Eugène van Puijenbroek

Tendon disorders attributed to fluoroquinolones: a study on 42 spontaneous reports in the period 1988 to 1998

OBJECTIVE Fluoroquinolone antibiotics have been associated with tendinitis and tendon rupture. In this paper we report on the followup of 42 spontaneous reports of fluoroquinolone-associated tendon disorders. METHODS This study is based on cases of fluoroquinolone-associated tendon disorders reported to the Netherlands Pharmacovigilance Foundation Lareb and the Drug Safety Unit of the Inspectorate for Health Care between January 1, 1988, and January 1, 1998. By means of a mailed questionnaire, we collected information on the site of injury, onset of symptoms, treatment, and course of the tendon disorder as well as information on possible risk factors and concomitant medication. RESULTS Of 50 mailed questionnaires, 42 (84%) were returned. The data concerned 32 patients (76%) with tendinitis and 10 patients (24%) with a tendon rupture. Sixteen cases (38%) were attributed to ofloxacin, 13 (31%) to ciprofloxacin, 8 (19%) to norfloxacin, and 5 (12%) to pefloxacin. There was a male predominance, and the median age of the patients was 68 years. Most of the reports concerned the Achilles tendon, and 24 patients (57%) had bilateral tendinitis. The latency period between the start of treatment and the appearance of the first symptoms ranged from 1 to 510 days with a median of 6 days. Most patients recovered within 2 months after cessation of therapy, but 26% had not yet recovered at followup. CONCLUSION These reports suggest that fluoroquinolone-associated tendon disorders are more common in patients over 60 years of age. Ofloxacin was implicated most frequently relative to the number of filled prescriptions in the Netherlands.

Use of measures of disproportionality in pharmacovigilance: three Dutch examples.

Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance. In The Netherlands ‘the Netherlands Pharmacovigilance Foundation Lareb’ maintains such a system. A primary aim in pharmacovigilance is the timely detection of either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved, i.e. signal detection. Adequate signal detection solely based on the human intellect (case by case analysis or qualitative signal detection) is becoming time consuming given the increasingly large number of data, as well as less effective, especially in more complex associations such as drug-drug interactions, syndromes and when various covariates are involved. In quantitative signal detection measures that express the extent in which combinations of drug(s) and clinical event(s) are disproportionately present in the database of reported suspected ADRs are used to reveal associations of interest. Although the rationale and the methodology of the various quantitative approaches differ, they all share the characteristic that they express to what extent the number of observed cases differs from the number of expected cases.In this paper three Dutch examples are described in which a measure of disproportionality is used in quantitative signal detection in pharmacovigilance: (i) the association between antidepressant drugs and the occurrence of non-puerpural lactation as an example of an association between a single drug and a single event; (ii) the onset or worsening of congestive heart failure associated with the combined use of nonsteroidal anti-inflammatory drugs and diuretics as an example of an association between two drugs and a single event (drug-drug interaction); and (iii) the (co)-occurrence of fever, urticaria and arthralgia and the use of terbinafine as an example of an association between a single drug and multiple events (syndrome).We conclude that the use of quantitative measures in addition to qualitative analysis is a step forward in signal detection in pharmacovigilance. More research is necessary into the performance of these approaches, especially its predictive value, its robustness as well as into further extensions of the methodology.

Motives for reporting adverse drug reactions by patient-reporters in the Netherlands

AimThe aim of this study was to quantify the reasons and opinions of patients who reported adverse drug reactions (ADRs) in the Netherlands to a pharmacovigilance centre.MethodA web-based questionnaire was sent to 1370 patients who had previously reported an ADR to a pharmacovigilance centre. The data were analysed using descriptive statistics, χ2 tests and Spearman’s correlation coefficients.ResultsThe response rate was 76.5% after one reminder. The main reasons for patients to report ADRs were to share their experiences (89% agreed or strongly agreed), the severity of the reaction (86% agreed or strongly agreed to the statement), worries about their own situation (63.2% agreed or strongly agreed) and the fact the ADR was not mentioned in the patient information leaflet (57.6% agreed or strongly agreed). Of the patient-responders, 93.8% shared the opinion that reporting an ADR can prevent harm to other people, 97.9% believed that reporting contributes to research and knowledge, 90.7% stated that they felt responsible for reporting an ADR and 92.5% stated that they will report a possible ADR once again in the future.ConclusionThe main motives for patients to report their ADRs to a pharmacovigilance centre were the severity of the ADR and their need to share experiences. The high level of response to the questionnaire shows that patients are involved when it comes to ADRs and that they are also willing to share their motivations for and opinions about the reporting of ADRs with a pharmacovigilance centre.

