INTRODUCTION
It is widely recognized that more than 70% of people aged 65 and above in China suffer from one or more chronic diseases, making polypharmacy extremely common. While taking medications as prescribed is the foundation of disease control, the concurrent use of multiple drugs—especially without professional guidance—can significantly increase the risk of adverse drug events, drug–drug interactions, and even hospitalization [1–2]. Consequently, the use of medications in older adults represents a complex safety management challenge rather than a simple accumulation of therapies. In this process, pharmacovigilance (PV), through systematic monitoring, evaluation, and prevention, plays an important role in identifying the risks of polypharmacy and optimizing medication regimens.
I. Terminology: What Is “Polypharmacy”?
“Polypharmacy” generally refers to the long-term concurrent use of five or more medications and is a common phenomenon in geriatric medicine [3].
In clinical practice, polypharmacy can be divided into “appropriate” and “inappropriate” types. “Appropriate polypharmacy” refers to the necessary combined use of multiple evidence-based medications for patients with multiple conditions. Of greater concern is “inappropriate polypharmacy,” which not only involves excessive numbers of medications but also includes the following common problems:
1. Inappropriate drug selection: Use of medications in which risks outweigh benefits for older adults [4].
2. Unreasonable dosing: Failure to adjust doses according to hepatic and renal function.
3. Drug–drug interactions: Concomitant use of multiple drugs leading to reduced efficacy or increased toxicity.
4. “Prescribing cascade”: Misinterpreting adverse drug reactions as new diseases, leading to additional prescriptions and a cascading cycle of medication use.
Thus, the key to evaluating polypharmacy lies not in the number of drugs, but in whether the regimen is truly reasonable, necessary, and safe.
II. Real-World Challenges: Potential Risks of Polypharmacy
Drug–drug interactions are among the most insidious risks associated with polypharmacy. As people age, changes in body composition occur—an increased proportion of fat and reduced body water—leading to prolonged retention of lipophilic drugs and decreased volume of distribution for hydrophilic drugs, thereby increasing their initial blood concentrations. At the same time, natural declines in liver and kidney function slow drug metabolism and excretion. Together, these physiological changes amplify both the risk and severity of drug interactions.
The following high-risk drug combinations commonly encountered in clinical practice require particular vigilance:
1. Warfarin + Ibuprofen: Concomitant use significantly increases the risk of gastrointestinal bleeding and may raise the international normalized ratio (INR) from the therapeutic range of 2–3 to dangerous levels (e.g., above 4.5).
2. Statins + Erythromycin: Competition for CYP450 metabolic pathways increases statin plasma concentrations, markedly raising the risk of myalgia and liver injury.
3. Antihypertensives + Diuretics + NSAIDs: The combined use of these three drug classes can synergistically impair renal function, reduce renal perfusion, and elevate creatinine levels—constituting the a three-fold impact of kidney injury.
In addition, inhibition of drug-metabolizing enzymes is an important mechanism underlying interactions. For example, when statins metabolized by CYP450 3A4 are used together with azole antifungal agents, statin plasma concentrations can increase by 5–10 times, significantly increasing the risk of rhabdomyolysis.
Therefore, the focus of polypharmacy management is the systematic review of medication regimens to proactively identify and avoid such high-risk combinations.
III. Safe Navigation: How to Traverse the “Minefields” of Polypharmacy
Addressing the complex challenge of polypharmacy requires coordinated efforts among policy guidance, professional intervention, and individual management to jointly build a medication safety net.
To systematically address medication safety challenges in older populations, the Center for Drug Evaluation (CDE) of the National Medical Products Administration has successively issued three technical guidelines covering preclinical research, clinical trials, and drug labeling, thereby strengthening lifecycle management from a regulatory perspective:
1. General Principles and Key Considerations for Age-Friendly Design in Innovative Drug Development
This document proposes age-friendly requirements from the earliest stages of development and regards polypharmacy as a core characteristic of older patients:
1) General principles: Clearly states that polypharmacy is common among older patients and must be systematically considered during development.
