CADTH Health Technology Review

Utilization of Cholinesterase Inhibitors for Alzheimer Disease in Canada

Technology Review

Authors: Ann Chang, Chris Vannabouathong, Christine Perras

Key Messages

• Due to upcoming Canadian market approvals of biologics for Alzheimer disease, a utilization study was conducted to assess the current utilization patterns and funding criteria for cholinesterase inhibitors (ChEIs) in selected Canadian jurisdictions from 2017 to 2020.

• Most jurisdictions list ChEIs as exception status, special authorization, or limited use drugs except Manitoba; as of 2018, Manitoba lists donepezil and galantamine as regular benefits and rivastigmine as an exception status drug. Additionally, British Columbia and New Brunswick fund galantamine and rivastigmine after a patient is deemed intolerant to donepezil.

• The following are insights from the utilization analysis.

  • Across Canada, there has been a decrease in the number of beneficiaries and claims for all ChEIs from 2017 to 2020 in all jurisdictions except Manitoba:

    • There was a 12% reduction in number of beneficiaries and a 17% reduction in the number of total claims from 2017 to 2020.

    • In Manitoba, there was an increase in the number of ChEI beneficiaries that peaked in 2018, which corresponds to the formulary changes for donepezil and galantamine during this period.

  • Across Canada, donepezil had the highest market share among all ChEIs each year from 2017 to 2020, which increased from 71.2% in 2017 to 75.8% in 2020. Galantamine had the second-highest market share each year. The market shares for both galantamine and rivastigmine decreased over time, indicating there is a preference for prescribing donepezil to patients with Alzheimer disease.

    • The greater use of donepezil may be explained by prescriber preferences or coverage criteria for ChEIs (e.g., donepezil is considered first line in British Columbia and New Brunswick).

  • The cumulative costs of all ChEIs paid for by public drug plans across Canada in 2020 was $20,659,136, a decrease of 43% from $36,325,781 in 2017, which corresponds with the decrease in the total number of ChEI beneficiaries.

    • Donepezil had the highest national total costs, followed by galantamine, then rivastigmine, which corresponds to the market share for each of these drugs. However, on a cost-per-beneficiary basis, donepezil was associated with the lowest cost estimates in each year from 2017 to 2020.

Background

Alzheimer disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide.¹ The prevalence of AD was 6.5% among Canadians 65 years and older as of 2017. This is expected to double in the next 10 years due to growth in the aging population, leading to a projected doubling of annual health care costs by 2031 from $8.3 billion to $16.6 billion.^1,2

AD is characterized by the accumulation of amyloid beta plaques and neurofibrillary tau tangles in the brain, which are hypothesized to play a role in the decline of cognition, function, and behaviour.^3,4 The degeneration of cholinergic neurons and reduction in acetylcholine transmission has been implicated in the pathophysiology of AD, contributing to symptoms such as memory loss, learning impairment, and behavioural changes.^5,6 First-line treatments for mild to moderate AD are the cholinesterase inhibitors (ChEIs) donepezil, galantamine, and rivastigmine, which increase concentrations of neuronal acetylcholine and improve symptoms such as memory loss and cognition.^7,8 In severe AD, memantine, an N-methyl-D-aspartate receptor antagonist, is used with or without ChEIs to reduce rates of cognitive decline.^9,10 ChEIs provide modest cognitive benefits that persist over time compared with untreated patients, but they do not modify disease progression.^11,12 ChEIs are also associated with a reduction in antipsychotic drug and anxiolytic drug use, and as a result may delay institutionalization.^13,14 All ChEIs have similar efficacy in maintaining Mini- Mental State Exam (MMSE) scores but vary in titration schedules and the frequency of side effects such as nausea, vomiting, dizziness, and headache, which may lead to discontinuation.^15,16 Currently, there is no cure for AD nor are there any disease-modifying therapies available in Canada.³