Different Risks for NSAID-Induced Anaphylaxis

BACKGROUND: After drugs are marketed, spontaneous reporting systems can provide valuable information regarding the occurrence of suspected adverse drug reactions. The Netherlands Pharmacovigilance Foundation has received a substantial number of anaphylactic reaction reports related to the use of nonsteroidal antiinflammatory drugs (NSAIDs). OBJECTIVE: To investigate whether the risk of anaphylactic reactions being reported during the use of various NSAIDs is greater than with other classes of drugs and if differences among NSAIDs exist. METHODS: In a case/noncase design, reporting odds ratios (RORs) were calculated using logistic regression analysis. Cases were defined as reports in which anaphylactic or anaphylactoid reactions were reported; all other reports were considered as noncases. The index group consisted of reports in which NSAIDs were mentioned as the suspected medication; the reference group consisted of all other reports. RESULTS: Between January 1985 and November 2000, the Netherlands Pharmacovigilance Foundation Lareb received 76 cases concerning anaphylactic reactions to NSAIDs. These drugs are strongly associated with anaphylactic reactions. The ROR adjusted for age, gender, and source of the reports was 9.4 (95% CI 6.9 to 12.7). Anaphylactic reactions associated with the use of naproxen, ibuprofen, and diclofenac were reported disproportionately with respect to other drugs. The corresponding RORs from logistic regression analysis adjusted for age, gender, and reporting source for diclofenac, naproxen, and ibuprofen were 17.2 (95% CI 12.1 to 24.5), 9.1 (95% CI 5.2 to 15.9), and 5.5 (95% CI 2.5 to 11.9), respectively. CONCLUSIONS: The results of this study strengthen previous findings concerning the relative high risk of developing an anaphylactic reaction during the use of NSAIDs, particularly diclofenac, ibuprofen, and naproxen.

Intensive Monitoring of Pregabalin Results from an Observational, Web-Based, Prospective Cohort Study in the Netherlands Using Patients as a Source of Information

Background: Pregabalin is one of the first drugs registered for the treatment of neuropathic pain. It is also indicated as adjuvant therapy in the treatment of epilepsy and for generalized anxiety disorder. Pregabalin is a GABA analogue and exerts its effect by binding to the α2-δ subunit of voltage-gated calcium channels, leading to a decreased synaptic release of neurotransmitters.Objective: To gain insight into the safety and user profile of pregabalin in daily practice, reported by patients via a web-based intensive monitoring system based at the Netherlands Pharmacovigilance Centre Lareb.Methods: Lareb Intensive Monitoring is an observational prospective cohort study with no limiting inclusion or exclusion criteria compared with clinical trials. First-time users of pregabalin were identified through the first prescription signal in intensive monitoring participating pharmacies between 1 August 2006 and 31 January 2008. Eligible patients received information about the pregabalin study in the pharmacy. When registering online, patient characteristics and information about pregabalin and other concomitant drug use were collected. After registration, the patient received questionnaires by e-mail 2 weeks, 6 weeks, 3 months and 6 months after the start of pregabalin. In these questionnaires, possible adverse drug reactions (ADRs) were addressed. Reactions not labelled in the Summary of Product Characteristics of pregabalin, and reactions that were labelled but were interesting for other reasons, were analysed on a case-by-case basis.Results: In total, 1373 patients filled in the online registration form. The average age of participants was 54.5 years (range 11–89), with 58.0% being female. The indication for pregabalin use was neuropathic pain in 85.9% of participants. The average daily dose was 201 mg, and 80.5% of all users used pregabalin capsule 75 mg. All patients who registered for the study were sent a questionnaire; 1051 (76.5%) patients filled in at least one questionnaire. There were no statistically significant differences found regarding sex, age or daily dosage between this latter group compared with the patients who registered for the study but did not fill in a questionnaire. At least one possible ADR was reported by 69.3% of patients and serious ADRs were reported by 11 patients. The five most frequently reported possible ADRs were dizziness, somnolence, feeling drunk, fatigue and increased weight. Four associations were further analysed. Headache was analysed because of its high frequency. The time to onset ranged from a few hours to 5 months, with a median time to onset of 2 days. In 15 reports the headache passed without withdrawing the drug, and in ten cases the headache disappeared after drug withdrawal. Upper abdominal pain, a possible drug interaction between pregabalin and blood glucose-lowering agents, and suicidal ideation were considered to be signals.Conclusions: Web-based intensive monitoring is an observational prospective cohort study. It will therefore provide a picture of the use of pregabalin and its ADRs in daily practice. This study indicates that pregabalin is a relatively safe drug. Eleven patients (<1.0%) experienced a serious ADR while using the drug. The most frequently reported possible ADRs correspond with the reactions most frequently reported during clinical trials. The study demonstrates that a web-based intensive monitoring system can contribute to greater knowledge about a reaction, such as headache, with quantification and information about latencies and time course of the reaction. It can also detect signals worth further investigation, such as abdominal pain and possible interaction with oral antidiabetics.

