BPS-034 (BPDO-1603 / DM Duo): A Comprehensive Analysis of a Fixed-Dose Combination for Alzheimer's Disease

1. Executive Summary

[BPS-034, also identified by the development code BPDO-1603 and marketed in South Korea as DM Duo, is an oral fixed-dose combination (FDC) medication developed by Hyundai Pharmaceutical Co., Ltd. for the treatment of moderate-to-severe Alzheimer's disease (AD). This report provides a comprehensive analysis of BPS-034, synthesizing available data on its pharmacology, clinical development, formulation, regulatory status, and safety profile.]

[The drug combines two established therapeutic agents: donepezil hydrochloride, an acetylcholinesterase inhibitor, and memantine hydrochloride, an N-methyl-D-aspartate (NMDA) receptor antagonist. This dual mechanism targets both the cholinergic deficit and glutamatergic excitotoxicity implicated in AD pathogenesis. The primary rationale for developing this FDC is to improve patient compliance and convenience by reducing pill burden, particularly as memantine is often dosed twice daily when administered separately, while donepezil is once daily.]

[The clinical development program for BPS-034 included a Phase 1 pharmacokinetic study (NCT05804279) in healthy adults, which likely finalized the formulation based on safety and bioavailability, following earlier bioequivalence studies. The pivotal Phase 3 trial (NCT04229927) evaluated the efficacy and safety of BPS-034 against donepezil monotherapy in patients with moderate-to-severe AD already stabilized on donepezil. This trial did not demonstrate statistical superiority of the combination over donepezil alone on its primary cognitive (Severe Impairment Battery - SIB) and global (Clinician's Interview-Based Impression of Change-plus - CIBIC-Plus) endpoints.]

[Despite the lack of superior efficacy, DM Duo (10mg donepezil / 20mg memantine tablet) received marketing approval from the South Korean Ministry of Food and Drug Safety (MFDS). This approval was primarily based on the argument of improved medication adherence through regimen simplification. This regulatory decision underscores a growing recognition of patient-centric factors in the management of chronic diseases like AD.]

[The safety profile of BPS-034 is generally reflective of its individual components. However, real-world pharmacovigilance data for the donepezil-memantine combination have highlighted additional adverse drug reactions (ADRs) and potential gender-specific safety signals, emphasizing the need for continued monitoring. Potential drug interactions associated with both donepezil (CYP450 metabolism, cardiovascular effects) and memantine (renal excretion, NMDA antagonism) must be carefully managed.]

[In conclusion, BPS-034 (DM Duo) represents a therapeutic option aimed at enhancing convenience and adherence for AD patients who are candidates for combination therapy with donepezil and memantine. Its clinical utility is positioned around simplifying the treatment regimen rather than offering enhanced pharmacological efficacy over donepezil monotherapy. The drug's market success will likely depend on the perceived value of this convenience by clinicians, patients, and caregivers, balanced against its overall safety profile and cost-effectiveness.]

2. Introduction to BPS-034 (BPDO-1603 / DM Duo)

Overview: Drug Names, Developer

[BPS-034 is a pharmaceutical agent known through various identifiers reflecting its development and marketing stages. Its primary development code is BPDO-1603, and it is also referred to as BPS-034 in some databases.][1][ Following its approval in South Korea, it is marketed under the brand name DM Duo.][2][ This product is a small molecule, fixed-dose combination (FDC) drug, meticulously developed by the South Korean company Hyundai Pharmaceutical Co., Ltd..][1][ The strategic choice of these identifiers is noteworthy; development codes like BPDO-1603 are standard during the research and clinical trial phases. The subsequent market name, "DM Duo," appears deliberately chosen to communicate the drug's core characteristic to healthcare providers: a combination of Donepezil and Memantine, thereby implying its dual mechanism of action. This naming and the focus on an FDC of two well-established drugs suggest a development strategy centered on enhancing patient convenience and adherence, rather than on the discovery of a novel molecular entity. This positions DM Duo within a specific therapeutic niche, targeting patients who would otherwise be prescribed these two medications separately. Its value proposition, therefore, largely depends on demonstrating benefits beyond the individual components, primarily through improved ease of use and adherence.]

Therapeutic Class: Cholinesterase Inhibitor & NMDA Receptor Antagonist Combination

[BPS-034 (DM Duo) integrates two distinct and well-established therapeutic classes used in the management of Alzheimer's disease. It combines an acetylcholinesterase inhibitor (AChEI), specifically donepezil hydrochloride, with an N-methyl-D-aspartate (NMDA) receptor antagonist, memantine hydrochloride.][1][ Consequently, the drug is classified as an antidementia and neuroprotectant agent, leveraging the mechanisms of both its constituent compounds.][6]

Target Indication: Moderate-to-Severe Alzheimer's Disease

[The primary therapeutic target for BPS-034 (DM Duo) is patients diagnosed with moderate-to-severe Alzheimer's disease.][1][ This indication aligns with the established clinical use of memantine, which is typically introduced for these later stages of the disease, often as an adjunct to ongoing cholinesterase inhibitor therapy, such as donepezil.][5]

Table 1: BPS-034 (BPDO-1603 / DM Duo) - Drug Profile Summary

Feature	Description
Alternative Names	BPDO-1603, BPS 034, DM Duo
Developer	Hyundai Pharmaceutical Co., Ltd.
Chemical Class	Small molecule, Fixed-Dose Combination
Key Components & Strength (Example)	Donepezil Hydrochloride 10mg, Memantine Hydrochloride 20mg (as in DM Duo Tab. 10/20mg) 11
Mechanism of Action	Acetylcholinesterase inhibitor (Donepezil component) & NMDA receptor antagonist (Memantine component)
Target Indication	Moderate-to-severe Alzheimer's Disease

3. Pharmacology and Mechanism of Action

Donepezil Component: Acetylcholinesterase Inhibition

[Donepezil, one of the active pharmaceutical ingredients in BPS-034, is a centrally acting, potent, selective, and reversible inhibitor of the enzyme acetylcholinesterase (AChE).][13][ The primary mechanism of donepezil in Alzheimer's disease involves enhancing cholinergic neurotransmission. In AD, there is a well-documented deficiency in acetylcholine (ACh), a neurotransmitter critical for cognitive functions such as memory, learning, and attention, primarily due to the degeneration of cholinergic neurons.][13][ By inhibiting AChE, the enzyme responsible for the hydrolysis of ACh in the synaptic cleft, donepezil effectively increases the concentration and prolongs the availability of ACh at cholinergic synapses.][13][ This action is thought to temporarily improve cognitive function or slow its decline. Donepezil exhibits relative specificity for AChE in the brain compared to butyrylcholinesterase found peripherally, which may contribute to its tolerability profile.][15][ While some non-cholinergic mechanisms have been investigated, such as the upregulation of nicotinic receptors or direct effects on ion channels, these are generally considered less likely to contribute significantly to its clinical efficacy at therapeutic doses.][15][ There is also some evidence suggesting that donepezil may modulate neuroinflammatory responses by downregulating microglial and astrocytic activation, which are pathological features of AD.][15]

Memantine Component: NMDA Receptor Antagonism

[Memantine, the second active component of BPS-034, functions as an uncompetitive (open-channel), low-to-moderate affinity, voltage-dependent N-methyl-D-aspartate (NMDA) receptor antagonist.][5][ The rationale for its use in Alzheimer's disease stems from the theory of glutamatergic excitotoxicity. Glutamate is the principal excitatory neurotransmitter in the central nervous system, and its interaction with NMDA receptors is crucial for synaptic plasticity, learning, and memory.][9][ However, in AD, it is hypothesized that chronic, low-level overactivation of NMDA receptors by glutamate leads to excessive calcium (Ca2+) influx into neurons. This sustained Ca2+ overload can trigger a cascade of intracellular events, ultimately resulting in neuronal dysfunction and degeneration.][7][ Memantine selectively blocks the ion channel of NMDA receptors when it is pathologically overstimulated, particularly targeting extrasynaptic NMDARs, thereby attenuating the detrimental effects of excessive glutamate. Importantly, due to its voltage-dependency and rapid off-rate kinetics, memantine does not interfere significantly with the normal, transient physiological activation of NMDA receptors required for cognitive processes, thus preserving their essential functions.][9]

Rationale and Potential Synergies of Combination Therapy

[The rationale for combining donepezil and memantine in a single formulation like BPS-034 is rooted in their distinct yet potentially complementary mechanisms of action, addressing different aspects of Alzheimer's disease pathophysiology.][5][ Donepezil aims to ameliorate the cholinergic deficit, while memantine seeks to protect against glutamatergic excitotoxicity. Clinical guidelines often recommend the combination of a cholinesterase inhibitor and memantine for patients with moderate-to-severe AD, reflecting the clinical experience that such a multi-target approach may offer broader symptomatic benefits.][5]

[A primary driver for the development of FDCs like BPS-034 is the potential to improve patient adherence by simplifying the treatment regimen.][2][ Alzheimer's patients, often elderly and cognitively impaired, may struggle with complex medication schedules. Memantine monotherapy typically requires twice-daily administration, whereas donepezil is usually taken once daily. An FDC allows for a once-daily administration of both drugs, thereby reducing pill burden and potentially enhancing compliance.][2]

[Regarding pharmacological synergy, the evidence is mixed. While some studies and clinical experience suggest that combining these two classes of drugs can lead to benefits beyond what is achieved with monotherapy, particularly in global function or behavior ][10][, the pivotal Phase 3 trial for BPS-034 (NCT04229927) did not demonstrate a statistically significant superiority in its primary cognitive and global endpoints when compared to donepezil monotherapy.][2][ This suggests that for the specific population and endpoints tested, the combination within BPDO-1603 might offer an additive effect or benefits primarily derived from improved adherence rather than a robust synergistic pharmacological enhancement. Notably, one independent study highlighted a significant beneficial additive drug-drug interaction effect between donepezil and memantine concerning five-year survival rates in AD patients, an outcome not typically assessed in standard registration trials but of considerable clinical importance.][17]

[The development of BPS-034 underscores a common strategic consideration in FDC development: the balance between pursuing enhanced efficacy through pharmacological synergy and achieving better real-world outcomes through improved patient convenience and adherence. Given the Phase 3 trial results for BPS-034, its value proposition appears to lean heavily towards the latter. While the distinct mechanisms of donepezil and memantine target different pathological pathways in AD, the failure to demonstrate superior efficacy in the NCT04229927 trial suggests that, for the chosen SIB and CIBIC-plus endpoints, the incremental benefit of adding memantine to stable donepezil therapy was not statistically significant within the trial's parameters. This does not negate the individual contributions of each drug or the rationale for their combined use based on existing guidelines and other studies, but it does frame the FDC's primary advantage as one of convenience. Real-world adherence to multi-drug regimens is a significant challenge in AD, and an FDC simplifies this, potentially leading to more consistent drug exposure and, consequently, better long-term management, an aspect that might not be fully captured in a traditional superiority trial focused on direct pharmacological effects over a relatively short duration.]

4. Clinical Development Program

Phase 1 Study (NCT05804279)

[The early clinical development of BPS-034 included a Phase 1 study, registered under NCT05804279, titled "Pharmacokinetics and Safety of BPDO-1603 or BPDO-16031 and BPDO-16033 Administration in Healthy Adults".][1]

Design, Objectives, Population:

This study was a randomized, open-label, single-dose, cross-over trial conducted in 24 healthy adult volunteers.1 Sponsored by Hyundai Pharmaceutical Co., Ltd., its primary objectives were to assess the pharmacokinetics (PK) and safety of BPDO-1603 and potentially related formulations or compounds designated as BPDO-16031 and BPDO-16033.1 The trial was reported as completed, with initiation on December 28, 2022, and completion dates cited as either February 21, 2023, or April 7, 2023.1

[The inclusion of "BPDO-16031" and "BPDO-16033" in this Phase 1 PK study is indicative of a thorough early-stage formulation development process. Pharmaceutical companies frequently evaluate multiple candidate formulations or minor molecular variations during early clinical phases to identify the optimal profile for further development. These variants could have represented different salt forms, polymorphs, excipient compositions, or slight dosage adjustments aimed at optimizing absorption, stability, or tolerability. The cross-over design employed is an efficient method for comparing the PK profiles of different formulations within the same subjects, minimizing inter-individual variability. While specific PK parameters (such as AUC and Cmax​) and detailed safety results from NCT05804279 are not available in the provided information, the progression to Phase 3 implies that BPDO-1603 was selected as the lead candidate. It is also pertinent to note that a news report concerning the approval of DM Duo mentioned an earlier Phase 1 trial, completed in 2018, which successfully demonstrated bioequivalence between the separate administration of donepezil and memantine and their combined formulation.][2][ This bioequivalence finding is a critical prerequisite for the regulatory acceptance of FDCs.]

Key Pharmacokinetic and Safety Findings:

Detailed results from NCT05804279 are not publicly available in the provided materials. However, the successful completion of this Phase 1 study and progression to Phase 3 implies that BPDO-1603 demonstrated an acceptable pharmacokinetic profile and was generally well-tolerated in healthy volunteers. The earlier 2018 Phase 1 study established the bioequivalence of the FDC to its individual components when administered concomitantly, confirming that the FDC delivers the drugs to the systemic circulation in a comparable manner to separate tablets.2

Phase 3 Study (NCT04229927)

[The pivotal trial in the development of BPS-034 was the Phase 3 study NCT04229927, officially titled "A Multicenter, Randomized, Double-blind, Active-controlled, Phase III Clinical Trial to Evaluate the Efficacy and Safety of BPDO-1603 in Patients With Moderate-to-severe Alzheimer's Disease".][1]

Design, Objectives, Patient Population, Control Arm:

This Phase 3 trial, sponsored by Hyundai Pharmaceutical Co., Ltd., commenced on February 27, 2020, and has since concluded.1 It was a large-scale, multicenter study conducted across 60 institutions in South Korea, enrolling 712 (or 713 in some reports) patients diagnosed with moderate-to-severe Alzheimer's disease.2 Eligible patients had a Mini-Mental State Examination (MMSE) score of ≥5 and ≤20, and a Clinical Dementia Rating-Global Score (CDR-GS) of 2-3 or Global Deterioration Scale (GDS) of 4-7. A key inclusion criterion was ongoing stable therapy with donepezil hydrochloride 10 mg/day for at least 12 weeks prior to screening.22

[The study employed a randomized, double-blind, active-controlled, parallel-assignment design.][1][ Patients were assigned to receive either BPDO-1603 (the fixed-dose combination, N=356) or continue with donepezil hydrochloride 10 mg/day monotherapy (active control group, N=356 or 357).][2][ The primary objective was to evaluate the efficacy and safety of BPDO-1603, with the specific aim of demonstrating superiority over donepezil monotherapy.][1][ The primary efficacy assessment period was 24 weeks (6 months).][2]

Primary and Secondary Endpoints:

The co-primary efficacy endpoints were the change from baseline in the Severe Impairment Battery (SIB) score at 6 months (24 weeks), and the Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIC-Plus) score, with some sources indicating assessment at 4 weeks for CIBIC-Plus.2 The SIB is a cognitive scale designed for individuals with moderate to severe dementia, while the CIBIC-Plus provides a global assessment of change.

Efficacy Results: Detailed Analysis (including failure to meet superiority)

The Phase 3 trial (NCT04229927) did not achieve its primary objective of demonstrating statistical superiority of BPDO-1603 (DM Duo) over donepezil monotherapy.2

Analysis of the SIB scores, using a repeated measures mixed effects model (MMRM), revealed a least squares mean difference between the BPDO-1603 group and the donepezil monotherapy group of 0.11 (95% Confidence Interval: -0.37, 0.58). This difference was not statistically significant, with a P-value of 0.6621.19 Similarly, the results for the CIBIC-Plus endpoint did not demonstrate superiority for the combination therapy.2 These outcomes indicate that, within the parameters of this trial and for this patient population already stabilized on donepezil, the addition of memantine via the FDC did not lead to a statistically significant greater improvement in cognitive or global function compared to continuing donepezil alone.

[The selection of donepezil monotherapy as an active control inherently sets a high benchmark for demonstrating superiority, as donepezil itself provides a degree of symptomatic benefit. The SIB and CIBIC-Plus are standard measures, but the failure to show superiority on these endpoints suggests that the incremental benefit of memantine, when added to robust donepezil therapy in this moderate-to-severe AD population, may be modest or not consistently detectable over a 24-week period with these specific instruments. This outcome does not necessarily nullify the potential value of memantine in this patient population, as other studies and clinical guidelines do support combination therapy.][10][ However, it significantly influenced the subsequent regulatory and marketing strategy for DM Duo, shifting the focus from enhanced efficacy to the benefits of improved patient compliance and convenience.][2]

Safety and Tolerability Profile from the Trial:

Specific adverse event data and detailed safety outcomes from the NCT04229927 trial are not extensively detailed in the provided source materials. Generally, the combination of donepezil and memantine is considered to have a manageable safety profile, although it carries the potential for side effects associated with both individual components, and possibly additive effects.10 The approval of DM Duo implies that no new, unexpected major safety concerns specifically attributable to the FDC emerged during the trial that would have precluded its marketing based on a risk-benefit assessment focused on convenience.

Table 2: Overview of Clinical Trial NCT05804279 (Phase 1)

Feature	Details
Official Title	Pharmacokinetics and Safety of BPDO-1603 or BPDO-16031 and BPDO-16033 Administration in Healthy Adults 1
Phase	1 1
Status	Completed 1
Sponsor	Hyundai Pharmaceutical Co., Ltd. 1
Population	Healthy Adult Volunteers (n=24) 1
Objectives	To assess the pharmacokinetics and safety of BPDO-1603 and its variants (BPDO-16031, BPDO-16033).1
Design	Randomized, Open-label, Single-dose, Cross-over 1
Interventions	BPDO-1603, BPDO-16031, BPDO-16033 1
Key PK/Safety Outcomes	Specific data not detailed in provided sources. An earlier 2018 Phase 1 study reportedly showed bioequivalence of the FDC to separate administration of components.2

Table 3: Overview of Clinical Trial NCT04229927 (Phase 3)

Feature	Details
Official Title	A Multicenter, Randomized, Double-blind, Active-controlled, Phase III Clinical Trial to Evaluate the Efficacy and Safety of BPDO-1603 in Patients With Moderate-to-severe Alzheimer's Disease 1
Phase	3 1
Status	Concluded, with results reported 2
Sponsor	Hyundai Pharmaceutical Co., Ltd. 3
Population	712 patients with moderate-to-severe Alzheimer's Disease, on stable donepezil 10mg/day 3
Objectives	To evaluate the efficacy (aiming for superiority) and safety of BPDO-1603 compared to donepezil monotherapy.1
Design	Randomized, Double-blind, Active-controlled (Donepezil HCl monotherapy), Parallel assignment 1
Interventions	BPDO-1603 vs. Donepezil hydrochloride 19
Primary Endpoints	Change from baseline in Severe Impairment Battery (SIB) score at 6 months; Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIC-Plus).2
Summary of Efficacy Results	Failed to demonstrate statistical superiority over donepezil monotherapy. SIB Least Squares Mean Difference vs. control: 0.11 (95% CI -0.37, 0.58), P=0.6621.2 CIBIC-Plus also not superior.2
Summary of Safety Results	General tolerability implied by subsequent regulatory approval; specific adverse event data from this trial not detailed in provided sources.

5. Formulation, Dosage, and Administration

Available Formulations and Strengths

[BPS-034 is marketed in South Korea as DM Duo Tab. 10/20mg, an oral tablet formulation.][2][ Each tablet contains Donepezil Hydrochloride Monohydrate 10.43mg (equivalent to 10mg of Donepezil Hydrochloride) and Memantine Hydrochloride 20mg.][11][ This specific strength combines standard maintenance doses for both components. The DM Duo tablet is described as a deep yellow, oval, film-coated tablet.][11][ The excipients listed for DM Duo Tab. 10/20mg include D-mannitol, microcrystalline cellulose, magnesium stearate, Opadry Yellow (03B52165), lactose hydrate, hydroxypropyl cellulose, and hypromellose.][11]

[It is important to note that other fixed-dose combinations of donepezil and memantine exist in different markets, such as Namzaric in the United States, which is available as extended-release capsules with varying strengths (e.g., 7mg memantine/10mg donepezil, 14mg/10mg, 21mg/10mg, and 28mg/10mg) to allow for titration of the memantine component.][28][ BPDO-1603 itself was developed as an oral formulation.][4]

[The choice of an immediate-release tablet for DM Duo by Hyundai Pharmaceutical, as opposed to an extended-release formulation seen in some other markets, may have been influenced by factors such as manufacturing simplicity, cost considerations, or specific bioequivalence targets relative to the existing separate immediate-release products available in South Korea. A key formulation challenge for any once-daily FDC of these two drugs is accommodating memantine's typical twice-daily dosing schedule (when given as immediate-release monotherapy) to align with donepezil's once-daily administration. Hyundai's DM Duo, being a once-daily tablet, has addressed this, likely through formulation design ensuring appropriate release characteristics for once-daily dosing while maintaining bioequivalence to the separate components, as suggested by their earlier Phase 1 study.][2][ The focus on a single combined strength (10mg donepezil / 20mg memantine) for DM Duo simplifies prescribing for patients who are either already stable on these maintenance doses or are targeted to reach them.]