The oral originator products Aricept (donepezil), Exelon (rivastigmine), Reminyl (galantamine), and Ebixa (memantine) were marketed in Canada in 1997, 2000, 2001, and 2004, respectively.¹⁷ Currently in Canada, donepezil is available as an oral tablet and oral rapid dissolving tablet (RDT), galantamine as a generic-only extended-release oral capsule, rivastigmine as an oral capsule, transdermal patch, and brand-only oral solution, and memantine as an oral tablet.¹⁷ The overall cost-effectiveness of ChEIs in AD treatment is uncertain due to lack of functional status improvement despite MMSE score changes and limited long-term benefit of ChEIs due to the progressive nature of the disease.^16,18 However, in some studies, donepezil was found to be the more cost-effective drug as monotherapy with better tolerability, which may explain its role as first-line treatment compared with galantamine and rivastigmine despite the lack of preference for a specific ChEI in the Canadian guidelines for the treatment of dementia.^15,19,20

Purpose of This Report

The aim of this project was to measure the utilization of ChEIs and memantine to determine prescribing patterns and expenditures in Canada. One component of the project was to compare reimbursement criteria for ChEIs and memantine across Canadian FPT federal, provincial, and territorial (FPT) jurisdictions. The current utilization of ChEIs and memantine in Canada may give an indication for the future use of drug products for the treatment of AD that are in clinical development.

Policy Issues

With the upcoming Health Canada reviews of several novel drugs for AD (e.g., donanemab, lecanemab, and aducanumab), an assessment of the current landscape of AD treatment is needed. The current iteration of the Canadian AD guidelines includes new recommendations on risk reduction and psychosocial and non-pharmacological interventions to current standard of care, leading to possible alternative treatment pathways for newly diagnosed patients.^20,21 Due to the prevalence of AD in Canada rising over the past few years, the utilization of drugs for AD needed to be proactively examined because of these recent shifts in policies and treatment paradigms.

Policy Question

What is the current utilization of cholinesterase inhibitors and memantine in Canada for AD?

Research Questions

1. What are the funding criteria for cholinesterase inhibitors and memantine across the FPT jurisdictions?

2. How many claims and users of cholinesterase inhibitors and memantine were there from 2017 to 2020?

3. What were the expenditures on cholinesterase inhibitors and memantine from 2017 to 2020?

Methods

Data Sources

To determine coverage criteria across FPT drug plans, formulary websites and documents containing lists of regular benefit and restricted access drugs were searched. The reimbursed formulations, the coverage criteria, and any coverage restrictions and notes were summarized for all FPT drug plans except Quebec, Nunavut, and Northwest Territories (Appendix 1).

Claims data for ChEIs and memantine were extracted from the National Prescription Drug Utilization Information System (NPDUIS) database for all public drug plans with the exception of Quebec, Yukon Territories, Canadian Armed Forces, Non-Insured Health Benefits, and Veterans Affairs Canada, between January 1, 2017, and December 31, 2020 (Appendix 2). Drugs were included based on their Anatomical Therapeutic Chemical (ATC) code Level 5 (Table 1). Only claims where at least part of the claim was accepted by the public plan/program, either toward a deductible or for payment were included in the analysis. In accordance with the privacy policy of the Canadian Institute for Health Information, in cases where the number of active beneficiaries was less than 5 (but greater than 0), this number along with other associated values were suppressed to ensure confidentiality. The NPDUIS database does not include information regarding prescriptions that were written but never dispensed, nor does it include diagnoses or conditions for which prescriptions were written.

Data Analysis

The utilization patterns were analyzed by calculating the market share of each drug as a proportion of all claimants who claimed a given drug from a public drug plan from 2017 to 2020. This calculation was performed within jurisdictions and at the national level. The total cost per beneficiary (amount paid by public drug plan) was calculated for each ChEI within jurisdictions and at the national level.

Findings

Funding Criteria for Cholinesterase Inhibitors Across Jurisdictions

Most jurisdictions reimburse all ChEIs under special authorization, limited use, or exception status criteria, except Manitoba (Table 2). In Manitoba, donepezil and galantamine are currently listed as regular benefit, whereas rivastigmine is listed under exception status (Appendix 1).^22,23 The reimbursement criteria in most jurisdictions include an MMSE score or similar psychometric questionnaire score submitted to the plan (Appendix 1).

