Drugs for cognitive loss and dementia

Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Drugs for Cognitive Loss and Dementia p 95 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF US AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 Treatment Guidelines from The Medical Letter® Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 11 (Issue 134) October 2013 www.medicalletter.org Take CME exams Tables FDA-Approved Drugs for Alzheimer’s Disease Page 97 Drugs for Cognitive Loss and Dementia Related article(s) since publication The drugs currently available for the treatment of Alzheimer’s disease and other dementias can provide limited symptomatic improvement The acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine and the NMDA-receptor antagonist memantine have produced modest but apparently persistent improvements in cognition, activities of daily living, and behavior in patients with disease severity ranging from mild to severe Among the acetylcholinesterase inhibitors, transdermal rivastigmine causes fewer gastrointestinal side effects than the oral formulation Whether adding memantine to an acetylcholinesterase inhibitor is more effective than an acetylcholinesterase inhibitor alone remains to be established; clinical trial results have been mixed None of these agents have been shown to stop or reverse the underlying neurodegenerative process iting, and diarrhea Bradycardia and syncope can occur, and an increased incidence of hip fracture has been reported in elderly patients taking these agents.2 Concurrent use of drugs with anticholinergic effects, including first-generation antihistamines, such as diphenhydramine (Benadryl, and others), drugs for overactive bladder, such as oxybutynin (Ditropan, and others), or tricyclic antidepressants, such as imipramine (Tofranil, and others), may decrease the activity of acetylcholinesterase inhibitors All three of the acetylcholinesterase inhibitors in Table are approved by the FDA for treatment of mild to moderate AD dementia; donepezil and transdermal rivastigmine are also approved for treatment of severe AD dementia Rivastigmine is the only acetylcholinesterase inhibitor approved for treatment of mild to moderate dementia associated with Parkinson’s disease Alzheimer’s disease (AD) is the most common cause of dementia, but cognitive loss is also associated with other neurological conditions such as Parkinson’s disease, dementia with Lewy bodies, and vascular dementia Mild cognitive impairment (MCI) is generally defined as cognitive decline greater than expected for an individual’s age and educational level, but not interfering with activities of daily living; it may be a transitional state between the cognitive changes of normal aging and dementia.1 DONEPEZIL — Donepezil (Aricept, Aricept ODT, and generics) is a centrally active, reversible inhibitor of acetylcholinesterase with little peripheral activity.3 It is approved for treatment of mild, moderate, or severe AD dementia Treatment of reversible dementia due to drug toxicity, infections, or metabolic disorders is not included here ACETYLCHOLINESTERASE INHIBITORS Cognitive loss in AD is associated with depletion of acetylcholine, which is involved in learning and memory Acetylcholinesterase inhibitors increase the concentration of acetylcholine and may have beneficial effects on the symptoms of dementia, but can also cause adverse cholinergic effects such as nausea, vom- Pharmacokinetics – Donepezil is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations in 3-4 hours with the 10-mg tablet and in about hours with the 23-mg tablet It is metabolized primarily by CYP2D6 and 3A4 and is excreted in urine Donepezil has a half-life of about 70 hours, allowing once-daily administration Clinical Studies – The results of a 3-year randomized, double-blind trial comparing donepezil 10 mg/day or vitamin E 2000 IU/day with placebo in 769 patients with MCI did not show any significant differences in the probability of progression from MCI to AD, except during the first year of the study when the donepezil group had a significantly lower rate of progression to AD.4 Another placebo-controlled trial in 821 patients Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines 95 Drugs for Cognitive Loss and Dementia with MCI followed for 48 weeks showed that donepezil had a small but significant effect on cognition, but no effect on global function.5 FDA approval of donepezil for treatment of severe AD dementia was based on studies One randomized, placebo-controlled, double-blind 24-week trial in 248 patients with severe AD dementia living in nursing homes found improvements in activities of daily