Long Term Care Formulary HCD Anti-Dementia Drugs (e.g. donepezil, galantamine, rivastigmine, memantine)

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1 1 of 8 USE OF CHOLINESTERASE (AChE) INHIBITORS The cholinesterase inhibitor anti-dementia drugs are indicated for the symptomatic treatment of patients with mild to moderate dementia of the Alzheimer s type. As per CMAJ guidelines from 2008, all three cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) can be considered modestly efficacious for mild-moderate dementia, and the 2011 NICE guidelines from the UK state that the three are equivalent in efficacy. There are no direct comparisons between the three; choice of agent will depend on cost, adverse effect profile, ease of use, and practioner familiarity practioner beliefs in the differences in mechanism of action. It should be noted that there is no cure for Alzheimer s and there is no treatment that will stop progression of the disease. Medications may to delay symptoms such as deficits in memory, language and cognition. Expectations should be modest, with relief in symptoms only temporary. It should be made clear that Alzheimer s is a terminal diagnosis, with median survival length being 6 years (range 1-16 years), with approximately one-third of time spent in each of the mild, moderate, and severe stages. Disease progression is directly related to the decline in quantity of acetylcholine available in the brain; once there is insufficient acetylcholine to facilitate cognition, the drugs are rendered useless. Of import is that there is no evidence that suggests AChE inhibitors affect survival, and that the expected benefit of these drugs should last a maximum of 2-3 years. Considerations of cholinesterase inhibitor use in the care setting 1. Pharmacoeconomic data suggest that the most cost effective benefit with these agents occurs in the phase prior to institutionalization. Once institutionalization occurs, incremental costs increase and cost advantage is lost. 2. The potential exists that agitation and aggression as the disease progresses may be worsened by the stimulating effect of donepezil, potentially requiring reduction in dose or discontinuation of the drug. Conversely, patients who are started on donepezil in later stage of the disease for agitation and/or aggression may benefit from use of donepezil. 3. Question has been raised around the issue that continued use in later stages of the disease does not contribute to quality of life. Notes: 1. Though actual incidences of cardiac adverse events are low, the practioner should consider a recent EKG prior to initiation of any AChE inhibitor. Recent is within 6 months, unless a change in clinical condition suggests that a repeat is required. It is recommended that cholinesterase inhibitors not be used with residents who have cardiac conduction disturbances (exception right bundle branch block), or who have sick-sinus syndrome. 2. Effectiveness and tolerability of the AChE inhibitor should be reassessed after 3-6 months of initiation. Withdrawal rates in clinical trials range are approximately 30% (vs. 18% for placebo),

2 2 of 8 possibly indicating intolerability of these agents due to adverse events. Likewise, if no positive effects are seen (i.e. improvement or stabilization of cognition), effectiveness of the medication should be re-evaluated. Note: GI side effects are the most commonly report adverse events. While the rivastigmine patch is purported to have better tolerability than the oral form, its use shall be restricted to those who have failed a reasonable trial of oral rivastigmine. 3. Reporting of ABS (Aggressive Behavior Scale) and ADL Short (Activities of Daily Living) scores from MDS-RAI data shall be required for drug funding. While these data are currently not conclusively linked to effectiveness of the anti-dementia drug products, the reporting may be used to i) measure progress and gradual deterioration of the client during his or her stay in LTC, and ii) to provide data as a means for future research into the use of MDS-RAI data for objective drug evaluation. 4. Individual cases will be considered depending on their merits. USE OF NMDA RECEPTOR ANTAGONIST The use of the NMDA receptor antagonists are indicated only for the symptomatic treatment of patients with moderate to severe dementia of the Alzheimer s type (it is not recommended in mild-stages of the disease). Cognitive benefits of memantine are uncertain, however, the drug is purported to be effective in managing behaviors associated with severe dementias and may reduce the use of antipsychotics (though the reduction has not be quantified by evidence). Combining Cholinesterase Inhibitors with NMDA Receptor Antagonists Although the combination of a cholinesterase inhibitor with memantine is rational (from the standpoint of mechanism of action), and is considered to be safe, there is no statistically significant evidence that suggests combination therapy is more effective than monotherapy (with either memantine or a cholinesterase inhibitor). Funding for multiple agents will not be considered by AHS. STOPPING ANTI-DEMENTIA MEDICATIONS No clear guidelines exist to guide the practice of stopping medications. Both NICE and CMAJ guidelines report a floor effect on the effects of cognition (generally accepted to be an MMSE score below 10), but benefits in behaviors and daily functioning are more difficult to quantify. Though some reports indicate that these medications are useful in severe dementias, the general recommendation is that the drug is continued until clinical benefit can no longer be determined. This includes patients who are: - Bedridden - Non-communicative