Within Ontario, all ChEIs (except rivastigmine oral solution) are listed under regular benefits but require a limited use code corresponding to the initial or continuation treatment stage.²⁴ In Ontario, rivastigmine oral solution is reimbursed under the Exceptional Access Program for patients who are unable to swallow capsules. In British Columbia and New Brunswick, donepezil is listed as the first-line treatment option, and galantamine and rivastigmine are reimbursed if patients experience an intolerance to donepezil (Appendix 1). Most jurisdictions only reimburse rivastigmine oral capsules and the brand-only oral solution, with the exception of Yukon, which reimburses the transdermal patch formulation for patients who cannot use oral capsules (Appendix 1).

Memantine received a negative listing recommendation by CADTH in 2005 and is not reimbursed in any jurisdiction.²⁵ Given this, memantine is not discussed further in this report.

Table 2: Overview of Listing Status of Cholinesterase Inhibitors by Public Drug Plans

^aIn Ontario, rivastigmine oral solution is reimbursed under the Exceptional Access Program for patients meeting the limited use criteria who are unable to swallow capsules.

Claims and Users of Cholinesterase Inhibitors From 2017 to 2020

Figure 1 provides the number of claims and beneficiaries nationally and all included drug products. There was a year-to-year decrease in the total number of beneficiaries for all ChEIs across Canada from 2017 to 2020 (Figure 1). Compared with 2017, the total number of beneficiaries decreased by 12% in 2020. There was also a year-to-year decrease in the number of claims for all ChEIs. Compared with 2017, the number of claims decreased by 17% in 2020.

Figure 1: Number of Claims and Number of Beneficiaries for All Cholinesterase Inhibitors in Canada Between 2017 and 2020

Figure 2 presents the number of beneficiaries according to drug for each calendar year from 2017 to 2020. Across Canada, donepezil had the highest number of beneficiaries and rivastigmine had the lowest (Figure 2). Donepezil is the most commonly prescribed ChEI across Canada, which may be explained by factors such as formulary restrictions (e.g., as in British Columbia and New Brunswick) (Appendix 1) or physician preference due to ease of titration and lower risk of gastrointestinal side effects compared with galantamine and rivastigmine.^19,26,27 A year-to-year decrease in the number of beneficiaries occurred for all ChEIs. In 2020, there was a 7% decrease in the number of donepezil beneficiaries compared with 2017. There was a 16% decline in beneficiaries for galantamine; rivastigmine exhibited the largest degree of change, with an 18% decrease in beneficiaries in 2020 compared with 2017.

Figure 2: Number of Beneficiaries by Cholinesterase Inhibitors in Canada Between 2017 and 2020

Across jurisdictions, Manitoba was the only jurisdiction with an increase in the number of beneficiaries for AD drugs, mostly driven by the number of donepezil and galantamine beneficiaries (data not shown). This is likely due to changes to the reimbursement criteria in Manitoba in 2018 for donepezil and galantamine, which facilitated easier patient access to these drugs.²² There was also a small yearly increase in the number of beneficiaries for donepezil in Prince Edward Island and Newfoundland and Labrador. However, the reimbursement criteria in both jurisdictions require MMSE scores to be within a certain range to be eligible for therapy, suggesting that there may be a higher population with AD or different prescribing patterns may be responsible for the rise in donepezil beneficiaries (Appendix 1).

Figure 3 shows the yearly percentage changes in beneficiaries for all ChEIs by province from 2017 to 2020. Across Canada, all provinces showed year-to-year decreases in the total number of beneficiaries except Manitoba, which had an increase in beneficiaries (Figure 3). As mentioned previously, this was likely driven by the changes to the listing status for donepezil and galantamine in 2018, which resulted in the number of beneficiaries increasing by 25.5% compared with the number in 2017. A downward trend and plateau were observed for beneficiaries in Manitoba, leading to a 0.8% change in 2020, indicating that growth in the number of new and existing users for all ChEIs in this province has slowed over time. British Columbia and Saskatchewan had the greatest reduction in all ChEI beneficiaries in 2018, which plateaued in 2019 and 2020.