living, cognition, and global function with donepezil, but no difference in behavior.6 In the second study, a 24-week randomized, double-blind, placebo-controlled trial in 343 ambulatory outpatients with severe AD dementia, donepezil was more effective than placebo on measures of cognition and global function.7 Discontinuation of donepezil in patients with moderate to severe AD dementia has been associated with cognitive and functional decline.8 A trial of donepezil for treatment of agitation in 272 patients with AD dementia failed to show improvement.9 GALANTAMINE — Galantamine (Razadyne, Razadyne ER, and generics) is a reversible, competitive inhibitor of acetylcholinesterase It also acts on nicotinic acetylcholine receptors; the clinical significance of its nicotinic activity remains to be established Galantamine is FDA-approved for treatment of mild to moderate AD dementia Pharmacokinetics – Galantamine is rapidly absorbed from the gastrointestinal tract Serum concentrations of the immediate-release (IR) formulation peak in about one hour without food and in about 2.5 hours with food The median time to peak (Tmax) with the extendedrelease (ER) formulation is 4.5-5 hours Galantamine is metabolized in the liver by CYP2D6 and 3A4 to metabolites that have little anticholinesterase activity Clinical Studies – In short-term (5-6 months) trials in patients with mild to moderate AD dementia, galantamine showed some benefits in cognitive and clinical global measures compared to placebo.17 The results of some small, short-term (10-26 weeks) placebo-controlled trials have suggested a modest improvement in cognition, global function, and activities of daily living with donepezil in patients with dementia associated with Parkinson’s disease and in those with dementia associated with Lewy bodies.10,11 In two 2-year randomized, placebo-controlled trials in 2048 patients with MCI, there was no difference in the rate of progression to AD dementia between the placebo- and galantamine-treated groups.18 In patients with vascular dementia treated with donepezil, some randomized, double-blind, placebo-controlled 24-week trials have shown statistically significant improvements in cognition and global functioning.12,13 Several trials (6-12 months) in AD dementia patients with vascular dementia have shown significant improvement in cognition, behavior, and activities of daily living with galantamine treatment.19,20 Dosage – The initial dosage of donepezil is mg once daily for at least 4-6 weeks The dose can then be increased to 10 mg once daily Donepezil mg per day has been safe and well tolerated in patients with impaired hepatic or renal function It is also available as 23-mg tablets marketed for patients with a suboptimal response to lower doses, but the larger dose has marginal benefits at best and causes a substantial increase in gastrointestinal side effects.14,15 Dosage – The initial dose of galantamine is mg daily with food, taken either as mg twice daily of the IR formulation or mg once daily of the ER formulation The dose can then be increased to 16 mg per day after weeks and then to 24 mg after another weeks The maximum dose should be limited to 16 mg/day in patients with moderate hepatic or renal impairment; the drug should be avoided in patients with severe hepatic or renal impairment If treatment is interrupted for >3 days, galantamine should be restarted at the lowest daily dose Adverse Effects – The most common adverse effects of donepezil have been nausea, vomiting, and diarrhea, particularly when the drug is started or the dose is increased Urinary incontinence, vivid dreams, bradycardia, and syncope have also occurred Fatigue and muscle cramps have been reported Higher plasma levels of the drug and possibly a higher incidence of adverse effects might occur in the 7% of the population who are CYP2D6 poor metabolizers Drug Interactions – In addition to interactions with drugs that have anticholinergic or cholinergic effects, donepezil could potentially interact with inhibitors or inducers of CYP3A4 or 2D6.16 96 Adverse Effects – The most common adverse effects of galantamine are nausea, vomiting, diarrhea, dizziness, anorexia, and weight loss, reported mostly during rapid dose escalation and less commonly during maintenance treatment Bradycardia and syncope can occur Depression, fatigue, and somnolence have been reported In one study in patients with MCI, more deaths occurred with galantamine treatment than with placebo, probably due to an unusually low mortality rate in the placebo group.18 A higher incidence of death has not been reported in patients with AD dementia treated with galantamine Higher plasma levels of the drug Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 Drugs for Cognitive Loss and Dementia Table FDA-Approved Drugs for Alzheimer’s Disease Drug Acetylcholinesterase Inhibitors Donepezil – generic Aricept (Eisai/Pfizer) orally disintegrating – generic Aricept ODT (Eisai/Pfizer) Formulations Usual Dosage Starting Dose/Titration 5, 10, 23 mg tabs 5-10 mg once/d Galantamine – generic Razadyne2 (Janssen) 4, 8, 12 mg tabs; mg/mL soln 16-24 mg divided bid with meals 8, 16, 24 mg ER caps 16-24 mg once/d with meals 1.5, 3, 4.5, mg caps 1.5, 3, 4.5, mg caps; mg/mL soln 9-12 mg divided bid with meals mg once/d; after 4-6 wks increase to 10 mg once/d; if suboptimal response to 10 mg after months, can consider increasing to 23 mg mg/d divided bid; after wks increase to 16 mg/d, then after wks more to 24 mg/d mg once/d; after wks increase to 16 mg/d, then after wks more to 24 mg/d mg/d divided bid; increased in increments of mg/d q wks3 to 12 mg/d 4.6 mg/24 hours, 9.5 mg/24 hours, 13.3 mg/24 hours 9.5 mg/24 hours 4.6 mg/24 hours; after wks increase to 9.5 mg/24 hours; after an additional wks increase to 13.3 mg/24 hours 5, 10 mg tabs; mg/mL soln 10 mg bid mg once/d; increase in increments of mg q wk to 20 mg/d divided bid 7, 14, 21, 28 mg ER caps 28 mg once/d extended-release – generic Razadyne ER (Janssen) Rivastigmine – generic Exelon (Novartis) transdermal Exelon Patch (Novartis) NMDA-Receptor Antagonist Memantine – Namenda (Forest) extended-release Namenda XR (Forest) 5, 10 mg orally disintegrating tabs mg once/d; increase to 28 mg/d in increments of mg q wk Cost1 $9.00 353.00 50.00 353.00 146.00 241.00 140.00 241.00 164.00 285.00 296.00 265.00 252.00 ODT = orally disintegrating tablet; ER = extended release Approximate cost for 30 days’ treatment with the lowest usual dosage Source: $ource® Monthly (Selected from FDB MedKnowledge™) September 5, 2013 Reprinted with permission by FDB, Inc All rights reserved ©2013 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Formerly Reminyl Every weeks for dementia associated with Parkinson’s disease and possibly a higher incidence of adverse effects might occur in the 7% of the population who are CYP2D6 poor metabolizers Drug Interactions – In addition to interactions with drugs that have anticholinergic or cholinergic effects, galantamine could potentially interact with drugs that inhibit or induce CYP2D6 or 3A4 RIVASTIGMINE — Rivastigmine (Exelon, and generics; Exelon Patch) is a carbamate-based, slowly reversible, non-competitive cholinesterase inhibitor with good penetration into the central nervous system.21 The drug is FDA-approved for treatment of mild to moderate dementia associated with AD or Parkinson’s disease; the transdermal patch is also approved for severe AD dementia Pharmacokinetics – The oral formulation of rivastigmine is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations in about hour without food and in about 2.5 hours with food The drug binds weakly to plasma proteins and has a short half-life in plasma (1.5 hours), but it has a halflife for cholinesterase inhibition in the central nervous system of about 10 hours, which permits twice-daily dosing Rivastigmine is metabolized mainly through hydrolysis by esterases and is excreted in urine Clinical Studies – A review of double-blind, randomized, placebo-controlled trials involving 4775 patients with mild to moderate AD dementia found that oral rivastigmine 6-12 mg per day slowed the rate of decline in cognitive function, improved activities of daily living, and decreased the severity of dementia.22 In a 24-week study in 1195 patients with severe AD dementia, a rivastigmine 9.5 mg/24 hours patch was as effective as the highest dose of capsules, with about three times fewer reports of nausea and vomiting.23 In another 24-week double-blind trial, 716 patients with severe AD dementia were randomized to receive rivastigmine patches containing 4.6 or 13.3 mg/24 hours At the end of the study, the mean decline from baseline on assessments of cognition and overall function was significantly less with the 13.3 mg patch.24 A randomized, double-blind, placebo-controlled 24week trial found statistically significant improvements in attention and cognition with rivastigmine in 541 patients with dementia associated with Parkinson’s disease.25 A double-blind, placebo-controlled 20-week trial of rivastigmine in 120 patients with dementia with Lewy bodies found clinically and statistically significant improvement in behavior in the treatment group.26 Dosage – The usual starting dosage of oral rivastigmine is 1.5 mg twice daily with food The dose can be Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 97 Drugs for Cognitive Loss and Dementia increased in 1.5-mg increments at 2-week intervals, up to a maximum daily dose of 12 mg No dosage adjustments are required for renal or hepatic impairment If treatment is interrupted for several days, rivastigmine should be restarted at the lowest daily dose Clinical Studies – In 252 patients with moderate to severe AD dementia, a 28-week double-blind trial found that memantine treatment resulted in modest, but statistically significant, benefits in global, functional, and cognitive scores, compared to placebo.31 The transdermal formulation, which requires daily applications of a rivastigmine patch, may be a more reliable method of administration in demented patients.27 The initial dose is one 4.6 mg/24 hours patch, placed in rotation around the back, chest, or upper arm After one month, the dose can be increased to 9.5 mg/24 hours; subsequent escalation after another weeks to a 13.3 mg/24 hours patch may provide additional benefit.28 If treatment is interrupted for >3 days, it should be restarted with the lowest-dose patch One placebo-controlled study in patients with moderate to severe AD dementia already receiving donepezil found that adding memantine led to significantly better outcomes on measures of cognition, behavior, activities of daily living, and global improvement.32 Addition of extended-release memantine to a cholinesterase inhibitor in patients with moderate to severe AD dementia also led to significantly better outcomes, compared to adding a placebo, on measures of cognition and global improvement.33 However, in a double-blind, placebo-controlled trial in 295 patients with moderate to severe AD dementia already receiving donepezil, adding memantine did not result in significantly better scores on measures of cognition and activities of daily living compared to continuing donepezil alone.8 In a prospective, doubleblind 24-week study in 433 patients with mild to moderate AD dementia already taking a cholinesterase inhibitor, adding memantine was no more effective than adding placebo.34 Adverse Effects – Oral rivastigmine causes a high incidence of nausea, vomiting, and diarrhea, which can be reduced if titration is slow and the drug is taken with food These effects appear to be substantially less frequent with the transdermal formulation Bradycardia and syncope can occur Drug Interactions – Except for interactions with drugs that have anticholinergic or cholinergic effects, rivastigmine has no well-documented drug interactions It is not metabolized by CYP450 isozymes CHOICE OF DRUG — Donepezil, galantamine, and rivastigmine appear to have similar efficacy and similar adverse effects, however independent comparative trials among the acetylcholinesterase inhibitors are lacking Transdermal rivastigmine may be better tolerated than the oral formulation Both donepezil and rivastigmine have documented efficacy in vascular dementia and dementia associated with Parkinson’s and Lewy body disease Galantamine has documented efficacy in vascular dementia NMDA-RECEPTOR ANTAGONIST MEMANTINE — An N-methyl-D-aspartate (NMDA)receptor antagonist, memantine (Namenda) is approved by the FDA for treatment of moderate to severe AD dementia.29 Its mechanism of action in AD is unclear; it may reduce glutamatergic overstimulation at the NMDA receptor, which could have symptomatic benefits.30 Pharmacokinetics – Memantine is well absorbed following oral administration, with peak plasma concentrations achieved in about 3-7 hours The terminal elimination half-life is between 60-80 hours Memantine is excreted primarily in urine 98 Memantine 20 mg/day has been reported to improve cognition in patients with mild to moderate vascular dementia35,36 and may be effective in dementia with Lewy bodies.37 Dosage – The initial dosage of memantine is mg once daily The dose can be titrated up in weekly increments of mg to a final dose of 20 mg daily, usually given as 10 mg twice a day The once-daily ER formulation is started at a dose of mg and titrated up in increments of mg weekly to a target dose of 28 mg daily No dosage adjustments are needed for patients with mild to moderate renal impairment; for those with severe renal impairment, the maximum recommended dose is mg twice daily or one 14-mg ER tablet daily Adverse Effects – Memantine is usually well tolerated Adverse effects have included dizziness, confusion, insomnia, hallucinations, and delusions Drug Interactions – Memantine does not affect the inhibition of acetylcholinesterase by cholinesterase inhibitors Amantadine, which is used to treat Parkinson’s disease, is also an NMDA-receptor antagonist and