3 3 of 8 - Can no longer perform basic activities of daily living Discontinuation is also recommended if rate of decline of global and cognitive measures of function does not slow (or increases after initiation of therapy). MDS-RAI measurements of CPS, ABS, and ADL scores on a regular basis can help to make this assessment. Lastly, discontinuation is also recommended if therapy becomes unacceptably risky (i.e. concurrent medical conditions) or futile (i.e. end-of-life). Discontinuation Monitoring After therapy has been discontinued, residents should be monitored for significant decline in cognitive status, functional abilities, or development or worsening of behaviors. If there is significant deterioration in any area, consideration should be given to re-initiate anti-dementia medications. This process would be carried out via the non-formulary/special-authorization approval process and be evaluated on a case-by-case basis. References: 1. Herrmann, N., Gauthier. S. Diagnosis and treatment of dementia: 6. Management of severe Alzheimer disease Can. Med. Assoc. J : ; doi: /cmaj Hogan et al. Diagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia. Can. Med. Assoc. J : ; doi: /cmaj Hogan et al. Diagnosis and treatment of dementia: 4. Approach to management of mild to moderate dementia. Can. Med. Assoc. J : ; doi: /cmaj NICE Technology Appraisal Guidance. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer s disease. March /13419/53619/53619.pdf 5. Qaseem et al. Current Pharmacologic Treatment of Dementia: A Clinical Practice Guideline from the American College of Physicians and the American Ann Intern Med. 2008;148:

4 4 of 8 PROTOCOL 1 Alzheimer Disease With the above considerations, cholinesterase inhibitors will be supplied for individuals who are admitted to care centres on one of these agents or for residents who develop Alzheimer Disease while in a care centre. Donepezil hydrochloride (5-10 mg po qd), galantamine hydrobromide ER (8-24 mg po qd), or rivastigmine tartrate oral(1.5 mg 6 mg po bid), and rivastigmine transdermal patch (if intolerant to oral form) Refer to algorithm for patch dose/conversion are approved for use under the following conditions: 1. The resident must have a diagnosis of Alzheimer Disease or a diagnosis of mixed dementia where Alzheimer Disease is a significant component; AND 2. The resident will have a Folstein MMSE score within 12 weeks prior to or following admission of between or a Cognitive Performance Scale (CPS) score between 1-4 AND 3. Initial reporting of both an ABS (Aggressive Behavior Scale) and ADL Short (Activities of Daily Living) score is required to establish a baseline functional assessment. For continuation of funding: 1. An annual MMSE score or a CPS is required; AND 2. Annual reporting of both an ABS (Aggressive Behavior Scale) and ADL Short (Activities of Daily Living) score For individuals admitted to a care centre who do not meet these criteria, the following will apply: 1. Recognizing the disruption to routine that occurs with translocation into a care centre, the drug will initially be continued. 2. At the first (intake) conference, discussion will ensue leading to initiation of tapering of the agent, where this has not already been undertaken. Tapering with all of the cholinesterase inhibitors is the recommended method of discontinuation to allow observation of changes that may occur as the drug is being discontinued. One suggested regimen is reduction of the dose by 50% monthly until the drug is discontinued, depending on availability of dose formats to allow this. For donepezil the minimum dose available is 2.5 mg po qd; for galantamine ER it is 8 mg po qd and for rivastigmine it is 1.5 mg po bid. It is recognized that there may be an increase in certain behaviours associated with Alzheimer Disease, such as repetitive speech. There may also be an improvement in behaviours with dose tapering if agitation or aggression has been a significant feature.

5 5 of 8 References: 1. Birks JS & Melzer D. Donepezil for mild to moderate Alzheimer s Disease (Review). Cochrane Database of Systemic Reviews Foster RH & Plosker GL. Donepezil Pharmacoeconomic Implications of Therapy. Pharmacoeconomics 1999; 16(1): Gauthier S. Managing Expectations in the Long-Term Treatment of Alzheimer s Disease Gerontology 1999;45(Suppl 1): O Brien BJ, Goeree R, et al. Economic Evaluation of Donepezil for the Treatment of Alzheimer s Disease in Canada JAGS 1999;47: Small GW, Donohue JA, & Brooks RL. An Economic Evaluation of Donepezil in the Treatment of Alzheimer s Disease Clin Ther 1998;20(4): Reisberg, B. Functional Assessment Staging (FAST). Psychopharmacology Bulletin, Vol 24 No.4, PROTOCOL 2 Lewy Body Disease Lewy Body Disease is a form of dementia characterized by: a. progressive, fluctuating cognitive impairment b. visual hallucinations c. spontaneous motor features of Parkinsonism that occurs within 1 year of development of the cognitive decline (as compared to the dementia associated with Parkinson s Disease where the features of Parkinson s Disease precede the development of dementia, usually by a number of years). An enhanced neuroleptic sensitivity may be seen. Rivastigmine tartrate oral(1.5 mg 6 mg po bid), and rivastigmine transdermal patch (if intolerant to oral form) Refer to algorithm for patch dose/conversion or donepezil hydrochloride (5-10 mg po qd) are approved for use under the following conditions (galantamine hydrobromide has not demonstrated usefulness for this disorder): 1. Trial of therapy for residents with a diagnosis of Lewy Body dementia where other options, such as low-dose atypical neuroleptics, have either not been tolerated or have failed to control symptoms of hallucinations and agitation associated with the disorder. Where symptoms are controlled, therapy will be long-term for ongoing management and will not require either an MMSE or a CPS score for continued funding. Notes: 1. This is a non-approved indication for the drug but may be useful.

6 6 of 8 2. These individuals will not require MMSE or CPS scores to be completed. References: 1. McKeith, I. Exelon Improves Behaviour in Dementia. The Alzheimer Examiner 1999 (reporting on abstract presented at the Ninth Congress of the International Psychogeriatric Association August 1999) 2. Rojas-Fernandez C. & MacKnight C. Dementia with Lewy Bodies: Review and Pharmacotherapeutic Implications. Pharmacotherapy 1999; 19(7): Shea C, MacKnight C, & Rockwood K. Donepezil for treatment of Dementia with Lewy Bodies: a case series of 9 patients. Int Psychogeriat 1998; 10: PROTOCOL 3 Behavioural Disturbance in Alzheimer Disease Initiation of either cholinesterase inhibitors or memantine may be considered for residents in later stages of the disease where behaviour disturbances persist and other agents have had a reasonable trial and have failed. Authorization is for 12 months at which time the efficacy of therapy must be reviewed. If therapy is to be continued, an application must be made for continuation of therapy. Donepezil hydrochloride (5-10 mg po qd), galantamine hydrobromide ER (8 24 mg po qd), rivastigmine tartrate (1.5 mg 6 mg po bid or transdermal patch) Refer to algorithm for patch dose/conversion, or memantine (10 mg po bid) are approved for use under the following conditions: 1. Behaviour mapping must be undertaken daily for 2 weeks prior to initiation of the agent and again daily for 2 weeks after initiation of the agent. Following this initial two week period, recording for 1 day every two weeks looking for beneficial effect on target behaviours and for side effects is required for 3 months; AND 2. There must be documented intolerance to or failure of at least 2 trials of 2 weeks duration with other agents specifically being used for behavioural management. These may include mood stabilizers or the following atypical anti-psychotics: risperidone, quetiapine, and olanzapine; AND 3. There must be a recommendation for use by a specialist in psychiatry, geriatrics or neurology (these will be very challenging individuals and the assumption is that a consultant will already be involved). 4. Initial reporting of both an ABS (Aggressive Behavior Scale) and ADL Short (Activities of Daily Living) score is required to establish a baseline functional assessment Notes: 1. These individuals will not require MMSE or CPS scores to be completed. 2. Coverage cannot be provided for two or more medications used in the treatment of Alzheimer Disease (cholinesterase inhibitors, memantine) when these medications are intended for use in

7 7 of 8 combination. In general, where an individual has been on a cholinesterase inhibitor and an NMDA antagonist is being added, the cholinesterase inhibitor must be tapered once the dose of the NMDA antagonist is stabilized. ALGORITHM FOR SWITCHING TO EXELON (rivastigmine) TRANSDERMAL PATCH Ensure patient has had an adequate trial of oral rivastigmine If poorly tolerated.. What dose of oral Exelon (rivastigmine) is the patient receiving? Start on Exelon (rivastigmine) Patch 5 Less than 6 mg/day 6 12 mg/day AT LEAST 4 WEEKS Increase to Exelon (rivastigmine) Patch 10 Switch directly to Exelon (rivastigmine) Patch 10 PROCEDURE Compliance with the procedure outlined under HCD 01 (High Cost Drug Use Conditions) is necessary for drug cost reimbursement. HCD Authorization and funding requires annual submission.

8 8 of 8 Cross Reference: 1. Dementia Behaviour/Symptom Mapping Tool (BSMT)