Figure 3: Yearly Percent Change in Beneficiaries for All Cholinesterase Inhibitors by Province Between 2017 and 2020

AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NS = Nova Scotia; ON = Ontario; PE = Prince Edward Island; SK = Saskatchewan.

Market Share

Figure 4 presents the proportion of beneficiaries by drug from 2017 to 2020. Across Canada, donepezil had the highest market share from 2017 to 2020, followed by galantamine then rivastigmine. Over time, donepezil also increased its Canadian market share (71.2% in 2017 to 75.8% in 2020), while both galantamine and rivastigmine market shares decreased (22.1% in 2017 to 18.7% in 2020 and 6.7% in 2017 to 5.5% in 2020, respectively). Over the study period, the proportion of beneficiaries for donepezil in British Columbia, Manitoba, Ontario, New Brunswick, and Prince Edward Island grew, whereas this proportion declined in Alberta, Saskatchewan, Nova Scotia, and Newfoundland and Labrador (Appendix 3). Across jurisdictions, Manitoba had the highest proportion of donepezil beneficiaries in 2020 (88%), while Nova Scotia had the lowest (59%) (Appendix 3). For galantamine, Nova Scotia had the highest percentage of beneficiaries (33%), and Manitoba had the lowest in 2020 (9%). Rivastigmine had the lowest proportion of beneficiaries, ranging from 2% (Prince Edward Island) to 7% (British Columbia, Alberta, and Nova Scotia) in 2020 (data not shown).

Figure 4: Proportion of Beneficiaries by Cholinesterase Inhibitors in Canada Between 2017 and 2020

Expenditures on Cholinesterase Inhibitors From 2017 to 2020

Figure 5 presents the cost paid by public drug plans by drug from 2017 to 2020. A year-to-year decrease in total costs paid for ChEIs was observed across Canada (Figure 5). The cumulative costs of all ChEIs paid for by public drug plans across Canada in 2020 totalled $20,659,136, a decrease of 43% from $36,325,781 in 2017. In 2020, there was a 49% decrease in donepezil costs, a 41% decrease in rivastigmine costs, and a 31% decrease in galantamine costs relative to 2017. For donepezil, total costs were driven by its high market share. Costs paid for rivastigmine were the lowest of all 3 ChEIs due to its low proportion of beneficiaries in Canada.

Figure 5: Costs Paid by Public Drug Plans for Cholinesterase Inhibitors in Canada Between 2017 and 2020

Figure 6 presents the average costs paid per individual beneficiary by drug from 2017 to 2020. Consistent with Figure 5, there was a year-to-year decline in the national cost per beneficiary for all ChEIs (Figure 6). Each year, donepezil had the lowest national cost per beneficiary, and rivastigmine had the highest. Across all jurisdictions, donepezil had the largest reduction in cost per beneficiary of all ChEIs (46% decrease in 2020 relative to 2017). Of all ChEIs, galantamine had the smallest reduction in costs per beneficiary (6% decrease in 2020 relative to 2017). Rivastigmine had a 17% decrease in costs per beneficiary in 2020 compared with 2017. Across jurisdictions in 2020, donepezil ranged from $71 per beneficiary (Saskatchewan) to $189 per beneficiary (Ontario), galantamine ranged from $176 per beneficiary (Manitoba) to $461 per beneficiary (Ontario), and rivastigmine ranged from $267 per beneficiary (Saskatchewan) to $891 per beneficiary (British Columbia) in 2020 (data not shown). Factors driving rivastigmine’s higher cost per beneficiary may be its higher original list price and that the brand-only oral solution is reimbursed in most jurisdictions (Appendix 1).¹⁷ Saskatchewan, Ontario, and Newfoundland and Labrador had a higher cost per beneficiary for galantamine compared with rivastigmine (data not shown).