Reporting of adverse drug reactions by general practitioners : a questionnaire-based study in the Netherlands

AbstractBackground: There has been a gradual decline over the years in the number of spontaneous reports of potential adverse drug reactions (ADRs) from general practitioners (GPs) in the Netherlands. Objective: To reveal aspects of knowledge, attitudes and behaviour that can stimulate GPs to submit (more) ADRs. Methods: Dutch GPs were divided into the following two groups based on their reporting behaviour during the period 2004–6: (i) active reporters; and (ii) non-reporters. A random selection from each group was sent a questionnaire, based on the Ajzen and Fishbein model, focussed on their reporting behaviour. The questions were subdivided into knowledge-related questions, attitude-related questions and questions about the influence of the professional environment. Results: 700 questionnaires were completed, corresponding with an overall response of 47%. GPs who actively reported ADRs differed from their non-reporting colleagues: they had more knowledge on ADR reporting, were more interested in pharmacotherapy and more often had a positive example in their professional environment. Both reporting and non-reporting GPs considered it very important to comply with their professional environment. Conclusion: Specific education and training of GPs on pharmacotherapy, preferably with extra attention to ADR reporting, is expected to improve ADR reporting. Improved communication of GPs with their fellow GPs and pharmacists as well as with their patients may further stimulate ADR reporting.

Adverse drug reaction reports of patients and healthcare professionals—differences in reported information†

This study aims to explore the differences in reported information between adverse drug reaction (ADR) reports of patient and healthcare professionals (HCPs), and, in addition, to explore possible correlation between the reported elements of information.

Uterine Perforation with the Levonorgestrel-Releasing Intrauterine Device Analysis of Reports from Four National Pharmacovigilance Centres

AbstractBackground: Levonorgestrel-releasing intrauterine devices (LNG-IUD) are commonly used for contraception and other indications in many countries. National pharmacovigilance centres have been receiving reports from healthcare professionals and patients of uterine perforation associated with the use of these LNG-IUDs. Methods: National pharmacovigilance centres in the Netherlands, New Zealand, Switzerland and Germany did a search on their adverse drug reaction databases for reports of cases of uterine perforation after insertion of a LNG-IUD received between the introduction of the LNG-IUD onto the market in the late 1990s and 15 July 2007.The number of women affected and patient characteristics such as age, parity and breastfeeding status were examined. In addition, the method of detection of the perforation and the time until discovery of the perforation were analysed. Results: Between the introduction of the LNG-IUD onto the market in each country and 15 July 2007, 701 cases of uterine perforation with a LNG-IUD were reported; 8.5% of the perforations were detected at the time of insertion. Abdominal pain and control/check-up visits were the most common events that lead to the detection of a perforation. Of 462 women known to be parous, 192 (42%) were breastfeeding at the time the perforation was discovered. Conclusions: Uterine perforations can be asymptomatic and may remain undetected for a long time after IUD insertion. Abdominal pain, control/ check-up visits or changes in bleeding patterns are triggers for detection of perforation and should therefore be taken seriously.

Monitoring Adverse Events of the Vaccination Campaign Against Influenza A (H1N1) in the Netherlands

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. CONCLUSIONS The method applied allowed for real-time monitoring for AEFIs during the mass vaccination campaign. The use of web-based forms, preferably with information on venue and used batch numbers, enabled an efficient monitoring of possible batch-related problems. No major safety issues occurred with respect to the type of reported AEFIs, or with the batches of either vaccine.AbstractBackground: 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. Conclusions: The method applied allowed for real-time monitoring for AEFIs during the mass vaccination campaign. The use of web-based forms, preferably with information on venue and used batch numbers, enabled an efficient monitoring of possible batch-related problems. No major safety issues occurred with respect to the type of reported AEFIs, or with the batches of either vaccine.

Use of angiotensin receptor antagonists in patients with ACE inhibitor induced angioedema

S.A. Fuchs: Department of Pediatrics, University Medical Center Utrecht, Utrecht, The Netherlands R.H.B. Meyboom: The WHO Uppsala Monitoring Center, Uppsala, Sweden; and Utrecht Institute for Pharmaceutical Sciences (UIPS), Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht, The Netherlands E.P. van Puijenbroek: Netherlands Farmacovigilance Centre Lareb, ’s-Hertogenbosch, The Netherlands H.J. Guchelaar (correspondence, e-mail: h.j.guchelaar@lumc.nl): Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands