731
Views
19
CrossRef citations to date
0
Altmetric
Review

Pharmacotherapeutic strategies in the treatment of severe Alzheimer’s disease

&
Pages 1789-1800 | Received 10 Jun 2016, Accepted 18 Jul 2016, Published online: 29 Jul 2016

References

  • Alzheimer’s Association. 2016 Alzheimer’s disease facts and figures. Alzheimer’s Dementia. 2016;12(4):459–509.
  • Arrighi HM, Neumann PJ, Lieberburg IM, et al. Lethality of Alzheimer disease and its impact on nursing home placement. Alzheimer Dis Assoc Disord. 2010;24(1):90–95.
  • Zemek F, Drtinova L, Nepovimova E, et al. Outcomes of Alzheimer’s disease therapy with acetylcholinesterase inhibitors and memantine. Expert Opin Drug Saf. 2014;13(6):759–774.
  • Schmitt FA, Ashford W, Ernesto C, et al. The severe impairment battery: concurrent validity and the assessment of longitudinal change in Alzheimer’s disease. The Alzheimer’s disease cooperative study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):S51–6.
  • Schmitt FA, Wichems CH. A systematic review of assessment and treatment of moderate to severe Alzheimer’s disease. Prim Care Companion J Clin Psychiatry. 2006;8(3):158–159.
  • Galasko D, Schmitt F, Thomas R, et al. Detailed assessment of activities of daily living in moderate to severe Alzheimer’s disease. J Int Neuropsychol Soc. 2005;11(4):446–453.
  • Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):2308–2314.
  • Winblad B, Kilander L, Eriksson S, et al. Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study. Lancet. 2006;367(9516):1057–1065.
  • Black SE, Doody R, Li H, et al. Donepezil preserves cognition and global function in patients with severe Alzheimer disease. Neurology. 2007;69(5):459–469.
  • Homma A, Imai Y, Tago H, et al. Donepezil treatment of patients with severe Alzheimer’s disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dement Geriatr Cogn Disord. 2008;25(5):399–407.
  • Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology. 2001;57(4):613–620.
  • Feldman H, Gauthier S, Hecker J, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer’s disease: a subgroup analysis from a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2005;20(6):559–569.
  • Winblad B, Black SE, Homma A, et al. Donepezil treatment in severe Alzheimer’s disease: a pooled analysis of three clinical trials. Curr Med Res Opin. 2009;25(11):2577–2587.
  • Kaasinen V, Nagren K, Jarvenpaa T, et al. Regional effects of donepezil and rivastigmine on cortical acetylcholinesterase activity in Alzheimer’s disease. J Clin Psychopharmacol. 2002;22(6):615–620.
  • Sabbagh M, Cummings J. Progressive cholinergic decline in Alzheimer’s disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology. BMC Neurol. 2011;11:21.
  • Farlow MR, Salloway S, Tariot PN, et al. Effectiveness and tolerability of high-dose (23 mg/d) versus standard-dose (10 mg/d) donepezil in moderate to severe Alzheimer’s disease: A 24-week, randomized, double-blind study. Clin Ther. 2010;32(7):1234–1251.
  • Salloway S, Mintzer J, Cummings JL, et al. Subgroup analysis of US and non-US patients in a global study of high-dose donepezil (23 mg) in moderate and severe Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2012;27(6):421–432.
  • Statistical review(s). Donepezil 23 mg tablets drug approval package. U.S. Food and Drug Administration; 2010 [cited 2016 Jun 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022568Orig1s000StatR.pdf
  • Homma A, Atarashi H, Kubota N, et al. Efficacy and safety of sustained release donepezil high dose versus immediate release donepezil standard dose in Japanese patients with severe Alzheimer’s disease: a randomized, double-blind trial. J Alzheimers Dis. 2016;52(1):345–357.
  • Farlow MR, Grossberg GT, Sadowsky CH, et al. A 24-week, randomized, controlled trial of rivastigmine patch 13.3 mg/24 h versus 4.6 mg/24 h in severe Alzheimer’s dementia. CNS Neurosci Ther. 2013;19(10):745–752.
  • Sabbagh M, Cummings J, Christensen D, et al. Evaluating the cognitive effects of donepezil 23 mg/d in moderate and severe Alzheimer’s disease: analysis of effects of baseline features on treatment response. BMC Geriatr. 2013;13:56.
  • Medical review(s). Donepezil 23 mg tablets drug approval package. U.S. Food and Drug Administration; 2010 [cited 2016 Jun 1]. Available from: www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022568Orig1s000MedR.pdf
  • Han SH, Lee JH, Kim SY, et al. Donepezil 23 mg in Asian patients with moderate-to-severe Alzheimer’s disease. Acta Neurol Scand. 2016 [cited 2016 Feb 29]. doi:10.1111/ane.12571.
  • Burns A, Bernabei R, Bullock R, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol. 2009;8(1):39–47.
  • Morris JN, Fries BE, Morris SA. Scaling ADLs within the MDS. J Gerontol A Biol Sci Med Sci. 1999;54(11):M546–53.
  • Grossberg GT, Farlow MR, Meng X, et al. Evaluating high-dose rivastigmine patch in severe Alzheimer’s disease: analyses with concomitant memantine usage as a factor. Curr Alzheimer Res. 2015;12(1):53–60.
  • Farlow MR, Sadowsky CH, Velting DM, et al. Evaluating response to high-dose 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer’s disease. CNS Neurosci Ther. 2015;21(6):513–519.
  • Lefevre G, Sedek G, Jhee SS, et al. Pharmacokinetics and pharmacodynamics of the novel daily rivastigmine transdermal patch compared with twice-daily capsules in Alzheimer’s disease patients. Clin Pharmacol Ther. 2008;83(1):106–114.
  • Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med. 2003;348(14):1333–1341.
  • Van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Alzheimer Dis Assoc Disord. 2007;21(2):136–143.
  • Nakamura Y, Kitamura S, Homma A, et al. Efficacy and safety of memantine in patients with moderate-to-severe Alzheimer’s disease: results of a pooled analysis of two randomized, double-blind, placebo-controlled trials in Japan. Expert Opin Pharmacother. 2014;15(7):913–925.
  • Winblad B, Poritis N. 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. 1999;14(2):135–146.
  • Rive B, Gauthier S, Costello S, et al. Synthesis and comparison of the meta-analyses evaluating the efficacy of memantine in moderate to severe stages of Alzheimer’s disease. CNS Drugs. 2013;27(7):573–582.
  • Winblad B, Jones RW, Wirth Y, et al. Memantine in moderate to severe Alzheimer’s disease: a meta-analysis of randomised clinical trials. Dement Geriatr Cogn Disord. 2007;24(1):20–27.
  • Matsunaga S, Kishi T, Iwata N. Memantine monotherapy for Alzheimer’s disease: a systematic review and meta-analysis. PLoS One. 2015;10(4):e0123289.
  • Bond M, Rogers G, Peters J, et al. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (review of Technology Appraisal No. 111): a systematic review and economic model. Health Technol Assess. 2012;16(21):1–470.
  • Donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s Disease. NICE Submission of Evidence: Memantine. National Institute for Health and Clinical Excellence; 2010 [cited 2016 Jun 1]. Available from: https://www.nice.org.uk/guidance/ta217/documents/alzheimers-disease-donepezil-galantamine-rivastigmine-and-memantine-review-lundbeck-uk2
  • Memantine for the treatment of moderate to severe Alzheimer’s disease. NICE Submission of Evidence: Memantine. National Institute for Health and Clinical Excellence; 2010 [cited 2016 Jun 1]. Available from: https://www.nice.org.uk/guidance/TA217/documents/alzheimers-disease-donepezil-galantamine-rivastigmine-and-memantine-review-lundbeck2
  • 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;5(1):83–89.
  • 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;291(3):317–324.
  • Grossberg GT, Manes F, Allegri RF, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs. 2013;27(6):469–478.
  • Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med. 2012;366(10):893–903.
  • Schmidt R, Hofer E, Bouwman FH, et al. EFNS-ENS/EAN guideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe Alzheimer’s disease. Eur J Neurol. 2015;22(6):889–898.
  • Grossberg G, Alva G, Hendrix S, et al. Efficacy and tolerability of memantine extended release added to stable donepezil regimen in individuals with moderate to severe Alzheimer’s disease: subset analysis of a randomized clinical trial. Alzheimer’s Dementia. 2014;10(4 Supplement):P450.
  • Withdrawal assessment report: Memantine FGK. Committee for Medicinal Products for Human Use. European Medicines Agency; 2012 [cited 2016 Jun 1]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/human/002687/WC500141943.pdf
  • Clinical pharmacology and biopharmaceutics review. Memantine extended release drug approval package. U.S. Food and Drug Administration; 2010 [cited 2016 Jun 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022525Orig1s000ClinPharmR.pdf
  • Bucks RS, Ashworth DL, Wilcock GK, et al. Assessment of activities of daily living in dementia: development of the Bristol activities of daily living scale. Age Ageing. 1996;25(2):113–120.
  • Shaw G. Two drugs are not better than one for treating moderate to severe Alzheimer disease, British investigators report: why some US neurologists don’t agree. Neurol Today. 2012;12(8):12–13.
  • Hendrix S, Ellison N, Stanworth S, et al. Post hoc evidence for an additive effect of memantine and donepezil: consistent findings from DOMINO-AD study and memantine clinical trial program. J Prev Alzheimers Dis. 2015;2(3):165–171.
  • Tariot PN. Cessation of donepezil is associated with clinical decline in patients with moderate-to-severe Alzheimer’s disease compared to continuation of donepezil or addition or substitution of memantine. Evid Based Med. 2013;18(2):62–63.
  • Farrimond LE, Roberts E, McShane R. Memantine and cholinesterase inhibitor combination therapy for Alzheimer’s disease: a systematic review. BMJ Open. 2012;2:3.
  • Matsunaga S, Kishi T, Iwata N. Combination therapy with cholinesterase inhibitors and memantine for Alzheimer’s disease: a systematic review and meta-analysis. Int J Neuropsychopharmacol. 2015;18:5.
  • Atri A, Hendrix SB, Pejovic V, et al. Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer’s dementia: a pooled area under the curve analysis. Alzheimers Res Ther. 2015;7(1):28.
  • Hansen RA, Gartlehner G, Webb AP, et al. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. Clin Interv Aging. 2008;3(2):211–225.
  • Farlow M, Veloso F, Moline M, et al. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer’s disease. BMC Neurol. 2011;11:57.
  • Winblad B, Grossberg G, Frolich L, et al. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology. 2007;69(4 Suppl 1):S14–22.
  • Alva G, Cummings JL, Galvin JE, et al. Skin reactions at the application site of rivastigmine patch (4.6 mg/24 h, 9.5 mg/24 h or 13.3 mg/24 h): a qualitative analysis of clinical studies in patients with Alzheimer’s disease. Int J Clin Pract. 2015;69(5):518–530.
  • Gauthier S, Robillard A, Cohen S, et al. Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer’s disease: the EMBRACE study. Curr Med Res Opin. 2013;29(8):989–1000.
  • Kim DH, Brown RT, Ding EL, et al. Dementia medications and risk of falls, syncope, and related adverse events: meta-analysis of randomized controlled trials. J Am Geriatr Soc. 2011;59(6):1019–1031.
  • Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009;169(9):867–873.
  • Hernandez RK, Farwell W, Cantor MD, et al. Cholinesterase inhibitors and incidence of bradycardia in patients with dementia in the veterans affairs new England healthcare system. J Am Geriatr Soc. 2009;57(11):1997–2003.
  • Park-Wyllie LY, Mamdani MM, Li P, et al. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. PLoS Med. 2009;6(9):e1000157.
  • Sheffrin M, Miao Y, Boscardin WJ, et al. Weight loss associated with cholinesterase inhibitors in individuals with dementia in a national healthcare system. J Am Geriatr Soc. 2015;63(8):1512–1518.
  • Hurt C, Bhattacharyya S, Burns A, et al. Patient and caregiver perspectives of quality of life in dementia. An investigation of the relationship to behavioural and psychological symptoms in dementia. Dement Geriatr Cogn Disord. 2008;26(2):138–146.
  • Yaffe K, Fox P, Newcomer R, et al. Patient and caregiver characteristics and nursing home placement in patients with dementia. JAMA. 2002;287(16):2090–2097.
  • Paulsen JS, Salmon DP, Thal LJ, et al. Incidence of and risk factors for hallucinations and delusions in patients with probable AD. Neurology. 2000;54(10):1965–1971.
  • Maust DT, Kim HM, Seyfried LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA Psychiatry. 2015;72(5):438–445.
  • Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191–210.
  • Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry. 2008;23(5):537–545.
  • Wilcock GK, Ballard CG, Cooper JA, et al. Memantine for agitation/aggression and psychosis in moderately severe to severe Alzheimer’s disease: a pooled analysis of 3 studies. J Clin Psychiatry. 2008;69(3):341–348.
  • 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.
  • Ballard C, Thomas A, Gerry S, et al. A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer’s disease (MAIN-AD). J Am Med Dir Assoc. 2015;16(4):316–322.
  • Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer’s disease in the nursing home setting. J Am Geriatr Soc. 2001;49(12):1590–1599.
  • Howard RJ, Juszczak E, Ballard CG, et al. Donepezil for the treatment of agitation in Alzheimer’s disease. N Engl J Med. 2007;357(14):1382–1392.
  • Reus VI, Fochtmann LJ, Eyler AE, et al. The American Psychiatric Association Practice Guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatry. 2016;173(5):543–546.
  • Garay RP, Citrome L, Grossberg GT, et al. Investigational drugs for treating agitation in persons with dementia. Expert Opin Investig Drugs. 2016 [cited 2016 Jun 7]. doi:10.1080/13543784.2016.1193155.
  • Herrmann N, Lanctot KL, Hogan DB. Pharmacological recommendations for the symptomatic treatment of dementia: the Canadian Consensus Conference on the Diagnosis and Treatment of Dementia 2012. Alzheimers Res Ther. 2013;5(Suppl 1):S5.
  • Herrmann N, Black SE, Li A, et al. Discontinuing cholinesterase inhibitors: results of a survey of Canadian dementia experts. Int Psychogeriatr. 2011;23(4):539–545.
  • Parsons C, Briesacher BA, Givens JL, et al. Cholinesterase inhibitor and memantine use in newly admitted nursing home residents with dementia. J Am Geriatr Soc. 2011;59(7):1253–1259.
  • Weschules DJ, Maxwell TL, Shega JW. Acetylcholinesterase inhibitor and N-methyl-D-aspartic acid receptor antagonist use among hospice enrollees with a primary diagnosis of dementia. J Palliat Med. 2008;11(5):738–745.
  • Shega JW, Ellner L, Lau DT, et al. Cholinesterase inhibitor and N-methyl-D-aspartic acid receptor antagonist use in older adults with end-stage dementia: a survey of hospice medical directors. J Palliat Med. 2009;12(9):779–783.
  • O’Regan J, Lanctot KL, Mazereeuw G, et al. Cholinesterase inhibitor discontinuation in patients with Alzheimer’s disease: a meta-analysis of randomized controlled trials. J Clin Psychiatry. 2015;76(11):e1424–31.
  • Herrmann N, O’Regan J, Ruthirakuhan M, et al. A randomized placebo-controlled discontinuation study of cholinesterase inhibitors in institutionalized patients with moderate to severe Alzheimer disease. J Am Med Dir Assoc. 2016;17(2):142–147.
  • Hatoum HT, Thomas SK, Lin SJ, et al. Predicting time to nursing home placement based on activities of daily living scores–a modelling analysis using data on Alzheimer’s disease patients receiving rivastigmine or donepezil. J Med Econ. 2009;12(2):98–103.
