State of the European Union's early notification obligation for drug shortages: enforcement and compliance in eight European countries (2020-2022).

BACKGROUND: Early notification of impending drug shortages is essential for mitigating or preventing shortages. Since 2019 pharmaceutical companies in the European Union (EU) and European Economic Area (EEA) must notify authorities of drug shortages at least two months in advance. This study's aim was to investigate how advance notification of pharmaceutical shortages is functioning in EU/EEA countries and factors possibly associated with differences in notification times. METHODS: This was a retrospective register study using data from publicly available drug shortage registers of all national authorities in the EU/EEA area having such a register. Actual notification times for all drug shortages during January 2020-November 2022 were calculated and included in the descriptive quantitative analysis. RESULTS: Data from eight countries (Belgium, Croatia, Finland, Germany, Norway, Slovakia, Slovenia, and Sweden) were available (18,987 notifications in total). Only 5.2% of all shortage notifications were made at least 60 days in advance and 56.2% of all notifications were made on the shortage's starting day or even later. Data on production-related shortages were available in Belgium, Croatia, Germany, and Norway (n = 2097 showing that 3.9% of those shortages were notified at least 60 days in advance, but 74.3% were made on the starting day or even later. The longest advance notification times for drug shortages were found in Finland during a 12-month period in June 2021-May 2022 when progressive notification fees were in effect. During this national policy experiment, 20.0% of the shortages (n = 1754) were notified at least 60 days in advance, while 24.9% of the notifications occurred on the starting day or even later. Data on notification times for permanent market withdrawals of drugs were available in three countries (Belgium, Slovenia, and Slovakia, n = 1737): 21.2% of these notifications were made at least 60 days in advance, while 45.5% of the notifications occurred on the starting day or even later. CONCLUSIONS: The EU regulatory requirement adopted in 2019 for early notification of drug shortages was unsuccessful in the eight countries having openly available statistics for follow-up. The national policy experiment in Finland with a progressive notification fee seemed to increase compliance with early notification.

National and transnational drug shortages: a quantitative descriptive study of public registers in Europe and the USA.

BACKGROUND: Drug shortages are a growing global problem, posing clinical and economic challenges. To understand them better, we conducted an inventory of national public drug shortage registers and their comparability in Europe and the USA. METHODS: The study was based on openly accessible drug shortage notifications published by national drug authorities. These data were obtained from all national data sources mentioned on the European Medicines Agency's (EMA's) web page and FDA in the USA. After selection of the countries with comparable data, descriptive statistics were used to present characteristics of the shortages both across countries and within countries for 9 months (January-September) in 2020. We studied whether the shortages that occurred in these countries were the same, and how shortages were distributed by therapeutic uses and formulations. We also investigated price variation between the United States and Finland among drugs in shortage in one formulation category (creams and gels). RESULTS: Finland, Sweden, Norway, Spain, and the United States had suitable registers and were included. Altogether 5132 shortage reports from Finland (n = 1522), Sweden (n = 890), Norway (n = 800), Spain (n = 814), and the United States (n = 1106) were published during the study period. Of active ingredient level shortages 54% occurred in only one country, and 1% occurred in all five. However, at the country level, where there was one or more shortage notifications in an ATC active ingredient category, 19-41% were in a single country. The distributions by ATC therapeutic class and drug formulation differed substantially between countries, particularly between the USA and European countries. Injectables had a high shortage risk in the USA (57% of all shortages versus 17-31% of all shortages in the European countries). By contrast, shortages in gels and creams occurred only in European data (4-6% of all shortages). In the price comparison, creams and gels in shortage in Finland were 160% more expensive in the USA where these shortages were not detected. CONCLUSIONS: Public drug shortage registers are vital data sources for proactively maintaining and managing a reliable drug supply. However, our study demonstrates that much work remains to standardize the contents and quality of public register data. Shortages may not be solely a consequence of manufacturing disruptions but may reflect other contributing factors in the international drug distribution and supply mechanisms, including price differences and profit margins between national pharmaceutical markets. Data to perform practical and useful international comparisons to understand these shortages are required.

An In-home Advanced Robotic System to Manage Elderly Home-care Patients' Medications: A Pilot Safety and Usability Study.

PURPOSE: We examined the safety profile and usability of an integrated advanced robotic device and telecare system to promote medication adherence for elderly home-care patients. METHODS: There were two phases. Phase I aimed to verify under controlled conditions in a single nursing home (n = 17 patients) that no robotic malfunctions would hinder the device's safe use. Phase II involved home-care patients from 3 sites (n = 27) who were on long-term medication. On-time dispensing and missed doses were recorded by the robotic system. Patients' and nurses' experiences were assessed with structured interviews. FINDINGS: The 17 nursing home patients had 457 total days using the device (Phase I; mean, 26.9 per patient). On-time sachet retrieval occurred with 97.7% of the alerts, and no medication doses were missed. At baseline, Phase II home-dwelling patients reported difficulty remembering to take their medicines (23%), and 18% missed at least 2 doses per week. Most Phase II patients (78%) lived alone. The device delivered and patients retrieved medicine sachets for 99% of the alerts. All patients and 96% of nurses reported the device was easy to use. IMPLICATIONS: This trial demonstrated the safety profile and usability of an in-home advanced robotic device and telecare system and its acceptability to patients and nurses. It supports individualized patient dosing schedules, patient-provider communications, and on-time, in-home medication delivery to promote adherence. Real time dose-by-dose monitoring and communication with providers if a dose is missed provide oversight generally not seen in home care.

Pharmacy Benefit Management Companies: Do They Create Value in the US Healthcare System?

Pharmacy benefit management companies (PBMs) perform functions in the US market-based healthcare system that may be performed by public agencies or quasi-public institutions in other nations. By aggregating lives covered under their many individual contracts with payers, PBMs have formidable negotiating power. They influence pharmaceutical insurance coverage, design the terms of coverage in a plan's drug benefit, and create competition among providers for inclusion in a plan's network. PBMs have, through intermediation, the potential to secure lower drug prices and to improve rational prescribing. Whether these potential outcomes are realized within the relevant budget is a function of the healthcare system and the interaction of benefit design and clinical processes-not just individually vetted components. Efficiencies and values achieved in price discounts and cost sharing can be nullified if there is irrational prescribing (over-utilization, under-utilization and mis-utilization), variable patient adherence to medication regimens, ineffective formulary processes, or fraud, waste and abuse. Rising prescription drug costs and the increasing prevalence of 'high deductible health plans', which require much greater patient out-of-pocket costs, is creating a crisis for PBM efforts towards an affordable pharmacy benefit. Since PBM rebate and incentive contracts are opaque to the public, whether they add value by restraining higher drug prices or benefit from them is debatable.

Handgrip strength and balance in older adults following withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotics.

BACKGROUND: Benzodiazepines and related drugs affect physical functioning negatively and increase fall and fracture risk. As impaired muscle strength and balance are risk factors for falls, we examined the effects of hypnotic withdrawal on handgrip strength and balance in older adult outpatients during and after long-term use of temazepam, zopiclone and zolpidem (here collectively referred to as "benzodiazepines"). METHODS: Eighty-nine chronic users (59 women, 30 men) of temazepam, zopiclone or zolpidem aged ≥55 years participated in a benzodiazepine withdrawal study. Individual physician-directed withdrawal was performed gradually over a one-month period and participants were followed up to six months. Handgrip strength was assessed using a handheld dynamometer, and balance using the Short Berg's Balance Scale during the period of benzodiazepine use (baseline), and at 1, 2, 3 weeks, and 1, 2 and 6 months after initiating withdrawal. Withdrawal outcome and persistence were determined by plasma benzodiazepine-determinations at baseline and at four weeks ("short-term withdrawers", n = 69; "short-term non-withdrawers", n = 20), and by interviews at six months ("long-term withdrawers", n = 34; "long-term non-withdrawers", n = 55). Also most of the non-withdrawers markedly reduced their benzodiazepine use. RESULTS: Within three weeks after initiating withdrawal, handgrip strength improved significantly (P ≤ 0.005) compared to baseline values. Among women, long-term withdrawers improved their handgrip strength both when compared to their baseline values (P = 0.001) or to non-withdrawers (P =0.004). In men, improvement of handgrip strength from baseline was not significantly better in withdrawers than in non-withdrawers. However, men did improve their handgrip strength values compared to baseline (P = 0.002). Compared to balance test results at baseline, withdrawers improved starting from the first week after withdrawal initiation. There was, however, only a borderline difference (P = 0.054) in balance improvement between the long-term withdrawers and long-term non-withdrawers. Of note, the non-withdrawers tended to improve their handgrip strength and balance compared to baseline values, in parallel with their reduced benzodiazepine use. CONCLUSIONS: Withdrawal from long-term use of benzodiazepines can rapidly improve muscle strength and balance. Our results encourage discontinuing benzodiazepine hypnotics, particularly in older women who are at a high risk of falling and sustaining fractures. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT2008000679530. Registered 31 October 2008.

Content validation of a tool for assessing risks for drug-related problems to be used by practical nurses caring for home-dwelling clients aged ≥65 years: a Delphi survey.

PURPOSE: Home care services are becoming a critically important part of health care delivery as populations are aging. Those using home care services are increasingly older, more frail than previously, and use multiple medications, making them vulnerable to drug-related problems (DRPs). Practical nurses (PN) visit home-dwelling aged clients frequently and, thus, are ideally situated to identify potential DRPs and, if needed, to communicate them to physicians for resolution. This study developed and validated the content of a tool to be used by PNs for assessing DRP risks for their home-dwelling clients aged ≥65 years. METHODS: The first draft of the tool was based on two systematic literature reviews and clinical experience of our research group. Content validity of the tool was determined by a three-round Delphi survey with a panel of 18 experts in geriatric care and pharmacotherapy. An agreement by ≥80% of the panel on an item was required. RESULTS: The final tool consists of 18 items that assess risks for DRPs in home-dwelling aged clients. It is divided into four sections: (1) Basic Client Data, (2) Potential Risks for DRPs in Medication Use, (3) Characteristics of the Client's Care and Adherence, and (4) Recommendations for Actions to Resolve DRPs. CONCLUSIONS: The Delphi process resulted in a structured DRP Risk Assessment Tool that is focused on the highest priority DRPs that should be identified and resolved. The tool also assists the PNs to identify solutions to these problems, which is a unique feature compared to similarly purposed prior tools.

Melatonin for sedative withdrawal in older patients with primary insomnia: a randomized double-blind placebo-controlled trial.

AIM: We compared the efficacy of melatonin and placebo as adjuvants in the withdrawal of patients from long term temazepam, zopiclone or zolpidem (here 'BZD') use. METHODS: A double-blind, placebo-controlled, randomized trial was conducted in a primary health care outpatient clinic. Ninety-two men or women (≥55 years) with primary insomnia and chronic BZD use received controlled release melatonin 2 mg (CRM) (n = 46) or placebo (n = 46) during the 1 month withdrawal from BZDs. Psychosocial support was provided. Follow-up continued for up to 6 months. Successful BZD withdrawal by the end of 1 month was confirmed by BZD plasma determinations, while reduction in BZD use and abstinence continuing for 6 months were noted. RESULTS: There were two drop-outs on CRM and one on placebo. After a 1 month withdrawal, 31 participants (67%; 95% CI 54, 81) on CRM and 39 (85%; 74, 95) on placebo had withdrawn completely (intention-to-treat analysis between groups, P = 0.051; per protocol P = 0.043). Reduction in BZD use was similar or even more rare in the CRM than in the placebo group (P = 0.052 per protocol). After 6 months, 14 participants in the CRM group and 20 in the placebo group remained non-users of BZD (NS between groups). BZD doses were higher in the CRM than in the placebo group at the end of the 6 month follow-up (P = 0.025). Withdrawal symptoms did not differ between the groups. CONCLUSIONS: Gradual dose reduction of BZDs combined with CRM or placebo, and psychosocial support produced high short term and moderate long term BZD abstinence. CRM showed no withdrawal benefit compared with placebo.

Effect of withdrawal from long-term use of temazepam, zopiclone or zolpidem as hypnotic agents on cognition in older adults.

PURPOSE: The aim of this study was to assess the effect of withdrawal from the long-term use of temazepam, zopiclone or zolpidem as hypnotics drugs (here referred to as BZD) on cognitive performance. METHODS: Ninety-two adults (age ≥55 years) with primary insomnia and who were long-term daily users of BZD volunteered to participate in a 1-month medically supported withdrawal attempt from BZD use, with a subsequent 5-month follow-up. Withdrawal was based on plasma BZD measurements at baseline, at 1 month and during subsequent regular clinical appointments. Attention and psychomotor performance were measured using the CogniSpeed® at baseline and at 1, 2 and 6 months. Reaction times were determined in the Simple Reaction Time (SRT), Two-Choice Reaction Time (2-CRT) and Vigilance tests, and errors were measured by the 2-CRT and Vigilance tests. The cognition data of the withdrawal group were also compared with a cohort of BZD non-users. RESULTS: Eighty-nine (97 %) participants (59 women, 30 men) were followed-up for a maximum of 6 months. During the follow-up period, changes in reaction times and errors did not differ between short-term withdrawers (no residual BZD at 1 month; N = 69), non-withdrawers (residual BZD at 1 month; N = 20) or long-term withdrawers (N = 34). Compared to the reaction times of the BZD-free cohort, those of BZD users were slower at baseline. The reaction times of BZD withdrawers based on the results of the SRT or 2-CRT tests during follow-up did not reach those of the BZD-free cohort, but there was no difference between these groups in the Vigilance test. CONCLUSIONS: Long-term use of BDZ as hypnotic drugs by older adults is related to prolonged impairment of attentional and psychomotor cognitive functioning that persists for at least 6 months after withdrawal.

Opioids, antiepileptic and anticholinergic drugs and the risk of fractures in patients 65 years of age and older: a prospective population-based study.

BACKGROUND: in men, the concomitant use of two or more benzodiazepines or two or more antipsychotics is associated with an increased risk of fracture(s). Potential associations between the concomitant use of drugs with central nervous system effects and fracture risk have not been studied. OBJECTIVE: the purpose was to describe the gender-specific risk of fractures in a population aged 65 years or over associated with the use of an opioid, antiepileptic or anticholinergic drug individually; or, their concomitant use with each other; or the concomitant use of one of these with a psychotropic drug. METHODS: this study was part of a prospective, population-based study performed in Lieto, Finland. Information about fractures in 1,177 subjects (482 men and 695 women) was confirmed with radiology reports. RESULTS: at 3 years of follow-up, the concomitant use of an opioid with an antipsychotic was associated with an increased risk of fractures in men. During the 6-year follow-up, the concomitant use of an opioid with a benzodiazepine was also related to the risk of fractures for males. No significant associations were found for females. CONCLUSION: the concomitant use of an opioid with an antipsychotic, or with a benzodiazepine may increase the risk of fractures in men aged 65 years and older.

Comprehensive medication review: development of a collaborative procedure.

This commentary describes the development and evidence-base of the Comprehensive Medication Review (CMR) procedure for community and hospital settings in Finland. The development was coordinated by a national steering group. The group collaborated with 26 experienced pharmacists who developed and tested CMR procedures during a 1.5 year accreditation training for CMR. The development consisted of: (1) a literature review and inventory of medication review procedures in different countries; (2) the creation of potential procedures and related documentation; (3) integration of potential procedures into a national standard procedure; and (4) piloting the standard procedure in practice settings. The resulting comprehensive medication review procedure requires access to a patient's clinical information, an in-home patient interview and a case conference with the collaborating physician. This procedure covers the four main dimensions critical for safe and appropriate geriatric pharmacotherapy: aging and safety; co-morbidities; polypharmacy; and adherence. The CMR measures and documentation build on these dimensions.

CNS medications as predictors of precipitous cognitive decline in the cognitively disabled aged: a longitudinal population-based study.

BACKGROUND/AIMS: Psychotropics and antiepileptics (AE) are medications commonly used among the aged with cognitive decline or dementia, although they may precipitate further cognitive decline. Our aim was to analyze the relationships between the use of (i) psychotropics (i.e. benzodiazepines or related drugs, BZD, antipsychotics, AP, or antidepressants, AD), opioids (Op), anticholinergics (ACh) or AEs or the concomitant use of two of these drugs, and (ii) the risk of precipitous cognitive decline in an older (≥65 years) cognitively disabled population. METHODS: A longitudinal population-based study of general aged community-dwelling patients was executed in two phases (1990-1991 and 1998-1999) in Lieto, Finland. Fifty-two individuals cognitively disabled (MMSE score 0-23) at the 1990-1991 baseline form this study's sample. Cognitive abilities were assessed in each phase with the Mini-Mental State Examination (MMSE) and medication utilization data were collected in both phases. The mean follow-up time was 7.6 years. Multivariate models were used to analyze the change in MMSE total score between medication users and non-users. RESULTS: BZD or any psychotropic use was associated with greater cognitive decline in elders aged ≥75 years compared to non-users (change in MMSE sum score: -8.6 ± 7.0 vs. -3.3 ± 5.6 and -5.9 ± 7.0 vs. -2.7 ± 6.4, respectively). A greater decline was also associated specifically with the concomitant use of BZD and AP (-16 vs. -1.4 ± 7.8); as were BZD and any drug with CNS effects (-9.6 ± 9.9 vs. -1.3 ± 7.2) compared to non-users. The concomitant use of BZD and AD (-10.7 ± 4.7 vs. -3.2 ± 5.6) or ACh (-15.0 ± 8.5 vs. -3.3 ± 5.6) or any drug with CNS effects (-13.3 ± 6.5 vs. -3.3 ± 5.6) was associated with cognitive decline in patients ≥75 years compared to non-users of any drug with CNS effects. CONCLUSION: The use of a BZD or any psychotropic medication may be an independent risk factor for cognitive decline in the cognitively disabled aged, and patients co-prescribed psychotropic medications had greater cognitive decline. Studies with larger sample sizes and studies on possible pathophysiologic mechanisms are needed.

