Risk Minimization Action Research Articles

Lessons learned from a cluster of immunization errors in newborns.

Vaccines are safe and effective, but adverse reactions can occur. Immunization errors (IEs) are one of the types of adverse events following immunization. The Moroccan Pharmacovigilance Centre (MPC) received a cluster of IEs from a maternity university hospital (MUH) regarding six newborns who were inadvertently administered rocuronium instead of hepatitis B (HepB) vaccine. The newborns experienced respiratory distress and one had a fatal outcome. The study aimed to describe the investigation findings, the underlying causes, and contributing factors of the IEs cluster, and proposed risk minimization actions. We carried out a descriptive analysis of the cluster of IEs related to the HepB vaccine reported to the MPC. An investigation was conducted by the Ministry of Health according to the World Health Organization guidance. The root cause analysis was performed to identify underlying causes and contributing factors that lead to IE occurrence. The cluster analysis showed that the main contributing factors were the look-alike rocuronium and HepB vaccine packaging, the first-time running HepB vaccination for newborns in the MUH, the lack of a full-time pharmacist, and the unsafe storage of rocuronium and vaccines. The administration of Sugammadex to the newborns followed by their transfer to the neonatal care unit resulted in the recovery of five of the six newborns. Proposed recommendations included (1) raising awareness of healthcare professionals to the risk related to look-alike medications, (2) training nurses to ensure vaccination to implement procedures related to immunization practices, (3) nomination of a full-time pharmacist, (4) reassessment of the safety of drug storage and dispensing at the hospital pharmacy, particularly for high-alert medications. Reporting IEs, particularly serious ones, allows us to identify causes and contributing factors that led to their occurrence. Lessons learned from errors are key to take risk minimization actions to improve vaccine safety worldwide.

Digital Additional Risk Minimization Measures: An Exploratory Study Using Qualitative Feedback from Healthcare Professionals and Patients Across Six Countries.

BackgroundAdditional risk minimization measures (aRMMs) are required for some pharmaceutical products when routine risk minimization measures (i.e., product labeling) are deemed insufficient. Measures often include educational materials, such as paper brochures, leaflets, and/or alert cards that provide information to healthcare professionals and patients on the key risks associated with a product and risk minimization actions to take should particular signs or symptoms arise. Paper-based educational aRMMs have several limitations. They do not present information in an interactive manner, and their update and distribution can be costly and often complex. Measuring how effective they are in achieving their aims can also be difficult. Digital methods offer design and delivery flexibility, easier updating processes, opportunities to increase engagement with important information, as well possibilities for tracking distribution, receipt, and potentially understanding of the materials. Pharmaceutical companies have started to look to digital methods as an option for educational aRMMs, alongside paper materials.ObjectivesResearch into healthcare professionals and patient needs and preferences, as well as the general acceptability of digital educational options is needed to establish a baseline. This was an exploratory study intended to provide initial insights on the acceptability of digital aRMMs and to inform future research directions.MethodsDigital concepts for educational aRMMs, one for healthcare professionals and one for patients, were evaluated with 30 healthcare professionals and 20 patients in six countries through 1:1 Zoom calls, with responses recorded in a structured Qualtrics-based survey. Criteria for selecting the six countries included local familiarity with aRMMs as well as interest in and capability to deliver a potential digital aRMM program by the sponsoring company’s affiliate teams. Of the healthcare professionals, 19 were rheumatologists and 11 were dermatologists. 16 patients had rheumatologic (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) conditions and four had atopic dermatitis. These conditions were chosen as they aligned to potential therapeutic areas where the sponsoring company may have the opportunity to use a digital aRMM. Participants were given an overview of the concept as well as the opportunity to interact with it directly via the “control screen” function in Zoom before questions were posed.ResultsThe results demonstrated that the majority of healthcare professionals (87%) and all patients interviewed would prefer website-based or app-based delivery, respectively, of aRMM information instead of, or alongside traditional paper-based approaches, with only 13% of healthcare professionals and no patients expressing a preference for paper-only communication.ConclusionsGiven new options offered by digital technology, its widespread use in many fields, and the importance of patient safety as a topic, there is an imperative for pharmaceutical companies and regulators to work together to establish a way forward for the use of digital options for aRMMs. This study is limited in its generalizability but offers some ideas for future research directions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40290-021-00415-7.

Risk Management Assessments of Adverse Drug Reactions: A Systematic Review of the Literature

Abstract Background Improving the quality of life of patients is a key concern in public health. In the context of improving therapeutic compliance, quality of life of patients undergoing anti-tuberculosis treatment, and prevention of antibiotic resistance, we conducted this systematic review to support risk minimization actions. Methods A literature review of risk management strategies targeting adverse drug reactions to anti-tuberculosis drugs was conducted, including published observational studies. Two independent reviewers identified studies through Medline, Scopus, and Web of Science. The methodological quality of the included studies was assessed using criteria defined by the Newcastle Ottawa Scale. Results Seven studies were included in this review, which identified four risk management strategies (psychological intervention, reduction of drug dose with or without prescription of adjunctive medications, change of medication, permanent or temporary discontinuation of medication). The strategies adopted were dependent on the nature and severity of the adverse events. All drugs responsible for serious adverse events were changed or discontinued. Three studies had a moderate risk of methodological bias. Conclusions Strategies to minimize the risk of adverse drug reactions and improve adherence to therapy have a strong potential to improve adherence to therapy, improve patient quality of life, and reduce antibiotic resistance. However, high-level evidence on the effectiveness of strategies to minimize the risk of adverse events is limited. Key messages Strategies to manage the risk of adverse drug reactions have a strong potential benefit for TB patients on treatment; and improve adherence to treatment. High-level evidence on the effectiveness of strategies to minimize the risk of adverse events is limited.

Materiovigilance in health centers: The role of notifiers to ensure safer use of medical devices

The implementation of efficient health and vigilance strategy is one of the essential aspects of the health policy of public and private health establishments, in order to reduce the risk of incidents due to medical devices. The objective of this study is to demonstrate the importance of user notification and to recognize the role of nursing staff in the materiovigilance process. This is a retrospective study of materiovigilance cases notified for three years (2016, 2017, and 2018) at the National Institute of Oncology. The evaluation of the incidents was carried out with the aim of taking the necessary measures to prevent and minimize risk. Seven thousand three hundred and eight cases of materiovigilance during the 3 years were collected. A spontaneous collection of reports was predominant (70%). The distribution of the number of incidents by the profile of notifiers shows that reports come from surgeons and much more from nurses. The surgical block (35.7%) and medical oncology services (14.3%) were the services that reported more; the majority of the observed adverse events were attributed to infusion sets (n=7105). Four serious cases of materiovigilance. reported during these 3 years at the level of the vigilance unit considered the most relevant were detailed with examples of immediate actions taken and risk minimization actions. This study highlights the characteristics of incidents reported. The role of the nursing staff and the strong presence of nurses in the vigilance system has been well demonstrated, thus reducing the risk of side effects due to medical devices.

Construction and analysis of a database for medication errors in a pharmacovigilance centre-the Moroccan experience.

The study aimed to describe the epidemiological profile of medication errors (MEs) reported to the Moroccan Pharmacovigilance Center (MPVC), to determine factors associated with serious MEs, and to describe signals related to them. We carried out a retrospective descriptive analysis of MEs reported to the MPVC from 2006 to 2016 and a secondary analysis of the seriousness of MEs with adverse drug reactions (ADRs). The reports were sorted by demographic profile and by ME and ADR characteristics. For signal detection, a quantitative approach was adopted, and the root cause analysis was completed. Epi info 7 software was used to perform descriptive and analytical statistics. The statistical significance level was set at p < 0.05. A total of 1618 ME reports were retrieved. The proportion of MEs associated with serious ADRs was 23.9%. The factors statistically associated with serious MEs were as follows: (i) the age group 16 years old and less (p < 0.001), (ii) the gender (p = 0.01), (iii) the administration and the prescription stages (p < 0.001), and (iv) the ME types related to inappropriate schedule of drug administration, drug prescribing error (p < 0.001), and incorrect drug administration dosage form (p = 0.04). Fourteen signals related to MEs were detected, for which risk minimization actions were implemented. The establishment of a ME unit within the MPVC was an opportunity to further improve the pharmacovigilance centre performance and consequently its contribution to medication safety. The lessons learned from MEs should be shared through pharmacovigilance networks and with institutions involved in medication safety for synergistic results to achieve patient safety worldwide.

IMPLEMENTASI METODE HOUSE OF RISK PADA PENGELOLAAN RISIKO RANTAI PASOKAN HIJAU PRODUK BOGIE S2HD9C (Studi Kasus: PT Barata Indonesia)

In carrying out its business processes, PT Barata Indonesia requires raw material supply and services from related partners to be able to complete work on time. But increasingly complex business competition makes the company inseparable from a risk that can disrupt the normal operation of the system. Therefore supply chain risk management is needed in managing supply chain activities to reduce the impact of the risk. This study uses the House of Risk (HOR) method with the GSCOR approach to minimize the occurrence of risks and potential risk events that can occur in the company's business processes. The results of the identification with the tools why why analysis and the calculation of the house of risk method, identified 82 risk events, 22 risk agents and 22 risk minimization actions. Of the 22 risk agents, 10 risk agents are prioritized based on the largest ARP value in the calculation of HOR1 and 10 risk minimization actions on HOR2 based on the greatest value of Effectiveness to Difficulty Ratio. Based on the results of the analysis of 10 priority risk minimization actions from the calculation of HOR2 obtained 5 risk mitigation strategies namely, 1) implementing the HR development strategy, 2) conducting information disclosure and a customer-focused approach, 3) Determining supplier selection policies that are green certified, 4) procurement planning inverter, 5) Good communication with third parties and partnersek).

Risk Management Assessments of Anti-tuberculosis Adverse Drug Reaction: A Systematic Review

To improve adherence to treatment, quality of life of patients on anti-tuberculosis drugs, and prevent antibiotic resistance, we conducted this systematic review to support risk minimization actions. Methods: Medline, Scopus, and Web of Science were searched with a focus on adverse drug reactions. Two independent reviewers assessed the methodological quality of the included studies using criteria defined by the Newcastle Ottawa Scale. Results: Seven studies were included, and four risk management strategies were identified (psychological intervention, drug dose reduction with or without prescription of adjunctive drugs, drug switching, permanent or temporary drug discontinuation). The strategies adopted were dependent on the nature and severity of the adverse events. All drugs responsible for serious adverse effects were changed or discontinued. Conclusions: The results highlight the relatively low frequency of adverse events leading to permanent discontinuation of 1st-line anti-tuberculosis drugs, but also emphasize the high incidence of adverse events leading to permanent discontinuation of cycloserine.

Use of tramadol and other analgesics following media attention and risk minimization actions from regulators: a Danish nationwide drug utilization study

PurposeTo describe the use of tramadol and other analgesics in Denmark focusing on the impact of media attention (June and December 2017) and regulatory actions (September 2017 and January 2018) on the use of tramadol.MethodsUsing nationwide registries, we identified all adults who filled a prescription for tramadol and other analgesics from 2014 to 2019. We described incidence rates, prevalence proportions, and total use of tramadol and other analgesics over time. We also described switching between analgesics, treatment duration, skewness in drug use, and doctor-shopping.ResultsFrom early 2017 until the end of 2019, total tramadol use decreased markedly while the use of morphine and oxycodone decreased slightly. The quarterly prevalence of tramadol use decreased from 32/1000 individuals in 2014 to 18/1000 at the end of 2019, dropping mainly at the time of media attention. Concomitantly, the quarterly prevalence increased for oxycodone (from 5.1 to 8.2) and morphine (from 8.5 to 9.8), mainly due to more short-term and sporadic users, and decreased for codeine (14 to 9.6). From 2014 to mid-2017, the incidence of tramadol use was stable (around 2.2/1000 person-months) but dropped in June 2017 to 1.7/1000, coinciding with the media attention. The incidence of tramadol use continued to decrease (to 1.1/1000 at the end of 2019).ConclusionWe identified a decline in tramadol use coinciding with the media attention in 2017 and continuing during regulatory actions. There was generally no evidence of unintended effects on the utilization of opioids related to the media attention and regulatory actions.

