Monitoring the safety of influenza A (H1N1) vaccine using web-based intensive monitoring

BACKGROUND: When adjuvant vaccines against the pandemic influenza A (H1N1) virus became available after an accelerated registration process, safety issues dominated the public debate. As part of the immunisation campaign, the Dutch government installed an active monitoring of possible adverse events following immunisation (AEFIs). As part of the monitoring we conducted an anonymous prospective cohort study to identify and quantify the occurrence of AEFIs related to pandemic vaccination among the population immunised in general practice. METHOD: Adults aged 60 years and older or persons with a risk-elevating medical condition recommended for vaccination in general practice were eligible for participation. After receipt of the first pandemic vaccine the administrator handed over an information flyer of the web-based monitoring program. The patient could sign up for study participation online. Within one week, three weeks and three months after the first immunisation questions were asked about demographics and health, immunisations, injections site reactions and labeled reactions as well as other possible new AEFIs. RESULTS: In all, 3569 participants filled in the first questionnaire. Corresponding figures for the second and third questionnaires were 3395 (95.1%) and 3162 (88.6%). Mean age was 58 years (SD 15) and 50.1% was female. Main indication was 60 years or older followed by presence of pulmonary or cardiovascular disease. Of all participants, 1311 (37%) reported an AEFI. Unexpected serious reactions were not reported nor were there signals of possible new AEFIs. The occurrence of an AEFI was determined by gender, age and type of co-morbidity. CONCLUSION: The web-based intensive monitoring system among patient immunised in general practice revealed AEFIs due to pandemic vaccination in one-third of participants. There were no unexpected serious adverse events in this population. This advanced methodology can be further developed to monitor real-time use and AEFIs of vaccines

Adverse drug reactions to tocolytic treatment for preterm labour: Prospective cohort study

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations. Design Prospective cohort study. Setting 28 hospitals in the Netherlands and Belgium. Participants 1920 consecutive women treated with tocolytics for threatened preterm labour. Main outcome measures Maternal adverse events (those suspected of being causally related to treatment were considered adverse drug reactions) leading to cessation of treatment. Results An independent panel evaluated the recorded adverse events, without knowledge of the type of tocolytic used. Of the 1920 women treated with tocolytics, 1327 received a single course of treatment (69.1%), 282 sequential courses (14.7%), and 311 combined courses (16.2%). Adverse drug reactions were categorised as serious or mild in 14 cases each. The overall incidence of serious adverse drug reaction was 0.7%. Compared with atosiban, the relative risk of an adverse drug reaction for single treatment with a (3 adrenoceptor agonist was 22.0 (95% confidence interval 3.6 to 138.0) and for single treatment with a calcium antagonist was 12 (1.9 to 69). Multiple drugtocolysis led to five serious adverse drug reactions (1.6%). Multiple gestation, preterm rupture of membranes, and comorbidity were not independent risk factors for adverse drug reactions. Conclusions The use of (3 adrenoceptor agonists or multiple tocolytics for preventing preterm birth is associated with a high incidence of serious adverse drug reactions. Indometacin and atosiban were the only drugs not associated with serious a

Web-based intensive monitoring:from passive to active drug surveillance

Introduction: Recently, the European pharmacovigilance legislative framework changed. Post-authorisation safety studies (PASS) and additional monitoring of drugs will be important tools in ensuring the safety of drugs. Methods that can facilitate gathering of the requested information are essential. In this article, web-based intensive monitoring is described and future applications of this method are discussed. Areas covered: Web-based intensive monitoring is a non-interventional observational cohort study using patients as a source of information. Eligible patients are identified in the pharmacy, and information about drug use and adverse events is collected through web-based questionnaires. An overview of the results as well as the pros and cons of this method is given. A discussion on how this methodology can be expanded to other settings and how it can be used in the future is included. Expert opinion: The main idea with web-based intensive monitoring, using a specific inclusion point, letting patients be the source of information and following the patients over time via web questionnaires, can be a useful tool in post-marketing surveillance. Aspects other than adverse drug reactions, such as information about indication for use and off-label use, dosage and compliance can also be collected

Results of the Experience with the Use of Varenicline in Daily Practice Using Intensive Monitoring

Background: Although a concise overview of Adverse Drug Reactions (ADRs) of varenicline is known, little is known about the time related information about ADRs of varenicline such as for example latencies. Objectives: To gain insight in the experience and safety of varenicline in daily practice as reported by patients through web-based questionnaires using an intensive monitoring system. Methods: Design A prospective, observational, non-interventional cohort study. Setting: First-time users of varenicline were defined as patients who have not filled in a prescription of varenicline in the previous 12 months using the first prescription signal in that particular pharmacy. Participants: All first-time users of varenicline in participating pharmacies between 1 December 2008 and 31 March 2012 were invited for the study. Patients could sign up for the study on a dedicated website. Electronic questionnaires were sent after 1, 2 and 6 weeks, 3 months and 4 months after they started to use varenicline. In these questionnaires questions about drug use and ADRs were asked for. Main outcome measurements: Information about the ADR, seriousness, and action taken when experiencing an ADR. Statistical analysis: Descriptive analysis was done using Microsoft Access. Results: About 1,418 patients signed up for the study. Response rates for the various questionnaires vary from 31.3% to 62.5%. 58.8% of the patients reported at least one ADR. The most frequently reported ADRs were nausea (30.8%), abdominal pain (11.2%) and abnormal dreaming (10.3%) which are listed in the Summary of Product Characteristics (SmPC) of varenicline. Median latency times were 3-7 days, with exception for depressed mood (10 days). The number of ADRs did not abate over time. No signals were detected. During treatment 43.9% of the patients stopped using varenicline. The main reasons for stopping were the occurrence of ADRs (42.2%) and other (40%) unspecified reasons. Conclusions: This study indicates that varenicline is a relatively safe drug. The reported ADRs correspond with the ADRs mentioned in the SmPC of varenicline with a median latency of 3-7 days. The number of ADRs do not abate over time

Longitudinal monitoring of the safety of drugs by using a web-based system:the case of pregabalin

Purpose Information about the time course of adverse drug reactions (ADRs) is often lacking. If this information would be available, it could help increase patient's adherence to drugs when experiencing an ADR. The aim of this study was to demonstrate how a web-based intensive monitoring system using the patient as a source of information can be used to gather longitudinal safety data of a drug. In this study, pregabalin was used as an example. Methods First-time users of pregabalin were approached in Dutch pharmacies between 1 August 2006 and 31 January 2008. After online registration, patients received questionnaires by email 2 weeks, 6 weeks, 3 months and 6 months after the start of the drug use. Data on patient characteristics, drug use and ADRs were collected and analysed. Results A total of 1373 patients registered for the pregabalin study. Of these patients, 1051 (76.5%) filled in at least one questionnaire. On an aggregated level, the ADR profile remained relatively stable over time. Incidence densities showed that the five most frequently reported reactions occurred early in the treatment. Initially, the majority of the patients did not undertake any action when experiencing an ADR. Recovery did not seem to be completely dependent of drug cessation. Conclusions With web-based intensive monitoring, it is possible to study the time course of ADRs. This method can be a valuable addition to pharmacovigilance because it can generate other types of information as compared with spontaneous reporting and other intensive monitoring methodologies. Copyright (C) 2011 John Wiley & Sons, Ltd

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting. Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented. In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated. Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were reanalysed using three categories. This demonstrated a better validity. Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance

Epistaxis and other haemorrhagic events associated with the smoking cessation medicine varenicline:a case series from two national pharmacovigilance centres

Purpose To present a case series of haemorrhagic events associated with varenicline identified from the New Zealand (NZ) and Netherlands national pharmacovigilance centres and propose a possible mechanism for these adverse events. Methods Reports of epistaxis and other haemorrhagic events (in all system organ classes excluding gynaecological) associated with varenicline were identified and assessed in both the NZ Intensive Medicines Monitoring Programme (IMMP) and the Netherlands Pharmacovigilance Centre Lareb (Lareb). Additional reports were identified from the World Health Organisation Uppsala Monitoring Centre (WHO-UMC) datasets, and these also underwent causality assessment. Results A total of 30 reports of haemorrhagic events were identified by the NZ IMMP (16 reports) and Lareb (14 reports). Six cases of epistaxis were identified, and four patients had a positive dechallenge on withdrawal of varenicline, suggesting a causal association. Another five reports of gingival bleeding were identified, with three patients having a positive dechallenge. Another patient who experienced haemoptysis while taking varenicline had a positive dechallenge and a positive rechallenge. In the WHO datasets, a further 49 reports of epistaxis, 39 reports of haemoptysis and 21 reports of thrombocytopenia were identified. A plausible mechanism for haemorrhagic events associated with varenicline may be a result of interaction with the serotonin (5-HT) receptor system and transporter. Conclusions This is the first specific investigation of haemorrhagic events associated with varenicline. The results of our assessment of reports identified by two national pharmacovigilance centres suggest that there may be causal relationship between varenicline and these adverse events

Online information discrepancies regarding safety of medicine use during pregnancy and lactation: a ConcePTION study

Abstract Introduction Inconsistencies in information concerning the safety of medicines during pregnancy and lactation might result in non-optimal treatment to pregnant and lactating women, subsequent risks to the fetus and to unnecessary weaning from breastfeeding. Objectives To analyze information discrepancies concerning medicines during pregnancy and lactation between different on-line sources for patients and health care professionals (HCPs) in four European languages. Methods The medicines analyzed were ibuprofen, ondansetron, olanzapine, fingolimod, methylphenidate and adalimumab. A standardized google search was performed in Swedish, Dutch, French and English. The identified recommendations were classified into data source categories, e.g regulatory sources, scientific sources and blogs/forums/social media for patients and for HCPs. The recommendations were compared between the data source categories for each medicine and language: 24 comparisons for pregnancy and 24 for lactation. Results For patients, 46% (11/24 comparisons) of the pregnancy recommendations were consistent between all information sources, while for lactation, 17% (4/24) were consistent. The corresponding figures for HCP data sources were 54% (13/24) and 21% (5/24). The regulatory sources were generally more conservative than other sources. Recommendations from five TIS centers (Teratology Information Services) were consistent in 93% (25/27) of the comparisons for pregnancy and 68% (15/22) for lactation. Conclusion Discrepancies in online information sources regarding medicines during pregnancy and lactation are common. These differences are more pronounced for lactation than for pregnancy. Recommendations from TIS centers showed better consistency, indicating more consensus on a scientific level. Additional work is needed to harmonize information within and between countries, to avoid conflicting messages

Safety Concerns Reported by Patients Identified in a Collaborative Signal Detection Workshop using VigiBase : Results and Reflections from Lareb and Uppsala Monitoring Centre

Introduction: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries. Objective: Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. Methods Data were retrieved from VigiBase in September 2016. Drug-event-combination series were restricted to those with[50% patient reports, defined as reporter type "Consumer/non-health professional'' per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a "signal.'' Results: Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments. Conclusions: Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance