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Pouwels K.B.,University of Groningen | Van Grootheest K.,University of Groningen | Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb
International Journal of Risk and Safety in Medicine | Year: 2012

In September 2010 the EMA decided to suspend the market authorisation of rosiglitazone, while the FDA decided to restrict the use of rosiglitazone. These actions were taken approximately 10 years after the introduction of rosiglitazone, because rosiglitazone might be associated with an increased risk of ischemic heart disease. It is often stated that the first signs of an increased risk of ischemic heart disease were noticed in 2004, however already in 2001 the FDA concluded, based on data available to the EMA at the time of initial approval, that rosiglitazone should not be used in combination with insulin, because this combination therapy was associated with an increased risk of cardiac failure and ischemic heart disease. Remarkably, in 2007, when the evidence against this combination therapy had increased, the EMA made a decision that encouraged the use of insulin in combination with rosiglitazone, while the FDA tried to restrict this combination therapy. Despite the publication of several studies, including a large randomized controlled study, the cardiovascular risk of rosiglitazone still has not been definitively established. The weight given to the benefits and the risks seems mainly a subjective decision. To prevent new cases like rosiglitazone, more attention should be given to evaluation of study protocols of safety trials prior to their starts. This paper gives a critical overview of the decision making process at the FDA and the EMA on the basis of public available information. © 2012 - IOS Press and the authors. All rights reserved.


Oosterhuis I.,Netherlands Pharmacovigilance Center Lareb | Van Hunsel F.P.A.M.,Netherlands Pharmacovigilance Center Lareb | Van Hunsel F.P.A.M.,University of Groningen | Van Puijenbroek E.P.,Netherlands Pharmacovigilance Center Lareb
Drug Safety | Year: 2012

Background: In 2010, the Netherlands Pharmacovigilance Centre Lareb received more than 4000 reports from healthcare professionals (HCPs). All HCPs received individual personal feedback containing information about the reported drug-adverse drug reaction (ADR) association. It is unclear what type of information HCPs expect in this feedback letter. Objective: The aim of the study was to examine the expectations of the personal feedback of HCPs who reported anADRto theNetherlands Pharmacovigilance Centre Lareb. Methods: A questionnaire survey was conducted among a random sample of 1200 pharmacists, general practitioners (GPs) and medical specialists who reported an ADR to the Netherlands Pharmacovigilance Centre Lareb between 1 January 2009 and 27 January 2010. Responders and non-responders were compared on the basis of profession, number of reports submitted to the pharmacovigilance since 2007 and their last report being serious or not. Questions were asked about the importance of personal feedback and the type of information reporters would like to see in their personal feedback. Both linear and logistic regression analysis were performed, with correction for possible confounding factors. Results: The response rate to the questionnaire was 34.6% (n = 399). The type of information the respondents generally would like to see in their personal feedback is information about the time course of the ADR and information about the pharmacological mechanism. However, GPs were, in general, less interested in receiving feedback than pharmacists and medical specialists. Most of the respondents were (very) unsatisfied if they received only a confirmation letter instead of personal feedback. Personalized feedback was considered to be (very) important for reporting an ADR in the future. Most of the respondents (80.3%) stated that the personal feedback increased their knowledge. Only 0.6% of respondents had not read the personalized feedback. No differences were found between responders and non-responders, with the exception that responders had reported statistically more often to the Netherlands Pharmacovigilance Centre Lareb in the past 3 years. Conclusions: Most of the respondents would like personal feedback instead of a standard confirmation letter. In general, pharmacists and medical specialists would like more information than GPs. The information in this study is useful in generating more customized personal feedback in the future, and could be useful for other pharmacovigilance centres that are interested in writing personalized feedback to make available to reporters. © 2012 Adis Data Information BV. All rights reserved.


