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DRUG RECORD

 

ALZHEIMER DISEASE AGENTS

 

OVERVIEW
Alzheimer Disease Agents

 

Alzheimer disease is a progressive degenerative brain condition that is the most common cause of dementia worldwide.  Alzheimer disease affects at least 5 million persons in the United States, including approximately 1% of individuals in their 60’s and up to 8% of those above the age of 85 years.  The usual presentation is insidious with impaired memory and cognition and change in personality.  The course is generally progressive with eventual mental and physical disability and death due to complications of immobility.  The cause of Alzheimer disease is not known, but it is characterized by marked atrophy of the cerebral cortex and loss of neurons.  Histologically, Alzheimer disease is marked by senile plaques, spherical accumulations of β-amyloid, degenerating neuronal processes and neurofibrillary tangles.  Functionally, there appears to be impairment of cholinergic transmission.  The increasing prevalence of Alzheimer disease in the population due to increases in the elderly population has led to an increasing appreciation of the importance and the medical and social burden of Alzheimer disease.  Early detection has led to attempts at therapy, the major goal being amelioration or slowing of its progressive course.  Several medications have been found to alleviate some of the symptoms and signs of Alzheimer disease, but none have been proven to affect its ultimate course and outcome.

The pharmacotherapy of Alzheimer disease has focused on increasing cholinergic function in the brain.  Acetylcholine precursors, such as choline and lecithin, have not proven beneficial, but inhibition of acetylcholine metabolism using inhibitors of acetylcholinesterase has been found to be partially successful in improving symptoms of Alzheimer disease.  Four acetylcholinesterase inhibitors have been approved for use for Alzheimer disease in the United States:  tacrine (Cognex: 1993), donepezil (Aricept: 1996), galantamine (Razadyne: 2001), and rivastigmine (Exelon: 2002).  An alternative approach to treatment of Alzheimer disease is inhibition of N-methyl-D-aspartate (NMDA) glutamate receptors which is thought to lead to less excitotoxic injury to the brain.  A single NMDA receptor inhibitor has been approved for use in Alzheimer disease in the United States:  memantine (Namenda: 2003). 

Therapy with tacrine has been associated with a very high rate of serum enzyme elevations, which can be dramatic although usually not associated with symptoms, jaundice or clinically apparent liver injury.  Nevertheless, because of this side effect and the availability of other better tolerated cholinesterase inhibitors, tacrine is now no longer used.  Except for tacrine, the drugs used for Alzheimer disease are rare causes of acute liver injury and have a low rate of associated serum enzyme elevations.  The references on hepatotoxicity of the drugs used are listed together immediately after this introductory section.  The agents referenced and discussed here include:

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REFERENCES
Alzheimer Disease Agents

 

References updated: 01 March 2016

 

  1. Zimmerman HJ. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 709-42.  (Expert review of hepatotoxicity published in 1999; tacrine, the first cholinesterase inhibitor approved for use in Alzheimer disease, was associated with a very high rate of serum ALT elevations [~50%], but rarely caused clinically apparent liver injury; the other Alzheimer disease agents are not discussed; riluzole is mentioned also for its potential to cause ALT elevations [~6%]).

  2. Larrey D, Ripault MP. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 518.  (Review of hepatotoxicity of psychotropic agents ; drugs for Alzheimer disease are not specifically discussed).

  3. Standaert DG, Roberson ED. Alzheimer's disease. Treatment of central nervous system degenerative disorders. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 609-28.  (Textbook of pharmacology and therapeutics).

  4. Chatellier G, Lacomblez L. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. Groupe Françs d'Etude de la Tetrahydroaminoacridine. BMJ 1990; 300: 495-9. PubMed Citation  (In a randomized controlled crossover trial of tacrine in 67 patients with Alzheimer disease, 9 patients [13%] developed significant ALT or AST elevations, usually arising after 2-8 weeks of therapy, ALT 85-2115 U/L, one patient developed jaundice which resolved within 3-4 weeks of stopping).

  5. Ames DJ, Bhathal PS, Davies BM, Fraser JR, Gibson PR, Roberts S. Heterogeneity of adverse hepatic reactions to tetrahydroaminoacridine. Aust N Z J Med 1990; 20: 193-5. PubMed Citation  (5 of 14 patients [36%] taking tacrine for Alzheimer disease developed abnormal liver tests [ALT 106-422 U/L, GTT 20-71 U/L, bilirubins normal], one was symptomatic; liver biopsies showed focal necrosis, fat and one patient with granulomas; all resolved with stopping the drug or lowering the dose).

  6. Hammel P, Larrey D, Bernuau J, Kalafat M, Fréaux E, Babany G, Degott C, et al. Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer's disease. J Clin Gastroenterol 1990; 12: 329-31. PubMed Citation  (A 76 year old woman with Alzheimer disease developed fever and jaundice 20 days after starting tacrine [bilirubin 5.0 mg/dL, ALT ~1800 U/L, Alk P 125 U/L, prothrombin index 40%] with rapid resolution on stopping, all liver tests falling to normal within 6 weeks).

  7. O'Brien JT, Eagger S, Levy R. Effects of tetrahydroaminoacridine on liver function in patients with Alzheimer's disease. Age Ageing 1991; 20: 129-31. PubMed Citation  (Prospective analysis of liver tests in 30 patients with Alzheimer disease treated with tacrine; 50% developed AST elevations within 17-38 days, 8 had clinical symptoms but none had jaundice, all resolved within 3-23 days after stopping or dose reduction; 6 were restarted and 5 tolerated therapy long term).

  8. Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer's disease. The Tacrine Study Group. JAMA 1992; 268: 2523-9. PubMed Citation  (Among 468 patients with Alzheimer disease treated with tacrine or placebo, ALT elevations [>3 times ULN] occurred in 25% of tacrine treated, but in none of placebo treated patients; all elevations were reversible and asymptomatic, usually in first 8 weeks and resolving within 7 to 71 days of stopping).

  9. Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA 1994; 271: 985-91. PubMed Citation  (In a randomized controlled trial of tacrine vs placebo in 653 patients with Alzheimer disease, some degree of ALT elevation occurred in 54% and elevations >3 times ULN in 28% of tacrine-treated patients, but no patient had jaundice and most were asymptomatic, all resolved on stopping tacrine).

  10. Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. JAMA 1994; 271: 992-8. PubMed Citation  (In depth analysis of liver test abnormalities occurring in 2446 patients on tacrine in multi-center trials; ALT elevations occurred in 49%, were >3 times ULN in 25%, >10 times ULN 6%, and >20 times ULN in 2%; usually arising in 6-8 weeks, with no symptoms or minimal nausea and fatigue at ALT >10 times ULN, eosinophilia in 23-44% but no rash, more rapid but less severe recurrence on rechallenge, nevertheless 88% could continue tacrine; more common in women than men).

  11. Fulton B, Benfield P. Galanthamine. Drugs Aging 1996; 9: 60-5. PubMed Citation  (Review of pharmacology, efficacy and safety of galantamine in Alzheimer disease; most side effects are due to its cholinergic properties, including nausea, vomiting, abdominal pain, diarrhea, anxiety and dizziness; "to date, elevations in liver enzymes or other signs of liver toxicity have not been reported with galanthamine").

  12. Gracon SI, Knapp MJ, Berghoff WG, Pierce M, DeJong R, Lobbestael SJ, Symons J, et al. Safety of tacrine: clinical trials, treatment IND, and postmarketing experience. Alzheimer Dis Assoc Disord 1998; 12: 93-101. PubMed Citation  (Review of safety including hepatotoxicity of tacrine based upon registration trials and post-marketing adverse event reporting; ALT levels rise to >3 times the ULN in at least 25% of patients but are usually asymptomatic and not associated with jaundice).

  13. Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, Stälin HB, et al. Efficacy and safety of rivastigmine in patients with Alzheimer's disease: international randomised controlled trial. BMJ 1999; 318: 633-8. PubMed Citation  (Controlled trial of two doses of rivastigmine vs placebo for 26 weeks in 725 patients with Alzheimer disease, no differences in ALT elevations between treatment and placebo arms; side effects included nausea, dizziness, headache, anorexia, fatigue and abdominal pain).

  14. Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomized controlled trial. Galantamine International-1 Study Group. BMJ 2000; 321: 1445-9. PubMed Citation  (Controlled trial of 6 months of two doses of galantamine vs placebo in 653 patients with Alzheimer disease: side effects included nausea, diarrhea, headache, anorexia and weight loss, but there were "no consistent trends or clinically important differences" in blood chemistry results).

  15. Barbare JC, Imbert A, Benkirane A. [Recent developments concerning drug- induced liver toxicity]. Presse Med 2001; 30: 673-6. French. PubMed Citation  (Review of importance of central reporting of drug induced liver injury, providing examples of recently described hepatotoxic reactions, including 3 recent cases of hepatocellular injury due to riluzole).

  16. Verrico MM, Nace DA, Towers AL. Fulminant chemical hepatitis probably associated with donepezil and sertraline therapy. J Amer Geriat Soc 2000; 48: 1659-63. PubMed Citation  (83 year old woman developed jaundice ten days after starting donepezil and 5 months after starting sertraline [bilirubin 5.6 rising to 22.6 mg/dL, ALT 529 U/L, Alk P 369 U/L, peak INR 1.8], resolving over the next 4 months).

  17. Reisberg B, Doody R, Stöer A, Schmitt F, Ferris S, Mös HJ; Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003; 348: 1333-41. PubMed Citation  (Controlled trial of 28 weeks of memantine vs placebo in 252 patients with Alzheimer disease: no differences in rates of any adverse event; serum ALT levels and hepatotoxicity not mentioned).

  18. Pirttilä T, Wilcock G, Truyen L, Damaraju CV. Long-term efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer's disease: multicenter trial. Eur J Neurol 2004; 11: 734-41. PubMed Citation  (Results of continuing galantamine for 24 months in 491 patients with Alzheimer disease; reported no instances of liver toxicity and "no clinically relevant trends" in "clinical laboratory parameters").

  19. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I; Memantine Study Group. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291: 317-24. PubMed Citation  (Controlled trial of 24 weeks of memantine vs placebo in 404 patients with Alzheimer disease receiving donepezil: side effects that were more common with memantine were confusion and headache; "No clinically significant differences were detected between treatment groups...in laboratory tests").

  20. Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, Richardson S; Donepezil "402" Study Group. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol 2004; 61: 1852-6. PubMed Citation  (Controlled trial of 24 weeks of donepezil vs placebo in 153 patients with early Alzheimer disease: side effects included diarrhea, nausea, fatigue, dizziness and insomnia; no mention of ALT elevations or hepatotoxicity).

  21. Winblad B, Wimo A, Engedal K, Soininen H, Verhey F, Waldemar G, Wetterholm AL, et al. 3-year study of donepezil therapy in Alzheimer's disease: effects of early and continuous therapy. Dement Geriatr Cogn Disord 2006; 21: 353-63. PubMed Citation  (Continuation of donepezil for 3 years in 81 patients with Alzheimer disease reported no clinically significant changes in laboratory test results).

  22. Winblad B, Kilander L, Eriksson S, Minthon L, Båman S, Wetterholm AL, Jansson-Blixt C, et al.; Severe Alzheimer's Disease Study Group. Donepezil in patients with severe Alzheimer's disease: double-blind, parallel-group, placebo-controlled study. Lancet 2006; 367: 1057-65. PubMed Citation  (Controlled trial of 6 months of donepezil vs placebo in 248 patients with severe Alzheimer disease; side effects were mostly mild and did not differ between donepezil and placebo treated patients; there were "no great changes in the results of laboratory tests").

