/5 mL [24] Pharmacokinetics: 1) 10-30 mg of memantine orally achieves serum levels of 0.4-1 uM 2) peak serum levels 6-8 hours after oral dose [9] 3) 1/2 life 60-100 hours [9] 4) protein-binding 10-45%, volume of distribution 9-11 L/kg 5) CSF levels 20-30% of serum levels [5] {rats} 6) eliminated in the urine -> partial elimination by tubular secretion Dosage adjustment in renal failure: a) no specific recommendations; consider dose reduction b) max dose 5 mg BID for creatinine clearance 5-29 mL/min Adverse effects: 1) dizziness & agitation same as placebo 2) NOT associated with psychosis (other higher affinity NMDA receptor antagonists are associated with psychosis) 3) other [6,12] all < 3% relative to placebo - fatigue, pain, hypertension, dizziness, headache, constipation, back pain, confusion, somnolence, hallucination, cough, dyspnea - drowsiness, change in behavior [24] 4) adverse effects significantly less than those of cholinesterase inhibitors [6] 5) case report of seizures 6) increases risk for somnolence, weight gain, confusion, hypertension, nervous system disorders, & falls [21] 7) increased risk of pneumonia (RR=1.6) relative to donepezil [25] Overdose: 1) supportive measures 2) contact poison control 3) clearance can be enhanced by acidification of the urine 4) after 400 mg of memantine: (1 case report) a) restlessness, psychosis, visual hallucinations, somnolence, stupor, loss of consciousness b) recovery without sequellae 5) also see animal toxicity of memantine Drug interactions: 1) drugs that alkalinize the urine may decrease clearance of memantine - 80% reduction at pH of 8 a) carbonic anhydrase inhibitors -> acetazolamide b) bicarbonate 2) interaction with trimethoprim may increase risk of myoclonus & delirium [24] 3) use in combination with other NMDA receptor antagonists has not been evaluated -> amantadine, ketamine, dextromethorphan 4) NO interaction with cholinesterase inhibitors Mechanism of action: 1) low-moderate affinity NMDA receptor antagonist a) Ki of 0.5 uM b) IC50 of 0.4 uM similar for NR2B, NR2C & NR2D receptors IC50 of 0.8 uM for NR2A c) uncompetitive binding d) rapid dissociation with physiologic activation of receptor 2) reduced need for caregiver assistance [3]; up to 11 hours/week less assistance * Testing by Forest Laboratories. Approved & used in several European countries. [8] Reduced need for caregiver assistance [3] Merz also producing & testing memantine. Also see memantine clinical trials Notes: Cost is slightly less than Aricept [10]

Related

memantine (Namenda) non-formulary drug request (NFDR) memantine clinical trials NMDA receptor

General

pharmaceutical agents for treatment of Alzheimer's disease (Alzheimer's agent) NMDA receptor antagonist

Properties

INHIBITS: NMDA receptor MISC-INFO: elimination route KIDNEY pregnancy-category B safety in lactation B protein-binding 10-45%

Database Correlations

PUBCHEM correlations

References

  1. Ruther et al A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine. Pharmacopsychiatry 33:103, 2000 PMID: 10855461
  2. Winblad & Poritis Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 14:135, 1999 PMID: 10885864
  3. Journal Watch 23(10):80, 2003 Resiberg B et al mantine in moderate-to-severe Alzheimer's disease. N Engl J Med 348:1333, 2003 PMID: 12672860
  4. Prescriber's Letter 10(7):40 2003
  5. http://www.memantine.com
  6. Prescriber's Letter 10(11) 2003; detail document 191102 http://www.namenda.com
  7. Forest Laboratory (Namenda) patient assistance (800) 851-0758
  8. Relkin N, 8th International Conference on Alzheimer's Disease & Related Disorders (ICADRC) 2002 http://www.medscape.com/viewarticle/440351
  9. Micromedex
  10. Prescriber's Letter 11(2):8 2004 Detail-Document#: 200202 (subscription needed) http://www.prescribersletter.com
  11. Areosa SA & Sheriff R, Cochrane Database Syt Rev (3):CD003154, 2003 PMID: 12917950 Areosa SA & Sheriff R,Cochrane Database Syst Rev. (1):CD003154, 2003 PMID: 12535459
  12. Tariot PN Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317, 2004 PMID: 14734594
  13. Department of Veterans Affairs, VA National Formulary - non formulary drug request
  14. LexiComp
  15. Wimo A et al, Resource utilization and cost analysis of memantine in patients with moderate to severe Alzheimer's disease. Pharmacoeconomics 2003, 21:327 PMID: 12627986
  16. Feldman HH et al, Activites of daily living in moderate-to-severe Alzheimer's disease: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment. Alzheimer Dis Assoc Disord. 2006, 20:263 PMID: 17132971
  17. Raina P et al Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008 Mar 4;148(5):379-97 PMID: 18316756
  18. Internal Medicine News, April 15, 2005, pg 12
  19. Atri A et al, Long-term course and effectiveness of combination therapy in Alzheimer's disease. Alzheimer Dis Assoc Disord. 2008 Jul-Sep;22(3):209-21. PMID: 18580597
  20. Schneider LS et al. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011 Apr 11; PMID: 21482915 http://archneur.ama-assn.org/cgi/content/abstract/archneurol.2011.69v1
  21. Yang Z1, Zhou X, Zhang Q. Effectiveness and safety of memantine treatment for Alzheimer's disease. J Alzheimers Dis. 2013 Jan 1;36(3):445-58. PMID: 23635410
  22. Muayqil T1, Camicioli R Systematic review and meta-analysis of combination therapy with cholinesterase inhibitors and memantine in Alzheimer's disease and other dementias. Dement Geriatr Cogn Dis Extra. 2012 Jan;2(1):546-72. PMID: 23277787
  23. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  24. Medical Knowledge Self Assessment Program (MKSAP) 17, American College of Physicians, Philadelphia 2015
  25. Lampela P, Tolppanen AM, Tanskanen A et al Use of antidementia drugs and risk of pneumonia in older persons with Alzheimer's disease. Ann Med. 2016 Oct 27:1-25. [Epub ahead of print] PMID: 27786552
  26. Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  27. Parsons C, Lim WY, Loy C et al Withdrawal or continuation of cholinesterase inhibitors or memantine or both, in people with dementia. Cochrane Database of Systematic Reviews. 2021. Feb 3. Not indexed in PubMed https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD009081.pub2/full

Component-of

donepezil/memantine (Namzaric)