Comparison of prescribing criteria to evaluate the appropriateness of drug treatment in individuals aged 65 and older: a systematic review.

Because inappropriate prescribing is prevalent in individuals aged 65 and older, various criteria to assess it have been developed. This study's aim was to systematically review articles that describe criteria for assessing inappropriate prescribing in individuals aged 65 and older and to define the circumstances of their use (explicit/implicit), origins, development processes, and content. A systematic search was conducted on MEDLINE and PubMed (1990-2010) and augmented with a manual search. Original articles written in English were included if they described the development of the criteria and were aimed at people aged 65 and older. Articles that described criteria applicable only in hospital settings, specific drugs, or a particular disease or condition were excluded. Sixteen of 535 articles met the inclusion criteria. They described 14 criteria, half originating in the United States. The English-language restriction limited the search results. Most criteria were explicit, consensus validated, based totally or partly on Beers criteria, and focused on pharmacological appropriateness of prescribing and some were old. Drug- and disease-oriented explicit criteria require regular updating and are country specific. Implicit, person-specific criteria are universal and do not need updating, although their use requires up-to-date professional skills. Unlike explicit criteria, implicit criteria have been validated in people. Some of the 14 criteria were noncomprehensive, mainly because of the intended purpose. To conclude, different criteria exist for optimizing prescribing for individuals aged 65 and older. Possible deficiencies must be recognized and trade-offs made when selecting criteria for use. In the future, more-comprehensive and -timely criteria are needed.

Impact of systems of care and blood pressure management on stroke outcomes.

Stroke is the third leading cause of death in the United States and the leading cause of disability. Stroke patients' outcomes are strongly determined by how long they remain untreated ("time is brain"). The Joint Commission's adoption of stroke performance improvement measures combined with the Centers for Medicare and Medicaid's more recent adoption in October 2009 make a systems approach to improving stroke outcomes a higher priority. As hospitals establish local and regional stroke care systems to meet these performance measures, treatment of emergent high blood pressure (BP) is a major consideration to improve rapid triage and management of acute stroke patients. Intravenous thrombolysis with tissue plasminogen activator (tPA) is a critical quality of care component for acute ischemic stroke (AIS) treatment, but its administration is contingent on BP management. For patients with AIS who are potentially eligible for tPA and patients with intracerebral hemorrhage, timely, controlled BP may improve patient outcomes. Appropriate BP management, however, is still controversial given the heterogeneity of stroke subtypes, the varying attributes of candidate antihypertensive agents, and both local and central hemodynamics. Additionally, organizational delivery system factors may be suboptimal at some hospitals. Under current hospital stroke performance measures, payment mechanisms, and emergency department throughput measures, the impact of BP management may become transparent to patients and payers, and have important consequences for hospital-derived stroke outcomes.

Potentially inappropriate medication use among Finnish non-institutionalized people aged ≥65 years: a register-based, cross-sectional, national study.

BACKGROUND: The Beers criteria and their modifications are the most frequently used tools for measuring potentially inappropriate medication (PIM) use among older people. The prevalence of such use in various settings has been high, but no data have been reported for an entire national non-institutionalized elderly population, nor is there information on the reimbursement costs for those medications. OBJECTIVE: To determine the prevalence of PIM use according to the Beers 2003 criteria, independent of diagnoses, among Finnish non-institutionalized people aged ≥65 years, and the reimbursement costs for these medications. METHODS: A register-based cross-sectional national study used drug reimbursement data from Finland's Social Insurance Institution (SII). These data cover the entire non-institutionalized population aged ≥65 years in 2007. The number of persons who received reimbursements for each PIM according to the Beers 2003 criteria and the total annual reimbursement costs for PIMs were calculated. Indirect costs were excluded. RESULTS: Of the non-institutionalized population aged ≥65 years in Finland (n = 841,509), 14.7% (n = 123,545) had received PIMs according to the Beers 2003 criteria. Temazepam >15 mg/day was clearly the most commonly reimbursed PIM (4.4% of the population aged ≥65 years), followed by amitriptyline (2.0%) and diazepam (1.8%). The SII paid drug reimbursements of €2.9 million for PIMs, which was 0.7% of the total drug reimbursements (€421 million) for people aged ≥65 years in Finland in 2007. CONCLUSIONS: The use of PIMs among outpatients aged ≥65 years in Finland (14.7%) was less than in several earlier large-scale studies in other countries (17-42%) and reimbursement costs were modest, mainly as a result of the limited availability in Finland of medicines identified as PIMs by the Beers 2003 criteria. However, benzodiazepines were commonly used and actions to improve medication safety should target reducing their use.