Implementation of risk minimization measures to reduce the risk of tuberculosis among tumor necrosis factor medication users.

PURPOSE: To examine the adherence to risk minimization measures (RMMs) in newly treated patients with anti-tumor necrosis factor-alpha (anti-TNF-α) medications at one of the largest tertiary care hospitals in Saudi Arabia. METHODS: We included patients who had at least one prescription of infliximab or adalimumab. The index date was the first recorded date of infliximab or adalimumab prescription. New users of anti-TNF-α were divided into pre- and post-RMM implementation groups. The outcome of interest was the proportion of patients that received tuberculosis (TB) screening, including a chest X-ray (CXR) or a QuantiFERON test within 1 month prior to the index date. RESULTS: A pre-post RMM implementation comparison of TB screening among infliximab users showed a significant increase in the rates of CXR tests (from 7.5% before RMM implementation to 13.8% after RMM implementation, p < 0.001) and the rates of QuantiFERON tests (4.5% before RMM implementation to 24.1% after RMM implementation, p < 0.001). RMMs were introduced to the study site at the same time as adalimumab was approved and the proportion of patients receiving TB screening was 25.2%. CONCLUSION: TB screening prior to initiation of infliximab or adalimumab was not optimal. However, we noted an improvement in TB screening after the implementation of RMMs for infliximab. Future research may address reasons for low adherence to testing requirements for TB prior to initiation of anti-TNF-α medications.

Are drug safety measures harmonized? A real-world evidence from three regulatory authorities.

Background: Risk minimization measures (RMMs) are interventions intended to mitigate or prevent the occurrence of adverse reactions associated with medications. Having consistent measures across regulatory bodies (i.e., the Saudi Food and Drug Authority (SFDA), the United States Food and Drug Administration (US FDA), and the European Medicines Agency (EMA)) benefits medication use and safety and ultimately the patient. Objectives: This study aimed to investigate whether there is variability in these published RMMs between the three regulatory bodies. Methods: A specific data collection form was created to extract information from the SFDA's RMM list, US FDA's Risk Evaluation and Mitigation Strategy (REMS) list, and EMA's Risk Management Plan (RMP) list, as of February 2022 all RMMs that were available on the websites were reviewed. Medications with the same trade name were matched across regulators, and unmatched medications were checked for approval status. For medication groups such as NSAIDs in the SFDA's RMM list, they were matched by searching for the groups individually in the regulatory websites. All risks and types of minimizing measures were compared. Results: A total of 317 medications were retrieved from the SFDA's RMM list. The majority of medication classes were immunosuppressants (n = 60), antihypertensive (n = 33), and oncology medication (n = 29). There were only 62 medications with REMS from the US FDA website, a total of 14 medications were approved by the SFDA, and only nine medications were matched with the SFDA's RMM list. Also, there were 828 medications with RMP from the EMA website, a total of 334 has RMM, 128 are approved by the SFDA, and 71 matched with the SFDA's RMM list. Furthermore, seven medications were matched between SFDA, US FDA and EMA. After content review, four medications had similar risks and measures across the regulators and three medications had different risks and measures across the regulators. For the medication groups, a total of 36 groups were in the SFDA's list, 18 groups were matched with the US FDA, and 14 were matched with the EMA. Conclusions: Our study showed substantial differences among the regulatory authorities regarding RMMs. Harmony in published risk measures can have a significant impact on medication safety.

Prescribing of valproate and oral antiepileptics for women of childbearing age and during pregnancy in Germany between 2010 and 2020.

PURPOSE: To examine prescriptions of valproate and oral antiepileptic drugs (OAED) in Germany irrespective of the indication in women in general and particularly in women of childbearing age (13-49 years) and during pregnancy between 2010 and 2020, that is, before, during and after the implementation of the EU risk minimization measures (RMMs). METHODS: Analysis of claims data. STUDY POPULATION: all women continuously insured with the AOK health insurance fund in the respective observation year (2010-2020) and the previous year. OAED were identified by ATC code N03. Period of pregnancy was calculated based on birth information in claims data. MAIN OUTCOMES MEASURES: (i) prevalent use of valproate/OAED: number of women with at least one prescription of valproate/OAED per year divided by all women of the study population (rate per 1000 women); (ii) percentage of OAED recipients with at least one valproate prescription during pregnancy (13-49 years) in the respective observation year. RESULTS: Prevalence rate/1000 women for valproate use decreased by -31.33% across all age groups (2010-2014: -7.48%; 2014-2018: -16.47%; 2018-2020: -11,17%) with a strong reduction in women 13-49 years between 2014 and 2018 (-28.74%). The rate for OAED across all age groups rose from 33.43/1000 women in 2010 to 41.03/1000 (+22,73%). Valproate use during pregnancy of women with OAED declined from 1.29% in 2010 to 0.59% in 2020 (-54,26%) (2010-2014: -5.14%; 2014-2018: -42.31%; 2018-2020: -16.69%). CONCLUSION: Even if, due to the descriptive nature of the study, no causal relationship can be postulated between the RMMs and the strong decrease in valproate prescriptions, our results are compatible with the hypothesis that the measures have improved drug therapy safety.

A drug utilization study of thiocolchicoside-containing medicinal products for systemic use in France and Italy: A cross-sectional electronic medical records database study.

PURPOSE: The risk minimization measures (RMM) for systemic use of thiocolchicoside (TCC) was implemented across Europe during 2014-2016. RMM included restriction of use in age <16 years, maximum dose and duration, chronic conditions, contraindication in pregnancy, lactation or in women of childbearing potential [WOCBP] without appropriate contraception. The current Drug Utilization Study was aimed to describe the prescribing practices of TCC in France and Italy. METHOD: The study analyzed data (demographic, prescription, diagnosis, and concomitant treatment) from electronic medical record databases. It compares drug utilization during pre-implementation (baseline: year 2013) and post-implementation (years 1, 2, and 3) of RMM. This study included panels of general practitioners (FGP) and rheumatologists (FRH) in France and Italy (IGP). RESULTS: TCC was largely prescribed as adjuvant therapy in both pre-implementation (FGP: 93.5%, FRH: 88.8%, IGP: 86.6%) and post-implementation (FGP: 92.3%, FRH: 89.5%, IGP: 89.0%) periods. Prescribing patterns were different in France and Italy, with FGP and FRH mainly prescribing oral formulation (>95% and >80%, respectively), while IGP prescribing intramuscular formulation (>70%). Prescriptions to patients aged ≥16 years were >99% in all panels during both periods. An improvement was observed in compliance with treatment duration for oral formulation in the FGP panel post-implementation versus pre-implementation (66.2% vs. 46.7%; p < 0.001). There was no change in prescription rate post RMM implementation in pregnant (FGP: 0.5%, IGP: 4.7%) and in WOCBP without appropriate contraception (FGP: 89.3%, IGP: 93.4%). CONCLUSION: These results highlighted changes in prescribing practices of TCC after RMM implementation, which varied across panels and measures.

Valproate Restrictions in Sweden and Norway: Online survey suggests implementation deficit.

OBJECTIVES: To assess knowledge among neurologists in Sweden and Norway on the restrictions issued by the European Medicines Agency (EMA) regarding use of valproic acid (VPA) to female patients of childbearing potential, their use of the pregnancy prevention programme and their VPA prescription habits. MATERIALS & METHODS: We conducted an online survey from May through September 2021 inviting neurologists in Sweden and Norway to participate. The questions assessed familiarity with the EMA restrictions, knowledge and use of the information material issued by Market Authorization Holders (MAH) of VPA, and experience of VPA prescriptions to women of childbearing age in the last 2 years. RESULTS: The survey received 202 responses (response rate ≈ 20%). Of the responders, 51% were well acquainted with the EMA restrictions, and 49% were aware of the MAH-issued educational material. Eighty-eight (44%) had prescribed VPA to women of childbearing age in the last 2 years, and of these, only a small minority (n = 13) regularly used the information brochure for patients, and even fewer (n = 8) the VPA risk acknowledgement forms. CONCLUSIONS: We found limited penetrance of the new EMA restrictions on VPA use as well as limited acceptance and use among prescribers of the current company-issued information material and risk acknowledgment forms. More information campaigns and closer collaboration with treating physicians are likely needed.

Turalio risk evaluation and mitigation strategy for treatment of tenosynovial giant cell tumor: framework and experience.

For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio® REMS aims to mitigate this risk by ensuring provider education on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic and irreversible hepatotoxicity. Through Turalio REMS, benefits of treating patients with pexidartinib may be preserved.

For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio^®) is approved for treatment of adults who have symptoms of severe tenosynovial giant cell tumor or have limitations in function that do not improve with surgery. Turalio^® has an REMS program because liver injuries that can be serious or fatal were seen in Pexidartinib clinical trials. This program aims to decrease the seriousness of the liver injuries by assuring doctors and pharmacists are educated on how to use the drug, patients are advised of this potential risk and that baseline and periodic monitoring of patients are conducted.

Are prescribers not aware of cardiovascular contraindications for diclofenac? A claims data analysis.

OBJECTIVES: To compare diclofenac use before and after implementation of European risk minimization measures in 2013, focusing on diclofenac initiators and prevalence of congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease and cerebrovascular disease (new contraindications) in these patients in Germany. METHODS: We included adults with health insurance coverage on 1 January 2011 (cohort 2011) or 1 January 2014 (cohort 2014) and during a 1-year pre-observation period. We defined diclofenac initiators as persons filling a prescription of systemic diclofenac in 2011 (cohort 2011) or 2014 (cohort 2014) and without such a prescription during the respective pre-observation period. RESULTS: Each cohort comprised >10 million persons. Between 2011 and 2014, the age-standardized proportion of persons initiating diclofenac decreased by 29% (from 8.2% to 5.8%) amongst female patients and by 26% (from 8.5% to 6.3%) amongst male patients; in the subgroup of persons with new contraindications, this proportion decreased by 33% (from 9.8% to 6.6%) amongst female patients and by 31% (from 10.0% to 6.7%) amongst male patients. Amongst diclofenac initiators, the proportion of those with new contraindications did not change between 2011 (12.0%) and 2014 (11.8%). CONCLUSION: The overall decline of about 30% in diclofenac initiation between 2011 and 2014 was largely independent of the presence or absence of new contraindications. The proportion of diclofenac initiators with a new contraindication remained at a high level (more than one in ten patients), demonstrating the need for research at the prescriber level (e.g. interventional studies) and further measures to improve patient safety.

Assessment of colistimethate sodium (COLOBREATHE) risk minimization measures implemented in the European Union: A cross-sectional study.

PURPOSE: To assess the effectiveness of additional risk minimization measures (aRMMs) implemented in Europe for colistimethate sodium (CMS) among healthcare professionals (HCPs) and patients/caregivers following safety concerns regarding incorrect use of CMS delivered via Turbospin inhaler. METHODS: A cross-sectional study was conducted among HCPs and patients/caregivers in Austria, Denmark, France, Germany, The Netherlands, and the United Kingdom between September 2016 and March 2018. Knowledge of the educational materials was assessed regarding common side effects, correct use of CMS and Turbospin inhaler, and capsule breakage. Awareness, receipt, and utilization of the aRMMs were also evaluated. RESULTS: Among 124 HCPs surveyed, the majority acknowledged awareness (86.2%), receipt (91.0%), and utilization (81.6%) of the CMS educational materials and were knowledgeable about the common CMS side effects (93.2%). Most HCPs correctly answered most questions regarding the proper use of CMS (>90%), yet only half knew how to correctly use the Turbospin inhaler (53.2%). Knowledge about capsule breakage was moderate (67.5%). Of the 29 patients/caregivers surveyed, almost half were aware of the educational materials (48.1%); of these, 69.2% received and used the materials. Most patients/caregivers were knowledgeable about the common CMS side effects (81.5%) and proper CMS use (>85%); however, knowledge about correct Turbospin inhaler use and potential for capsule breakage was moderate to low (48.1% and 37.9%, respectively). CONCLUSIONS: HCPs and patients/caregivers have good knowledge about the common side effects associated with CMS. However, knowledge of correct use of the Turbospin inhaler and capsule breakage was moderate to low.

Physicians' Perceptions of the Use of a Chatbot for Information Seeking: Qualitative Study.