theoretically might have an undesirable additive effect if used concurrently Memantine does not appear to interact with drugs metabolized by CYP450 isozymes Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 Drugs for Cognitive Loss and Dementia ANTIPSYCHOTICS Although not approved for such use by the FDA, antipsychotic drugs are widely used to treat agitation and other behavioral symptoms in elderly patients, especially those with dementia.38 Second-generation antipsychotics used in low doses have generally been preferred because they have fewer extrapyramidal effects than the first-generation drugs Efficacy in AD Dementia – Although many clinicians believe that use of second-generation antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), risperidone (Risperdal), or olanzapine (Zyprexa) to calm agitated or aggressive patients with dementia is beneficial, controlled-trial evidence for the efficacy of antipsychotic medications in dementia is limited One placebo-controlled 36-week trial in 421 outpatients with AD dementia found some benefit from antipsychotics for behavioral symptoms such as anger, aggression, and paranoid ideation, but no improvement in functioning, care needs, or quality of life.39 Adverse Effects – Common adverse effects of antipsychotic drugs include somnolence, gait changes, and extrapyramidal effects One study in 421 patients with AD dementia found that cognitive function declined more in patients receiving antipsychotics than in those given a placebo.40 The FDA has reported that elderly patients with dementia treated with secondgeneration antipsychotics in randomized, controlled trials had a 1.6-1.7 times higher mortality rate than those receiving placebo Most of the deaths were due to cardiovascular or infectious causes The FDA requires manufacturers of antipsychotics to include a warning in the labeling about an increased risk of death among elderly patients with dementia The FDA also requires all manufacturers of secondgeneration antipsychotics to include product-label warnings about the risk of hyperglycemia and diabetes Some second-generation drugs, particularly clozapine (Clozaril, and others) and olanzapine, probably cause more weight gain than first-generation drugs.41 The second-generation drugs are less likely to cause extrapyramidal symptoms, tardive dyskinesia, and neuroleptic malignant syndrome Extrapyramidal effects of antipsychotics have been reported to increase in patients also taking an acetylcholinesterase inhibitor.42 QTc prolongation has been reported, particularly with ziprasidone (Geodon) GINKGO BILOBA The dietary supplement Ginkgo biloba has been used worldwide and is heavily promoted in the US for pre- vention of dementia and other indications Doubleblind, randomized trials have found that it was not effective in preventing or treating dementia or for preventing cognitive decline in older adults.43,44,45 MEDICAL FOODS Two “medical foods”, Axona and CerefolinNAC, are currently marketed for use in AD Their effectiveness remains to be established and their long-term safety is unknown.46,47 10 11 12 13 14 15 16 17 18 19 20 21 MS Albert et al The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease Alzheimers Dement 2011; 7:270 SS Gill et al Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors A population-based cohort study Arch Intern Med 2009; 169:867 Donepezil (Aricept) for Alzheimer’s disease Med Lett Drugs Ther 1997; 39:53 RC Petersen et al Vitamin E and donepezil for the treatment of mild cognitive impairment N Engl J Med 2005; 352:2379 RS Doody et al Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial Neurology 2009; 72:1555 B Winblad et al Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study Lancet 2006; 367:1057 SE Black et al Donepezil preserves cognition and global function in patients with severe Alzheimer disease Neurology 2007; 69:459 R Howard et al Donepezil and memantine for moderate-to-severe Alzheimer’s disease N Engl J Med 2012; 366:893 RJ Howard et al Donepezil for the treatment of agitation in Alzheimer’s disease N Engl J Med 2007; 357:1382 M Rolinski et al Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease Cochrane Database Syst Rev 2012; (3):CD006504 E Mori et al Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial Ann Neurol 2012; 72:41 D Wilkinson et al Donepezil in vascular dementia: a randomized, placebo-controlled study Neurology 2003; 61:479 GC Román et al Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size Stroke 2010; 41:1213 MR Farlow 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; 32:1234 DS Knopman Donepezil 23 mg: An empty suit Neurol Clin Pract 2012; 2:352 