Read 2004 ADMC pocket tables w_discl Prim care.qxd text version

PRIMARY CARE CONSENSUS REPORTS

Consensus Panel Statements For Outcome-Effective and Evidence-Based Patient Management

Alzheimer's Disease: Risk Stratification, Patient Evaluation, and Outcome-Effective Pharmacologic Therapy-- Year 2004 Clinical Update

ADMC

Alzheimer's Disease Management Council Consensus Panel and Scientific Roundtable

Recommendations and Treatment Guidelines of the Alzheimer's Disease Management Council (ADMC) Clinical Consensus Panel

Guidelines, Protocols, and Recommendations

Supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

ADMC Clinical Consensus Panel Chairman: Steven G. Potkin, MD, Professor, Department of Psychiatry, Director, Clinical of Psychiatric Research, Robert R. Sprague Director of Brain Imaging Center, University of California, Irvine. Distinguished ADMC Panel Members: David B. Arciniegas, MD, Director, Neuropsychiatry Service, Assistant Professor of Psychiatry and Neurology, University of Colorado Health Sciences Center; Gideon Bosker, MD, Editor-in-Chief, Clinical Consensus Reports, Editor-in-Chief, Neurology Consensus Reports®, Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT; Alan Dengiz, MD, Director of Geriatric Medicine, St. Joseph Mercy Health System, Medical Director Glacier Hills Retirement Community, and Huron Woods Alzheimer's Residential Center, Ann Arbor, MI; Bijan Etemad, MD, Department of Psychiatry, University of Pennsylvania, Philadelphia, PA; Martin R. Farlow, MD, Professor and Vice Chairman for Research, Department of Neurology, Indiana University-Purdue University, Indianapolis; Kevin Gray, MD, Director, Geriatric Neuropsychiatry Clinic, Dallas Veteran Affairs Medical Center, Associate Professor of Psychiatry and Neurology, The University of Texas Southwestern Medical Center, Dallas, Texas; Joseph Gruber, RPH, CGP, FASCP, Certified Geriatric Pharmacist, Certified Gerontologist, Regional Director of Clinical Services, Omnicare, Inc.; Joseph Micca, MD, Medical Director Subacute Services, Beverly Healthcare, Northside, Medical Director, A.G. Rhodes Home, Cobb, Medical Director, Georgia EMS, Atlanta, GA; Patricio F. Reyes, MD, Professor of Neurology, Pathology & Psychiatry, Deputy Chair of Neurology, Director, Center for Aging, Alzheimer's Disease & Neurodegenerative Disorders, Creighton University School of Medicine, Omaha, NE; Sandra Saint-Eloi, RN, MSN, AGNP-C, Geriatric Nurse Practitioner, Clinical Nurse Specialist, Adult and Geriatric Institute of Florida; Joshua R. Shua-Haim, MD, FACP, AGSF, CMD, Medical Chief, Meridian Institute for Aging-Senior Health Center and Memory Disorders Institute, Director, Geriatric Fellowship Program, Jersey Shore University Medical Center, Manchester Township, NJ; Paul E. Stander, MD, FACP, Medical Director, Banner Good Samaritan Medical Center, Clinical Assistant Professor of Medicine, Department of Internal Medicine, Arizona Health Sciences Center, Phoenix, AZ; and Edward G. Zurad, MD, Clinical Assistant Professor, Department of Family and Community Medicine, Temple University School of Medicine, Philadelphia, PA.

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PRIMARY CARE CONSENSUS REPORTS

Figure 1: Alzheimer's Disease: Evidence-Based and Outcome-Effective Pharmacologic Management

Recommendations, Strategies, and Treatment Guidelines Endorsed by the ADMC (Alzheimer's Disease Management Council) Clinical Consensus Panel

Diagnosis of Mild-to-Moderate Alzheimer's Disease Confirmed or Strongly Suspected

Medical Conditions That May Cause Dementia Have Been Excluded

ADMC

Alzheimer's Disease Management Council Consensus Panel and Scientific Roundtable

Patient Manifests Clinical Criteria That Support Initiation of Drug Therapy

There are objective, documented progressive, and clearly worsening deficits in new learning and memory in an elderly patient, accompanied by signs of functional impairment

STAGING

Mild-to-Moderate Alzheimer's Disease

Moderate-to-Severe Alzheimer's Disease

Severe, De novo Patient With Previously Untreated Alzheimer's Disease

Mild-to-Moderate Alzheimer's Disease: Evidence-Based and Outcome-Effective Pharmacologic Management ADMC Guidelines

See Figure 2

Moderate-to-Severe Alzheimer's Disease: Evidence-Based and Outcome-Effective Pharmacologic Management ADMC Guidelines

See Figure 3

Severe Alzheimer's Disease: Evidence-Based and OutcomeEffective Pharmacologic Management ADMC Guidelines

See Figure 4

PRIMARY CARE CONSENSUS REPORTS

3

Figure 2: Mild-to-Moderate Alzheimer's Disease: EvidenceBased and Outcome-Effective Pharmacologic Management

Recommendations, Strategies, and Treatment Guidelines Endorsed by the ADMC (Alzheimer's Disease Management Council) Clinical Consensus Panel

Diagnosis of Mild-to-Moderate Alzheimer's Disease Confirmed or Strongly Suspected

Medical Conditions That May Cause Dementia Have Been Excluded

ADMC

Alzheimer's Disease Management Council Consensus Panel and Scientific Roundtable

Patient Manifests Clinical Criteria That Support Initiation of Drug Therapy

There are objective, documented progressive, and clearly worsening deficits in new learning and memory in an elderly patient, accompanied by signs of functional impairment

INITIATE THERAPY WITH CHOLINESTERASE INHIBITOR1,2

FIRST-LINE THERAPY3,4,5

Rivastigmine

OR

Donepezil

OR

Galantamine

STARTING DOSES AND TITRATION STRATEGIES FOR RECOMMENDED, FIRST-LINE CHOLINESTERASE INHIBITORS6,7

Rivastigmine: Initiate oral therapy at 1.5 mg twice daily, taken with food, after a full meal; at 4-week intervals increase each dose by 1.5 mg, up to a maximally effective, tolerated therapeutic dose. The maximum dose is 6 mg twice daily. The minimum therapeutic dose for rivastigmine is 3 mg twice daily. Donepezil: Initiate oral therapy at 5 mg once daily, at bedtime; after 6 weeks, increase dose by 5 mg to 10 mg once daily. The minimum therapeutic dose for donepezil is 5 mg once daily. Donepezil may be taken with or without food.

Galantamine: Initiate oral therapy at 4 mg twice daily, with food. At 4-week intervals, increase each dose by 4 mg up to a maximally effective, tolerated therapeutic dose. The maximum dose is 12 mg twice daily; the minimum therapeutic dose for galantamine is 8 mg twice daily. Continued on next page

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PRIMARY CARE CONSENSUS REPORTS

Mild-to-Moderate Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

IF PATIENT HAS BEEN SUCCESSFULLY TITRATED TO-- AND IS TOLERATING--A THERAPEUTICALLY EFFECTIVE DOSE OF A CHOLINESTERASE INHIBITOR, WHILE DEMONSTRATING CLINICAL BENEFITS WITH THIS THERAPY, THEN THE PATIENT SHOULD BE MAINTAINED ON INITIAL AGENT UNLESS THERE ARE INDICATIONS FOR WITHDRAWING, ADDING TO, RETITRATING DOSE,7 OR7 SWITCHING THERAPY

TREATMENT FAILURE OR LOSS OF CLINICAL BENEFIT

YES

NO

MAINTAIN PATIENT ON THERAPY

IF PATIENT HAS BEEN TITRATED TO A MAXIMALLY TOLERATED AND EFFECTIVE THERAPEUTIC DOSE BUT THEN BECOMES INTOLERANT TO OR FAILS TO SHOW CLINICAL BENEFIT--OR DEMONSTRATES LOSS OF BENEFIT--FROM INITIAL AGENT, THEN PATIENT SHOULD BE SWITCHED TO ANOTHER CHOLINESTERASE INHIBITOR AS FOLLOWS

Recommended Switching Sequence for Patients Failing Therapy With or Intolerant To A Specific Cholinesterase Inhibitor

· If patient has been on rivastigmine, it is recommended that he/she be switched to galantamine (dual mode of action postulated), or alternatively, donepezil. · If patient has been on donepezil, it is recommended that he/she be switched to rivastigmine (dual mode of action postulated), or alternatively, galantamine (dual mode of action postulated). · If patient has been on galantamine, it is recommended that he/she be switched to rivastigmine (dual mode of action postulated), or alternatively, donepezil.

Switching agents also should be strongly considered if patient achieves clinical benefits with initial cholinesterase inhibitor, but requires withdrawal of the medication due to intolerable, drug-related adverse effects (AEs). Occasionally, patients who develop intolerable side effects at the maximum target dose of a specific agent can be down-titrated to the minimally effective therapeutic dose of that agent, and still maintain acceptable clinical benefits. Note: Intolerance to one cholinesterase inhibitor does not preclude tolerance to another agent. Similarly, failure to respond to one cholinesterase inhibitor does not preclude a favorable response to another cholinesterase inhibitor. Rivastigmine demonstrated significant response rates in patients who either failed or showed diminishing clinical benefits or intolerable side effects on donepezil monotherapy. Clinical judgment will determine optimal approaches-- switching, adding, discontinuation, down-titration, etc.--for the individual patient.

Continued on next page

PRIMARY CARE CONSENSUS REPORTS

5

Mild-to-Moderate Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

PATIENTS WHO DEMONSTRATE CLINICAL BENEFITS SHOULD BE MAINTAINED ON THE EFFECTIVE AGENT

IF PATIENT HAS BEEN SWITCHED AND TITRATED TO AN EFFECTIVE THERAPEUTIC DOSE OF A SECOND CHOLINESTERASE INHIBITOR BUT BECOMES INTOLERANT TO OR FAILS TO SHOW CLINICAL BENEFIT ON THIS AGENT--OR DEMONSTRATES LOSS OF BENEFIT--THEN PATIENT CAN BE CONSIDERED FOR SWITCHING TO ANOTHER CHOLINESTERASE INHIBITOR

Please see section above: Switching Sequence for Patients Failing or Intolerant of Cholinesterase Inhibitor Therapy. Patients failing or intolerant of two first-line cholinesterase inhibitors may be treated with the third available agent, based on clinical response, and physician judgment.

PATIENTS DEMONSTRATING CLINICAL BENEFITS SHOULD BE MAINTAINED ON THE EFFECTIVE AGENT

IS THERE FAILURE OR LOSS OF CLINICAL BENEFIT?

YES NO

MAINTAIN PATIENT ON THERAPY

IF PATIENT, DUE TO INTOLERANCE OR POOR CLINICAL RESPONSE, HAS FAILED CHOLINESTERASE INHIBITOR THERAPY--DESPITE SWITCHING AND TITRATION STRATEGIES--ADDITION OR SUBSTITUTION OF A NMDA INHIBITOR8,9 (MEMANTINE) MAY BE CONSIDERED, ESPECIALLY IN PATIENTS WITH MODERATE AD

Note: There is no current published evidence-based support for memantine in mild AD. However, poster presentations have shown memantine is effective in mild AD.

Continued on next page

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PRIMARY CARE CONSENSUS REPORTS

Mild-to-Moderate Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

INADEQUATE OR POOR CLINICAL RESPONSE TO CHOLINESTERASE INHIBITOR MONOTHERAPY

INADEQUATE OR POOR CLINICAL RESPONSE TO ALL CHOLINESTERASE INHIBITORS

ADDITION OF NMDA INHIBITOR MAY BE CONSIDERED IN MODERATE AD

SUBSTITUTION WITH NMDA INHIBITOR MAY BE CONSIDERED IN MODERATE AD

Memantine: The recommended starting dose for memantine is 5 mg once daily with or without food. The recommended target dose is 20 mg/d. The dose should be titrated in 5 mg increments to 10 mg/d (5 mg twice daily), 15 mg/d (5 mg and 10 mg as separate doses), and 20 mg/d (10 mg/d twice daily).8 The minimum recommended interval between doses is one week.

TREATMENT FAILURE OR LACK OF CLINICAL EFFECTS DESPITE APPROPRIATELY TITRATED THERAPY

WITHDRAWAL OF CHOLINESTERASE INHIBITOR AND/OR NMDA INHIBITOR THERAPY10,11,12 MAY BE APPROPRIATE OR NECESSARY IF:

· Patient has failed attempts at monotherapy with at least two or more cholinesterase inhibitors, a NMDA inhibitor, or combination therapy with agents from the two aforementioned classes · Patient demonstrates loss of clinical effect, manifested by accelerated and progressive cognitive deterioration · Patient demonstrates intolerance (due to unmanageable drug-related side effects) requiring drug cessation · Patient deteriorates to the point of having no meaningful social interactions or quality of life benefit as determined by caregivers and health care providers · Other criteria and recommendations for discontinuing drug therapy have been proposed by national associations, working groups, advisory councils, and consensus panels, and may be employed to assess need for drug cessation13

PRIMARY CARE CONSENSUS REPORTS

7

Mild-to-Moderate Alzheimer's Disease--ADMC Treatment Guidelines

Comments and Additional Information:

1. Side effects of the cholinesterase inhibitors may include nausea, vomiting, weight loss, and diarrhea, which tend to subside after the titration period. The patient and family should be provided information about side effects but should be reassured that side effects usually resolve with continued therapy, appropriate (i.e., gradual) up-titration techniques, and when appropriate, consumption of medications after a full meal. 2. Some clinicians may attempt to treat drug-related side effects with other medications. It should be noted that anticholinergic antiemetics may precipitate delirium, particularly in frail patients; therefore, they are discouraged or should be used with caution. Over-the-counter phosphorated carbohydrate solution (e.g., Emetrol) may be an appropriate choice for patients with nausea and vomiting, while over-the-counter pectin (e.g., Kaopectate) may provide symptomatic relief for diarrhea. 3. Clinical benefits with cholinesterase inhibitors may be limited to decreasing the pace of cognitive decline, improving cognition, delaying deterioration in global functioning, delaying institutionalization, and/or improving activities of daily living (ADLs). Such benefits can have a positive and salutary effect on overall patient care and disease progression. However, the caregivers of patients with Alzheimer's disease may see little effect from these agents despite the aforementioned benefits documented in clinical trials. 4. Beneficial effects with rivastigmine therapy on the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild-to-moderate Alzheimer's disease (AD). Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer's trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations and consuming the medication after a full meal. 5. Most drug-related adverse effects with rivastigmine occurred chiefly during the titration phase of the protocols (34%) vs. a much lower rate of occurrence during the maintenance phases (13%). Adverse gastrointestinal effects, if they occurred, generally were within the first 1 or 2 doses after up-titration and usually were transient and self-limited. Adverse cholinergic symptoms are minimized by titrating dosages upward monthly rather than every 2 weeks as was originally recommended at the drug's approval by the FDA. No drug-drug interactions have been demonstrated. Analyses of previous trials have suggested that the magnitude of clinical benefit may be greater in patients with moderate stage or rapidly progressive disease. Benefit also is suggested for patients with cerebrovascular risk factors and Lewy body disease. 6. Significant stabilization and/or improvement in behavioral symptoms have been observed in nursing home patients receiving cholinesterase inhibitors. These benefits are notable as the natural history of Alzheimer's disease is for behavioral symptoms to increase as the illness progresses. Significant reductions in the use of psychotropic medications also have been documented with these improvements in behavior. Some experts recommend addition of vitamin E early in the natural history of the disease, although studies are not conclusive and there is controversy about the optimal dose. Generally, vitamin E is considered to be safe and nontoxic, although patients may complain of nausea, intestinal cramping, fatigue, or blurred vision. 7. For patients who have discontinued a cholinesterase inhibitor for longer than 1 week, it is recommended that they be retitrated up to their therapeutic dose as a precaution, since few data are available concerning possible adverse effects with immediate resumption of high-dose therapy. 8. Adverse events observed with memantine generally are mild to moderate, and include agitation, urinary incontinence, insomnia, and constipation. A slightly higher frequency of hallucinations (5% vs 2% on placebo) was observed in a patient safety database comprising 3000 patients. Confusion may be observed during the titration phase of the medication and is usually transient. The primary reason for discontinuation is agitation. Memantine is not FDA-approved for treatment of mild Alzheimer's disease. 9. The effects and tolerability of combination therapy with a cholinesterase inhibitor (donepezil) plus memantine have been evaluated in a randomized, double-blind, placebo-controlled, parallel group study. The results suggest beneficial effects from combining memantine (20 mg/d) with a stable dose of donepezil (5 or 10 mg/d) in patients with moderate-to-severe Alzheimer's disease (mean baseline mini-mental status examination [MMSE], 10) were consistently observed on measures of cognition, daily functioning, clinical global status, and behavior. 10. In end stage disease, clinical judgment should guide the decision to continue or terminate use of these medications. Reasons for stopping a medication might include the onset of a serious illness or the physician's assessment that the patient's cognition is too impaired or life expectancy too short to benefit from a costly drug. In cases where the mini-mental status examination (MMSE) has been used to guide therapy, patients should be monitored at 6month intervals, and cholinesterase inhibitors should be continued until the MMSE is less than 10 and there is dependency in all basic activities of daily living (ADLs). Follow-up studies on patients who have discontinued agents from this drug class suggest there are no withdrawal effects. 11. In patients who initially have responded to therapy, slight deteriorations (e.g., 1 or 2 points on the mini-mental status examination [MMSE]) may not be significant, or result in an intercurrent illness (e.g., infection). Changes in MMSE should be correlated with changes in ADLs and/or functional abilities--and it may be prudent to repeat the MMSE in 4 weeks--before making definitive assessments about lack of clinical benefits or drug cessation. 12. The durability of beneficial clinical effects with cholinesterase inhibitors has not been fully clarified. However, there are open-label data available suggesting that patients taking cholinesterase inhibitors may progress less rapidly than would be suggested by the natural rate of disease deterioration observed in epidemiological studies. During these open-label trials, it appears that patients treated from the start did better than those who were originally on placebo in the preceding double-blind phase, suggesting a possible effect of this cholinesterase inhibitor on disease progression. 13. Criteria proposed by various organizations for discontinuing drug therapy include the following: (a) discontinuation after 6 months if there is no improvement, stabilization, or reduction in the rate of cognitive decline, or when mini-mental status examination (MMSE) score is less than 10 points; (b) physician's judgment; (c) discontinuation if after 6-12 months of treatment deterioration occurs at the pretreatment rate; and (d) no treatment recommendations for discontinuation. Evidence-based medicine does not support discontinuing therapy when MMSE < 10 as nursing home studies and subgroup analyses show substantial benefit for such patients.

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PRIMARY CARE CONSENSUS REPORTS

Figure 3: Moderate-to-Severe Alzheimer's Disease: EvidenceBased and Outcome-Effective Pharmacologic Management

Recommendations, Strategies, and Treatment Guidelines Endorsed by the ADMC (Alzheimer's Disease Management Council) Clinical Consensus Panel

Diagnosis of Moderate-to-Severe Alzheimer's Disease Confirmed or Strongly Suspected

Medical Conditions or Drug-Related Toxicity That May Trigger Dementia Have Been Excluded

ADMC

Alzheimer's Disease Management Council Consensus Panel and Scientific Roundtable

Patient Manifests Clinical Criteria That Support Initiation of Drug Therapy

There are objective, documented progressive, and clearly worsening deficits in new learning and memory in an elderly patient, accompanied by signs of functional impairment

FIRST-LINE THERAPY INITIATE THERAPY WITH CHOLINESTERASE INHIBITOR1,2,3

Rivastigmine4,5

OR

Donepezil

OR

Galantamine

STARTING DOSES AND TITRATION STRATEGIES FOR RECOMMENDED, FIRST-LINE THERAPY CHOLINESTERASE INHIBITORS6,7

Rivastigmine: Initiate oral therapy at 1.5 mg twice daily, taken with food, after a full meal; at 4-week intervals increase each dose by 1.5 mg, up to a maximally effective, tolerated therapeutic dose. The maximum dose is 6 mg twice daily. The minimum therapeutic dose for rivastigmine is 3 mg twice daily. Donepezil: Initiate oral therapy at 5 mg once daily, at bedtime; after 6 weeks, increase dose by 5 mg to 10 mg once daily. The minimum therapeutic dose for donepezil is 5 mg once daily. Donepezil may be taken with or without food.

Galantamine: Initiate oral therapy at 4 mg twice daily, with food. At 4-week intervals, increase each dose by 4 mg up to a maximally effective, tolerated therapeutic dose. The maximum dose is 12 mg twice daily; the minimum therapeutic dose for galantamine is 8 mg twice daily. Continued on next page

PRIMARY CARE CONSENSUS REPORTS

9

Moderate-to-Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

OR

FIRST-LINE THERAPY (ALTERNATIVE) NMDA INHIBITOR8 Memantine

Memantine: The recommended starting dose for memantine is 5 mg once daily with or without food. The recommended target dose is 20 mg/d. The dose should be titrated in 5 mg increments to 10 mg/d (5 mg twice daily), 15 mg/d (5 mg and 10 mg as separate doses), and 20 mg/d (10 mg/d twice daily). The minimum recommended interval between dose increases is one week.

IF PATIENT HAS BEEN SUCCESSFULLY TITRATED TO-- AND IS TOLERATING--A THERAPEUTICALLY EFFECTIVE DOSE OF A CHOLINESTERASE INHIBITOR (OR, ALTERNATIVELY, A NMDA INHIBITOR), WHILE DEMONSTRATING CLINICAL BENEFITS WITH THIS THERAPY, THEN THE PATIENT SHOULD BE MAINTAINED ON INITIAL AGENT(S) UNLESS THERE ARE INDICATIONS FOR WITHDRAWING, ADDING TO, RETITRATING DOSE, OR SWITCHING THERAPY

OPTIMIZING CLINICAL BENEFITS OF PHARMACOLOGIC THERAPY IN MODERATE-TO-SEVERE AD

IN PATIENTS WITH MODERATE-TO-SEVERE AD, EVEN IN THOSE RESPONDING WELL AND TOLERATING A SINGLE, FIRST-LINE AGENT (i.e., CHOLINESTERASE INHIBITOR), CLINICIANS MAY CONSIDER COMBINATION9 THERAPY WITH A CHOLINESTERASE INHIBITOR PLUS A NMDA INHIBITOR. SUCH COMBINATION THERAPY HAS BEEN SHOWN TO BE SUPERIOR TO CHOLINESTERASE INHIBITOR MONOTHERAPY IN PATIENTS WITH MODERATETO-SEVERE AD.9

Note: Cholinesterase inhibitors currently are not FDA-approved as monotherapy for patients with severe AD.

TREATMENT FAILURE OR LOSS OF CLINICAL BENEFIT?

YES

NO

MAINTAIN PATIENT ON THERAPY

Continued on next page

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PRIMARY CARE CONSENSUS REPORTS

Moderate-to-Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

IF A PATIENT WITH MODERATE AD HAS BEEN TITRATED TO A MAXIMALLY TOLERATED AND EFFECTIVE THERAPEUTIC DOSE OF A CHOLINESTERASE INHIBITOR, BUT THEN BECOMES INTOLERANT TO, OR FAILS TO SHOW CLINICAL BENEFIT--OR DEMONSTRATES LOSS OF BENEFIT--WITH A SPECIFIC AGENT, THEN PATIENT SHOULD BE CONSIDERED FOR SWITCHING TO ANOTHER CHOLINESTERASE INHIBITOR AS FOLLOWS

Switching Sequence for Patients Failing Therapy With or Intolerant to A Specific Cholinesterase Inhibitor

· If patient has been on rivastigmine, it is recommended that he/she be switched to galantamine (dual mode of action postulated), or alternatively, donepezil. · If patient has been on donepezil, it is recommended that he/she be switched to rivastigmine (dual mode of action postulated), or alternatively, galantamine. · If patient has been on galantamine, it is recommended that he/she be switched to rivastigmine (dual mode of action postulated), or alternatively, donepezil.

Switching agents also should be strongly considered if patient achieves clinical benefits with initial cholinesterase inhibitor, but requires withdrawal of the medication due to intolerable, drug-related adverse effects (AEs). Occasionally, patients who develop intolerable side effects at the maximum target dose of a specific agent can be down-titrated to the minimally effective therapeutic dose of that agent, and still maintain acceptable clinical benefits. Note: Intolerance to one cholinesterase inhibitor does not preclude tolerance to another agent. Similarly, failure to respond to one cholinesterase inhibitor does not preclude a favorable response to another cholinesterase inhibitor. Rivastigmine demonstrated significant response rates in patients who failed or showed diminishing benefits or intolerable side effects on donepezil monotherapy. Clinical judgment will determine optimal approaches--switching, adding, discontinuation, down-titration, etc.--for the individual patient.

PATIENTS DEMONSTRATING CLINICAL BENEFITS SHOULD BE MAINTAINED ON THE EFFECTIVE AGENT(S)

TREATMENT FAILURE OR LOSS OF CLINICAL BENEFIT?

YES

NO

MAINTAIN PATIENT ON THERAPY

Continued on next page

PRIMARY CARE CONSENSUS REPORTS

11

Moderate-to-Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

ADD OR SWITCH TO NMDA INHIBITOR (OR CHOLINESTERASE INHIBITOR) IF NOT ALREADY ON COMBINATION THERAPY9

OPTIMIZING TREATMENT BENEFITS IN PATIENTS WITH MODERATE-TO-SEVERE AD REQUIRES ESTABLISHMENT OF A TOLERABLE MONOTHERAPEUTIC OR COMBINATION REGIMEN BEST SUITED FOR THE INDIVIDUAL PATIENT BASED ON CLINICAL JUDGMENT. AS A RULE, COMBINATION THERAPY (CHOLINESTERASE PLUS NMDA INHIBITOR) IS RECOMMENDED IN PATIENTS WITH MORE SEVERE DISEASE.

Clinical judgment and ongoing patient assessment will determine optimal drug selection and modification approaches--switching, adding, discontinuation, or down- or up-titration--for the individual patient. Methodical attention to drug titration and observing for drug-related adverse effects--while monitoring cognitive, behavioral, and functional effects of pharmacological therapy--will maximize clinical success.

TREATMENT FAILURE OR LACK OF CLINICAL BENEFITS DESPITE MAXIMALLY TOLERATED COMBINATION THERAPY?

WITHDRAWAL OF CHOLINESTERASE INHIBITOR AND/OR NMDA INHIBITOR THERAPY10,11,12 MAY BE APPROPRIATE OR NECESSARY IF:

· Patient has failed attempts at monotherapy with at least two or more cholinesterase inhibitors, a NMDA inhibitor, and combination therapy with agents from the two aforementioned classes · Patient demonstrates loss of clinical effect, manifested by accelerated and progressive cognitive deterioration · Patient demonstrates intolerance (due to unmanageable drug-related side effects) requiring drug cessation · Patient deteriorates to the point of having no meaningful social interactions or quality of life benefit as determined by caregivers and health care providers · Other criteria and recommendations for discontinuing drug therapy have been proposed by national associations, working groups, advisory councils, and consensus panels, and may be employed to assess need for drug cessation13

12

PRIMARY CARE CONSENSUS REPORTS

Moderate-to-Severe Alzheimer's Disease--ADMC Treatment Guidelines

Comments and Additional Information

1. Side effects of the cholinesterase inhibitors may include nausea, vomiting, weight loss, and diarrhea, which tend to subside after the titration period. The patient and family should be provided information about side effects but should be reassured that side effects usually resolve with continued therapy, appropriate (i.e., gradual) uptitration techniques, and when appropriate, consumption of medications after a full meal. 2. Some clinicians may attempt to treat drug-related side effects with other medications. It should be noted that anticholinergic antiemetics may precipitate delirium, particularly in frail patients; therefore, they are discouraged or should be used with caution. Over-the-counter phosphorated carbohydrate solution (e.g., Emetrol) may be an appropriate choice for patients with nausea and vomiting, while over-the-counter pectin (e.g., Kaopectate) may provide symptomatic relief for diarrhea. 3. Clinical benefits with cholinesterase inhibitors may be limited to decreasing the pace of cognitive decline, improving cognition, delaying deterioration in global functioning, delaying institutionalization, and/or improving activities of daily living (ADLs). Such benefits can have a positive and salutary effect on overall patient care and disease progression. However, the caregivers of patients with Alzheimer's disease may see little effect from these agents despite the aforementioned benefits documented in clinical trials. 4. Beneficial effects with rivastigmine therapy on the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild-to-moderate Alzheimer's disease. Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer's trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations and consuming the medication after a full meal. 5. Most drug-related adverse effects with rivastigmine occurred chiefly during the titration phase of the protocols (34%) vs. a much lower rate of occurrence during the maintenance phases (13%). Adverse gastrointestinal effects, if they occurred, generally were within the first 1 or 2 doses after up-titration and usually were transient and self-limited. Adverse cholinergic symptoms are minimized by titrating dosages upward monthly rather than every 2 weeks as was originally recommended at the drug's approval by the FDA. No drug-drug interactions have been demonstrated. Analyses of previous trials have suggested that the magnitude of clinical benefit may be greater in patients with moderate stage or rapidly progressive disease. Benefit also is suggested for patients with cerebrovascular risk factors and Lewy body disease. 6. Significant stabilization and/or improvement in behavioral symptoms have been observed in nursing home patients receiving cholinesterase inhibitors. These benefits are notable as the natural history of Alzheimer's disease is for behavioral symptoms to increase as the illness progresses. Significant reductions in the use of psychotropic medications also have been documented with these improvements in behavior. Some experts recommend addition of vitamin E early in the natural history of the disease, although studies are not conclusive and there is controversy about the optimal dose. Generally, vitamin E is considered to be safe and nontoxic, although patients may complain of nausea, intestinal cramping, fatigue, or blurred vision. 7. For patients who have discontinued a cholinesterase inhibitor for longer than 1 week, it is recommended that they be retitrated up to their therapeutic dose as a precaution, since few data are available concerning possible adverse effects with immediate resumption of high-dose therapy. 8. Adverse events observed with memantine generally are mild to moderate, and include agitation, urinary incontinence, insomnia, and constipation. A slightly higher frequency of hallucinations (5% vs 2% on placebo) was observed in a patient safety database comprising 3000 patients. Confusion may be observed during the titration phase of the medication and is usually transient. The primary reason for discontinuation is agitation. Memantine is not FDA-approved for treatment of mild Alzheimer's disease. 9. The effects and tolerability of combination therapy with a cholinesterase inhibitor (donepezil) plus memantine have been evaluated in a randomized, double-blind, placebo-controlled, parallel group study. The results suggest beneficial effects from combining memantine (20 mg/d) with a stable dose of donepezil (5 or 10 mg/d) in patients with moderate-to-severe Alzheimer's disease (mean baseline mini-mental status examination [MMSE], 10) were consistently observed on measures of cognition, daily functioning, clinical global status, and behavior. 10. In end stage disease, clinical judgment should guide the decision to continue or terminate use of these medications. Reasons for stopping a medication might include the onset of a serious illness or the physician's assessment that the patient's cognition is too impaired or life expectancy too short to benefit from a costly drug. In cases where the mini-mental status examination (MMSE) has been used to guide therapy, patients should be monitored at 6-month intervals, and cholinesterase inhibitors should be continued until the MMSE is less than 10 and there is dependency in all basic activities of daily living (ADLs). Follow-up studies on patients who have discontinued agents from this drug class suggest there are no withdrawal effects. 11. In patients who initially have responded to therapy, slight deteriorations (e.g., 1-2 points on the mini-mental status examination [MMSE]) may not be significant or result in intercurrent illness (e.g., infection). Changes in MMSE should be correlated with changes in ADLs and/or functional abilities--and it may be prudent to repeat the MMSE in 4 weeks--before making definitive assessments about lack of clinical benefits or drug cessation. 12. The durability of beneficial clinical effects with cholinesterase inhibitors has not been fully clarified. However, there are open-label data available suggesting that patients taking cholinesterase inhibitors may progress less rapidly than would be suggested by the natural rate of disease deterioration observed in epidemiological studies. During these open-label trials, it appears that patients treated from the start did better than those who were originally on placebo in the preceding double-blind phase, suggesting a possible effect of this cholinesterase inhibitor on disease progression. 13. Criteria proposed by various organizations for discontinuing drug therapy include the following: (a) discontinuation after 6 months if there is no improvement, stabilization, or reduction in the rate of cognitive decline, or when mini-mental status examination (MMSE) score is less than 10 points; (b) physician's judgment; (c) discontinuation if after 6-12 months of treatment deterioration occurs at the pretreatment rate; and (d) no treatment recommendations for discontinuation. Evidence-based medicine does not support discontinuing therapy with MMSE < 10 as nursing home studies and subgroup analyses show substantial benefit for such patients.

PRIMARY CARE CONSENSUS REPORTS

13

Figure 4: Severe Alzheimer's Disease--De novo Patient Not Previously Treated with Drug Therapy: Evidence-Based and Outcome-Effective Pharmacologic Management

Recommendations, Strategies, and Treatment Guidelines Endorsed by the ADMC (Alzheimer's Disease Management Council) Clinical Consensus Panel

Diagnosis of Severe Alzheimer's Disease Confirmed or Strongly Suspected (De novo Patient Who Has Not Been Previously Treated for AD)

Medical Conditions or Drug-Related Toxicity That May Trigger Dementia Have Been Excluded

ADMC

Alzheimer's Disease Management Council Consensus Panel and Scientific Roundtable

Previously Untreated Patient With Severe AD Manifests Clinical Criteria That Support Initiation of Drug Therapy

There are objective, documented progressive, and clearly worsening deficits in new learning and memory in an elderly patient, accompanied by signs of functional impairment

FIRST-LINE THERAPY NMDA INHIBITOR

Memantine1

Memantine: The recommended starting dose for memantine is 5 mg once daily with or without food. The recommended target dose is 20 mg/d. The dose should be titrated in 5 mg increments to 10 mg/d (5 mg twice daily), 15 mg/d (5 mg and 10 mg as separate doses), and 20 mg/d (10 mg/d twice daily). The minimum recommended interval between dose increases is one week.

ARE ACCEPTABLE CLINICAL BENEFITS--STABILIZATION AND/OR IMPROVEMENT IN COGNITIVE OR BEHAVIORAL IMPAIRMENTS--OBSERVED IN THE PATIENT WITH SEVERE AD STARTED ON INITIAL THERAPY WITH MEMANTINE?

NO

YES

MAINTAIN PATIENT ON MEMANTINE AND MONITOR CLINICAL RESPONSE

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Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

A PATIENT WITH SEVERE AD WHO SHOWS POOR RESPONSE TO INITIAL THERAPY WITH A NMDA INHIBITOR MAY BE CONSIDERED FOR COMBINATION THERAPY--i.e., ADDITION OF A CHOLINESTERASE INHIBITOR .

NOTE: CHOLINESTERASE INHIBITORS ARE NOT FDA-APPROVED FOR MONOTHERAPY OR AS COMBINATION THERAPY IN PATIENTS WITH SEVERE AD. HOWEVER, IN PATIENTS WITH SEVERE AD WHO: (A) FAIL TO TOLERATE UP-TITRATION TO A THERAPEUTIC DOSE WITH MEMANTINE AND MUST BE DISCONTINUED FROM THIS AGENT; OR (B) ARE TOLERATING THIS FIRSTLINE THERAPY (i.e., MEMANTINE) FOR AD, BUT MAY BE RESPONSIVE TO ADDITIONAL THERAPY, COMBINATION THERAPY WITH A CHOLINESTERASE INHIBITOR PLUS A NMDA INHIBITOR, MAY BE CONSIDERED. CLINICAL JUDGMENT--BASED ON TOLERABILITY, PATIENT RESPONSE, SIDE EFFECTS, AND COST--WILL DETERMINE THE RISK/BENEFIT RATIO FOR USING CHOLINESTERASE INHIBITORS IN COMBINATION WITH A NMDA INHIBITOR IN SEVERE AD.

IS ADDITION OF CHOLINESTERASE2,3,4 INHIBITOR TO MEMANTINE BEING CONSIDERED? CONTINUE MEMANTINE THERAPY BASED ON CLINICAL RESPONSE

YES

NO

STARTING DOSES AND TITRATION STRATEGIES FOR CHOLINESTERASE INHIBITORS (RIVASTIGMINE,5,6 DONEPEZIL, AND GALANTAMINE) ARE AS FOLLOWS:7,8

Rivastigmine: Initiate oral therapy at 1.5 mg twice daily, taken with food, after a full meal; at 4-week intervals, increase each dose by 1.5 mg, up to a maximally effective, tolerated therapeutic dose. The maximum dose is 6 mg twice daily. The minimum therapeutic dose for rivastigmine is 3 mg twice daily. Donepezil: Initiate oral therapy at 5 mg once daily, at bedtime; after 6 weeks, increase dose by 5 mg to 10 mg once daily. The minimum therapeutic dose for donepezil is 5 mg once daily. Donepezil may be taken with or without food.

Galantamine: Initiate oral therapy at 4 mg twice daily, with food. At 4-week intervals, increase each dose by 4 mg up to a maximally effective, tolerated therapeutic dose. The maximum dose is 12 mg twice daily; the minimum therapeutic dose for galantamine is 8 mg twice daily.

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Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

IF A PATIENT WITH SEVERE AD HAS BEEN SUCCESSFULLY TITRATED TO--AND IS TOLERATING--A THERAPEUTICALLY EFFECTIVE DOSE OF A NMDA INHIBITOR (OR COMBINATION THERAPY9), AND DEMONSTRATES ACCEPTABLE CLINICAL BENEFITS ON THIS TREATMENT, THEN HE/SHE SHOULD BE MAINTAINED ON THIS REGIMEN UNLESS THERE ARE INDICATIONS FOR WITHDRAWING, ADDING TO, RETITRATING DOSE, SWITCHING AGENTS, OR INSTITUTING THERAPY AIMED AT MANAGING BEHAVIORAL MANIFESTATIONS OF AD

DOES PATIENT MANIFEST BEHAVIORAL DISTURBANCES OF SEVERE AD?

YES

NO

MAINTAIN PATIENT ON EXISTING REGIMEN AND MONITOR RESPONSE

TREATMENT TRIGGERS FOR MANAGING BEHAVIORAL DISTURBANCES IN SEVERE AD INCLUDE BUT ARE NOT LIMITED TO:

· Aggressive behavior · Psychosis · Hallucinations · Paranoia · Delusions · Delirium (investigate reversible causes) · Other Triggers

ARE BEHAVIORAL TREATMENT TRIGGERS PRESENT?

YES

NO

MAINTAIN PATIENT ON EXISTING REGIMEN AND MONITOR CLINICAL RESPONSE

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Severe Alzheimer's Disease--ADMC Treatment Guidelines

Continued from previous page

AGENTS THAT MAY BE CONSIDERED OR REQUIRED FOR MANAGEMENT OF BEHAVIORAL DISTURBANCES IN SEVERE AD

Atypical Antipsychotics o Risperidone o Olanzapine o Quetiapine Anticonvulsants o Valproate/divalproex o Carbamazepine o Trileptal Benzodiazepines o Clonazepam o Others Antidepressants o SSRI

MAINTAINING OPTIMAL CLINICAL BENEFITS IN THOSE WITH SEVERE AD REQUIRES ESTABLISHMENT OF A REGIMEN BEST SUITED FOR THE INDIVIDUAL PATIENT BASED ON CLINICAL JUDGMENT. COMBINATION THERAPY MAY BE REQUIRED AND BENEFICIAL IN PATIENTS WITH MORE SEVERE DISEASE. PHARMACOLOGICAL THERAPY AIMED AT BEHAVIORAL DISTURBANCES AND/OR DEPRESSION SHOULD BE INITIATED AS REQUIRED

Clinical judgment and ongoing clinical assessment will determine optimal drug selection and modification approaches--switching, adding, discontinuation, or down- or up-titration--for the individual patient. Methodical attention to drug titration and observing for drug-related adverse effects--while monitoring cognitive, behavioral, and functional effects of pharmacological therapy--will maximize clinical success. Agents for cognition and behaviors may be needed.

TREATMENT FAILURE OR LACK OF CLINICAL BENEFITS DESPITE MAXIMIZATION OF MEDICAL THERAPY IS OBSERVED

WITHDRAWAL10,11,12 OF CHOLINESTERASE INHIBITOR AND/OR NMDA INHIBITOR THERAPY MAY BE APPROPRIATE OR NECESSARY IF:

· Patient has failed attempts at monotherapy with at least two or more cholinesterase inhibitors, a NMDA inhibitor, and combination therapy with agents from the two aforementioned classes · Patient demonstrates loss of clinical effect, manifested by accelerated and progressive cognitive deterioration · Patient demonstrates intolerance (due to unmanageable drug-related side effects) requiring drug cessation · Patient deteriorates to the point of having no meaningful social interactions or quality of life benefit as determined by caregivers and health care providers · Other criteria and recommendations for discontinuing drug therapy have been proposed by national associations, working groups, advisory councils, and consensus panels, and may be employed to assess need for drug cessation13

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Severe Alzheimer's Disease--ADMC Treatment Guidelines

Comments and Additional Information

1. Adverse events observed with memantine generally are mild to moderate, and include agitation, urinary incontinence, insomnia, and constipation. A slightly higher frequency of hallucinations (5% vs 2% on placebo) was observed in a patient safety database comprising 3000 patients. Confusion may be observed during the titration phase of the medication and is usually transient. The primary reason for discontinuation is agitation. Memantine is not FDA-approved for treatment of mild Alzheimer's disease. 2. Side effects of cholinesterase inhibitors may include nausea, vomiting, weight loss, and diarrhea, which tend to subside after titration period. Patient and family should be provided information about side effects and reassured that side effects usually resolve with continued therapy, appropriate (i.e., gradual) up-titration techniques, and when appropriate, consumption of medications after a full meal. 3. Some clinicians may attempt to treat drug-related side effects with other medications. It should be noted that anticholinergic antiemetics may precipitate delirium, particularly in frail patients; therefore, they are discouraged or should be used with caution. Over-the-counter phosphorated carbohydrate solution (e.g., Emetrol) may be an appropriate choice for patients with nausea and vomiting, while over-the-counter pectin (e.g., Kaopectate) may provide symptomatic relief for diarrhea. 4. Clinical benefits with cholinesterase inhibitors may be limited to decreasing the pace of cognitive decline, improving cognition, delaying deterioration in global functioning, delaying institutionalization, and/or improving activities of daily living (ADLs). Such benefits can have a positive and salutary effect on overall patient care and disease progression. However, the caregivers of patients with Alzheimer's disease may see little effect from these agents despite the aforementioned benefits documented in clinical trials. 5. Beneficial effects with rivastigmine therapy on the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild-to-moderate Alzheimer's disease. Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations and consuming the medication after a full meal. 6. Most drug-related adverse effects with rivastigmine occurred chiefly during the titration phase of the protocols (34%) vs. a much lower rate of occurrence during the maintenance phases (13%). Adverse gastrointestinal effects, if they occurred, generally were within the first 1 or 2 doses after up-titration and were usually transient and self-limited. Adverse cholinergic symptoms are minimized by titrating dosages upward monthly rather than every 2 weeks as was originally recommended at the drug's approval by the FDA. No drug-drug interactions have been demonstrated. Analyses of previous trials have suggested that the magnitude of clinical benefit may be greater in patients with moderate stage or rapidly progressive disease. Benefit also is suggested for patients with cerebrovascular risk factors and Lewy body disease. 7. Significant stabilization and/or improvement in behavioral symptoms have been observed in nursing home patients receiving cholinesterase inhibitors. These benefits are notable as the natural history of Alzheimer's disease is for behavioral symptoms to increase as the illness progresses. Significant reductions in the use of psychotropic medications also have been documented with these improvements in behavior. Some experts recommend addition of vitamin E early in the natural history of the disease, although studies are not conclusive and there is controversy about the optimal dose. Generally, vitamin E is considered to be safe and nontoxic, although patients may complain of nausea, intestinal cramping, fatigue, or blurred vision. 8. For patients who have discontinued a cholinesterase inhibitor for longer than 1 week, it is recommended that they be retitrated up to their therapeutic dose as a precaution, since few data are available concerning possible adverse effects with immediate resumption of high-dose therapy. 9. The effects and tolerability of combination therapy with a cholinesterase inhibitor (donepezil) plus memantine have been evaluated in a randomized, double blind, placebo-controlled, parallel group study. The results suggest beneficial effects from combining memantine (20 mg/d) with a stable dose of donepezil (5 or 10 mg/d) in patients with moderate-to-severe Alzheimer's disease (mean baseline mini-mental status examination [MMSE], 10) were consistently observed on measures of cognition, daily functioning, clinical global status, and behavior. 10. In end stage disease, clinical judgment should guide the decision to continue or terminate use of these medications. Reasons for stopping a medication might include the onset of a serious illness or the physician's assessment that the patient's cognition is too impaired or life expectancy too short to benefit from a costly drug. In cases where the mini-mental status examination (MMSE) has been used to guide therapy, patients should be monitored at 6month intervals, and cholinesterase inhibitors should be continued until the MMSE is less than 10 and there is dependency in all basic activities of daily living (ADLs). Follow-up studies on patients who have discontinued agents from this drug class suggest there are no withdrawal effects. 11. In patients who initially responded to therapy, slight deteriorations (e.g., 1-2 points on the mini-mental status examination [MMSE]) may not be significant, or result in an intercurrent illness (e.g., infection). Changes in MMSE should be correlated with changes in ADLs and/or functional abilities--and it may be prudent to repeat MMSE in 4 weeks--before making definitive assessments about lack of clinical benefits or drug cessation. 12. The durability of beneficial clinical effects with cholinesterase inhibitors has not been fully clarified. However, there are open-label data available suggesting that patients taking cholinesterase inhibitors may progress less rapidly than would be suggested by the natural rate of disease deterioration observed in epidemiological studies. During these open-label trials, it appears that patients treated from the start did better than those who were originally on placebo in the preceding double-blind phase, suggesting a possible effect of this cholinesterase inhibitor on disease progression. 13. Criteria proposed by various organizations for discontinuing drug therapy include the following: (a) discontinuation after 6 months if there is no improvement, stabilization, or reduction in the rate of cognitive decline, or when mini-mental status examination (MMSE) score is less than 10 points; (b) physician's judgment; (c) discontinuation if after 6-12 months of treatment deterioration occurs at the pretreatment rate; and (d) no treatment recommendations for discontinuation. Evidence-based medicine does not support discontinuing therapy when MMSE < 10 as nursing home studies and subgroup analyses show substantial benefit for such patients.

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First-Line Agents Approved for Alzheimer's Disease: Starting Dose, Minimum and Maximum Therapeutic Dose, Cost*, and Titration Strategies1-6

CHOLINESTERASE INHIBITORS

Rivastigmine: (Exelon®)

Initiate oral therapy at 1.5 mg twice daily, taken at the end of a full meal. At 4-week intervals, increase each dose by 1.5 mg, up to a maximally effective, tolerated therapeutic dose. The maximum dose is 6 mg twice daily. The minimum therapeutic dose for rivastigmine is 3 mg twice daily. Cost: $134. Rivastigmine has been shown to be both an acetylcholinesterase inhibitor and a butyrylcholinesterase inhibitor. The minimum recommended interval between dose increases is 4 weeks. Initiate oral therapy at 5 mg once daily, at bedtime; after 6 weeks, increase dose by 5-10 mg once daily. The minimum therapeutic dose for donepezil is 5 mg once daily. Cost: $142. Initiate oral therapy at 4 mg twice daily, with food. At 4-week intervals, increase each dose by 4 mg up to a maximally effective, tolerated therapeutic dose. The maximum dose is 12 mg twice daily; the minimum therapeutic dose for galantamine is 8 mg twice daily. Cost: $130. Galantamine has been shown to be both a cholinesterase inhibitor and to have nicotinic receptor actions.

NMDA INHIBITOR

Donepezil: (Aricept®) Galantamine: (Reminyl®)

DRUG-RELATED ADVERSE EVENTS

Memantine: (Namenda®)

The recommended starting dose for memantine is 5 mg once daily with or without food. The recommended target dose is 20 mg/d. The dose should be titrated in 5 mg increments to 10 mg/d (5 mg twice daily), 15 mg/d (5 mg and 10 mg as separate doses), and 20 mg/d (10 mg/d twice daily). The minimum recommended interval between dose increases is one week. Cost: $135.

*Estimated cost to the pharmacist for one month of therapy at the target dose based on average wholesale prices in Red Book, Montvale, NJ. Cost to patient will be higher depending upon prescription filling fee and other factors.

1. 2. 3. 4. 5. 6. Aricept [package insert]. Teaneck, NJ: Eisai Inc; 2000. Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2001; and ADMC panel opinion statement. Reminyl [package insert]. Titusville, NJ: Janssen Pharmaceutical Products, LP; 2001. Namenda [package insert]. St. Louis, MO: Forest Laboratories; 2003. DeLaGarza VW. Pharmacologic treatment of Alzheimer's disease: An update. Am Fam Physician. 2003;68:1365-1372. Farlow MR. Update on rivastigmine. Neurologist. 2003;9:230-234.

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Behavioral Triggers* and Antipsychotic Medications in Patients With Alzheimer's Disease

BEHAVIORAL TRIGGERS

Aggressive behaviors Psychosis Hallucinations Paranoia Delusions Delirium

MEDICATIONS USED TO TREAT DISTURBED BEHAVIORS

Atypical Antipsychotics

Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole

Anticonvulsants

Valproate/divalproex Carbamazepine

Benzodiazepines

Clonazepam Others

* Antipsychotics should be used in patients who manifest disturbed behaviors only if medical therapy and non-pharmacologic approaches to AD have been maximized Reversible causes of delirium should be investigated and treated appropriately

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Objectives, Topic Areas, and Issues Considered or Addressed by The Alzheimer's Disease Management Council (ADMC) Consensus Panel--A Mandate to Apply Evidence and Expert-Endorsed Guidelines to Clinical Practice

GENERAL PRINCIPLES AND INITIAL APPROACH: PATIENT SELECTION AND BARRIERS

Suspecting and/or confirming diagnosis of Alzheimer's disease (AD) DSM-IV diagnostic entry criteria* Overcoming the "failure to treat" syndrome in AD Identifying early-stage treatment triggers Overcoming barriers to initiation of drug therapy Recognizing early symptoms of AD Managing patient and caregiver expectations related to clinical benefits of drug therapy Dispelling misperceptions about pharmacological therapy of AD Monitoring and assessing effects of drug therapy

DRUG-RELATED ADVERSE EVENTS PHARMACOLOGIC MANAGEMENT: EXPECTATIONS, END POINTS, AND IMPLEMENTATION

Approaches to risk- and stage-directed pharmacologic therapy Articulating benefits of cholinesterase inhibitors Identifying possible benefits of cholinesterase inhibitors with postulated dual mechanism of action Articulating benefits of NMDA inhibitor therapy Differentiating roles and indications for cholinesterase inhibitors and NMDA inhibitors Generate practical, experience-based approaches focusing on drug titration, indications for switching or adding medications, and combining drug classes Importance of gradual, methodological, and persistent approach to drug dosing, up- and down-titration, and administration Approaches to managing medication-related side effects Identifying behavioral disturbances that trigger introduction of antipsychotics, mood stabilizers, anticonvulsants, and/or benzodiazepines Emphasizing improvement, stabilization, and/or delay in progression of cognitive and/or behavioral dysfunction as valuable end point for monitoring benefits of drug therapy Patient and family counseling issues related to drug therapy Impact of drug therapy on quality of life for AD patient and caregiver Ethics of not treating patients eligible for and amenable to clinical benefits of drug therapy

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(Continued): Objectives, Topic Areas, and Issues Considered or Addressed by The Alzheimer's Disease Management Council (ADMC) Consensus Panel--A Mandate to Apply Evidence and Expert-Endorsed Guidelines to Clinical Practice

TREATMENT TRIGGERS, MONITORING, AND PATIENT RESPONSE TO THERAPY

Identifying and forging simple, utilitarian, and practical criteria--accompanied by a simple disease definition statement--for confirming the diagnosis of AD Role of hallmark ABCs (Activities of Daily Living [ADLs], Behavior, Cognition, and Cost) criteria and parameters in determining management strategies Importance of investigating changes in cognition and/or behavior to accelerate diagnostic evaluation/ confirmation and treatment of AD Explaining disconnect between national guidelines and current practice patterns in AD Institutionalization and implications for prompt initiation of pharmacologic therapy Focusing on both cognition and behavioral domains as trigger points for drug therapy Awareness that spectrum of improvement crosses domains (cognitive, behavioral, and function), and preservation may occur in one domain but not another Decline in relative worsening as treatment objective Responses to drug therapy are unpredictable; not infrequently, drug-induced benefits--most notably, a decline in relative worsening--may not be perceived by patient, caregiver, or family Approach to patients with mild cognitive impairment (MCI) Identifying AD patient subgroups likely to benefit from combination therapy with cholinesterase plus NMDA inhibitor Importance of patient monitoring every 6 months to guide drug therapy Management approach to patients with vascular dementia or Lewy body dementia

APPROACH TO LACK OF LOSS OF DRUG EFFECT GUIDELINES: APPLYING EVIDENCE AND EXPERT ANALYSIS TO PRACTICE

Developing expert-endorsed practice guidelines and treatment algorithms for mild, moderate, and severe AD Articulating practical implications of clinical trials Producing treatment algorithm that accounts for bifurcation points in the overall management of patients with AD Generating practical, evidence-based guidelines for pharmacological management of AD Articulating clinical benefits of sustained therapy Identify end points that trigger withdrawal of drug therapy Identifying value of physician-pharmacist working relationship

* DSM-IV criteria for Alzheimer's disease include slowly progressive, impaired memory and global function inferior to peak in an older individual, which represents a decline from usual, baseline functional status, in whom a medical illness has been excluded.

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Scales and Evaluation Instruments Used To Monitor Natural History of Alzheimer's Disease And Patient Response To Pharmacological Therapy1-8

MINI-MENTAL STATE EXAMINATION

Measures cognition Assesses orientation, registration, recall, language, and attention Uses a 30-point scale Requires approximately 5-10 minutes to complete Minimal training needed to administer in outpatient setting Administered by and useful for primary care practitioners and nurses On average, score decreases about 2-4 points per year in patients with Alzheimer's disease

FUNCTION ACTIVITIES QUESTIONNAIRE

APPROACH TO LACK OF LOSS OF DRUG EFFECT

Intended to quantify level of disability Scores functional capacity on a scale of 1 (normal) to 7 (severely incapacitated) Requires 5-10 minutes to complete Easy to administer by caregiver

PHYSICAL SELF-MAINTENANCE SCALE AND INSTRUMENTAL ACTIVITIES OF DAILY LIVING (ADLs)

Evaluates patient's ability to perform basic and instrumental tasks Assesses eight areas of higher functioning on a scale of 1 to 5, and six basic tasks that are fundamental to daily function Requires about 10 minutes to complete scale Very useful in clinical practice Minimal training required to administer

NEUROPSYCHIATRIC INVENTORY

Measures disturbed behaviors Assesses frequency and severity of 12 symptoms (agitation, irritability, depression, hallucinations, etc.) Measures caregiver distress Can be completed in 10-20 minutes Most useful in a research setting In practice, the inventory can be used as a global approach to assessing disturbed behaviors Based on interview of caretaker

ALZHEIMER'S DISEASE ASSESSMENT SCALE: COGNITIVE SECTION (ADAS-COG)

Measures cognition Designed to assess multiple cognitive domains using an 11-item, 70-point scale Requires 25-60 minutes to complete exam Used as core measure in clinical trials to evaluate effects of drug therapy Scores decrease by about 6-12 points per year in patients with AD Primarily a research instrument Requires training to administer and quantify

1. 2. 3. 4. 5. 6. 7. 8.

Cummings JL, Frank JC, et al. Guidelines for managing Alzheimer's disease: Part I. Assessment. Am Fam Physician. 2002;65:2263-2272. Folstein MF, Folstein SE, et al. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. Rosen WG, Mohs RC, et al. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:1356-1364. Knopman DS, Knapp MJ, et al. The Clinician Interview-Based Impression (CIBI): A clinician's global change rating scale in Alzheimer's disease. Neurology. 1994;44:2315-2321. Guy W, ed. ECDEU assessment manual for psychopharmacology, revised. Rockville, Md: U.S. Department of Health and Human Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, 1976. Cummings JL, Mega M, et al. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology. 1994;44:2308-2314. Lawton MP, Brody EM. Assessment of older people: Self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9:179186. Pfeffer RI, Kurosaki TT, et al. Measurement of functional activities in older adults in the community. J Gerontol. 1982;37:323-329.

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Medical Conditions and Drug-Related Adverse Effects to be Excluded In Patients Suspected of Alzheimer's Dementia

Depression Medication-related Substance abuse Alcoholism Infection Structural CNS conditions History of trauma Sensory impairments Nutritional deficiencies Drug-induced delirium Metabolic organic failure Aphasia Psychosis Mental retardation Anemia Other

Neuropsychiatric Changes Associated with Aging: Distinguishing Among And Identifying Changes in Cognition, Behavior, and Global Functioning That Are Consistent and Inconsistent with Growing Old

EXPECTED CHANGES OF AGING OR BENIGN SENILE FORGETFULNESS

Occasional naming or word finding difficulty Psychomotor functioning General preservation of global function and ADLs Reaction time decreased Takes longer time to learn Slower but not impaired learning Annoying but benign retrieval impairments that benefit from prompting

INCONSISTENT WITH EXPECTED CHANGES OF AGING*

Principles and Goals of Pharmacological Treatment of Alzheimer's Disease*

Symptomatic stabilization Preservation of function Slowing of inevitable decline in cognition Slowing appearance and severity of behavioral disturbances Slowing onset and rate of functional impairment Slowing emergence of declining behaviors Delaying emergence and onset of agitation, aggressive behavior, violent behaviors, and psychosis Preservation of function and activities of daily living (ADLs) Delaying institutionalization Delaying requirements for antipsychotic use Cost savings Preservation of ABCs reduces cost of comorbid conditions ______________________________________________

Impaired function Impaired new learning Impairment in activities of daily living (ADLs) Apathy and agitation Behavioral disturbances Detachment and passivity Social withdrawal Significant change in normal patterns Withdrawal from social patterns Slowly progressive decline from usual/baseline functioning

* Some minor disturbances in this list may be consistent with aging, especially in response to situational events Consider fronto-temporal dementia, which occurs in younger individuals (< 60 years of age) and is characterized by prominent disordered social conduct in the setting of personality change, without memory change

* Patients will vary in the degree of response in each domain

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Clinical Benefits That Have Been Claimed or Documented for Cholinesterase Inhibitors in Alzheimer's Disease1-17

Improvement in or delay in decline of cognition 24- to 26-week trials show statistically significant benefits in ADAS-Cog and MMSE In pooled, aggregate data, about 30-60% of treated patients with mild-to-moderate AD had a 4-point ADAS-Cog improvement compared to those treated with placebo In some studies, patients with significant comorbid conditions were excluded Cognitive benefits sustained over 3-5 years Improvement in global impressions In 24- to 26-week trials, improvement was seen in about 20-40% of patients Improvement in functional ability Prevent or slow decline in ADL over treatment periods of 1-2 years Delays in nursing home placement Pharmacoeconomic benefits demonstrated Improvement in disturbed behaviors May reduce need for psychotropic medications

Possible Consequences of Failure to Implement Pharmacological Management in Patients With Alzheimer's Disease

More rapid institutionalization Aggression Caregiver stress and burden Violent behavior Cognitive decline Behavioral disturbances Failure to perform to standard of care Impaired activities of daily living (ADLs) Increased need for additional anxiolytics, antipsychotics, and other agents Hallucinations Potential decrease in ability to fully respond to later pharmacological intervention

1. Aricept [package insert]. Teaneck, NJ: Eisai Inc; 2000.

2.Exelon [package insert]. East Hanover, NJ: Novartis Corp; 2001. 3. Reminyl [package insert]. Titusville, NJ: Janssen Pharmaceutical Products, LP; 2001. 4.Tariot PN, Solomon PR, et al. Neurology. 2000;54:2269-2276. 5.Rogers SL, Friedhoff LT. Eur Neuropsychopharmacol. 1998;8:6775. 6.Farlow M, Anand R, et al. Eur Neurol. 2000;44:236-241. 7.Clegg A, Bryant J, et al. Health Technol Assess. 2001;5:1-137. 8.Mohs RC, Doody RS, et al. Neurology. 2001;57:481-488. 9.Knopman D, Schneider L, et al. Neurology. 1996;47:166-177. 10.Reuters Health News. Donepezil delays nursing home placement. Accessed April 2003 at: http://www.druginfozone.org/docs/pcjw _51st_edition_in. pdf. 11.Feldman H, Gauthier S, et al. Neurology. 2001;57:613-620. 12.Farlow MR, Anand R, et al. Proc Am Psych Assoc 2001:208 (NR770). 13. Farlow MR, Messina J, et al. Proc Am Geriat Soc. 2000;172 (P396). 14.Small G. Poster Presentation. 5-year rivistagmine data. 42nd American College of Neuropsychopharmacology meeting. Dec. 711, 2003. Puerto Rico. 15.Lopez OL, Becker JT, et al. J Neurol Neurosurg Psychiatry. 2002;72:310-314. 16.Raskind MA, Peskind, ER, et al. Arch Neurol. 2004;61:252-256. 17.Potkin SC, Anand R, et al. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:713-720.

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References

1. Small GW, et al. Diagnosis and treatment of Alzheimer disease and related disorders. Consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer's Association, and the American Geriatrics Society. JAMA. 1997;278:1363-1371. Alzheimer's Association. Caregiver stress: Signs to watch for--steps to take. Chicago: Alzheimer's Association; 1995. Accessed April 2003 at: www.alz.org/Resource Center/FactSheets/Brochure _%20CaregiverStress.pdf. Alzheimer's Association. Prevalence of Alzheimer's disease in the USA. Paper presented at the 8th International Conference on Alzheimer's Disease and Related Disorders; July 20-25, 2002; Stockholm, Sweden. Rocca WA, et al. Prevalence of clinically diagnosed Alzheimer's disease and other dementing disorders: A door-to-door survey in Appignano, Macerata Province, Italy. Neurology. 1990;40:626-631. Williams BR. Geriatric dementias. In: Koda-Kimble MA, Young LY, eds. Applied Therapeutics--The Clinical Use of Drugs. 7th ed. Philadelphia, Pa: Lippincott, Williams & Wilkins; 2001. Selkoe DJ. Amyloid protein and Alzheimer's disease. Sci Am. 1991;265:68-78. Cummings JL, et al. Alzheimer's disease: Etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998;51 (Suppl l):S2-517. Aricept [package insert]. Teaneck, NJ: Eisai Inc; 2000. Exelon [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2001. Reminyl [package insert]. Titusville, NJ: Janssen Pharmaceutical Products, LP; 2001. Namenda [package insert]. St. Louis, Mo: Forest Laboratories; 2003. Delagarza VW. Pharmacologic management of Alzheimer's disease. Am Fam Physician. 2003;68:13651721. www.aafp.org/afp. Farlow MR. Update on rivastigmine. Neurologist. 2003;9:230-234. Cummings JL, et al. Guidelines for managing Alzheimer's disease: Part I. Assessment. Am Fam Physician. 2002;65:2263-2272. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189198. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J Psychiatry. 1984;141:13561364. Knopman DS, et al. The Clinician Interview-Based Impression (CIBI): A clinician's global change rating scale in Alzheimer's disease. Neurology. 1994;44:23152321. Guy W, ed. ECDEU Assessment Manual for Psychopharmacology, Revised. Rockville, Md: U.S. Department of Health and Human Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch; 1976. Cummings JL, et al. The Neuropsychiatric inventory:

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Statement of Financial Disclosure In order to reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Bosker (Editor-inChief, Clinical Consensus Reports, Editor-in-Chief, Neurology Consensus Reports®, Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT; ) is on the speaker's bureau for Pfizer, Aventis, Roche, and Bayer. Dr. Bosker also acknowledges that he receives royalties, commissions, and other compensation relating to the sale of symposia, textbooks, reprints of articles, and other written materials to the following pharmaceutical companies: Pfizer, Aventis, Roche, SanofiSynthelabo, and Bayer. Dr. Arciniegas (Director, Neuropsychiatry Service, Assistant Professor of Psychiatry and Neurology, University of Colorado Health Sciences Center) reports that he has received support for investigator-initiated research from Forest Laboratories and Pfizer Inc.; and also acknowledges receipt of consultants' honoraria and educational program grants from Novartis Pharmaceuticals, AstraZeneca, & Eli Lilly and Company. Dr. Dengiz (Director of Geriatric Medicine, St. Joseph Mercy Health System, Medical Director Glacier Hills Retirement Community, and Huron Woods Alzheimer's Residential Center) reports that he has received financial compensation as a consultant and speaker for Novartis, Pfizer, Janssen, Forrest, Reliant, and Proctor and Gamble. Dr. Farlow (Professor and Vice Chairman for Research, Department of Neurology, Indiana University-Purdue University) reports that he has received grants from Forest Labs, Pfizer, Inc., Novartis Pharm. Eli Lilly and Co., Eunoe Inc., Janssen Pharm and SYN-X Pharma Inc. and is on speaker's bureau for Pfizer, Novartis, Janssen, and Forest. Dr. Farlow also acknowledges that he is a consultant for Janssen, Novartis, Forest, Eli Lilly, Willmar Schwabe GmbH& Co., Cerebrecon, Ono Pharmaceuticals, BristolMyersSquibb, and GlaxoSmithKline. Dr. Gray (Director, Geriatric Neuropsychiatry Clinic, Dallas Veteran Affairs Medical Center, Associate Professor of Psychiatry and Neurology, The University of Texas Southwestern Medical Center) reports that he is on the speaker's bureau for Pfizer, Eli Lilly, Novartis, Forest, and Bristol-Myers Squibb; and that he has received other compensation, including honoraria, consultant fees, and educational program development funds from Eli Lilly, Novartis, Pfizer, and Janssen. Mr. Gruber (Certified Geriatric Pharmacist, Certified Gerontologist, Regional Director of Clinical Services, Omnicare, Inc.) reports that he is on the speaker's bureau for Pfizer, BristolMyers Squibb, and Amgen. Mr. Gruber also acknowledges that he has received other compensation relating to consultants' honoraria, educational program development and/or presenta-

tion, and research grants within the last 12 months from Forest, Pfizer, BMS, J&J, Novartis, TAP, Abbott, Organon, AstraZeneca, Wyeth, the American Society of Consultant Pharmacists/Senior Rx Solutions, Procter and Gamble, Amgen, Eli Lilly, Insight Therapeutics, Inc., and Braintree. Dr. Micca (Medical Director Subacute Services Beverly Healthcare, Northside, Medical Director, A.G. Rhodes Home, Cobb, Medical Director, Georgia EMS) reports that he is on the speaker's bureau for Abbott, Eli Lilly, Forest, and Novartis; and that he has received other compensation relating to consultants' honoraria and educational program development from Eli Lilly and Novartis. Dr. Potkin (Professor, Department of Psychiatry, Director, Clinical Psychiatric Research, Robert R. Sprague Director of Brain Imaging Center, University of California, Irvine) reports that he has received grant/funding from Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen Pharmaceutica, Novartis, Organon, Otsuka, Pfizer, and Sanofi-Synthelabo; and consultancy/advisory board/honoraria from Acadia Pharmaceuticals, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Novartis, Organon, Otsuka, Pfizer, and Praecis. He also reports that he is on the speaker's bureau for AstraZeneca, Bristol-Myers Squibb, Novartis, and Pfizer. Dr. Reyes (Professor of Neurology, Pathology & Psychiatry, Deputy Chair of Neurology. Director, Center for Aging, Alzheimer's Disease & Neurodegenerative Disorders, Creighton University School of Medicine) reports that he is on the speaker's bureau for Novartis Pharmaceuticals and Pfizer, is a principal clinical investigator for Novartis, AstraZeneca, and ONO Pharmaceuticals, and has received educational grants from Pfizer, Janssen, Novartis, and AstraZeneca. Dr. Stander (Medical Director, Banner Good Samaritan Medical Center, Clinical Assistant Professor of Medicine, Department of Internal Medicine, Arizona Health Sciences Center) reports that he is a stock shareholder (directly purchased) in Pfizer. Dr. Zurad (Clinical Assistant Professor, Department of Family and Community Medicine, Temple University School of Medicine) reports that he serves as a consultant for Novartis, Wyeth, AstraZeneca, and Proctor & Gamble; and that he is on the speaker's bureau for AstraZeneca, Janssen and Novartis. At time of printing, the following panel members had not returned any disclosure information: Dr. Etemad (Department of Psychiatry, University of Pennsylvania); Ms. Saint-Eloi (Geriatric Nurse Practitioner, Clinical Nurse Specialist, Adult and Geriatric Institute of Florida); and Dr. Shua-Haim (Medical Chief, Meridian Institute for Aging-Senior Health Center and Memory Disorders Institute, Director, Geriatric Fellowship Program, Jersey Shore University Medical Center).

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