Pharmacovigilance Risk Assessment Committee Research Articles

Patient Preferences for Rituximab Additional Risk Minimization Measures: Results From an International Online Survey.

ObjectivePatients’ opinions are essential in optimizing risk minimization measures (RMMs) because they bring their real-life experience of disease management and medicines’ use into the regulatory assessments. The aim of the survey launched in 2018 by the European Medicines Agency, in collaboration with the Pharmacovigilance Risk Assessment Committee, was to consult targeted patient groups treated with rituximab for nononcology indications to evaluate their preferences on how to receive information on progressive multifocal leukoencephalopathy and (serious) infections. Additional RMMs such as educational materials for physicians and patients including a patient alert card (PAC) and a patient brochure (PB) are in place to minimize these risks.MethodsA question-based online survey in English created on the EU-Survey platform and disseminated primarily via relevant European patient organizations.ResultsMost patients (47 of 61) had knowledge of these potential adverse effects. Mostly, they were informed by a healthcare professional. Both a PAC and a PB were supported as useful tools to raise awareness of these adverse effects and thus minimize the potential risks among patients. Where the participants had to choose only 1 of these educational materials, 43 of them preferred a PAC, a shorted description that is always held by the patient and reaches the relevant healthcare professional when needed.ConclusionsCollecting patients’ preferences supports periodic assessment of additional RMMs and increase transparency of regulatory processes. Considering the limitations of this initial survey, further investigation is needed to generalize the results into patients’ safety outcomes.

APROTININ USE IN HIGH-RISK CARDIAC SURGERY: RECENT INSIGHTS FROM THE BELGIAN APROTININ PATIENT REGISTRY

Introduction In 2007, the use of aprotinin was temporarily suspended following several publications raising serious safety concerns.(1.2.3) However, Canadian and European Health Authorities concluded that these studies suffered from major flaws and lifted the suspension in 2013.(4,5) The reintroduction of aprotinin in 2016 was accompanied by a mandatory registry [Nordic Aprotinin Patient Registry (NAPaR)] in order to monitor the pattern of use, the effect of risk minimization measures, and overall safety. Objective of this study was to analyse the use of aprotinin in Belgium. Methods NAPaR is a non-interventional Post-Authorisation Safety Study (PASS), endorsed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency. Results Between October 2018 and August 2020, six Belgian NAPaR centers included 694 patients [median age 70 (range 13-90y); 62% male; median EuroSCORE II 4.6 (range 0.5-93.4)]. 25% of the patients had an EuroSCOREII > 10. 57% of the patients were under an active antiplatelet therapy and 17% were treated with novel oral anti-coagulants. Preoperative renal impairment was present in 2/3 of patients. Only 4% of the patients received aprotinin on-label, i.e. for isolated coronary artery bypass grafting (CABG) on cardiopulmonary bypass (CPB). In 96% of the patients, aprotinin was used off-label, mainly for redo surgery (32%), CABG + valve surgery (29%), aortic surgery (20%) and multiple valve surgery (17%). One third of the procedures were urgent (23%) or emergent (9%). Median bypass time was 128min (range 13-600min). Median hospital stay was 11 days (range 3-151 days). Main reported indications for the use of aprotinin were active dual antiplatelet therapy (68% in iCABG), redo surgery (16%) and expected prolonged CPB time (55%). In 83% of the cases, aprotinin was administered at the Half Hammersmith dose (1 Mio KIU loading- and priming-dose + 250.000 KIU/h); most patients received the appropriate test dose (98%), none developed anaphylactic reactions. Median perioperative blood loss was 400ml (range 40 -10050 ml), 44% of the patients had RBC transfusion and 6% underwent reoperation for bleeding or tamponade. Overall mortality at discharge was 5%, i.e. within the range or lower than predicted by the EuroSCORE II. 2% of the patients had a postoperative stroke. Postoperative AKI as defined by a serum creatinine increase of 0,3mg/dL or more within 48 hours after surgery was present in 13% of cases. Most of these patients (76%) suffered from preoperative moderate or severe renal impairment including dialysis. Notably, in patients with postoperative AKI median CPB time was significantly higher than in patients without AKI: 172min (range 56-402) vs 125min (range 13-600min) (p Discussion In the Belgian centers, aprotinin was mainly used off-label and predominantly administered to older patients with significant comorbidities undergoing high-risk procedures. The observed safety outcomes are in line with published data within this high risk patient population. The data from the Belgian NAPaR suggest that aprotinin has an excellent safety profile in adult cardiac surgery.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - Part 2: Treatment monitoring and specific clinical or comorbid situations.

Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System.

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings.

A Quantitative Benefit-Risk Analysis of ChAdOx1 nCoV-19 Vaccine among People under 60 in Italy.

The Oxford-AstraZeneca ChAdOx1 nCoV-19 is a vaccine against the COVID-19 infection that was granted a conditional marketing authorization by the European Commission in January 2021. However, following a report from the Pharmacovigilance Risk Assessment Committee (PRAC) of European Medicines Agency, which reported an association with thrombo-embolic events (TEE), in particular disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), many European countries either limited it to individuals older than 55–60 years or suspended its use. We used publicly available data to carry out a quantitative benefit–risk analysis of the vaccine among people under 60 in Italy. Specifically, we used data from PRAC, Eudravigilance and ECDC to estimate the excess number of deaths for TEE, DIC and CVST expected in vaccine users, stratified by age groups. We then used data from the National Institute of Health to calculate age-specific COVID-19 mortality rates in Italy. Preventable deaths were calculated assuming a 72% vaccine efficacy over an eight-month period. Finally, the benefit–risk ratio of ChAdOx1 nCoV-19 vaccination was calculated as the ratio of preventable COVID-19 deaths to vaccine-related deaths, using Monte-Carlo simulations. We found that among subjects aged 20–29 years the benefit–risk (B-R) ratio was not clearly favorable (0.70; 95% Uncertainty Interval (UI): 0.27–2.11). However, in the other age groups the benefits of vaccination largely exceeded the risks (for age 30–49, B-R ratio: 22.9: 95%UI: 10.1–186.4). For age 50–59, B-R ratio: 1577.1: 95%UI: 1176.9–2121.5). Although many countries have limited the use of the ChAdOx1 nCoV-19 vaccine, the benefits of using this vaccine clearly outweigh the risks in people older than 30 years. Study limitations included risk of underreporting and that we did not provide age-specific estimates. The use of this vaccine should be a strategic and fundamental part of the immunization campaign considering its safety and efficacy in preventing COVID-19 and its complications.

Sodium valproate prescribing safety in women of childbearing potential

AimsThe purpose of this audit was to identify all women being prescribed Sodium Valproate under the Bassetlaw Local Mental Health Team (LMHT) caseload to see how well latest prescribing guidelines are being met, and help set up a system allowing efficient monitoring of Sodium Valproate prescribing in the future.BackgroundDespite early concerns regarding potential teratogenicity, Sodium Valproate became a widely used anticonvulsant and mood stabiliser and is licensed for use in Epilepsy, Migraine prophylaxis and Bipolar affective disorder. Research evidence now shows its use in pregnancy increases risk of neurodevelopmental disorders to 40%, and serious birth defects to 10%. Despite research finding these risks prescribing practice did not significantly change. To better reflect these findings in clinical practice in 2018 the Pharmacovigilance Risk Assessment Committee recommended Sodium Valproate should not be used in pregnancy unless they have a form of epilepsy unresponsive to other anti-epileptic drugs, and all with childbearing potential should be enrolled in a pregnancy prevention programme (PPP). This was endorsed by UK Medicines and Healthcare Devices Regulatory Agency in April 2018 with launch of the PPP.Standards:Must be offered counselling about risks of valproate to unborn child and importance of effective contraception.Annual specialist Review by a specialist now mandatoryRisk acknowledgement form must be updated at least annually.MethodThe electronic RiO records for all female patients on the Bassetlaw LMHT caseload in the year 2019 were checked to identify those prescribed Valproate. For those prescribed Valproate, evidence of annual risk acknowledgement form, date of last appointment, underlying diagnosis and contraceptive method was checked. This data was stored together on an excel file and used to create a patient list to help allow future monitoring.ResultFrom 594 female patients identified, 27 (4.5%) were prescribed Sodium Valproate. Of these, 14 (52%) had PPP documentation uploaded, 24 (89%) had been reviewed within the last 12 months, and 13 (48%) had no documentation of contraceptive method.ConclusionThis audit helped highlight there is likely a large population of patients not yet on the Pregnancy Prevention Programme. Creating a monitoring system in excel for female patients being prescribed Valproate can help improve adherence to latest guidelines, with a colour coding system to highlight those needing risk acknowledgement forms/appointments within the next three or six months. Educating patients and other healthcare professionals about risks will also help improve prescribing practice and avoid use in pregnancy.

Hypotheses behind the very rare cases of thrombosis with thrombocytopenia syndrome after SARS-CoV-2 vaccination

As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA's Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S).Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.