Recommended Dosing Regimen

[The specific dosing regimen for DM Duo Tab. 10/20mg is not explicitly detailed beyond its strength in the provided information, but FDCs of this nature are typically administered once daily, often in the evening to align with donepezil's common administration time and to potentially mitigate certain side effects.][28]

[For patients new to memantine or transitioning from donepezil monotherapy, a gradual dose titration of the memantine component is standard practice to enhance tolerability. For instance, with FDCs like Namzaric, treatment is often initiated with a lower dose of memantine (e.g., 7mg in a 7mg/10mg FDC) and escalated weekly to the target maintenance dose.][28][ While DM Duo is presented as a 10mg/20mg strength, it is unclear from the snippets if lower-strength versions for titration are available in the Korean market or if the expectation is for patients to be stabilized on separate components before switching. However, the product information for Namzaric (an analogous FDC) indicates that patients stabilized on memantine hydrochloride (10 mg twice daily or 28 mg extended-release once daily) and donepezil hydrochloride 10 mg once daily can be switched directly to the 28 mg/10 mg FDC.][29][ By analogy, patients stable on donepezil 10mg and memantine 20mg (as 10mg BID) might be directly switched to DM Duo 10/20mg.]

6. Regulatory Status and Market Information

South Korean MFDS Approval (DM Duo): Basis and Implications

[DM Duo Tab. 10/20mg, the marketed formulation of BPDO-1603, received approval from the South Korean Ministry of Food and Drug Safety (MFDS) for the treatment of moderate-to-severe Alzheimer's disease.][2][ News of this approval emerged around October/November 2024 (based on a November 2024 article referencing "last month").][2][ This marked it as the first fixed-dose combination of donepezil 10mg and memantine 20mg to be approved in South Korea.][2]

[The basis for this regulatory approval is particularly noteworthy. Despite the pivotal Phase 3 trial (NCT04229927) failing to demonstrate statistical superiority in efficacy of the combination over donepezil monotherapy, the MFDS granted approval.][2][ The primary justification cited for this decision was the ]improvement in medication compliance[ (복약순응도 개선) anticipated from the simplified regimen.][2][ By reducing the number of pills a patient needs to take—especially consolidating memantine's typical twice-daily dosing with donepezil's once-daily schedule into a single tablet—the FDC is expected to enhance adherence. Hyundai Pharmaceutical emphasized that medication adherence is a critical factor in the long-term management and prognosis of dementia patients, and a simplified regimen can significantly ease the burden on both patients and their caregivers.][2]

[This approval by the MFDS reflects a pragmatic regulatory stance, acknowledging that benefits beyond direct superior efficacy, such as enhanced patient adherence and convenience, can hold significant clinical value. This is especially pertinent for chronic conditions like Alzheimer's disease, which affect vulnerable elderly populations who often struggle with polypharmacy and complex medication schedules. The decision implies that if the individual components are well-established standards of care and their combination is clinically rational, an FDC that demonstrably improves ease of use can be considered for approval even without showing enhanced pharmacological effect over one of its components.]

Patent Landscape

[The development of fixed-dose combinations of memantine and donepezil is supported by intellectual property protections. Patent documents such as EP2243475A1 (with a 2006 priority date, linked to Korean application KR1020077025686A) cover combinations of these two active ingredients for treating CNS disorders, including Alzheimer's disease.][32][ More recent patents, like WO2020240505A1 and its European counterpart EP3843702A1, specifically describe immediate-release fixed-dose pharmaceutical compositions comprising memantine and donepezil, detailing formulation aspects such as being lactose-free and having specific dissolution rates.][33][ These patents provide a framework for the commercial exclusivity of such FDC products.]

Availability and Market Presence

[DM Duo is slated for launch in the South Korean domestic market.][2][ Notably, Hyundai Pharmaceutical was not the sole entity involved in the development of this specific FDC; seven other companies reportedly participated in the initiative and are also expected to seek regulatory approval for their respective versions of the donepezil 10mg/memantine 20mg combination.][2][ This suggests an anticipated emergence of a new market segment for this FDC in South Korea, likely leading to competition among these eight companies and potentially broader patient access to this convenience-focused treatment option.]

[The regulatory decision by the MFDS may also influence or reflect a broader trend in how FDCs are evaluated for chronic diseases where adherence is a significant challenge. By prioritizing patient-centric benefits, regulators can facilitate access to treatments that, while not necessarily more potent pharmacologically, may lead to better overall real-world outcomes due to more consistent use. This creates a viable pathway for pharmaceutical companies to develop and market FDCs based on improving the practicality of existing, evidence-based combination therapies.]

7. Comprehensive Safety Profile

[The safety profile of BPS-034 (DM Duo) is intrinsically linked to the known safety profiles of its individual components, donepezil and memantine, as well as potential additive or unique adverse effects arising from their combination. Information is derived from clinical trials of the components, studies of their combination, and post-marketing pharmacovigilance data.]

Adverse Drug Reactions (from clinical trials and post-marketing/FAERS data)

[A real-world pharmacovigilance study utilizing the FDA Adverse Event Reporting System (FAERS) database (January 2004 – January 2024) analyzed 712 reports involving the concomitant use of Donepezil and Memantine in AD patients, identifying 42 distinct adverse drug reactions (ADRs).][26][ Several of these were highlighted as newly reported signals for the combination, including:]

• [Hypertensive crisis]
• [Hyperglycemia]
• [Hyperosmolar nonketotic syndrome]
• [Proteinuria]
• [Hydronephrosis ][26]

[Other ADRs identified in this FAERS analysis for the combination included hyperkalemia, sinus bradycardia, and extrapyramidal disorders.][26]

[The study also noted significant differences in ADR profiles between genders:]

• Males[ were more likely to experience prostate hypertrophy, acute kidney injury, and cerebral infarction.]
• Females[ were more prone to severe cardiovascular events, such as complete atrioventricular (AV) block and ventricular extrasystoles.][26]

[More generally, common side effects associated with memantine/donepezil FDCs (such as Namzaric, an analogous product) include gastrointestinal disturbances (diarrhea, nausea, vomiting, constipation, decreased appetite), neurological symptoms (dizziness, headache), and upper respiratory tract infections.][27]

[Serious, though less common, adverse events (with unknown specific incidence for DM Duo but recognized for the combination) can include:]

• [Gastrointestinal bleeding (bloody or black, tarry stools, severe stomach pain, vomiting of blood)]
• [Significant cardiovascular events (chest pain, lightheadedness, fainting, slow or irregular heartbeat)]
• [Decreased urination]
• [Seizures]
• [Severe fatigue or breathing difficulties.][27]

[The emergence of new ADR signals and gender-specific ADRs from the FAERS database for the donepezil-memantine combination, which may not have been prominent in individual drug trials or even initial FDC registration trials, highlights the value of post-marketing surveillance. Clinical trials, even large Phase 3 studies, have inherent limitations in detecting rarer ADRs or those that manifest predominantly with long-term exposure or in more diverse, real-world patient populations with multiple comorbidities and concomitant medications. Pharmacovigilance systems capture data from a broader spectrum of use, providing crucial insights into the evolving safety landscape of a drug or combination. The potential for pharmacokinetic or pharmacodynamic interactions between the two drugs in an FDC might also lead to ADR profiles that differ subtly from those of the individual components. The observed gender-specific ADRs warrant further investigation to understand if they stem from differences in drug metabolism, distribution, or underlying physiological susceptibility. This underscores the necessity for ongoing monitoring of DM Duo's safety profile in the Korean population post-launch, providing clinicians with a more comprehensive understanding of risks beyond what is detailed in initial product labeling.]

Drug Interactions (Donepezil, Memantine, and the combination)

Donepezil:

• [Metabolized primarily by cytochrome P450 (CYP) isoenzymes CYP2D6 and CYP3A4. Consequently, inhibitors of these enzymes (e.g., ketoconazole, quinidine) may increase donepezil plasma concentrations, while inducers (e.g., rifampin, phenytoin, carbamazepine, dexamethasone) may decrease them.][15]
• [As a cholinomimetic, donepezil may have synergistic effects with other cholinergic agonists (e.g., succinylcholine, other ChEIs) and antagonistic effects with anticholinergic medications.][15]
• [It can cause bradycardia and AV block, and this risk may be potentiated by concomitant use of other drugs that slow heart rate or AV conduction (e.g., beta-blockers, certain calcium channel blockers, digoxin).][15]
• [Donepezil itself can prolong the QTc interval, and co-administration with other QTc-prolonging drugs should be approached with caution.][28]

Memantine:

• [Primarily excreted unchanged in the urine. Its elimination can be affected by urinary pH; alkaline urine (e.g., due to carbonic anhydrase inhibitors, sodium bicarbonate) can significantly decrease its clearance and increase plasma levels.][9]
• [May have additive effects or potentiate the side effects of other NMDA receptor antagonists such as amantadine, ketamine, and dextromethorphan. Co-administration with dextromethorphan is listed as contraindicated for Namzaric.][28]
• [May reduce the effects of hydrochlorothiazide.]

Combination (BPS-034 / DM Duo):

• [The FDC will carry the interaction risks of both components.]
• [Specific FDCs like Namzaric are reported to have severe interactions with drugs like dronedarone and thioridazine, and numerous other serious and moderate interactions have been identified.][28]
• [Clinicians must carefully review all concomitant medications.]

Contraindications, Warnings, and Precautions

Contraindications:

• [Known hypersensitivity to memantine hydrochloride, donepezil hydrochloride, piperidine derivatives (e.g., from donepezil structure), or any excipients in the formulation. (This is standard; not explicitly stated for BPDO-1603 in snippets but applicable).]

Warnings and Precautions (based on component properties and general FDC knowledge) [27]:

• Cardiovascular Conditions:[ Risk of bradycardia, AV block, syncope (primarily due to donepezil's vagotonic effects). Use with caution in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions.]
• Peptic Ulcer Disease and GI Bleeding:[ Cholinesterase inhibitors like donepezil may increase gastric acid secretion. Monitor patients at increased risk (e.g., history of ulcers, concomitant NSAID use).]
• Respiratory Conditions:[ Use with caution in patients with a history of asthma or chronic obstructive pulmonary disease (COPD) due to potential for bronchoconstriction from cholinomimetic activity.]
• Seizure Disorders:[ Both donepezil and memantine have been associated with seizures, though causality is not always clear. Use with caution in patients with a history of seizures.]
• Genitourinary Conditions:[ Cholinomimetics may cause bladder outflow obstruction. Conditions that significantly raise urine pH (e.g., renal tubular acidosis, severe urinary tract infections) can decrease the elimination of memantine, leading to increased plasma levels.]
• Renal Impairment:[ Memantine is predominantly excreted renally. Dose adjustment is recommended for the memantine component in severe renal impairment (e.g., for Namzaric, the recommended maintenance dose is 14mg memantine/10mg donepezil).][28][ DM Duo's fixed 20mg memantine dose may require careful consideration or may not be suitable for patients with severe renal impairment.]
• Hepatic Impairment:[ Use with caution in severe hepatic impairment, as both drugs are metabolized or affect liver function to some extent.]
• Anesthesia:[ Donepezil may exaggerate succinylcholine-type muscle relaxation during anesthesia.]
• Weight Loss:[ Nausea, vomiting, and diarrhea associated with donepezil may lead to weight loss, especially in underweight patients.]

Table 4: Summary of Key Adverse Drug Reactions for Donepezil/Memantine Combination (BPS-034/DM Duo)

Adverse Reaction	Reported Frequency/Severity (Examples)	Data Source Example(s)	Notable Subgroup Differences (from FAERS study )
Gastrointestinal	Diarrhea, Nausea, Vomiting, Constipation, Decreased appetite, Severe stomach pain, GI bleeding (tarry stools, hematemesis)	General combination data 27	N/A from snippets
Neurological/Psychiatric	Dizziness, Headache, Agitation, Confusion, Depression, Insomnia, Somnolence, Seizures, Extrapyramidal disorders	General combination data 27; FAERS 26	Cerebral infarction (Males)
Cardiovascular	Bradycardia, Syncope, AV block, Ventricular extrasystoles, Hypertensive crisis, Chest pain	General combination data 27; FAERS 26	Complete AV block, Ventricular extrasystoles (Females)
Metabolic/Renal	Hyperglycemia, Hyperosmolar nonketotic syndrome, Proteinuria, Hydronephrosis, Hyperkalemia, Acute kidney injury	FAERS 26	Acute kidney injury (Males)
General/Other	Fatigue, Upper respiratory tract infection, Pain, Weight loss	General combination data 27	Prostate hypertrophy (Males)

Note: Frequencies are often not specified or vary. "N/A from snippets" indicates no specific subgroup difference was highlighted for that ADR category in the provided material.

Table 5: Potential Drug Interactions with BPS-034 (DM Duo) Components

Interacting Drug/Class	Component Affected	Potential Effect	Management Recommendation (General)	Data Source Example(s)
Anticholinergic agents (e.g., atropine, benztropine)	Donepezil	Antagonism of donepezil's effects; reduced efficacy of both.	Avoid or use with caution; monitor for reduced donepezil efficacy.	General pharmacology
Other Cholinesterase Inhibitors / Cholinomimetics	Donepezil	Additive cholinergic effects, increased risk of cholinergic crisis (e.g., SLUDGE syndrome, bradycardia).	Generally avoid concurrent use.	15
CYP3A4 inhibitors (e.g., ketoconazole, itraconazole)	Donepezil	Increased donepezil levels, potential for increased side effects.	Monitor for donepezil toxicity; consider dose adjustment if needed.	15
CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin)	Donepezil	Decreased donepezil levels, potential for reduced efficacy.	Monitor for reduced donepezil efficacy; consider dose adjustment.	15
CYP2D6 inhibitors (e.g., paroxetine, fluoxetine)	Donepezil	Increased donepezil levels, potential for increased side effects.	Monitor for donepezil toxicity; consider dose adjustment if needed.	15
Drugs that prolong QTc interval (e.g., certain antiarrhythmics, antipsychotics)	Donepezil	Increased risk of Torsades de Pointes and other serious arrhythmias.	Avoid or use with extreme caution; ECG monitoring.	28
Beta-blockers, other heart rate-lowering drugs	Donepezil	Potentiation of bradycardia and AV block.	Use with caution; monitor heart rate and rhythm.	27
NMDA Antagonists (e.g., amantadine, ketamine, dextromethorphan)	Memantine	Additive effects, increased risk of CNS side effects (e.g., dizziness, confusion, hallucinations).	Avoid or use with caution (Dextromethorphan co-use contraindicated for Namzaric per 28).	28
Drugs that alkalinize urine (e.g., carbonic anhydrase inhibitors, sodium bicarbonate)	Memantine	Decreased memantine clearance, increased plasma levels and potential toxicity.	Avoid or use with caution; monitor for memantine toxicity.	9
Hydrochlorothiazide	Memantine	Memantine may reduce the effects of hydrochlorothiazide.	Monitor diuretic efficacy.	General pharmacology

8. Discussion

Clinical Significance of BPS-034 (DM Duo) in Alzheimer's Disease Management

[The primary clinical significance of BPS-034 (DM Duo) in the management of moderate-to-severe Alzheimer's disease does not stem from enhanced pharmacological efficacy but rather from its potential to improve medication adherence by simplifying the daily dosing regimen.][2][ Patients with AD, particularly in the moderate to severe stages, often face challenges with managing multiple medications due to cognitive decline, and their caregivers bear a significant portion of this burden. Polypharmacy is common in this elderly demographic. By combining two standard-of-care treatments, donepezil (typically once daily) and memantine (typically twice daily as immediate-release), into a single once-daily tablet, DM Duo directly addresses the issue of pill burden. This simplification can lead to better adherence, which is crucial for achieving consistent therapeutic effects from any medication.]

Balancing Efficacy, Safety, and Patient Compliance

[The development and regulatory approval of DM Duo highlight a critical balance in therapeutic evaluation.]