Van Hunsel F.,Netherlands Pharmacovigilance Center Lareb | Van Hunsel F.,University of Groningen | Harmark L.,Netherlands Pharmacovigilance Center Lareb | Harmark L.,University of Groningen | And 4 more authors.
Drug Safety | Year: 2012

Background: Patients are important stakeholders in pharmacovigilance; however, little formal evaluation has been undertaken of existing patient reporting schemes within and outside Europe. If patient reporting is to be recognized as beneficial for pharmacovigilance and further optimized, methodology and best practice must be internationally shared and promoted. Objective: This study aims to review the methods of patient reporting of adverse drug reactions (ADRs) in 11 countries worldwide and to compare different aspects of their experiences. Methods:A survey based on telephone interviews, e-mail discussions and field visits of existing practices in consumer and patient reporting of ADRs was performed in the second half of 2010. Results: The start dates of the patient reporting schemes vary from 1964 (Australia) to 2010 (Norway). The number of patient reports per country varies widely. Most countries would ideally spend more resources on making the public aware of the possibility that patients can report ADRs. Most countries have three different ways for patients to report ADRs-a paper form, an electronic form on a website or by telephone. The level of sophistication of the electronic forms varies. The route of handling of patients' and healthcare professionals' ADR reports is the same for most countries. Personalized feedback on the reported association for each report is only given by four organizations. All countries have guidelines for the identification of patients in the database and most undertake checks for duplicate reports. In all countries, with the exception of Norway, it is possible to ask patients for follow-up. None of the organizations seek medical confirmation for each patient report. There is a difference between countries that do a causality assessment for each incoming ADR report and countries that only do a causality assessment of reports when they are looking at a potential signal. All countries assess the seriousness of reports, mostly by using the criteria of the CIOMS committee. In all countries, patient reports are used for signal detection purposes and in publications about ADRs. The Netherlands and the UK are actively evaluating their patient reporting schemes. None of the organizations hired additional staff when they started with patient reporting. Conclusions: This study provides a comprehensive review on the methods used in patient reporting of ADRs. Although there are some differences in the way various countries handle patient reports of ADRs, the importance of giving the public the opportunity to report and the additional scientific value of the collected data is widely recognized by the countries who participated in this survey.


Hrmark L.,Netherlands Pharmacovigilance Center Lareb | Hrmark L.,University of Groningen | Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,University of Groningen
Expert Opinion on Drug Safety | Year: 2012

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. © 2011 Informa UK, Ltd.


Harmark L.,Netherlands Pharmacovigilance Center Lareb | Harmark L.,University of Groningen | Van Puijenbroek E.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,University of Groningen
European Journal of Clinical Pharmacology | Year: 2013

Purpose: Duloxetine (Cymbalta®) is a serotonin (5-HT) and norepinephrine (NE) re-uptake inhibitor indicated for the treatment of depression, diabetic peripheral neuropathic pain and general anxiety disorder. The aim of this study is to gain insight in the user and safety profile of duloxetine in daily practice, reported by patients via a web-based intensive monitoring system during their first 6 months of use. Methods: First-time users of duloxetine were identified through the first dispensing signal in the pharmacy. Patient demographics and information about drug use and adverse drug reactions, ADRs, were collected through electronic questionnaires sent 2 and 6 weeks, 3 and 6 months after the start of duloxetine administration. ADRs were quantified and signal detection was performed on a case by case basis. Results: Three hundred and ninety-eight patients registered for the study; 69.1 % were female. Depression was the main indication. Three hundred and three patients (76.1 %) filled in at least one questionnaire and 78.9 % of these reported an ADR. Serious ADRs were reported by 4 patients. Three new signals were identified, amenorrhea, shock-like paraesthesias and micturition problems. Conclusions: Web-based intensive monitoring is an observational prospective cohort study mirroring the use and ADRs of duloxetine in daily practice. This study indicates that duloxetine is a relatively safe drug as used by patients for six months in daily practice, but the aforementioned signals need to be evaluated in more detail. © 2012 The Author(s).


Van Gaalen J.,Donders Institute for Brain | Kerstens F.G.,Donders Institute for Brain | Maas R.P.P.W.M.,Donders Institute for Brain | Harmark L.,Netherlands Pharmacovigilance Center Lareb | Van De Warrenburg B.P.C.,Donders Institute for Brain
CNS Drugs | Year: 2014

Background and Objectives: Cerebellar ataxia can be induced by a large number of drugs. We here conducted a systemic review of the drugs that can lead to cerebellar ataxia as an adverse drug reaction (ADR).Methods: We performed a systematic literature search in Pubmed (1966 to January 2014) and EMBASE (1988 to January 2014) to identify all of the drugs that can have ataxia as an ADR and to assess the frequency of drug-induced ataxia for individual drugs. Furthermore, we collected reports of drug-induced ataxia over the past 20 years in the Netherlands by querying a national register of ADRs.Results: Drug-induced ataxia was reported in association with 93 individual drugs (57 from the literature, 36 from the Dutch registry). The most common groups were antiepileptic drugs, benzodiazepines, and antineoplastics. For some, the number needed to harm was below 10. Ataxia was commonly reversible, but persistent symptoms were described with lithium and certain antineoplastics.Conclusions: It is important to be aware of the possibility that ataxia might be drug-induced, and for some drugs the relative frequency of this particular ADR is high. In most patients, symptoms occur within days or weeks after the introduction of a new drug or an increase in dose. In general, ataxia tends to disappear after discontinuation of the drug, but chronic ataxia has been described for some drugs. © 2014 Springer International Publishing Switzerland.


Broos N.,Netherlands Pharmacovigilance Center Lareb | Van Puijenbroek E.P.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb
Drug Safety | Year: 2010

Background: In November 2009, all children in the Netherlands from6 months up to 4 years of age were indicated to receive the Influenza A (H1N1) vaccine. Fever is a common adverse event following immunization in children. Pandemrix®, an inactivated, split-virus influenza A (H1N1) vaccine, was used for this age group. A clinical study mentioned in the Summary of Product Characteristics of Pandemrix® found an increased reactogenicity after the second dose in comparison with the first dose, particularly in the rate of fever. In the Netherlands, this adverse reaction was a point of concern for the parents or caregivers of these children. Objective: To investigate the course and height of fever following the first and second dose of Pandemrix® in children aged from 6 months up to 4 years. The secondary aim was to evaluate the use of an online survey during a vaccination campaign. Design: Survey-based descriptive study. Setting: Adverse drug reaction reporting database of the Netherlands Pharmacovigilance Centre (Lareb). Participants: Parents or caregivers (n = 839) of vaccinated children who reported fever to Lareb following the first immunization with Pandemrix®. Questionnaires were sent by email to parents or caregivers of eligible children following the first and second doses of Pandremix®. Main Outcome Measures: Time between vaccination and the occurrence of fever, the maximum measured temperature, the occurrence of other adverse events after first and second vaccination, the decision to get the second vaccination and the social implication of the fever in terms of absence from work, nursery or school, and hospitalization. Results: Following the first vaccination against Influenza A (H1N1), the height of the fever was between 39.0 and 40.0C in 359/639 (56.2%) of the children. In most of these children (235/639 [36.8%]), the onset of fever was between 6 and 12 hours following vaccination. 450/639 (70.4%) children recovered within 2 days. Of the 539 responders to the second questionnaire, 380 (70.5%) received the second vaccination against Influenza A (H1N1) and 213 (56.1%) of these children experienced fever again. The height of the fever was significantly lower (t-test; p = 0.001) and the duration was significantly shorter (Pearson's Chisquare; p = 0.002) in comparison with the first vaccination. The height of the fever after the first vaccination was associated with the decision to receive the second vaccination (t-test; p = 0.000). In the studied group, 342 (53.5%) parents or caregivers needed to stay home from work and 405 (63.4%) children stayed home from nursery or school due to fever following the first vaccination. Conclusions: The results of this study can be used in future vaccination campaigns to be able to inform people in an evidence-based manner about the risks and benefits of the vaccine and to avoid unnecessary concern and negative media attention. This could contribute to improved immunization levels. A web-based survey is demonstrated to be a useful tool to quickly gather information about a current safety concern and consequently inform the public to support an ongoing vaccination campaign. © 2010 Adis Data Information BV. All rights reserved.


Van Puijenbroek E.P.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest A.C.,Netherlands Pharmacovigilance Center Lareb
International Journal of Risk and Safety in Medicine | Year: 2011

In November 2009, a vaccination campaign against Influenza A (H1N1) was started in the Netherlands. The accelerated registration procedure of the vaccines used in this campaign and the use of these vaccines on a large scale indicated a need for real-time safety monitoring. This article looks at the way in which the safety monitoring of the pandemic influenza vaccines was organized in the Netherlands and it gives an overview of the main findings with respect to the two pandemic influenza vaccines, Focetria and Pandemrix, used in the Netherlands. Close monitoring, an efficient processing and analyzing the reports resulted in a close and real-time monitoring of the safety of the vaccines. From 1 November 2009 until 1 March 2010, 7534 reports concerning one or more events possibly related to the administration of both vaccines were received. 2788 of the reports related to Focetria and 4746 of the reports related to Pandemrix. No signals of possible batch-related problems were detected for either vaccine. The profile of the reported adverse events is comparable with the information provided in the Summary of Product Characteristics (SPC). Differences in reported events between both vaccines may be caused by bias and confounding due to the different populations for which these vaccines have been used. © 2011 - IOS Press and the authors. All rights reserved.