Analysis of Thrombotic Adverse Reactions of COVID-19 AstraZeneca Vaccine Reported to EudraVigilance Database.

The development of safe, effective, affordable vaccines against COVID-19 remains the cornerstone to mitigating this pandemic. Early in December 2020, multiple research groups had designed potential vaccines. From 11 March 2021, several European countries temporarily suspended the use of the Oxford–AstraZeneca vaccine amid reports of blood clot events and the death of a vaccinated person, despite the European Medicines Agency (EMA) and the World Health Organization’s assurance that there was no indication that vaccination was linked. This study aimed to identify and analyse the thrombotic adverse reactions associated with the Oxford–AstraZeneca vaccine. This was a retrospective descriptive study using spontaneous reports submitted to the EudraVigilance database in the period from 17 February to 12 March 2021. There were 54,571 adverse reaction reports, of which 28 were associated with thrombotic adverse reactions. Three fatalities were related to pulmonary embolism; one fatality to thrombosis. With 17 million people having had the AstraZeneca vaccine, these are extremely rare events The EMA’s Pharmacovigilance Risk Assessment Committee (18 March 2021) concluded that the vaccine was safe, effective and the benefits outweighed the risks. Conducting further analyses based on more detailed thrombotic adverse event reports, including patients’ characteristics and comorbidities, may enable assessment of the causality with higher specificity.

Management of women with uterine fibroids in reproductive center: retrospective analysis of clinical and reproductive outcomes.

Uterine fibroids are the most common benign tumor in women. According to literature, submucosal myomas have a negative effect on reproductive outcomes in women undergoing assisted reproductive techniques (ART) but there are fewer data concerning intramural fibroids. During last years, ulipristal acetate (UPA) 5 mg was widely used as medical option of fibroid's treatment, but from 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) has revoked the marketing authorization after some cases of liver toxicity. In this observational, retrospective study we collected data from a sample of 23 women affected by symptomatic uterine fibroids (from type 1 to type 7 according FIGO classification) followed in our center for assisted reproduction from 2016-2019. All patients received 5 mg/day UPA for three months, followed by two months of wash-out therapy. A group of 13 women treated with UPA, with intramural fibroid not distorting the uterine cavity, after wash-out therapy, affected by tubal or idiopathic factors of infertility too, underwent ART. We also evaluated a control group of women, not affected by fibroids, randomly selected from a general group of our ART patients, similar by age, BMI, and cause of infertility only idiopathic or tubal factors. We evaluated the impact of UPA on reduction of fibroid volume, symptomatology and distortion of the cavity in all the women treated, and the IVF (in-vitro fertilization) outcome between the fibroid group of women affected by intramural fibroids who underwent ART, and the control group. In all the women treated with UPA the overall median fibroid volume pretreatment was 45.168±35.360 mm3, that decreased to a mean value of 22.592±22.116 mm3 post one cycle of UPA, with an overall mean decrease of -22.586 mm3 (of 49%) statistically significant (P=0.00001). After treatment, the distortion of the uterine cavity reduced in high percentage of cases: 85,71% (type 1-2), χ2 difference in respect to the value pretreatment of 0.3941, and 86.96% of patients subjectively referred an improvement in the symptomatology. In the group of 13 women that undergone ART, after one IVF cycle for each patient, we obtained 61% of positivity of dosage of beta human chorionic gonadotropin (hCG) after UPA treatment, and we obtained a similar value in the control group. In our little sample we have observed that UPA represented a valid non-invasive medical treatment strategy for fibroids in women candidate for (IVF, not only in women affected by sub-mucosal, but also by intramural fibroids not distorting uterine cavity. After a single, three months course of treatment, we obtained good results in terms of reduction of fibroid's volume and improvement of symptomatology, without side effects, preparing a more favorable environment for ART.

Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria.

Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication. To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports. While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA. It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders. CLINICALTRIALS. NOT APPLICABLE.

Ondansetron in pregnancy revisited: Assessment and pregnancy labelling by the European Medicines Agency (EMA) & Pharmacovigilance Risk Assessment Committee (PRAC).

Ondansetron is an effective antiemetic that is being widely used as a second-line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has-following publication of controversial and seemingly contradictory results-been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step-which has important clinical consequences-is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision.

Proposals for Engaging Patients and Healthcare Professionals in Risk Minimisation from an Analysis of Stakeholder Input to the EU Valproate Assessment Using the Novel Analysing Stakeholder Safety Engagement Tool (ASSET).

IntroductionUnderstanding the impact of regulatory actions for medicines and enablers/barriers for positive health outcomes is fundamental to effective risk minimisation measures (RMM). Therefore, the Impact Strategy of the European Union (EU) Pharmacovigilance Risk Assessment Committee (PRAC) includes engagement with patient communities and healthcare professional (HCP) bodies regarding RMM. However, there is uncertainty on how best to obtain stakeholder input.ObjectivesThe objectives of this study were to (1) analyse stakeholder input at a public hearing and dedicated meeting for the 2017–18 EU procedure on valproate teratogenicity and (2) draw proposals for enhancing PRAC engagement.MethodsFor the content analysis, the novel ‘Analysing Stakeholder Safety Engagement Tool’ (ASSET) was developed with 21 themes in six domains (appropriateness, access, audience, compatibility, integrability, time), based on implementation theories.ResultsStakeholders provided a wide range of RMM proposals, some beyond the regulatory remit. Patients and most HCPs converged remarkably, but there was some divergence among HCPs on the informed choice objective, the therapeutic place of valproate, the RMM appropriateness, and RMM delivery to HCPs and patients. Ethical aspects emerged as relevant for regulatory decision making, and crucial input gaps were identified from an RMM implementation perspective. Nine pilotable proposals for PRAC were made regarding: (A) Agreeing on appropriate RMM with stakeholders and catalysing healthcare leadership for implementation; (B) Building-up stakeholder input on all elements critical to RMM implementation guided by the ASSET; and (C) Collaborating with all stakeholders for monitoring implementation and evaluating RMM.ConclusionsNew implementation theory-based approaches are promising for enhancing the valuable dialogue between regulators, patients and HCPs and achieving patient safety.EU PAS Register number:EUPAS35947Electronic supplementary materialThe online version of this article (10.1007/s40264-020-01005-3) contains supplementary material, which is available to authorized users.

Pharmacovigilance: procedures for uniform assessment of periodic safety update reports and their implementation in national settings. Focus on analgesics

Pharmacovigilance activities are of vital importance for ensuring effective and safe medicinal products. In order to clarify to which extent marketing authorisation holders (MAHs) meet the requirements of the Law and the Directives related to this activities, we conducted a systematic search among the procedures submitted to the Bulgarian Drug Agency (BDA) related to the implementation of the decisions of the Pharmacovigilance Committee and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) for a period of 6 years. The results of the study showed significant discrepancies between regulatory requirements and the behavior of the MAH at the national level. This could be a serious problem, as inadequate or late implementations of the PRAC (Pharmacovigilance Risk Assessment Committee)/CMDh/EC recommendations can lead to untimely informing of healthcare professionals and patients about potential safety concerns and risks related to the use of medicinal products.

Drug-induced skin ulcers: A disproportionality analysis from the WHO pharmacovigilance database

Drug-induced skin ulcers: A disproportionality analysis from the WHO pharmacovigilance database

A description of medicines-related safety issues evaluated through a referral procedure at the EU level after 2012

ABSTRACT Introduction Important drug safety issues are evaluated through a referral procedure in the EU by the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency. We aim to describe all safety-related referrals assessed by the PRAC by June 2019. Methods Publicly available data on safety issues assessed through referral procedures that reached a final decision during July 2012–June 2019 were identified, analyzed and classified according to predefined criteria. Results Fifty-one safety issues were assessed by PRAC for 45 medicines/combinations/therapeutic classes during this timeframe. Referrals were initiated mostly by the European Commission (16) and France (8). Nine medicines were authorized in the last five years, the rest being well-established drugs. In four cases (flupirtine, hydroxyethyl-starch, valproate, codeine) PRAC re-assessed the same risks as previous recommendations have not been effective. Post-referral recommendations consisted of updates of the summary of product characteristics and package leaflet (42), Direct Healthcare Professional Communication (32), and other additional risk minimization measures (RMMs). Withdrawal was recommended for seven active substances. Conclusions PRAC recommended routine or additional RMMs for most referrals. Complete withdrawal of a drug or withdrawal of certain pharmaceutical forms or concentrations was advised only when the risk could not be managed by RMMs.

Ability of Primary Care Health Databases to Assess Medicinal Products Discussed by the European Union Pharmacovigilance Risk Assessment Committee.

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data‐UK, IQVIA Medical Research Data‐France, IQVIA Medical Research Data‐Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes. Coverage of advanced therapies was worse for those typically administered in a specialized rather than primary care setting. This study shows that to enable better informed regulatory decisions there is a need to access complementary data sources, particularly capturing secondary care prescribing.