• Efficacy:[ The pivotal Phase 3 trial (NCT04229927) did not demonstrate that BPDO-1603 was superior to donepezil monotherapy in improving scores on the SIB or CIBIC-Plus.][2][ This finding is a significant limitation if the expectation for a combination product is inherently superior efficacy over its components.]
• Safety:[ The FDC carries the combined adverse effect profiles of both donepezil and memantine. Real-world pharmacovigilance data from FAERS also suggest potential for new or more frequent ADRs with the combination, including gender-specific concerns.][26][ Therefore, careful patient selection, monitoring for adverse events, and management of drug interactions are paramount.]
• Compliance:[ This is where DM Duo's primary value proposition lies. For patients already indicated for both drugs, or for whom memantine is being added to donepezil, the reduction in the number of daily administrations is a tangible benefit. Improved compliance due to a simpler regimen ]could[ theoretically translate into better long-term, real-world outcomes, even if direct pharmacological superiority is not evident in a controlled trial setting. This was the cornerstone of its approval in South Korea.][2]

Comparison with Monotherapies and Separately Administered Combination

• Versus Donepezil Monotherapy:[ As established, BPDO-1603 did not show superior efficacy in the Phase 3 trial. Patients on donepezil monotherapy who are not yet candidates for memantine would not be prescribed this FDC.]
• Versus Memantine Monotherapy:[ Donepezil is generally initiated earlier in AD (mild to moderate stages), while memantine is added or used as monotherapy in moderate to severe stages. The FDC is intended for patients suitable for the combination, typically those already on donepezil and progressing to a stage where memantine is indicated.]
• Versus Separate Pills:[ The FDC offers convenience and potentially better adherence than taking donepezil and memantine as separate tablets, especially if memantine is taken twice daily. However, an FDC reduces dosing flexibility; if individual dose adjustments of one component are needed (e.g., due to side effects or renal impairment for memantine), the FDC may not be suitable. An earlier Phase 1 study reportedly demonstrated bioequivalence of the FDC to the co-administration of separate tablets, ensuring comparable systemic exposure.][2]

Unmet Needs and Future Directions for BPS-034 (DM Duo) or Similar Combinations

A significant unmet need in Alzheimer's disease is the lack of truly disease-modifying therapies that can halt or reverse the underlying pathology. Symptomatic treatments like donepezil, memantine, and their combination in DM Duo play a role in managing symptoms and potentially improving quality of life for a period.

For DM Duo specifically, future directions could include:

• [Conducting real-world evidence studies to assess its impact on long-term patient outcomes, actual adherence rates in routine clinical practice, caregiver burden, and healthcare resource utilization. Such studies would be crucial to substantiate the benefits derived from improved compliance.]
• [Further investigation into the gender-specific ADRs and other new signals identified in pharmacovigilance databases to better characterize the safety profile of the combination in diverse populations.]
• [Exploring the utility of the FDC in specific patient subgroups who might derive greater benefit from the convenience aspect.]

[The approval of DM Duo, despite not achieving superiority in efficacy, reflects a broader shift in evaluating therapeutic value in chronic diseases. For conditions where long-term medication adherence is a major challenge and significantly impacts outcomes, patient-centric factors like convenience and regimen simplification are gaining increasing regulatory and clinical importance. This is particularly true when an FDC combines well-established drugs with known safety profiles and a strong clinical rationale for their co-administration. Pharmaceutical development strategies may increasingly leverage FDCs not solely for potential synergistic efficacy but as a practical means to improve real-world effectiveness by enhancing patient adherence. This approach necessitates a different kind of value demonstration, focusing on patient-reported outcomes, adherence data, and potentially health economic benefits, especially in diseases like Alzheimer's where caregiver burden and quality of life are also significant considerations.]

9. Conclusion

[BPS-034, marketed as DM Duo by Hyundai Pharmaceutical, is a fixed-dose combination of donepezil hydrochloride (10mg) and memantine hydrochloride (20mg) approved in South Korea for the treatment of moderate-to-severe Alzheimer's disease. Its development and approval highlight a strategic focus on improving patient compliance and convenience rather than demonstrating superior pharmacological efficacy over its individual components.]

[The dual mechanism of action, targeting both the cholinergic deficits (via donepezil's acetylcholinesterase inhibition) and glutamatergic excitotoxicity (via memantine's NMDA receptor antagonism), aligns with established therapeutic strategies for Alzheimer's disease. However, the pivotal Phase 3 clinical trial (NCT04229927) did not show that BPS-034 offered statistically significant superiority in cognitive or global outcomes compared to donepezil monotherapy.]

[Consequently, the primary clinical value of DM Duo lies in its potential to simplify the medication regimen for patients who are candidates for, or already stabilized on, both donepezil and memantine. By reducing pill burden, particularly by offering a once-daily alternative to regimens involving twice-daily memantine, DM Duo aims to enhance medication adherence, which is a critical factor in the long-term management of a chronic and debilitating condition like Alzheimer's disease, especially in an elderly and often cognitively impaired population.]

[The safety profile of DM Duo is generally consistent with the known adverse effects of its individual components. However, emerging real-world pharmacovigilance data suggest the possibility of additional or nuanced adverse drug reactions associated with the combination, including potential gender-specific safety signals, underscoring the need for vigilant post-marketing surveillance and careful patient monitoring. Prescribers must also consider potential drug interactions associated with both active ingredients.]

[In summary, BPS-034 (DM Duo) occupies a specific niche in the therapeutic armamentarium for Alzheimer's disease. It is a rational option for patients where simplification of the treatment regimen is a clinical priority to support adherence, provided that the fixed-dose combination is appropriate for the individual patient's needs and that its safety profile is carefully managed. Its approval reflects a pragmatic regulatory approach that values patient-centric benefits in chronic disease management.]

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