  23. Bullock R. Efficacy and safety of memantine in moderate-to-severe Alzheimer disease: the evidence to date. Alzheimer Dis Assoc Disord 2006; 20: 23-9. PubMed Citation  (Review of the safety of memantine from 3 pivotal controlled trials and more than 100,000 patient-years of use: overall rates of side effects were not different from placebo, were mild-to-moderate, and often considered unrelated; no mention of hepatotoxicity).

  24. Seltzer B. Donepezil: an update. Expert Opinion Pharmacother 2007; 8: 1011-23. PubMed Citation  (Review of safety and efficacy of donepezil, the most commonly used agent in therapy of Alzheimer disease; no discussion of ALT elevations or hepatotoxicity).

  25. Farlow MR, Cummings JL. Effective pharmacologic management of Alzheimer's disease. Am J Med 2007; 120: 388-97. PubMed Citation  (Review of safety and efficacy of medications for Alzheimer disease; no discussion of hepatotoxicity).

  26. 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; 13: 97-107. PubMed Citation  (Controlled trial of 24 weeks of memantine vs placebo in 470 patients with Alzheimer disease: adverse events occurred in similar rates with memantine and placebo, were all mild-to-moderate, and there "were no clinically meaningful differences between treatment groups" in laboratory tests).

  27. Ferrara N, Corbi G, Capuano A, Filippelli A, Rossi F. Memantine-induced hepatitis with cholestasis in a very elderly patient. Ann Intern Med 2008; 148: 631-2. PubMed Citation  (92 year old woman developed jaundice and pruritus 16 days after starting memantine for dementia [bilirubin 4.3 mg/dL, ALT 132 U/L, Alk P 912 U/L], resolving within 3 weeks of stopping).

  28. Dierckx RIR, Vandewoude MFJ. Donepezil-related toxic hepatitis. Acta Clinica Belg 2008; 63: 339-42. PubMed Citation  (90 year old man with Alzheimer disease developed abdominal pain and jaundice 2 weeks after starting donepezil [bilirubin 5.9 rising to 22.6 mg/dL, ALT 329 U/L, Alk P 944 U/L], resolving over the next 3 months).

  29. Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. 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: 211-25. PubMed Citation  (Systematic review of 3 cholinesterase inhibitors in Alzheimer disease; most common adverse events were nausea [19%], vomiting [13%], diarrhea [11%] and weight loss [9%] and withdrawal for adverse events in 11-21%; no mention of ALT elevations or hepatotoxicity).

  30. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008; none were attributed to a drug used to treat Alzheimer disease). 

  31. Mumoli N, Carmignani G, Luschi R, Cei M, Chiavistelli P. Hepatitis with cholestasis caused by rivastigmine transdermal patch. Am J Gastroenterol 2009; 104: 2859-60. PubMed Citation  (84 year old woman developed jaundice and rash 2 months after starting transdermal rivastigmine for Alzheimer disease [bilirubin 3.0 mg/dL, ALT 857 U/L, Alk P 344 U/L, eosinophils 8%], resolving within 5 weeks of stopping).

  32. Mayeux R. Early Alzheimer's disease. N Engl J Med 2010; 362: 2194-201. PubMed Citation  (Case discussion and review of current understanding of Alzheimer disease including role of therapy; common side effects of cholinesterase inhibitors include nausea, vomiting, anorexia, diarrhea, dizziness, muscle cramps, insomnia and vivid dreams; memantine can cause constipation, dizziness, headache and body pains; no mention of hepatotoxicity).

  33. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to drugs used to treat Alzheimer disease). 

  34. Farlow M, Veloso F, Moline M, Yardley J, Brand-Schieber E, Bibbiani F, Zou H, et al. Safety and tolerability of donepezil 23 mg in moderate to severe Alzheimer's disease. BMC Neurol 2011; 11: 57. PubMed Citation  (Among 1434 patients with Alzheimer disease treated with 10 vs 23 mg of donepezil daily for 24 weeks, cholinergic side effects were more common with the higher dose, but there were no differences in frequency of "clinically important" abnormal laboratory values). 