Signals of adverse drug reactions communicated by pharmacovigilance stakeholders: protocol for a scoping review of the global literature

BackgroundSignals of adverse drug reactions (ADRs) form the basis of some regulatory risk-minimization actions in pharmacovigilance. Reviews of limited scope have highlighted that such signals are mostly supported by reports of ADRs or multiple types of evidence. The time that elapses between a report of a suspected ADR and the communication of a signal has not been systematically characterized. Neither has the features of reports of suspected ADRs that authors used to support putative causal relationships, although difficulties with establishing causal relationships between medicinal products and adverse events have been highlighted. The objectives of this study will be to describe the evidence underpinning signals in pharmacovigilance, the features of reports of ADRs supporting signals, and the time that it takes to communicate a signal.MethodsWe shall retrieve records from PubMed, EMBASE, Web of Science, and PsycINFO (from inception onwards), without language/design restrictions, and apply backward citation screening. We shall hand-search the websites of 35 regulatory agencies/authorities, restricted publications from the Uppsala Monitoring Centre, and drug bulletins. Signals will be requested from the competent stakeholder, if absent from websites. We shall use VigiBase, the World Health Organization’s Global Individual Case Safety Report database, to determine the dates on which ADRs were reported. We shall manage records using EndNote (v. 8.2); one reviewer will screen titles/abstracts and full texts, a second will cross-validate the findings, and a third will arbitrate disagreements. Data will be charted via the Systematic Reviews Data Repository, following the same procedures as for data retrieval. Evidence will be categorized according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Features of reports of ADRs will be coded. Tables will display frequencies of types of evidence and features of reports of ADRs. We shall use plots or pictograms (if appropriate) to represent the time from the first report of a suspected ADR to a signal.DiscussionWe expect the findings from this review will allow a better understanding of global patterns of similarities or differences in terms of supporting evidence and timing of communications and identify relevant research questions for future systematic reviews.Systematic review registrationosf.io/a4xns

A Novel Approach to Visualize Risk Minimization Effectiveness: Peeping at the 2012 UK Proton Pump Inhibitor Label Change Using a Rapid Cycle Analysis Tool.

Evaluation of risk minimization (RM) actions is an emerging area of regulatory science, often without tools to rapidly and systematically assess their effectiveness. The aim of this study was to evaluate whether chronographs, typically used for rapid signal detection in observational longitudinal databases, could be used to visualize RM effectiveness. We evaluated the UK Medicines and Healthcare products Regulatory Agency (MHRA) 2012 proton-pump inhibitors (PPIs) class-wide label change that warned of increased risk of bone fracture, advocated to limit duration of use, and recommended to treat those at risk for osteoporosis according to clinical guidelines. The cohort consisted of adults aged 18years and above prescribed one of the five PPIs available in the UK The Health Improvement Network (THIN) database through September 2015. Four chronographs were compared using drug episodes that started before (PRE) and after (POST) the 20 April 2012 MHRA warning; fracture and osteoporosis were evaluated separately. Chronographs show a measure of observed/expected events, the Information Component (IC) and 95% credibility interval (CI), calculated at monthly time intervals relative to the start date of a prescription, and summed to estimate IC over a 3-year period; IC > 0 indicates observed > expected events. We hypothesized that chronographs may assess RM effectiveness if stratified by PRE/POST an RM intervention such as a label change. There were 1,588,973 and 664,601 PPI users in the PRE and POST periods, respectively. We observed a 4.6% reduction in the proportion of long-term PPI episodes and a 4.1% reduction in the overall proportion of the THIN population using PPIs. Compared with the PRE chronographs, when both visually comparing and when examining the summed ICs for fracture in the POST period, a significant reduction was observed overall (IC = 0.024 [95% CI 0.015 to 0.33] PRE vs - 0.141 [95% CI - 0.162 to - 0.120] POST), suggesting less observed events than expected, and prior to PPI start, suggestive of strong channeling (IC = - 0.027 [95% CI - 0.037 to - 0.017] PRE vs - 0.291 [95% CI - 0.308 to - 0.274] POST). Results were qualitatively similar for osteoporosis. This pilot demonstrated a novel application of a visual, rapid analysis technique to assess RM effectiveness, and supported a hypothesis that prescribers altered some behaviors after the MHRA label change, such as channeling patients at risk of fracture or osteoporosis away from PPI use and potentially reducing fracture outcomes. Limitations include lack of confounding control and outcomes defined only by diagnosis code. Results demonstrate the potential to use large healthcare databases with chronographs to rapidly assess RM effectiveness, similar to signal detection in pharmacovigilance, and may help design more comprehensive RM evaluation studies.

Belgian community pharmacists' pharmacovigilance perspective and practice.

Pharmacovigilance legislation was introduced back in 2012 with new concepts such as the inverted black triangles and risk minimisation activities. Healthcare professionals need to familiarize themselves with these new notions in order to comply with their obligations such as risk mitigation and reporting of adverse drug reactions. To measure the magnitude and relevance of these new concepts and the impact on everyday dispensing in Belgian community pharmacies. An inventory database was constructed containing all relevant pharmacovigilance information at product level, and this data was made available within the pharmacy dispensing software. Furthermore, for a typical community pharmacy, the number of concerned products and the number of dispensed products with supplementary pharmacovigilance responsibilities was determined. The number of available and dispensed medicines with black triangle or additional risk minimisation activities has increased significantly since July 2014. During July 2017, each pharmacy dispensed around 120 packs with risk minimisation obligations and around 70 with a black triangle, clearly illustrating the relevance of having all information at hand. With relevant safety information available at the point of dispensing, pharmacists can now focus on complying with their pharmacovigilance responsibilities.

Pharmacovigilance, signal detection using statistical data mining methods

Pharmacovigilance programmes monitor and help safeguarding the use of medicines which is grave to the success of public health programmes. Identifying new possible risks and developing risk minimization action plans to prevent or ease these risks is at the heart of all pharmacovigilance activities throughout the product lifecycle. In this paper we examine the use of data mining algorithms to identify signals from adverse events reported. The capabilities include screening, data mining and frequency tabulation for potential signals, including signal estimation using established statistical signal detection methods. We have standard processes, algorithms and follow current requirements for signal detection and risk management activities.

Considerations for Successful Risk-Minimisation Strategies in the EU

Determining the appropriate risk-minimisation strategies for a product requires careful consideration. An EU market authorisation provides authorisation for a product to be marketed in all EU member states. However, many factors, including healthcare practice and organisation, culture and local regulations, vary among member states, presenting challenges in determining which and how risk-minimisation activities can be implemented across the EU. This article sets out some points for consideration when implementing risk-minimisation activities in the EU.

Use of Fentanyl Patch for Treatment of Moderate-to-severe Chronic Noncancer Pain: Postmarketing Surveillance of Medical Practice in Japan Using a Risk Minimization Action Plan.

The purpose of this study was to discuss the safety, treatment profile, and clinical effectiveness of 12-month treatment with fentanyl patch (FP), a strong opioid, in medical practice in Japan under the risk minimization action plan (RMAP). Patients with moderate-to-severe chronic noncancer pain who had switched to FP from another opioid were registered to take this survey to assess adverse drug reactions (ADRs), therapeutic effect, and pain intensity for up to 12 months. A total of 517 patients were enrolled, and 499 patients (male, 50.9%; mean [SD] age, 63.0 [15.4] years) were included in the safety population. During the 12-month observation period, an ADR occurred in 262 patients (52.5%); most frequent ADRs included nausea (24.2%), somnolence (22.4%), constipation (18.2%), vomiting (9%), and dizziness (4.6%). The prespecified priority survey items, including respiratory depression, drug dependence, and drug withdrawal syndrome, occurred in 2 (both nonserious), 3 (all serious), and 9 (all serious) patients, respectively. In 418 patients from the efficacy population, the response rate was 77.3%, the rate of achievement of the therapeutic goal was 64.5%, and the visual analog scale (VAS) scores for pain severity decreased by 22.3 (26.9) mm. Our results identified a reasonable risk-benefit profile for the management of moderate-to-severe chronic noncancer pain in patients previously treated with opioids under long-term treatment with FP under the RMAP. Respiratory depression, drug dependency, and drug withdrawal were rarely observed even under the RMAP in Japan.

Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice.

BackgroundOlanzapine long-acting injection (LAI) for the treatment of schizophrenia was associated with a cluster of symptoms termed post-injection delirium/sedation syndrome (PDSS) in a small percentage (~2%) of patients during clinical trials. The objective of this analysis was to evaluate the rate and clinical characteristics of PDSS since olanzapine LAI entered commercial use.MethodsCases of PDSS were identified from all reported adverse events during worldwide commercial use of olanzapine LAI through to 1 March 2014. Data sources included two ongoing post-marketing safety studies as well as spontaneously reported adverse events from routine clinical practice over a 5-year period (1 March 2009 to 1 March 2014).ResultsA total of 338 PDSS events were identified. Of these, 91% occurred within 1 hour of injection, and 52% of these occurred within 15 minutes. None of the PDSS events in this analysis were fatal, and most resolved within 72 hours. The most common symptoms (occurring in >30% of cases) were sedation (61%), confusion (56%), dysarthria (54%), somnolence (46%), dizziness (45%) and disorientation (35%). Overall, PDSS occurred with approximately 0.07% of injections and in 0.46–1.03% of patients (reporting and incidence rates from spontaneous reports and post-marketing safety studies, respectively).ConclusionsThe PDSS events reported during routine clinical use of olanzapine LAI are generally similar in incidence and presentation to those reported in clinical trials. Caution should be applied when interpreting spontaneously reported rates of adverse events, however, due to potential under-reporting. Implemented risk-minimisation activities may contribute substantially to the identification and appropriate management of patients with PDSS in clinical practice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12888-015-0450-9) contains supplementary material, which is available to authorized users.

Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.

BackgroundThere is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in ’90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines.AimTo investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries.MethodsWe identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance.ResultsAntihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible.ConclusionsSome second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.

Bortezomib therapy-related lung disease in Japanese patients with multiple myeloma: incidence, mortality and clinical characterization.

Because of the potentially high mortality rate (6.5%) associated with bortezomib-induced lung disease (BILD) in Japanese patients with relapsed or refractory multiple myeloma, we evaluated the incidence, mortality and clinical features of BILD in a Japanese population. This study was conducted under the Risk Minimization Action Plan (RMAP), which was collaboratively developed by the pharmaceutical industry and public health authority. The RMAP consisted of an intensive dissemination of risk information and a recommended countermeasure to health-care professionals. All patients treated with bortezomib were consecutively registered in the study within 1 year and monitored for emerging BILD. Of the 1010 patients registered, 45 (4.5%) developed BILD, 5 (0.50%) of whom had fatal cases. The median time to BILD onset from the first bortezomib dose was 14.5 days, and most of the patients responded well to corticosteroid therapy. A retrospective review by the Lung Injury Medical Expert Panel revealed that the types with capillary leak syndrome and hypoxia without infiltrative shadows were uniquely and frequently observed in patients with BILD compared with those with conditions associated with other molecular-targeted anticancer drugs. The incidence rate of BILD in Japan remains high compared with that reported in other countries, but the incidence and mortality rates are lower than expected before the introduction of bortezomib in Japan. This study describes the radiographic pattern and clinical characterization of BILD in the Japanese population. The RMAP seemed clinically effective in minimizing the BILD risk among our Japanese population.

新規 DIC 治療薬リコモジュリン&lt;sup&gt;®&lt;/sup&gt;の安全対策

Recomodulin® Inj. 12800 (thrombomodulin alfa) was first approved in Japan for the treatment of disseminated intravascular coagulation (DIC). For marketing of Recomodulin, we designed post-marketing surveillance and safety measures with the aim to confirm proper use of the product and to ensure patient safety, according to the ICH E2E Guideline on Risk Management Plan (RMP), which was released by the Ministry of Health, Labour and Welfare. Following the RMP, we first selected safety specifications (SS) according to the results of clinical studies. For the SS chosen, all-case surveillance was designed as a pharmacovigilance plan (PVP), and strict control of both patient selection and product distribution was undertaken as a risk minimization action plan (RiskMAP). After launching of Recomodulin, we evaluated the information from all-case surveillance periodically. The safety measures were adjusted accordingly, taking into consideration the advice received from the Recomodulin Post-Marketing Surveillance Committee of the Japanese Society on Thrombosis and Hemostasis, as well as the feasibility in the clinical setting. Based on the information from 4260 cases in all-case surveillance, it was possible to identify the safety profile of Recomodulin at the early stage of marketing. In addition, strict control of both patient selection and product distribution was useful in confirming patient safety and ensuring the proper use of Recomodulin early after release on the market. (Jpn J Clin Pharmacol Ther 2013; 44(2): 61-69)

Quantitative Evaluation of Compliance with Recommendation for Sulfonylurea Dose Co-Administered with DPP-4 Inhibitors in Japan

After the launch of dipeptidyl peptidase-4 (DPP-4), a new oral hypoglycemic drug (OHD), in December 2009, severe hypoglycemia cases were reported in Japan. Although the definite cause was unknown, co-administration with sulfonylureas (SU) was suspected as one of the potential risk factors. The Japan Association for Diabetes Education and Care (JADEC) released a recommendation in April 2010 to lower the dose of three major SUs (glimepiride, glibenclamide, and gliclazide) when adding a DPP-4 inhibitor. To evaluate the effectiveness of this risk minimization action along with labeling changes, dispensing records for 114,263 patients prescribed OHDs between December 2008 and December 2010 were identified in the Nihon-Chouzai pharmacy claims database. The adherence to the recommended dosing of SU co-prescribed with DPP-4 inhibitors increased from 46.3% before to 63.8% after the JADEC recommendation (p < 0.01 by time-series analysis), while no change was found in those for SU monotherapy and SU with other OHD co-prescriptions. The adherence was significantly worse for those receiving a glibenclamide prescription. The JADEC recommendation, along with labeling changes, appeared to have a favorable effect on the risk minimization action in Japan. In these instances, a pharmacy claims database can be a useful tool to evaluate risk minimization actions.

Preventable drug-related morbidity in community pharmacy: development and piloting of a complex intervention

Preventable drug-related morbidity (PDRM) arising in the community is a problem of unacceptable magnitude. Effective interventions to reduce this problem will avoid unnecessary patient harm and waste of resources for the health care system. To develop and pilot an intervention to manage the risk of PDRM in community pharmacy, underpinned by validated PDRM indicators. Setting Portuguese community pharmacy. Our work was informed by the Medical Research Council framework for the development and evaluation of complex interventions. Human error theory was considered as a theoretical framework for developing the intervention. Additionally, this stage consisted of a literature review, followed by two focus groups (17 community pharmacists) and interviews with 8 professional leaders. A 4-component intervention, was developed: (1) operationalisation of 4 validated PDRM indicators in dispensing encounters ('dispensing' indicators), and operationalisation of 25 validated indicators in patients enrolled in pharmaceutical care programmes ('follow-up' indicators), (2) pharmacist resource pack, (3) pharmacists' training and (4) support scheme. Piloting consisted of a feasibility study in 15 community pharmacies and an acceptability study with participating pharmacists (n = 16). Main outcome measures Proportion of cases with counselling (dispensing indicators); proportion of cases assessable, proportion of cases at risk and proportion of cases with risk minimisation actions (follow-up indicators). Operationalization of dispensing indicators resulted in counselling in 44.1 % of cases (n = 666). Factors influencing acceptability included pharmacists' perceptions of patients' characteristics, interest and informational needs, as well as perceptions on the relevance of safety information. For follow-up indicators, data were available to assess most cases (93/105, 88.6 %). About half of the assessable cases were at risk of a PDRM event (n = 49; 51.6 %); pharmacists undertook risk minimization actions in 23 cases (46.9 %). Lack of time and inter-professional issues emerged as important factors influencing acceptability. A novel risk management intervention was developed. Feasibility and acceptability of the 4-component intervention in Portuguese community pharmacy provided 'proof of concept', whilst highlighting aspects that need further refinement to better measure and maximise efficacy in future evaluative research.