Scholl J.H.G.,Netherlands Pharmacovigilance Center Lareb | Van Puijenbroek E.P.,Netherlands Pharmacovigilance Center Lareb
Drug Safety | Year: 2012

Background: The Netherlands Pharmacovigilance Centre Lareb received reports of six cases of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database for spontaneous adverse drug reaction (ADR) reporting and from Vigibase™, the ADR database of the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre. Objectives: The objective of the current study was to identify whether the observed association between oral terbinafine use and hearing impairment, based on cases received by Lareb, constitutes a safety signal. Methods: Cases of hearing impairment in oral terbinafine users are described. In a case/non-case analysis, the strength of the association in Vigibase™ and the Lareb database was determined (date of analysis August 2011) by calculating the reporting odds ratios (RORs), adjusted for possible confounding by age, sex and ototoxic concomitant medication. For the purpose of this study, RORs were calculated for deafness, hypoacusis and the combination of both, defined as hearing impairment. Results: In the Lareb database, six reports concerning individuals aged 31-82 years, who developed hearing impairment after starting oral terbinafine, were present. The use of oral terbinafine was disproportionally associated with hypoacusis in both the Lareb database (adjusted ROR 3.9; 95% CI 1.7, 9.0) and in Vigibase™ (adjusted ROR 1.7; 95% CI 1.0, 2.8). Deafness was not disproportionally present in either of the databases. Discussion: Based on the described cases and the statistical analyses from both databases, a causal relationship between the use of oral terbinafine and hearing impairment is possible. The mechanism by which terbinafine could cause hearing impairment has not been elucidated yet. The pharmacological action of terbinafine is based on the inhibition of squalene epoxidase, an enzyme present in both fungal and human cells. This inhibition might result in a decrease in cholesterol levels in human cells, among which are the outer hair cells of the cochlea. It may be possible that the reduction in cochlear cholesterol levels leads to impaired cochlear function and possibly hearing impairment. Conclusion: In this study we describe hearing impairment as a possible ADR of oral terbinafine, based on six case reports and statistical support from Vigibase™ and the Lareb database. To our knowledge this association has not been described before. © 2012 Springer International Publishing AG. All rights reserved.


Van Puijenbroek E.P.,Netherlands Pharmacovigilance Center Lareb | Broos N.,Netherlands Pharmacovigilance Center Lareb | Van Grootheest K.,Netherlands Pharmacovigilance Center Lareb
Drug Safety | Year: 2010

Background: In November 2009, a vaccination campaign against Influenza A (H1N1) was started in the Netherlands. The accelerated registration procedure of the vaccines used in this campaign and the use of these vaccines on a large scale indicated a need for real-time safety monitoring. Objective: To describe the processing, analysing and performing of signal detection by the Netherlands Pharmacovigilance Centre (Lareb) on reports of adverse events following immunization (AEFI) with respect to the two pandemic influenza vaccines, Focetria® and Pandemrix®, used in the Netherlands. The secondary aim is to provide a summary of the results of the safety monitoring of both vaccines. Study Design: Description of the process of collecting information and analysis of the safety monitoring of the pandemic vaccines during the vaccination campaign against H1N1 in the Netherlands. An observational study on adverse events following immunization (AEFIs) associated with vaccines used in this campaign was conducted. Results: The use of a dedicated web form with predefined AEFIs enabled an efficient way of processing and analysing the reports, resulting in a close to real-time monitoring of the safety of the vaccines. From 1 November 2009 until 1 March 2010, 7534 reports concerning one or more AEFIs possibly related to the administration of both vaccines were received. 2788 of the reports related to Focetria® and 4746 of the reports related to Pandemrix®. The total time between receiving the reports and completion was longer for the serious reports (average 2.8 days) compared with the non-serious reports (average 0.8 days). The profile of the reported adverse events is comparable with the information provided in the Summary of Product Characteristics (SPC). Differences in reported AEFIs between both vaccines may be caused by bias and confounding due to the different populations for which these vaccines have been used. No signals of possible batch-related problems were detected for either vaccine. © 2010 Adis Data Information BV. All rights reserved.

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