  35. Dubois B, Tolosa E, Katzenschlager R, Emre M, Lees AJ, Schumann G, Pourcher E, et al. Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord 2012; 27: 1230-8. PubMed Citation  (Among 550 patients with Alzheimer disease treated with two doses of donepezil or placebo for 24 weeks, nausea, tremor, diarrhea, insomnia and anorexia were more frequent in patients on donepezil, but "Laboratory tests and physical examination data remained largely unchanged").

  36. Tariot P, Salloway S, Yardley J, Mackell J, Moline M. Long-term safety and tolerability of donepezil 23 mg in patients with moderate to severe Alzheimer's disease. BMC Res Notes 2012; 5: 283. PubMed Citation  (Among 915 patients with Alzheimer disease treated with donepezil in a dose of 23 vs 10 mg daily, cholinergic side effects were more common at the higher dose, but "there were no changes in laboratory test values"). 

  37. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, Jiang T, et al. Efficacy and Safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis 2014 Mar 24. [Epub ahead of print] PubMed Citation  (Systematic review of safety and efficacy of 4 Alzheimer drugs does not mention ALT elevations or hepatotoxicity).

  38. Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, Chen MH, Hemmelgarn B, Straus SE. Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis. CMAJ. 2013 Nov 5; 185 (16): 1393-401. PubMed Citation  (Systematic review of 8 clinical trials and 3 reports on the safety and efficacy of Alzheimer drugs mentions that side effects of nausea, diarrhea, vomiting and headaches were usually more frequent with the active drugs compared to placebo; no mention of ALT elevations or clinically apparent liver injury).

  39. Ikeda M, Mori E, Kosaka K, Iseki E, Hashimoto M, Matsukawa N, Matsuo K, Nakagawa M; Donepezil-DLB Study Investigators. Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord. 2013; 36 (3-4): 229-41. doi: 10.1159/000351672. Epub 2013 Aug 15. PubMed Citation  (Among 108 patients with dementia treated with donepezil for up to 52 weeks, no patient developed clinically apparent liver injury; 12 patients developed CPK elevations, but ALT elevations were not mentioned).

  40. Salloway S, Mintzer J, Cummings JL, Geldmacher D, Sun Y, Yardley J, Mackell J. 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: 421-32. PubMed Citation  (Reanalysis of safety and efficacy of a multinational trial of donepezil in Alzheimer disease found that rates of nausea, vomiting, anorexia, weight loss, fatigue and incontinence where twice as high in patients receiving higher doses of donepezil; no mention of ALT elevations or hepatotoxicity).

  41. Hager K, Baseman AS, Nye JS, Brashear HR, Han J, Sano M, Davis B, Richards HM. Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease. Neuropsychiatr Dis Treat 2014; 10: 391-401. PubMed Citation  (Among 2045 patients with Alzheimer disease treated with galantamine or placebo for up to 2 years, symptoms of nausea, vomiting, and fatigue were sligtly more frequent with galantamine than placebo, but serious adverse events were similar in the two groups and "No clinically meaningful changes were observed in... laboratory tests").

  42. Wang HF, Yu JT, Tang SW, Jiang T, Tan CC, Meng XF, Wang C, et al.  Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry 2014 May 14. PubMed Citation  (Systematic review of 10 trials of Alzheimer drugs in Parkinson disease and other forms of dementia reported that the common adverse events were cholinergic in nature [anorexia, nausea, diarrhea] and were generally mild-to-moderate in severity; serious adverse events were similar to rates with placebo; no mention of ALT elevations or hepatotoxicity).

  43. Nakamura Y, Kitamura S, Homma A, Shiosakai K, Matsui D. 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: 913-25. PubMed Citation  (Among 633 Japanese patients with Alzheimer disease treated with either memantine or placebo, the rate of adverse events was similar in the two groups; no mention of ALT elevations or clinically apparent liver injury).

  44. Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, Love S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial JAMA 2014; 311: 33-44. PubMed Citation  (Among 561 patients with Alzheimer disease treated with vitamin E, memantine, the combination or placebo for an average of 2.3 years, overall adverse events were similar in the 4 groups, but serious infections were more common with memantine than placebo (15% vs 7%); no mention of ALT elevations or hepatotoxicity).

