Effects of Valproic Acid Supply Shortage on Pharmacy Operations in a Region of Japan

Introduction Valproic Acid (VPA) is an essential drug in epilepsy treatment, yet it has faced supply instability in Japan. The extent of the VPA shortage and the associated increase in pharmacists' workload and collaboration with healthcare organizations remains unclear. This study investigates the potential effects of these disruptions on the roles of pharmacists. Methods A questionnaire was administered to pharmacies in Hachioji City, Japan. The survey addressed inventory management, patient complaints, and the potential effects on pharmacy operations during VPA supply instability. A chi-squared test of independence was conducted to compare the most unstable VPA supply period with the current supply situation. Supply stability according to pharmacy characteristics such as the number of prescriptions received per day and primary patient age group was also evaluated. Results Of the 42 pharmacies surveyed, 76.2% reported changes in prescription processing due to VPA supply issues. The main challenges were increased workload in inventory management and patient concerns regarding medication availability and quality. Pharmacies primarily serving clinical prescriptions and pediatric patients were the most affected by the supply instability. Discussion This study highlighted the potential effects of VPA supply instability on pharmacy operations. Pharmacists are expected to provide continuous treatment to patients through effective counseling and medication guidance to alleviate anxiety and concerns related to supply shortages.


Introduction
Valproic acid (VPA) possesses high efficacy and safety for generalized and unclassified epilepsy and is an essential antiseizure medication (ASM) in Japan [1].A network meta-analysis concluded that VPA has the best profile compared to all other ASMs and is the first-choice drug for generalized epilepsy per the guidelines of the Japanese Society of Neurology [2,3].According to calculations using the Defined Daily Dose by the World Health Organization and prescription amounts obtained from the National Database of Health Insurance Claims and Specific Health Checkups Open Data Japan, VPA had the largest proportion of ASM prescriptions in Japan for the fiscal year 2020 [4,5].
Following administrative actions against two generic drug manufacturers in Japan for legal violations, the supply of VPA decreased, leading to unstable supply nationwide [6].Since August 2021, various pharmaceutical companies began halting and adjusting VPA shipments, and in October 2021, the Japan Epilepsy Society issued recommendations concerning the instability of VPA supply.Subsequently, the supply situation gradually improved.By October 2023, all shipment adjustments for VPA had been lifted.Although lamotrigine and levetiracetam are recommended as alternative monotherapy drugs for generalized epilepsy to replace VPA, the choice of ASMs depends on the individual patient profiles, and not all patients experience unchanged seizure frequency when their medication is switched [2].Seizures can lead to serious consequences such as injury or death to a patient or others, and the loss of a driving license.Therefore, pharmacists can bear a large burden in ensuring VPA is stocked and adjusting prescription volumes compared to other medications.The aforementioned guidelines recommend not switching from brand-name to generic drugs when seizure management is under control [3].However, in situations where certain medications are unavailable, changes have been unavoidable due to stock situations.Psychological changes in patients due to medication adjustments can affect the control of seizures [7], which underscores the importance of pharmacist medication guidance.From the perspective of providing medication guidance, the burden on pharmacists is likely to have increased.
A questionnaire survey conducted by the Japan Epilepsy Society in 2022 revealed that 28% of physicians chose ASMs other than VPA when starting new treatments, and 6% attempted to discontinue or change VPA administration in existing therapies [8].Furthermore, 55% of the respondents indicated that they were aware of this supply instability.However, the unavailable portion of the initial VPA supply remains uncertain.Additionally, the extent to which the decreased VPA supply has heightened the burden on pharmacists and the adequacy of collaboration with medical institutions to address this issue are both unclear.
This study investigated the effects of an unstable VPA supply on the roles of pharmacists in local pharmacies in Japan using a questionnaire survey.

Study subjects and period
We surveyed member pharmacists of the Hachioji Pharmacists Association in Hachioji City, Tokyo, Japan, to investigate the impact of VPA supply instability on their work.Pharmacies that had not received prescriptions for VPA for epilepsy treatment since January 2020 were excluded to remove pharmacies that had not handled VPA prescriptions since before the VPA shipment adjustment.The survey period was from July 10, 2023 to August 25, 2023.

Questionnaire development
The questionnaire was developed based on the guidelines for questionnaire surveys [9].This involved generating, reducing, and revising question items, followed by a pre test.Responses were primarily binary options or Likert scales.The questionnaire is written in Japanese and includes sections on the target respondents, time required to complete the questionnaire, implementation period for the questionnaire, study overview, ethical considerations, and question statements.The questions mainly focus on pharmacy characteristics, current and past VPA supply situations, patient complaints, the impact on pharmacists' work, and recommendations for medication adjustments.

Questionnaire testing
Referring to the previously mentioned guidelines, pre-tests were conducted [9].To test the questionnaire's comprehensiveness and clarity, we administered the questionnaire in person to two pharmacists from the study group.Subsequently, we assessed the questionnaire's clinical sensibility (ability to discriminate among responses, face validity, content validity, and ease of use) and specificity tables (to determine the relevance and appropriateness of the questions in relation to collected items and research participants) using a 4-point Likert scale by administering it to five pharmacists from the Hachioji Pharmacists Association excluding study group members.The questionnaire was revised and finalized based on the results of the pre tests.Supplementary Material S1 (see Appendices) presents the content of the questionnaire.An English-translated version of the questionnaire is also available as Supplementary Material S2 (see Appendices).

Questionnaire administration
Google Forms (Google LLC, Mountain View, CA, USA) was used to collect and compile the responses.The Hachioji Pharmacists Association sent respondents e-mails containing the link to the questionnaire.If more than one pharmacist at a given pharmacy was a member of the Hachioji Pharmacists Association, they were asked to combine their answers; therefore, one questionnaire per pharmacy was provided.If multiple responses were received from the same pharmacy, the most recent one was used.A reminder e-mail was sent during the implementation period to reduce non-response errors.Only the pharmacy name and e-mail address were collected for personal information to avoid duplicate responses.The collected information was stored on an external hard drive with a password and maintained in a locked cabinet.

Statistical analyses
A chi-squared test of independence was conducted to compare the most unstable VPA supply period with the current supply situation.The number of prescriptions handled daily by each pharmacy was categorized into two groups using the median as the cut-off value.The chi-squared test was also used to assess differences in supply stability based on the number of prescriptions received daily, the primary source of prescriptions (clinic or hospital), and the primary patient age group (adult or pediatric).Unanswered responses were excluded from the analyses.Statistical analyses were performed using SPSS version 29 (IBM, Armonk, NY, USA).The level of statistical significance was set at 5%.The sample size was calculated based on the assumption of detecting a 30% absolute change in the proportion of prescription changes experienced, shifting from 50% in the control group to 20% in the treatment group.This calculation considered a standard deviation of ±5, aiming to achieve a study power of 80% and a significance level of 5%.The sample size was calculated to be 78 based on these conditions.

Ethical approval and participant consent statement
This study was performed in accordance with the Declaration of Helsinki and was approved by the Tokyo Medical University Ethics Committee (Approval No. T2023-0034).Participation in the survey was voluntary, and consent was obtained from the respondents before they completed the questionnaire.

Pharmacist responses and anxiety levels during supply instability
The responses regarding supply instability at each pharmacy are shown in Figure 1.

FIGURE 1: Pharmacist reactions to valproic acid supply instability.
Statistical analysis was performed using the chi-squared test.
During the most unstable period, 57.1% (n=24) of pharmacists reported "severe anxiety," whereas 28.6% (n=12) reported "moderate anxiety."In the current situation, there were no reports of both "severe anxiety" and "moderate anxiety," and this change in response was statistically significant (p < 0.01).The reactions, categorized by the daily number of prescriptions received, main source of prescriptions, and primary patient age groups, are presented in Table 1.Statistical analysis was performed using the chi-squared test.
Regarding adjustments made in response to VPA supply instability, 76.2% (n=32) of pharmacists performed at least one form of modification during prescription processing (Fig. 2).The most common modification was switching from generic to brand-name drugs (57.1%, n=24), followed by switching from brand-name to generic drugs (54.8%, n=23).Some pharmacies referred patients to other pharmacies (38.1%, n=16  Statistical analysis was performed using the chi-squared test. The rate of prescription modifications was higher in pharmacies serving both adult and pediatric patients than in those serving only adults, although the difference was not significant (93.3% vs. 66.7%, p = 0.052).
Similarly, no significant variation was observed in the rates of prescription adjustments based on primary sources of prescriptions or number of prescriptions received daily.

Patient complaints and pharmacy adjustments
Patient complaints received by pharmacists are shown in Figure 3. Responses were collected if the pharmacy had encountered the situation at least once.The frequent issue reported was anxiety about not being able to obtain medication (61.9%, n=26) and anxiety about medication quality (28.6%, n=12).There were no reports of increased epileptic seizures or emergence or worsening of side effects due to medication changes.

Workload of pharmacists and cooperation with other health care providers
Questions on the impact of VPA supply instability on pharmacists' roles consisted of three items: "medication guidance to patients," "inventory and supply status management," and "inquiries to medical The greatest increase in workload was reported in "inventory and supply status management," with 64.3% (n=27) of pharmacists indicating a "substantial increase in burden" and 23.8% (n=10) reporting a "moderate increase in burden." The results regarding the collaboration of pharmacists with physicians and medical institutions are presented in Figure 5.Only 7.1% (n=3) of pharmacists reported making medication changes using protocol-based pharmaceutical management (PBPM) without the need for clarification inquiries, and merely 11.9% (n=5) conducted conferences or exchanged opinions.

Status of recommendation to switch medication
Figure 6 shows pharmacist recommendations to patients regarding switching to generic ASMs before and after supply instability.VPA, valproic acid.
According to the epilepsy clinical guidelines in Japan, "It is recommended not to switch to generics in patients whose seizures are well-controlled," thus responses were obtained based on the seizure control status of the patients [3].There was no notable change in the recommendations for generics before and after VPA supply instability for all patients.Approximately 40% of pharmacists reported that they recommended a switch to generic ASMs for patients under seizure control during the two periods.

Discussion
This study was the first to investigate in detail the impact of the unstable VPA supply in Japan on community pharmacies and clarified the specific effects on pharmacist workloads and patient care.
The study results revealed that the unstable VPA supply had a serious impact on pharmacy operations.Notably, pharmacists experienced a significant increase in workload related to inventory and supply management.According to the survey, 76.2% (n=32) of respondents were forced to request prescription changes from their physicians due to supply shortages.Pharmacies that primarily handled prescriptions from clinics and those serving pediatric patients were particularly affected.Pharmaceutical wholesalers often supply medicines according to the purchasing history of pharmacies.Therefore, pharmacies that receive prescriptions from clinics may have been affected more by the supply instability because they have a smaller supply than pharmacies servicing hospitals due to the smaller number of patients they serve.The high prevalence of generalized epilepsy and the frequent use of VPA as a first-line drug in pediatric epilepsy may explain why pharmacies dealing with pediatric patients were particularly affected [10,11].
Regarding the complaints pharmacists received from patients, "anxiety about not being able to obtain medication" and "anxiety about medication quality" were the most common.These complaints suggest that they may have impacted patients' psychological health.Anxiety is known to be associated with worsening epilepsy and reduced quality of life [7,12].A survey of patients with epilepsy in Germany found that patients with supply difficulties used treatments with more ASMs and had higher adverse event scores [13].
Medication guidance and counselling by pharmacists may improve patients' quality of life regarding their anxieties [14].In situations of unstable ASM supply, counseling patients about medication changes and follow-up after changes are crucial.
According to existing literature, medication shortages have a severe impact on healthcare settings and patient safety [15][16][17][18].Medication shortages force ingredient changes and switch to generics, which are highly stressful for all stakeholders, including pharmacists, doctors, pharmaceutical wholesalers, nurses, and patients [19,20].The unstable supply of many medicines, not just VPA, in Japan, is probably increasing the burden of pharmacist inventory management.Changing the class of ASMs may cause seizure recurrence if the drugs control epileptic seizures.Furthermore, worsening of clinical conditions has been reported in several cases due to switches to generic ASMs; the pros and cons of switching to generics are debated [21][22][23].In the aforementioned survey, a switch to a generic drug occurred in 39.4% of patients affected by supply difficulties [13].Seizure occurrence can lead to significant events such as life-threatening situations.Therefore, pharmacists may be more burdened in responding to supply instability for ASMs than for other drugs.
The expansion of the generic drug market and intensified price competition have made economic sustainability particularly challenging for small pharmaceutical companies, resulting in unstable supplies [24].One of the reasons behind these incidents is the Japanese government's policies to reduce medical costs to protect the country's universal health coverage, which is in a state of crisis due to the super-aging society.Aggressive policies promoting generic drugs hinder quality assurance and the improvement of domestic regulations, thereby reducing supply reliability.These impacts extend to medications such as ASMs, which are difficult to substitute.According to a study that analyzed the Australian drug shortage reporting database, 93% of the ASM supply shortages were for generic drugs [25].Lowering drug prices, including those of generics, contributes to reducing national healthcare expenditures.However, in addition to the increased burden and labor costs for medical staff due to unstable supply and patient anxiety, the cost of medical care in the event of seizure recurrence must also be considered.Medical costs for the treatment of recurrent epileptic seizures and the transition to status epilepticus superimposed are estimated at 4 billion USD per year in the United States of America and over 83 million EUR in Germany [26,27].To avoid causing these unnecessary increases in healthcare costs, strategies need to be developed to mitigate drug shortages, avoid medication misallocation, and ensure the long-term quality and security of medicines [28].

Limitations
This study had several limitations.The questionnaire survey was limited to a specific region in Japan, and the findings may not be applicable to other regions.The perception of anxiety is subjective, and this may have led to potential bias.Since it was unclear when the period of greatest VPA supply instability occurred, it could not be predefined.The determination of the most unstable period was dependent on respondents' subjective judgment, which may have introduced bias into the research findings.The changes in response rates due to various factors did not align with the calculated sample size.Patient complaints are not reliable indicators of the status epileptic or adverse effects.We were unable to obtain information regarding the mental health and well-being of pharmacists, and the impact on their work motivation remains a subject for future investigation.Despite these limitations, this was the first study to investigate the effect of VPA supply instability on pharmacies.

Conclusions
This survey has clarified the impact of the unstable VPA supply on pharmacists in specific regions of Japan.Pharmacies dispensing prescriptions from clinics and those dispensing for pediatric patients struggled to secure VPA and found stock management tasks to be a significant burden.Policymakers are expected to ensure a stable supply of essential medications, including VPA, even if additional costs must be accepted.Any change in medication requires close follow-up, especially monitoring of epileptic seizures and adverse effects after a change.Pharmacists are expected to provide adequate counselling and medication guidance to reduce patient anxiety and provide ongoing treatment.

Appendices
Supplemental material S1: Content of the questionnaire (Japanese)

FIGURE 2 :
FIGURE 2: Adjustments to prescription filling due to valproic acid supply instability.VPA, valproic acid.

FIGURE 3 :
FIGURE 3: Patient complaints associated with valproic acid supply instability.

FIGURE 4 :
FIGURE 4: Pharmacist workload burdens due to valproic acid supply instability.

FIGURE 5 :
FIGURE 5: Pharmacist collaborations with physicians and medical institutions due to valproic acid supply instability.PBPM, protocol-based pharmaceutical management.

FIGURE 6 :
FIGURE 6: Pharmacist recommendations to patients regarding switching to generic alternative antiseizure medicines.

7- 5 . 8 . 6 .
Switched from one generic to another (different manufacturer) Please tell us about the impact of the supply instability of valproate preparations on pharmacy operations.8-1.Explanation and guidance to patientsSubstantial increase in burdenSlight increase in burdenModerate increase in burdenNo increase in burden 8-2.Inventory management (including checking supply status with wholesalers or pharmaceutical companies)Substanial increase in burdenSlight increase in burdenModerate increase in burdenNo increase in burden 8-3.Inquiries and communication with medical institutions Substantial increase in burden Slight increase in burden Moderate increase in burden No increase in burden 9. Have you received any complaints from patients (or their families) due to the supply instability of valproate preparationsDifficulty swallowing due to change in form (tablets, powders, liquids) Yes No 2024 Matsunuma et al.Cureus 16(7): e65324.DOI 10.7759/cureus.65324

TABLE 1 : Pharmacy characteristics and pharmacists' reactions to the valproic acid supply instability.
). Changing to non-VPA ASMs was the least common adjustment (4.8%, n=2).The responses, categorized by the daily number of prescriptions received, main source of prescriptions, and primary patient age groups, are presented in table 2.