2) Formulation design: Recommends sustained-release formulations to reduce dosing frequency or the development of auxiliary medication devices to reduce complexity; also emphasizes the risk of excipient and electrolyte overload when multiple formulations are used concomitantly.
3) Clinical trials: Risk management plans should assess older participants’ understanding of and ability to comply with requirements to avoid concomitant medications.
2. Key Elements and Trial Design Considerations for the Participation of Older Adults in Innovative Drug Clinical Trials
This guideline focuses on clinical trial design and emphasizes early consideration of real-world concomitant medication use during development, including:
1) Inclusion and exclusion criteria: Representative older populations with concomitant medications should be included.
2) Interaction assessment: Drug–drug interactions should be evaluated through clinical pharmacology studies (e.g., plasma concentration monitoring) or physiologically based pharmacokinetic (PBPK) modeling.
3) Post-marketing studies: Continued collection of real-world data is encouraged to optimize dosing regimens for older adults in polypharmacy settings.
3. Key Points for Writing Medication Information for Older Adults in Drug Labels
This document aims to standardize drug labeling and strengthen information disclosure and risk warnings related to polypharmacy. Core requirements include:
1) Drug interactions: Differences between older patients and the general adult population must be described; if interactions are more severe in older adults, this must be clearly stated.
2) Dosage and administration: Drugs that may be co-administered or should be avoided must be specified.
3) Contraindications: Specific drugs that are prohibited due to serious risks should be clearly listed, avoiding vague statements.
4) Precautions: Comprehensive warnings related to polypharmacy, including adverse reaction monitoring, risks of excipient overload, and guidance on medication adherence.
In clinical practice, healthcare institutions and pharmacists are key to preventing medication-related risks. By establishing “personal medication records,” providing medication reconciliation services, and conducting medication reviews, pharmacists and physicians can systematically assess all of a patient’s medications, identify inappropriate polypharmacy and potential interactions, and offer professional recommendations to simplify regimens—an important practical application of pharmacovigilance.
In addition, patients and their families should become proactive “health managers” by regularly organizing medicine cabinets, creating and carrying medication lists, actively asking about drug indications, usage, adverse reactions, and contraindications during medical visits, remaining alert to potential “prescribing cascades” caused by new medications, and embracing the concept of “medication deprescribing.” Regular reviews with physicians should be conducted to assess whether some medications can be safely discontinued.
Conclusion
Polypharmacy is a double-edged sword. It is both a powerful tool of modern medicine for managing complex chronic diseases and a source of significant safety risks. However, this challenge does not warrant excessive concern. From national-level age-friendly regulatory initiatives, to professional pharmaceutical services provided by healthcare institutions, to increased self-management awareness among patients and families, a multi-level, comprehensive medication safety system grounded in pharmacovigilance principles is steadily taking shape.
References
[1] Cheng T, Tu H, Guo T, et al. Summary of best evidence for polypharmacy management in older patients. Chinese Journal of Nursing Education, 2023, 20(2): 217–222.
[2] Deng J, Wang L, Li Y, et al. Clinical study on optimizing polypharmacy in older adults using comprehensive geriatric assessment. Southwest Military Medical Journal, 2021, 23(2): 167–169.
[3] Li C, Lin X, Chen M. Meta-analysis of the clinical effects of prescription simplification interventions for polypharmacy in older patients. Chinese Journal of Geriatric Multi-Organ Diseases, 2019, 18(3): 161–168.
[4] Li C. Construction of an intervention system for polypharmacy in hospitalized older patients [D]. Chinese PLA Medical School, 2019.
[5] Center for Drug Evaluation, NMPA. General Principles and Key Considerations for Age-Friendly Design in Innovative Drug Development (Trial). October 2025.
[6] Center for Drug Evaluation, NMPA. Key Elements and Trial Design Considerations for the Participation of Older Adults in Innovative Drug Clinical Trials (Trial). October 2025.
[7] Center for Drug Evaluation, NMPA. Key Points for Writing Medication Information for Older Adults in Drug Labels (Trial). October 2025.