  • Howard R, McShane R, Lindesay J, et al. Nursing home placement in the donepezil and memantine in moderate to severe Alzheimer’s disease (DOMINO-AD) trial: secondary and post-hoc analyses. Lancet Neurol. 2015;14(12):1171–1181.
  • Geldmacher DS, Frolich L, Doody RS, et al. Realistic expectations for treatment success in Alzheimer’s disease. J Nutr Health Aging. 2006;10(5):417–429.
  • Rountree SD, Atri A, Lopez OL, et al. Effectiveness of antidementia drugs in delaying Alzheimer’s disease progression. Alzheimers Dement. 2013;9(3):338–345.
  • Winblad B, Kawata AK, Beusterien KM, et al. Caregiver preference for rivastigmine patch relative to capsules for treatment of probable Alzheimer’s disease. Int J Geriatr Psychiatry. 2007;22(5):485–491.
  • Molinuevo JL, Arranz FJ. Impact of transdermal drug delivery on treatment adherence in patients with Alzheimer’s disease. Expert Rev Neurother. 2012;12(1):31–37.
  • Riepe M, Weinman J, Osae-Larbi J, et al. Factors associated with greater adherence to and satisfaction with transdermal rivastigmine in patients with Alzheimer’s disease and their caregivers. Dement Geriatr Cogn Disord. 2015;40(1–2):107–119.
  • Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer’s disease under daily practice conditions. Int J Clin Pract. 2014;68(4):465–470.
  • Boada M, Arranz FJ. Transdermal is better than oral: observational research of the satisfaction of caregivers of patients with Alzheimer’s disease treated with rivastigmine. Dement Geriatr Cogn Disord. 2013;35(1–2):23–33.
  • Alagiakrishnan K, Bhanji RA, Kurian M. Evaluation and management of oropharyngeal dysphagia in different types of dementia: a systematic review. Arch Gerontol Geriatr. 2013;56(1):1–9.
  • Summary Review. Donepezil 23 mg tablets drug approval package. U.S. Food and Drug Administration; 2010 [cited 2016 Jun 1]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022568Orig1s000SumR.pdf
  • Cummings JL, Geldmacher D, Farlow M, et al. High-dose donepezil (23 mg/day) for the treatment of moderate and severe Alzheimer’s disease: drug profile and clinical guidelines. CNS Neurosci Ther. 2013;19(5):294–301.
  • Optimal Dose Escalation Strategy to Successful Achievement of High Dose Donepezil 23mg (ODESA). ClinicalTrials.gov; 2015 [cited 2016 Jun 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT02550665
  • Rountree SD, Chan W, Pavlik VN, et al. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer disease. Alzheimers Res Ther. 2009;1(2):7.
  • Atri A, Shaughnessy LW, Locascio JJ, et al. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):209–221.
  • Karlawish JH, Klocinski JL, Merz J, et al. Caregivers’ preferences for the treatment of patients with Alzheimer’s disease. Neurology. 2000;55(7):1008–1014.
  • Touchon J, Lachaine J, Beauchemin C, et al. The impact of memantine in combination with acetylcholinesterase inhibitors on admission of patients with Alzheimer’s disease to nursing homes: cost-effectiveness analysis in France. Eur J Health Econ. 2014;15(8):791–800.
  • Schneider LS. Discontinuing donepezil or starting memantine for Alzheimer’s disease. N Engl J Med. 2012;366(10):957–959.
  • National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. NICE technology appraisal guidance 217; 2011 [cited 2016 Jun 1]. Available from: https://www.nice.org.uk/guidance/ta217/resources/donepezil-galantamine-rivastigmine-and-memantine-for-the-treatment-of-alzheimers-disease-82600254699973
  • Lopez OL, Becker JT, Wahed AS, et al. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009;80(6):600–607.
  • Assessment report: Acrescent. Committee for Medicinal Products for Human Use. European Medicines Agency; 2012 [cited 2016 Jun 1]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002424/WC500139831.pdf

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.