  45. Emre M, Poewe W, De Deyn PP, Barone P, Kulisevsky J, Pourcher E, van Laar T, et al. Long-term safety of rivastigmine in parkinson disease dementia: an open-label, randomized study. Clin Neuropharmacol 2014; 37 (1): 9-16. PubMed Citation  (Among 583 patients with Parkinson disease dementia treated with either rivastigmine capsules or patch, adverse events were more frequnet with capsules, particularly tremor, nausea, vomiting, diarrhea and syncope; no mention of ALT elevations or hepatotoxicity).

  46. Gauthier S, Robillard A, Cohen S, Black S, Sampalis J, Colizza D, de Takacsy F, et al; EMBRACE investigators. 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: 989-1000. PubMed Citation  (Among 969 Canadian patients with Alzheimer disease treated with rivastigmine patch for 18 months, 18% stopped treatment because of adverse events, usually skin reactions or nausea/vomiting; no mention of ALT elevations or clinically apparent liver injury).

  47. Mäurer M, Ortler S, Baier M, Meergans M, Scherer P, Hofmann W, Tracik F. Randomised multicentre trial on safety and efficacy of rivastigmine in cognitively impaired multiple sclerosis patients. Mult Scler 2013; 19: 631-8. PubMed Citation  (Among 86 patients with multiple sclerosis and cognitive decline treated with rivastigmine or placebo patches for 16 weeks, side effects were similar in the two groups; no mention of ALT elevations or hepatotoxicity). 

  48. Ikeda M, Mori E, Kosaka K, Iseki E, Hashimoto M, Matsukawa N, Matsuo K,
    Nakagawa M; Donepezil-DLB Study Investigators. Long-term safety and efficacy of donepezil in patients with dementia with Lewy bodies: results from a 52-week, open-label, multicenter extension study. Dement Geriatr Cogn Disord 2013; 36: 229-41. PubMed Citation  (Among 108 patients with dementia treated with open-label donepezil for 52 weeks, there were no hepatic serious adverse events; no mention of ALT levels).

  49. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none of the cases were attributed to a drug used to treat Alzheimer disease). 

  50. Chew AP, Lim WS, Tan KT. Donepezil-induced hepatotoxicity in an elderly adult taking fluoxetine. J Am Geriatr Soc 2014; 62: 2009-11. PubMed Citation  (A 79 year old man with depression, Alzheimer disease and cirrhosis due to hepatitis was taking high doses of fluoxetine [80 mg daily] and lamivudine and developed fatigue and anorexia with abnormal liver tests 6 weeks after starting donepezil [bilirubin 1.5 mg/dL, ALT 177 U/L, Alk P 127 U/L], which resolved within 8 weeks of stopping both and did not recur on starting sertraline and memantine).    

  51. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to a drug for Alzheimer disease).

  52. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were due to a drug for Alzheimer disease). 

  53. Kröger E, Mouls M, Wilchesky M, Berkers M, Carmichael PH, van Marum R, Souverein P, et al. Adverse drug reactions reported with cholinesterase inhibitors: an analysis of 16 rears of individual case safety reports from VigiBase. Ann Pharmacother 2015; 49: 1197-206. PubMed Citation  (Analysis of spontaneous adverse event reports made between 2006 and 2013 to a WHO drug monitoring database identified 16,995 serious adverse events in patients receiving cholinesterase inhibitors, 121 of which were hepatobiliary, including 47 for donepezil, 53 rivastigmine and 21 galantamine; no details provided).

  54. Ikeda M, Mori E, Matsuo K, Nakagawa M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial. Alzheimers Res Ther 2015; 7: 4. PubMed Citation  (Among 142 patients with dementia with Lewy bodies treated with donepezil [5 or 10 mg] vs placebo for 12 weeks, adverse events were mild-to-moderate and those more frequent with donepezil were anorexia, nausea and Parkinson disease symptoms; no mention of ALT elevations or hepatotoxicity).

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