Sleep medicines are often prescribed for older adults (≥75 years) without appropriate dosing instructions: A nationwide retrospective register study in Finland

Sleep medicines should be prescribed cautiously, accompanied by instructions that ensure appropriate use and reduce risks. This is especially important for older adults, for whom many of these medicines are classified as potentially inappropriate medicines.

dispensed via automated multi-dose dispensing systems, which is aimed for long-term treatment.Interpretation: It is common to prescribe sleep medicines for older adults without appropriate dosing instructions, particularly excluding warnings against long-term, regular use.Actions to change the current prescribing practices are warranted.

| INTRODUCTION
Sleep disorders, especially insomnia, are highly prevalent and often follow a chronic course. 1 Cognitive behavioral therapy for insomnia (CBT-I) is the primary choice of treatment for insomnia, regardless of the underlying etiology, or the patient's age or sex. 1,2Yet, in practice the treatment is often initiated with pharmacological treatments and CBT-I remain rarely routinely implemented.2][3] However, these drugs alter sleep structure and reduce the amount of deep, non-rapid eye movement (NREM) sleep and rapid-eye movement (REM) sleep. 1,4Potential adverse effects and other clinical problems include dizziness, problems in motor functions and coordination (e.g., impaired walking), and drug dependency. 5]10 Notably, the European Guidelines for the Treatment and Diagnosis of Insomnia 1 do not recommend treatment of insomnia with sedative antihistamines or antipsychotics due to lack of evidence and the risk of developing tolerance (see Reference [11]).In general, pharmacological intervention-mainly benzodiazepines, benzodiazepine-like drugs, or orexin receptor antagonists-is recommended only for short-term (≤4 weeks) treatment of insomnia. 1Long-term pharmacotherapy is warranted but should be restricted to specific circumstances on an individual basis, for example, when insomnia may aggravate psychiatric symptoms (e.g., schizophrenia and bipolar disorder).
Older adults are especially vulnerable to several adverse effects associated with the use of benzodiazepines and Z-drugs.These adverse effects include increased risk of falls, 12 cognitive decline, and dementia, 1,5,13,14 perhaps through a reduction in NREM sleep and glymphatic clearance of amyloid beta. 15Older adults are also at higher risk for long-term use of benzodiazepines and Z-drugs than younger individuals. 16,17Therefore, many international criteria consider sedative sleep medicines as

Significant Outcomes
• Nearly half of the medicine purchases were dispensed via automated dose dispensing, which is a practice that can maintain regular, long-term treatment.• Dosing instructions for prescribed sleep medicines are often insufficient.• Only a minority of dosing instructions contained warnings/remarks concerning longterm use.

Limitations
• The data included only medicine purchases covered by the national public reimbursement scheme.• The analysis included only prescriptions with the written dosing instructions with keyword(s) indicating the treatment of insomnia.• Dosing instructions of sleep medicines dispensed through automated multi-dose dispensing were excluded although they made almost half of all purchases.
potentially inappropriate medications (PIMs) for geriatric care. 18,19PIMs are medications that pose a higher risk of adverse effects or inefficacy when prescribed for older adults. 18PIMs are usually best avoided or used with caution in geriatric patients.There is also a wide consensus that the benzodiazepines and Z-drugs should be restricted to only short-term use, 1,2 and most prescribing guidelines recommend limiting the treatment duration to a maximum of 2 weeks. 1,18,20However, according to a systematic review, the use and long-term use of benzodiazepines and Z-drugs is common in older age groups. 21n Finland, the overall prevalence of benzodiazepine and Z-drug use was 21.0% still in 2014, long-term use among older adults (aged ≥75 years) being 6.5%. 22ood prescribing practices support the rational and safe use of medicines.Medicine users should be provided with instructions to ensure appropriate use and to avoid risks and unnecessary (long-term) use.In Finland, each time a medicine is prescribed, the prescriber is obliged to write dosing instructions for the patient, which are transferred to the label attached to the medicinal product package when the medicine is dispensed from the community pharmacy. 23According to the regulations in Finland, every prescription should contain written dosing instructions that cover information about single and daily dose(s), time of intake, indication of the medicine, and regularity or duration of use (i.e., length of drug therapy). 23The dosing instructions should be written in plain language. 24The written instructions are especially important for older patients, as they often use multiple medicines concomitantly and may mix their medicines.It is also important for them to understand how their medicines work.However, in real-life practice, older adults are only rarely aware of the potential risks of benzodiazepines that they use on a long-term basis. 25he aim of this nationwide retrospective register study was to investigate the use and appropriateness of the dosing instructions for sedative sleep medicines prescribed to older adults in Finland.We focused on ≥75-year-old individuals because this age group typically starts experiencing more age-related health issues (incl.polypharmacy), and impaired functional changes owing to the cumulative effects of aging.

| Utilized register-based data
The data for this nationwide retrospective study were derived from the electronic "Dispensations reimbursable under the National Health Insurance Scheme" register (later Prescription Register) 26 maintained by KELA (the Finnish Social Insurance Institution, SII) to investigate the extent of use and content of dosing instructions for sleep medicines among Finnish residents aged ≥75 years.The Prescription Register contains the records of all prescription medicine purchases reimbursed by the public National Health Insurance covering all permanent Finnish residents living in noninstitutional settings. 26,27The study was based on the dosing instructions of medicine purchases potentially used for the treatment of insomnia by persons aged ≥75 years during a 1-year period from January 1, 2020, to December 31, 2020.We focused on purchases of pharmacologically sedative drugs and defined sleep medicines as the following medicines included in the Finnish National Current Care Guideline of Insomnia 20 : zolpidem, oxazepam, quetiapine, lorazepam, trimipramine, diazepam, alprazolam, doxepin, mirtazapine, pregabalin, zopiclone, and trazodone.Thus, purchases of sleep medicines not included in the Finnish reimbursement scheme (e.g., temazepam products) were excluded.Moreover, melatonin was also excluded from the analysis.Data about the date of dispensation, Anatomical Therapeutic Chemical (ATC) classification, the pharmaceutical form of the medicine dispensed, its strength, package size, and the number of packages dispensed during the study period were collected.All available strengths of medicines were included in the data.The dosing instructions for each medicine are recorded in the Prescription Register in their original format.Of the background variable data of the patients, sex and age data were used.
The steps used for data selection are shown in Figure 1.The sleep medicine purchases, and dose instructions related to these medicines were collected from the Prescription Register (1,080,843 purchases).Data of purchases from automated multi-dose dispensing systems were separated from the data.The dosing instructions for the remaining medicines purchased were divided into separate datasets according to their ATC codes.These dosing instructions for each individual medicine were separately searched by using predetermined keywords or their parts referring to the treatment of insomnia or insomnia symptoms (Tables S1 and  S2).For this study, only dosing instructions written in Finnish language were included for further analysis as they constituted 95.5% of the instructions related to sleep medicine purchases (Figure 1).Each of the dosing instruction was analyzed separately.We validated the keywords with dosing instructions related to purchases of zolpidem and trazodone.As a result, the keywords or parts of the keywords were found in 99.5% of the zolpidem data and 99.3% of the trazodone data.With these keywords, we identified the dosing instructions for each of the medicine purchases included in the further analyses (n = 328,285 dosing instructions).

| Analysis of the instruction labels
Every prescription medicine package dispensed from the community pharmacy must contain an instruction label for the medicine user.It must contain instructions for use (single and daily dose(s)), and may contain the purpose of the use, if indicated by the prescriber in the prescription.In this study, the instruction labels refer to the instructions for use provided to the medicine user on the dispensing label attached to the medicine package when it is dispensed.The dosing instructions are required to be written exactly as specified in the prescription.We examined the appropriateness of dosing instructions according to four pre-determined criteria shown in Table 1 (criteria 1-4).The criteria were self-specified but based on national legislation 23,24 and Finnish National Current Care Guideline for Insomnia. 20It was assessed whether each dosing instruction fulfilled the criteria 1-4.The number of fulfilled criteria, including the information, was summed for each medicine.
A random sample of 1000 dosing instructions was used to assess the validity of the analysis.Dosing instructions for all drugs except clobazam were included in the analysis.These dosing instructions were read individually, and the aforementioned criteria (1-4, Table 1) were used for the analysis.In addition, instructions for dose reduction or planned discontinuation (deprescribing) and explicit instructions for the duration of use were assessed (criterion 5, Table 1).This extra criterion was based on the recommendation of the Finnish National Current Care Guideline for Insomnia. 18escriptive data analyzes were performed using IBM SPSS Statistics (version 28.0).Microsoft Excel was used for data handling and processing.

| RESULTS
This register study resulted in a dataset of 1,080,843 sedative sleep medicine purchases by 143,886 individuals aged ≥75 years in year 2020 (Figure 1).The three most dispensed medicines in the whole dataset were mirtazapine, quetiapine, and zopiclone (Table 2).Most purchases were subsequent partial deliveries of prescriptions, and the average number of annual dispensations was 3.8 per person, indicating long-term use.Almost half (47.7) of the medicine purchases were made through automated multi-dose dispensing systems, and were thus likely intended for regular, long-term use.Of the remaining purchases, 328,285 purchases by 87,396 different individuals contained keyword(s) potentially referring to the T A B L E 1 Criteria for sufficient information content in sleep medicine dosing instructions (based on national legislation (References [23, 24]) and National Current Care Guideline for Insomnia (Reference [20]).

Criteria
Rationale for the assessment (1) Single dose Medicine user must know how much to take the medicine at a time (2) Time of intake The exact time of dosing for sleep medicines is important to ensure optimal efficacy, align with desired sleep schedules, minimize side effects and risks, and avoid potential interactions.
( F I G U R E 1 (A) Flowchart for analyzing dosing instructions of sleep medicine purchases and their characteristics.SII, the Finnish Social Insurance Institution.
treatment of insomnia.Of these, the three most dispensed drugs were zopiclone (41.0%), mirtazapine (34.3%), and zolpidem (11.5%) (Table 2).Notably, of all the 12 drugs included in the study, only zopiclone and zolpidem have insomnia as their primary and only indication.Despite this, approximately one-tenth of the dosing instructions for zopiclone (9.0%) and zolpidem (10.0%) did not contain words referring to the treatment of insomnia.Most (98.4%) of the dosing instructions that indicated the treatment of insomnia included the dose of the medication and time of intake (83.4%) (Table 3).Temporary short-term use was mentioned in 57.3% of the dosing instructions, whereas only 2.8% included warnings, such as "not suitable for long-term use" (n = 8895) (Table 3).Overall, only 2.1% of the dosing instructions fulfilled all the four criteria for sufficient instructions, as we defined based on the national legislation 23,24 and the Finnish Current Care Guideline for Insomnia. 20None of the dosing instructions for five drugs (doxepin, midazolam, trimipramine, alprazolam, and lorazepam) fulfilled all the criteria for sufficient instructions.The dosing instructions fulfilling all four criteria were most often, although very rarely, found for zopiclone (4.0%), zolpidem (3.3%), and oxazepam (1.3%).
The dosing instructions for different medicines differed most significantly in the frequency of expressing the time of intake.This parameter was most frequently present in the instructions for doxepin (95.5%), trimipramine (91.8%) and quetiapine (86.4%) and less frequent in those for lorazepam (57.7%), diazepam (60.9%,) and oxazepam (63.9%).In addition, a mention of temporary use was most frequently observed in the instructions for zolpidem (86.0%) and zopiclone (85.8%) and least frequently observed in those for trazodone (15.6%), pregabalin (16.8%), and mirtazapine (19.0%).Other remarks and warnings concerning appropriate use were more rarely included in the dosing instructions, most commonly for zopiclone (5.0%) and zolpidem (4.4%).For other medicines, remarks or warnings were included in 0%-2.7% of the dispensed prescriptions.
In a randomized sample of 1000 dosing instructions, the dose was included in almost all instructions (98.8%, n = 988).The time of drug intake was specified in 82.5% (n = 825) of the instructions, and warnings or remarks were included in 5.5% (n = 55).The instruction for gradual discontinuation/deprescribing of the medicine was clearly mentioned in 5.2% of the dosing instructions (n = 52).Only three drugs had these instructions: zopiclone (n = 35), zolpidem (n = 15), and oxazepam (n = 2).Original examples of sufficient and inadequate dosing instructions are given in Table 4.

| DISCUSSION
This nationwide study indicates significant shortcomings in the dosing instructions accompanying the prescriptions of sleep medicines for older adults in Finland.Although nearly all screened dosing instructions included the information about a single dose and the time of intake, only a minority (2%) of the instructions contained sufficient information to ensure appropriate use of the medicines that are classified as potentially inappropriate medicines (PIMs) for older adults. 18,19herefore, the dosing instructions frequently missed information that is required to be provided in a prescription according to the Finnish legislation.Most worrying finding was that the missing information often concerned warnings or notes regarding regular and long-term use of sleep medicines.Notably, the pitfalls in dosing instructions were similar across all assessed medicines.This suboptimal prescribing practice may be one of the contributing factors to the regular long-term use of sleep medicines, and contrary to guidelines. 20Thus, our study implies that sufficient, readily available dosing instructions could be a feasible, but currently undervalued method to support appropriate and safe medication use in outpatient care.Further research is needed to evaluate the impact of improved dosing instructions on appropriateness and prevalence of sleep medicine use for insomnia in older adults.
Our findings indicate that automated multi-dose dispensing may be another contributing factor to regular, long-term use of sleep medicines in older adults.Most strikingly, nearly a half of the reimbursed medicine purchases in our study were multi-dose dispensations, meaning that sedative medicines were regularly administered as part of the standard daily medication regimen.In our dataset, mirtazapine and quetiapine were the most commonly dispensed medicines through automated multidose dispensing.Importantly, these medicines are widely used also for other indications than insomnia (mirtazapine as an antidepressant and quetiapine as an antipsychotic drug).However, regardless of indication, most drugs in our dataset are considered as PIMs for older adults.The finding that these drugs are so commonly dispensed via automated multi-dose dispensing systems raises concerns that should be examined in future studies.Automated multi-dose dispensing systems should be assessed to determine whether the practices, believed to promote rational pharmacotherapy and medication safety, maintains long-term use of PIMs, and exposes older outpatients to preventable harm.Regular medication reviews have been recommended to be integrated into the automated dose dispensing process to prospectively manage medication-related risks. 29,28Notably, automated multidose dispensing is expected to become more common practice in geriatric outpatient care as the population is aging.
More research is needed to assess the potential association between long-term use of sleep medicines   The dosing instruction included the dose, time of intake, warnings or remarks, and mention of irregular use. f The dosing instructions did not contain critical information (e.g., dose).
and the content of dosing instructions.It is also important to investigate whether the content of dosing instructions differs according to the age of patients.Furthermore, clear, explicit content of dosing instructions and instructions for gradual discontinuation/ deprescribing may reduce the long-term use of sleep medicines and promote safer pharmacotherapy among older adults.Our findings indicate that it is important to take action regarding to the common pitfalls in prescribing practices and to enhance the use of dosing instructions in guiding patients in appropriate medicine-taking behaviors.This is especially important when prescribing high-risk medicines such as sleep medicines to older adults.

| Strengths and limitations
Although dosing instructions are a vital source of customized information for medicine users, to our knowledge, this is the first study assessing the content of the dosing instructions.The present study is based on all the purchases of reimbursed sedative sleep medicines, including their dosing instructions, in Finns aged ≥75 years in 2020.Therefore, it offers a relatively comprehensive and timely overview of the quality of sleep medicine prescribing practice in Finland, with a special focus on appropriateness of dosing instructions.However, this study has limitations.First, our approach may give an overly positive impression of the content of use instructions, as it only includes those dosing instructions that were, based on keyword(s) in the labels, indicated for the treatment of insomnia or insomnia symptoms.For example, nearly 20,000 purchases of the hypnotics zopiclone and zolpidem were prescribed and dispensed with dosing instructions without clear indication for insomnia.Second, the data consisted only of medicines reimbursed according to the Finnish Health Insurance Act in 2020.Therefore, purchases of non-reimbursable but widely used sleep medicines such as melatonin or temazepam are not included in the data.Third, the indication (or its severity) to which the medicine was prescribed is not possible to specify in our study.Relatedly, owing to potential typographical errors in the dosing instructions, some instructions might have been excluded from the actual analysis.However, the qualification of the research material was done carefully and validated.Moreover, the study was conducted during the pandemic, which may have also produced mixed effects on the prescribing and use of sleep medicines, and prevalence of insomnia and insomnia symptoms.However, the data describe the first year of the COVID-19 pandemic, with radically diminished contacts between patients and health care professionals.Finally, we only considered prescription labels as a source of dosing instructions.
Dosing instructions and other critical information could have been passed on verbally, or medications could have been dispensed by caregivers with sufficient knowledge about dosing and potential harms.
To conclude our findings indicate that appropriate instructions, particularly warnings about long-term regular use, are neglected in routine practice in prescribing sedative sleep medicines for older adults (≥75 years).Urgent actions to change current clinical prescribing practices are warranted.

T A B L E 3
Analyzed purchase data for medicines indicated for the treatment of insomnia (n = 328,285), their suitability for older adults, and the content of the dosing instructions by active substance.
Drugs are listed according to the proportion (%) of labels that included an indication (keyword(s)) for insomnia treatment.Abbreviations: CCG, National Current Care Guideline for Insomnia (Ref.20); NA, not available.a Insomnia is the only official indication.b Dose >6 mg per day.c Dose reduction in renal impairment.d Parkinson's disease.e Comparison of sleep medicine dispenses included in the original material.Note: Drugs are listed according to the number of pharmacy purchases of dispenses with dosing instructions containing keywords referring to the treatment of insomnia.Abbreviations: CCG, National Current Care Guideline for Insomnia (Reference[20]), NA, not available.The total person number does not sum to persons with all dispenses as individual may have bought studied medicines via dose-dispensing or as sleep medicines or other indications during the study period.
T A B L E 2 a Dosing instructions contain keyword(s) referring to the treatment of insomnia.b Examples of original dosing instructions (sufficient or inadequate) selected from a random sample of 1000 dosing instructions."0.25 tablets in the evening 1-2 hours before going to bed.Use the lowest effective dose.There is no need to use Imovane at the same time.Treatment of insomnia."tablets in the evening as needed to help to get sleep.Melatonin is the first choice.The lower the dose the more effective is the effect on sleep and insomnia."tablets as needed for night.Weakens the quality of sleep.Continuous use worsens insomnia.Worsens memory and other cognitive function.Increases falls.Total weekly use must be decreased by 0.5 tablets during 1 week" Future studies should identify subgroups of older adults who are more vulnerable to the side effects of (long-term) use of sleep medicines, such as nocturnal confusion and falls.
"Sleep medicine" "1/2-1 tablets as needed in the evening just before going to bed.Maximum three nights a week.Long term use can weaken memory and balance.It is recommended to slip the dose in to half and quitting the use.Treatment of insomnia.""1-2aday.Sleep medicine""1/2-1 tablets as needed for night, not over 2 weeks regular use.May cause dependence.