What does non-eligibility for myoma surgery mean in the context of sequential prescription of ulipristal acetate?

Ulipristal Acetate (UPA) is the only selective progesterone receptor modulator currently approved for medical management of myomas. Following several cases of liver toxicity during UPA treatment, new recommendations of PRAC (Pharmacovigilance Risk Assessment Committee) and EMA (European Medicines Agency) have been proposed, including a pre-therapeutic assessment of liver function and a close monitoring during treatment. Repeated courses of UPA have also been restricted to women who are defined as “non-eligible” for surgery. This article raises important questions and tries to provide clarification about the concept of ‘non-eligibility’ for myoma surgery.

Improving the Safety of Medicines in the European Union: From Signals to Action.

Pharmacovigilance and risk minimization must be planned during drug development and forms a critical part of the regulator's decision on whether a medicinal product can be authorized. Pharmacovigilance systems should ensure proactive monitoring of all authorized medicines throughout their lifecycle in clinical use. Signal detection and management are core activities in pharmacovigilance, rapidly delivering new information on the safety of medicines in real‐world use which helps to fill knowledge gaps. The first 6 years of the European Union (EU) signal management system resulted in 453 recommendations issued by the Pharmacovigilance Risk Assessment Committee (PRAC), of which more than half were for drug labeling changes. The EU pharmacovigilance network has demonstrated its ability to detect and evaluate new drug safety signals. This has resulted in new warnings to guide the safe and effective use of medicines in Europe.

Awareness of, and Compliance with, Domperidone Revised Labeling After a Risk-Minimization Activity in Europe.

Background and ObjectiveRisk-minimization measures (RMM), including label revisions were implemented in Europe for domperidone because of evidence of increased incidence of cardiac arrhythmia and sudden cardiac death. In accordance with the guideline on good pharmacovigilance practices, the European Medicines Agency Pharmacovigilance Risk Assessment Committee requested to conduct two studies to evaluate the effectiveness of these risk minimization measures.MethodsIn Belgium, France, Germany, Spain, and the UK, surveys were conducted to assess physicians’ knowledge on the updated domperidone labeling information, and a drug-utilization study (DUS) was conducted using healthcare databases to assess domperidone prescribing patterns before and after the RMM. Four DUS sensitivity analyses (scenarios) evaluated uncertainty regarding domperidone treatment duration and indication.ResultsAmong 1805 physicians participating in the survey, most were aware of the approved indication (nausea and vomiting, 80%), treatment duration (≤ 7 days, 70%), and maximum adult daily dose (10 mg three times daily, 84%). Only 33% selected the on-label indication from a list of indications for which they would prescribe domperidone. Awareness was low for medications contraindicated for concomitant use (26%) and contraindicated conditions (4%). In the DUS, under the optimistic scenario, a large improvement in labeling compliance from pre- to post-implementation period was observed in France (27% vs. 69%), while Belgium, Germany, Spain, and the UK showed small improvements (< 10%). In the other scenarios, there was little to no improvement in compliance with the revised labeling from the pre- to post-implementation periods in most countries.ConclusionsThe survey findings documented that most physicians in all five countries were aware of the main aspects of the revised labeling. Results of the DUS were inconclusive regarding the effect of the RMM and compliance with the revised labeling for all countries except France.Electronic supplementary materialThe online version of this article (10.1007/s40261-019-00831-3) contains supplementary material, which is available to authorized users.

Interest of pharmacoepidemiology in pharmacovigilance: Post-authorization safety studies in regulatory pharmacovigilance activity

During the past few decades, it has been stated that a paradigm shift has occurred in the assessment and management of patient related drug safety. Some of these changes have resulted in a significant increase in the importance of pharmacoepidemiology and its use in pharmacovigilance. For European member states, the Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for assessing the protocols and results of imposed and non-imposed post-authorization safety studies (PASS). Between 2013 and 2017, the total number of PASS during this 5-years period of the different products, including protocols and results, was 1062. The number of protocols of PASS is increasing over time, except in 2017 where a 25% decrease has been observed. Whereas, PASS results steadily increased over the 5years period. Between 2014 and 2017, about 29% (n=137) of PRAC reviewed protocols were imposed. The number of imposed PASS was almost constant over time with a mean of 34.3±7.6 imposed protocols per year and 3.5±1.74imposed results per year. The need for the implementation of PASS for pharmacovigilance regulatory activities is increasing. Nevertheless, conducting such studies remains difficult.