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Galantamine (Reminyl) for Alzheimer’s disease Med Lett Drugs Ther 2001; 43:53 B Winblad et al Safety and efficacy of galantamine in subjects with mild cognitive impairment Neurology 2008; 70:2024 T Erkinjuntti et al Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial Lancet 2002; 359:1283 R Bullock et al Management of patients with Alzheimer’s disease plus cerebrovascular disease: 12-month treatment with galantamine Dement Geriatr Cogn Disord 2004; 17:29 Rivastigmine (Exelon) for Alzheimer’s disease Med Lett Drugs Ther 2000; 42:93 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 99 Drugs for Cognitive Loss and Dementia 22 J Birks et al Rivastigmine for Alzheimer’s disease Cochrane Database Syst Rev 2009; (2): CD001191 23 B Winblad et al A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s disease – rivastigmine patch versus capsule Int J Geriatr Psychiatry 2007; 22:456 24 MR Farlow 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 Aug (epub) 25 M Emre et al Rivastigmine for dementia associated with Parkinson’s disease N Engl J Med 2004; 351:2509 26 I McKeith et al Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study Lancet 2000; 356:2031 27 A Wentrup et al Once-daily transdermal rivastigmine in the treatment of Alzheimer’s disease Drug Des Devel Ther 2008; 2:245 28 J Cummings et al Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs 10 cm2) in Alzheimer’s disease Dement Geriatr Cogn Disord 2012; 33:341 29 Memantine for Alzheimer’s disease Med Lett Drugs Ther 2003; 45:73 30 PT Francis et al Rationale for combining glutamatergic and cholinergic approaches in the symptomatic treatment of Alzheimer’s disease Expert Rev Neurother 2012; 12:1351 31 B Reisberg et al Memantine in moderate-to-severe Alzheimer’s disease N Engl J Med 2003; 348:1333 32 PN Tariot et al Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial JAMA 2004; 291:317 33 GT Grossberg 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; 27:469 34 AP Porsteinsson 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; 5:83 35 JM Orgogozo et al Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300) Stroke 2002; 33:1834 36 G Wilcock et al A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500) Int Clin Psychopharmacol 2002; 17:297 37 M Emre et al Memantine for patients with Parkinson’s disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial Lancet Neurol 2010; 9:969 38 DV Jeste et al ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia Neuropsychopharmacology 2008; 33:957 39 DL Sultzer et al Clinical symptom responses to atypical antipsychotioc medications in Alzheimer’s disease: phase outcomes from the CATIE-AD effectiveness trial Am J Psychiatry 2008; 165:844 40 CL Vigen et al Cognitive effects of atypical antipsychotic medications in patients with Alzheimer’s disease: outcomes from CATIE-AD Am J Psychiatry 2011; 168:831 41 Drugs for psychiatric disorders Treat Guidel Med Lett 2013; 11:53 42 HC Liu et al Extrapyramidal side-effect due to drug combination of risperidone and donepezil Psychiatry Clin Neurosci 2002; 56:479 43 ST DeKosky et al Ginkgo biloba for prevention of dementia: a randomized controlled trial JAMA 2008; 300:2253 44 LS Schneider et al A randomized, double-blind, placebo-controlled trial of two doses of Ginko biloba extract in dementia of the Alzheimer’s type Curr Alzheimer Res 2005; 2:541 45 BE Snitz et al Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial JAMA 2009; 302:2663 46 A medical food for Alzheimer’s disease Med Lett Drugs Ther 2009; 51:49 47 P Thaipisuttikul and JE Galvin Use of medical foods and nutritional approaches in the treatment of Alzheimer’s disease Clin Pract (Lond) 2012; 9:199 100 Coming Soon in Treatment Guidelines: Drugs for Parkinson’s Disease – November 2013 Drugs for Migraine – December 2013 Follow us on Twitter @MedicalLetter Treatment Guidelines ® from The Medical Letter EDITOR IN CHIEF: Mark Abramowicz, M.D EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School EDITOR: Jean-Marie Pflomm, Pharm.D ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School Eric J Epstein, M.D., Albert Einstein College of Medicine Jane P Galiardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine Jules Hirsch, M.D., Rockefeller University David N Juurlink, BPhm, M.D., PhD, 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Guidelines The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare professionals through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants or donations GOAL: Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable and timely educational content that they will use to make independent and informed