Figure 6: Costs Paid by Public Drug Plans per Beneficiary by Cholinesterase Inhibitors in Canada Between 2017 and 2020

Discussion: Overall Utilization of Cholinesterase Inhibitors in Canada From 2017 to 2020

Although there was an overall increase in the Canadian elderly population between 2017 to 2020, the total number of ChEI users in Canada have declined over the same period. In 2020, the total amount paid by jurisdictions for all ChEIs was $20,659,136, a decrease of 43% since 2017. This was driven by the 12% decline in total ChEI beneficiaries since 2017. It is possible that more prescribers and patients were looking to alternative methods of AD management given the recent Canadian guideline updates on non-pharmacological strategies and psychosocial interventions, leading to reduced utilization of ChEIs across the country.²⁰ Across Canada, donepezil has the highest utilization rates throughout the study period, followed by galantamine then rivastigmine. The decline in total ChEI costs was driven by donepezil’s large market share, as 71.2% to 75.8% of beneficiaries across the study period in Canada received donepezil. These results correspond to physician and formulary preference for donepezil as first-line treatment because of ease of titration and better tolerability.

On a per beneficiary basis, donepezil is the lowest priced ChEI, and its national costs paid per beneficiary decreased the most, followed by rivastigmine then galantamine. These findings are consistent with the length of time that donepezil generics have been available on the Canadian market, physician preference because of ease of titration, and high rates of use in Canada which drove down costs.^26,27 The cost per beneficiary for rivastigmine is the highest of all ChEIs in Canada, but when compared between jurisdictions, galantamine costs in 2020 surpassed rivastigmine costs in Saskatchewan, Ontario, and Newfoundland and Labrador. However, these costs did not follow a trend from year-to-year and costs were still comparable between the 2 drugs in these jurisdictions in 2020. Because reimbursement criteria for these drugs were similar across jurisdictions, this may reflect increased utilization of galantamine due to prescriber and patient preferences, especially considering the gastrointestinal burden of rivastigmine formulations.^15,27

Limitations

One of the limitations of this study was that the claims data used were not indication-specific because ChEIs may also be used as treatment for Lewy body dementia. Rivastigmine is also approved for use in Parkinson disease, which may overestimate its utilization for the AD indication.²⁸ Second, off-formulary products, such as memantine, donepezil RDT, and rivastigmine transdermal patch, were not included, thus these utilization trends were not reviewed in this report. Because tolerance and adherence may be an issue with these products, the transdermal patch or RDT formulations may be prescribed to patients in some provinces and purchased out-of-pocket by the patient or caregiver, which would be a gap in our data, especially if there is a large population using these off-formulary formulations.^19,27 A third limitation is related to the cost-per-beneficiary estimates, which are a function of utilization, dosing, and list prices. Interjurisdictional and interpatient variations in these factors limit the comparability of the cost-per-beneficiary estimates between jurisdictions.

Information on patients’ history of previously trialled ChEIs were not included and, because some provinces require patients to trial donepezil first before receiving other ChEIs, the market share for existing donepezil users may be underestimated. Differences in drug plan product listing prices, coverage criteria and access, and patient and caregiver preferences all play a role in treatment decisions, and it is unclear to what degree each of these factors influences ChEI utilization.

Conclusions and Implications for Decision- or Policy-Making

Utilization of ChEIs within the past 5 years has been declining across Canada despite the increasing size of the elderly population. Provincial reimbursement criteria, clinical evidence, and physician preference drove widespread use of donepezil as first-line treatment in AD, contributing to its large market share and decreasing costs per beneficiary in the past 5 years. Manitoba recently revised the reimbursement criteria for ChEIs, listing both donepezil and galantamine as a regular benefit, which explains the increase in the number of ChEI users in 2018. This important finding demonstrates how formulary policy changes can have a direct influence on uptake and utilization of drugs within a jurisdiction. Overall costs for ChEIs have also been declining, possibly due to the increasing availability of generics and provincial price negotiations. The relative cost per beneficiary for ChEIs in Saskatchewan, Ontario, and Newfoundland and Labrador do not align with national patterns and could be an area of further investigation for payers. Because ChEI use has been declining across Canada, ongoing assessment of the clinical value and cost-effectiveness of ChEIs should be conducted, especially in light of new AD therapies coming onto the Canadian market.

References

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Appendix 2: List of Public Drug Plans and Programs Within the NPDUIS Database

Table 4: Public Drug Plans and Programs Within the NPDUIS Database

NPDUIS = National Prescription Drug Utilization Information System.