BACKGROUND: Seeking medical information can be an issue for physicians. In the specific context of medical practice, chatbots are hypothesized to present additional value for providing information quickly, particularly as far as drug risk minimization measures are concerned. OBJECTIVE: This qualitative study aimed to elicit physicians' perceptions of a pilot version of a chatbot used in the context of drug information and risk minimization measures. METHODS: General practitioners and specialists were recruited across France to participate in individual semistructured interviews. Interviews were recorded, transcribed, and analyzed using a horizontal thematic analysis approach. RESULTS: Eight general practitioners and 2 specialists participated. The tone and ergonomics of the pilot version were appreciated by physicians. However, all participants emphasized the importance of getting exhaustive, trustworthy answers when interacting with a chatbot. CONCLUSIONS: The chatbot was perceived as a useful and innovative tool that could easily be integrated into routine medical practice and could help health professionals when seeking information on drug and risk minimization measures.

A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children.

PURPOSE: In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the "real-world" setting and (b) test feasibility of a study using a common protocol by regulators with access to databases. METHODS: The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated. RESULTS: Over the 5-year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany. CONCLUSIONS: Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.

Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk-minimization measures.

PURPOSE: This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study. METHODS: This was a multinational (five European countries) chart review study with two study periods: pre-RMM and post-RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow-up, and no concomitant use of verapamil or diltiazem. RESULTS: Overall, 711 and 506 eligible patients were included in the pre-RMM and post-RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post-RMM period (70.6% and 78.4% in the pre- and post-RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow-up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007). CONCLUSIONS: The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris.

A drug utilization study to evaluate effectiveness of risk minimization measures for trimetazidine in France, Hungary, Romania and Spain.

WHAT IS KNOWN AND OBJECTIVE: The approved indication for trimetazidine (TMZ) was restricted to "add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies" in 2012 by the Committee for Medicinal Products for Human Use (CHMP). TMZ was no longer indicated for ophthalmology and otolaryngology (ENT) indications. This drug utilization study analysed actual utilization of TMZ before and after the restriction on its indications to evaluate the effectiveness of risk minimization measures (RMM). METHODS: This was a multi-national, cross-sectional, non-interventional drug utilization study using European databases: IMS Prescribing Insights (PI) for France and Spain, National Diagnostic Index (NDI) for Romania and National Prescription Audit (NPA) for Hungary. TMZ prescriptions issued by Ear-Nose-Throat (ENT) specialists, ophthalmologists, cardiologists and General Physicians (GPs)/others were analysed during the 24-month period before (reference period) and after RMM implementation (assessment period). RESULTS AND DISCUSSION: During the assessment period, most of the TMZ prescriptions for ENT and ophthalmology indications (un-authorized indications) were made by GPs/others followed by ENT specialists, ophthalmologists and cardiologists in most of the countries. The proportion of TMZ prescriptions for ENT or ophthalmological indications after the restrictions on indication was reduced in Hungary (by 0.4%) and Spain (by 11.8%), remained the same in Romania and increased in France (by 3.7%). WHAT IS NEW AND CONCLUSION: This study showed that a significant proportion of TMZ prescriptions was off-label for ENT or ophthalmological indications following the RMM implementation. More effective RMM strategies are required to reduce off-label prescriptions of TMZ.

Evaluation of the effectiveness of risk minimization measures for trimetazidine: A cross sectional joint PASS survey among physicians in selected European countries.

PURPOSE: In 2012, the Committee for Medicinal Products for Human Use (CHMP) restricted prescription of trimetazidine (TMZ) to "add-on therapy for patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line therapies." TMZ was no longer indicated for ophthalmology and otolaryngology. Risk minimization measure (RMM) was communicated to physicians. The survey presented here evaluated effectiveness of the RMM and assessed physicians knowledge and compliance with RMM. It also analyzed actual prescribing pattern of TMZ. METHODS: A cross sectional, web-based survey was developed and conducted among prescribing physicians of TMZ across 12 European countries. Physicians' samples were weighted to account for the actual proportion of specialties within and across countries. RESULTS: Using weighted samples, data from 1123 physicians and 8332 prescriptions were analyzed. Most (74.0%) of the physicians assumed stable angina pectoris to be an indication for TMZ. Three quarter of (75.7%) of these physicians were aware of the approved indication. Vertigo (62.1%), tinnitus (42.5%), declined visual acuity, and visual field disturbances (45.1%) were also presumed to be approved indications for TMZ, and physicians actually prescribed for these indications. Only 29.8% of the physicians remembered receiving RMM communications regarding TMZ. Most (90.5%) of the physicians expressed their interest to know and comply with the safety communications. Of all prescriptions, 33.9% were issued for add-on therapy for patients with stable angina pectoris. CONCLUSIONS: RMM for TMZ prescription have been moderately effective. Improvement in physician's compliance with safety information of TMZ is necessary for patient's safety.

Tumor Necrosis Alpha (TNF-α) Antagonists Used in Chronic Inflammatory Rheumatic Diseases: Risks and their Minimization Measures.

Tumor necrosis factor alpha (TNF- α) inhibitors are widely employed for the management of chronic inflammatory rheumatism. However, their usage carries significant risks, including site and infusion reactions, serious infections, malignancy, heart failure autoimmune and demyelinating disorders. These risks are comprehensively outlined in risk management plans (RMPs) associated with these molecules. RMP provides information on the safety profile of a medicinal product as well as the measures that will be taken to minimize risks; these are known as risk minimization measures. These measures are divided into routine measures related to elements, such as the summary of product characteristics, labeling, pack size, package leaflet, or legal supply status of the product, while additional measures may include educational programs, including tools for healthcare providers and patients, controlled access or pregnancy prevention programs, among others. Additional measures can consist of one or more interventions that need to be implemented in a sustainable way in a defined target group, while respecting the timing and frequency of any intervention and procedures to reach the target population. An evaluation of the effectiveness of these measures is required to determine whether or not an intervention has been effective. This comprehensive review offers an in-depth exploration of the current treatment, uses, and associated risks of TNF-α inhibitors. Additionally, it provides a detailed account of risk minimization measures and risk management practices while shedding light on their real-world implementation and effectiveness.

Evaluating patient and physician knowledge of risks and safe use of rivaroxaban: a survey across four countries.

BACKGROUND: At the request of the European Medicines Agency, a Prescriber Guide and Patient Alert Card were developed to increase awareness and understanding about the initiation of rivaroxaban and potential bleeding risk associated with its use. This study evaluated physician and patient awareness and understanding of key safety messages in these educational materials in three waves. RESEARCH DESIGN AND METHODS: Three cross-sectional surveys were administered to physicians and one survey was administered to patients (wave 1 only) with recent rivaroxaban experience in France, Germany, Spain, and the United Kingdom. RESULTS: Patient and physician knowledge of key safety information in the educational materials was generally high. Patients' knowledge was high for questions related to bleeding risk (80% responded correctly), indication (96%), consulting their doctor (86%-91%), and informing other physicians they are taking rivaroxaban (95%). Physicians' knowledge was particularly high for questions related to bleeding risk (92%-94% across waves), populations at increased risk of serious side effects (76%-94%), contraindications (70%-92%), and invasive procedures (76%-82%). CONCLUSIONS: Among patients and physicians, the highest levels of knowledge were on the most important risks, as expected. The Prescriber Guide and Patient Alert Card were found to be useful sources of information.

The implementation of risk minimization measures to prevent teratogenic pregnancy outcomes related to oral retinoid and valproate use in Belgium.

INTRODUCTION: Both oral retinoid and valproate containing medicines are highly teratogenic. Their use by women of childbearing age is controlled by risk minimization measures (RMMs) introduced by the European Medicine Agency, including the pregnancy prevention programme (PPP). In 2018, the RMMs were revised as previous measures were insufficient to prevent the use of these medicines during pregnancies. AIM & METHODS: A cross-sectional survey was conducted among patients, physicians and pharmacists to evaluate the implementation of the revised RMMs in Belgium. The primary outcome was compliance with key aspects of the PPP. Differences in compliance between oral retinoid and valproate stakeholders were investigated. The relationship between potential determinants (population characteristics and RMM usage) and compliance was studied via multiple logistic regression. RESULTS: A total of 317 eligible patients, physicians and pharmacists participated. The majority of the studied patients fail to comply with the PPP, mainly driven by poor implementation of pregnancy testing. A large number of healthcare providers is unaware of the available educational materials. CONCLUSION: It is likely that a substantial part of Belgian women of childbearing age using oral retinoids or valproate insufficiently meet the PPP requirements. We propose to better inform healthcare providers about the mandatory PPPs and available educational materials as well as to support them with the implementation of such programmes to improve the safe use of these teratogenic medicines.

Effectiveness of risk minimization measures for valproate: a drug utilization study based on implementation of a risk minimization programme in Europe, analysis of data from the UK.

OBJECTIVE: Since 2014, valproate has not been recommended for use in girls and women of childbearing potential unless other treatments are ineffective or not tolerated. Risk minimization measures (RMMs) of valproate were implemented to reduce the potential risks of developmental disorders among pregnant women. A drug utilization study was carried out to assess the effectiveness of RMMs. METHODS: This was a multinational, non-interventional cohort study. For the UK, existing data from the Clinical Practice Research Datalink database were used. The primary study endpoint was a change in the proportion of valproate initiations preceded by other medications relevant for valproate indications before and after implementation of RMMs. RESULTS: The proportion of valproate initiations preceded by medications related to valproate indications increased after RMM implementation in incident female users in the UK from 66.4% to 72.4%. The proportion of incident prescriptions for epilepsy and bipolar disorder with prior medication related to valproate indications increased, from 36.2% to 44.1% and 72.9% to 77.8%, respectively. The incidence rate of valproate-exposed pregnancies decreased from 16.9 to 10.9 per 1000 person-years in the pre- and post-implementation periods, respectively. CONCLUSIONS: Results from this study indicated some improvement in physician prescribing and a potential reduction in valproate-exposed pregnancies in the UK. Given only modest improvement has been achieved, additional RMMs were implemented in 2018.

Implementation of Interventions and Policies on Opioids and Awareness of Opioid-Related Harms in Canada: A Multistage Mixed Methods Descriptive Study.

In Canada, interventions and policies have been implemented to minimize the risk of opioid-related harms. This mixed methods study aimed at describing trends over time in implementation, as well as in awareness and health outcomes. For implementation, we conducted a scoping review to identify opioids interventions and policies implemented in Canada between 1 January 2016 and 15 November 2019. Awareness was measured through a descriptive analysis of opioid-related harm cases reported by consumers and health care professionals (HCPs) to the national spontaneous reporting system and of social media coverage, while health outcome consisted of opioid-related deaths recorded in the coroner's reports database of the province of Quebec, Canada. Trends over time in implementation of interventions were compared to trends in awareness and opioid-related deaths, without implying causality. There were 413 national or provincial interventions on opioids implemented over the study period, with a four-fold increase in 2016. The most common (31.5%) was harm reduction strategies, such as naloxone distribution. The reporting rate of opioid-related harms ranged between 0.1 and 0.2 per 100,000 persons with no observed time trend. Compared to 2015, the number of social media posts increased in 2016 by 35.4% (Reddit), 329.0% (Facebook), and 381.5% (Twitter). Between 2016 and 2019, there was a slight decrease in the number of opioid-related deaths recorded in the coroner's database. Overall, the increase in the number of policies did not see a parallel increase in spontaneous reports of opioid-related harms as an indicator of consumer or HCP awareness. Conversely, the dramatic increase in social media coverage was consistent with heightened public awareness. Although no inferences of causality were made in this study, the decrease in opioid-related deaths observed in the recent years may indicate a potential effectiveness of interventions and policies.

Regulatory experience of handling Risk Management Plans (RMPs) for medicinal products in the EU.

Introduction: Risk Management Plans (RMPs) aim to optimize a medicinal product's benefit/risk balance for the individual patient and the target population. Despite differences in regulatory RMP requirements between jurisdictions worldwide, their ultimate aim is to protect public health.Areas covered: The review presents findings of different RMP requirements by different regulatory authorities and additional risk minimization measures (issued between January 2010 and December 2018) indicate how RMPs and additional risk minimization measures translate into actions to protect public health within the European Union (EU) member states and worldwide. Areas covered also include the different International Council for Harmonization (ICH) regional requirements of RMPs by the different regulatory authorities as well as data regarding the number of RMP assessments carried out by the EMA, FDA and Japan, and number of safety communications issued in Malta (taken as an example of a typical small EU member state) and in the United States of America (USA).Expert opinion: The EU legislation adopted in 2010 required RMPs to be included in all new applications for medicinal products in the EU, both for EU centrally authorized and nationally authorized medicinal products. Lessons learnt by EU regulators during this process are discussed in this review.