therapeutic choices in their practice LEARNING OBJECTIVES: The objective of this activity is to meet the need of healthcare professionals for unbiased, reliable and timely information on treatment of major diseases The Medical Letter expects to provide the healthcare community with educational content that they will use to make independent and informed therapeutic choices in their practice Participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of the drugs and other therapeutic modalities discussed in Treatment Guidelines with specific attention to clinical evidence of effectiveness, adverse effects and patient management Upon completion of this program, the participant will be able to: Explain the current approach to the management of Alzheimer's dementia and mild cognitive impairment Discuss the pharmacologic options available for treatment of Alzheimer's dementia and mild cognitive impairment and compare them based on their efficacy, dosage and administration, potential adverse effects and drug interactions Determine the most appropriate therapy given the clinical presentation of an individual patient Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 134 Questions The most common cause of dementia is: a Parkinson’s disease b Alzheimer’s disease c dementia with Lewy bodies d vascular dementia Acetylcholinesterase inhibitors: a increase concentrations of acetylcholine b have been shown to improve symptoms of dementia c interact with drugs that have anticholinergic effects d all of the above Which one of the following has been shown to reverse the underlying neurodegenerative process of Alzheimer’s disease? a ginkgo biloba b memantine c donepezil d none of the above An 82-year-old woman with Alzheimer’s disease dementia recently started taking rivastigmine mg orally twice daily and has been experiencing significant nausea, vomiting and diarrhea You could tell the patient and her daughter that: a rivastigmine is available as a transdermal patch that is less likely to cause gastrointestinal adverse events b other cholinesterase inhibitors not cause any gastrointestinal adverse events c quickly increasing the dose should alleviate these adverse events d none of the above Donepezil: a is approved for mild, moderate or severe Alzheimer’s disease dementia b is taken once daily c is available generically d all of the above Adverse effects of acetylcholinesterase inhibitors include: a nausea b vomiting c diarrhea d all of the above The FDA requires manufacturers to include a warning in the labeling about an increased risk of death among elderly patients with dementia on all: a acetylcholinesterase inhibitors b NMDA-receptor antagonists c antipsychotics d ginkgo biloba products Which of the following have been shown to produce modest improvements in cognition, activities of daily living, and behavior in patients with Alzheimer’s disease dementia? a donepezil b memantine c galantamine d all of the above Memantine: a interferes with the action of acetylcholinesterase inhibitors b is FDA-approved for treatment of moderate to severe Alzheimer’s disease dementia c is the preferred initial treatment for patients with mild cognitive impairment d all of the above 10 Adverse effects of memantine include: a dizziness b hallucinations c delusions d all of the above 11 A 68-year-old man who requires treatment for moderate dementia associated with Parkinson’s disease comes to your office Which of the following is true? a rivastigmine is FDA-approved for treatment of mild to moderate dementia associated with Parkinson’s disease b the use of medical foods has been proven to be safe and effective for treatment of Parkinson’s disease dementia c the most common side effect of memantine is vomiting d all of the above 12 Which of the following would not be affected by concurrent use of a CYP2D6 inhibitor? a rivastigmine b donepezil c galantamine d none of the above ACPE UPN: 0379-0000-13-134-H01-P; Release: September 2013, Expire: September 2014 Treatment Guidelines from The Medical Letter • Vol 11 ( Issue 134) • October 2013 ... FDA-Approved Drugs for Alzheimer’s Disease Page 97 Drugs for Cognitive Loss and Dementia Related article(s) since publication The drugs currently available for the treatment of Alzheimer’s disease and. .. 134) • October 2013 Drugs for Cognitive Loss and Dementia ANTIPSYCHOTICS Although not approved for such use by the FDA, antipsychotic drugs are widely used to treat agitation and other behavioral... law prohibits unauthorized reproduction by any means and imposes severe fines 95 Drugs for Cognitive Loss and Dementia with MCI followed for 48 weeks showed that donepezil had a small but significant