Non-response in a pharmacy and patient-based intensive monitoring system: a quantitative study on non-response bias and reasons for non-response.

OBJECTIVE: Worldwide pharmacists play an increasingly important role in pharmacovigilance. Lareb Intensive Monitoring (LIM) in the Netherlands is a new form of active pharmacovigilance where pharmacists play a key role. Patients using drugs which are monitored are identified in the pharmacy and invited to participate in the active monitoring. Not all invited patients participate. This study aimed to investigate non-response bias in LIM, as well as reasons for non-response in order to identify barriers to participation. METHODS: The study population consisted of patients who received a first dispensation of an antidiabetic drug monitored with LIM between 1 July 2010 and 28 February 2011. Possible non-response bias was investigated by comparing age, gender and the number of drugs used as co-medication. Reasons for non-response were investigated using a postal questionnaire. KEY FINDINGS: Respondents were on average 4.5 years younger than non-respondents and used less co-medication. There were no differences regarding gender. The main reason for non-response was that information in the pharmacy was lacking. CONCLUSION: Differences between respondents and non-respondents should be taken into account when analysing and generalising data collected through LIM, as this might contribute to non-response bias. The relatively high response to the postal questionnaire, together with the answers about reasons for non-response, show that patients are willing to participate in a web-based intensive monitoring system, when they are informed and invited in the pharmacy.

[Adverse reactions to herbal remedies: analysis of reported adverse reactions in the Netherlands]. / Bijwerkingen van kruidenpreparaten: analyse van gemelde bijwerkingen in Nederland.

OBJECTIVE: To analyse reports of suspected adverse reactions in the use of herbal remedies in the Netherlands. DESIGN: Descriptive, retrospective. METHOD: All reports of suspected adverse reactions to herbal remedies in the database of the Netherlands Pharmacovigilance Centre Lareb during the period 1991 - March 2013 were assessed on causal link between use of the medication and the reported adverse reaction. Adverse reactions were classified by severity according to international standards. An overview was made of all reports of severe adverse reactions. RESULTS: The Lareb database contained 336 reports of suspected adverse reactions to herbal remedies. Of the 336 herbal remedies in the reports, 247 cases contained a single herbal ingredient. In total, the herbal remedies contained 221 different herbs, some ingredients being used in multiple products. 518 adverse reactions to the use of various herbal remedies were reported. Fifty-five reports were classified as serious. CONCLUSION: Herbs can cause adverse reactions or interactions with medicinal products, but herbal remedies can also be adulterated with regular medicines or illegal - even toxic - ingredients. Reporting adverse reactions significantly contributes to our knowledge about this subject. Physicians and pharmacists should ask patients about the use of alternative medications, particularly those based on herbs.

Monitoring adverse events of vaccines against Mexican flu.

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.

Pancreatitis associated with the use of itraconazole.

BACKGROUND: We call attention to the assumed association between itraconazole and pancreatitis by presentation of four Dutch case reports. METHODS AND RESULTS: The Netherlands Pharmacovigilance Centre Lareb received four reports of pancreatitis associated with the use of itraconazole, all reported by health professionals. The diagnosis of pancreatitis was confirmed by diagnostic tests. All four patients had been using relatively high doses of itraconazole. In two of these cases, recurrent use of itraconazole resulted in recurrent symptoms. We describe these four cases and discuss the possible mechanism. CONCLUSIONS: The presented cases suggest a causal relation between itraconazole and pancreatitis. Given the often mild indication for the use of itraconazole and the seriousness of this possible adverse drug reaction, it is essential that more data are obtained in order to strengthen the causality of this association. Physicians are invited to report their experiences on the subject.

Pharmacovigilance: methods, recent developments and future perspectives.

BACKGROUND: Pharmacovigilance, defined by the World Health Organisation as 'the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem' plays a key role in ensuring that patients receive safe drugs. Our knowledge of a drug's adverse reactions can be increased by various means, including spontaneous reporting, intensive monitoring and database studies. New processes, both at a regulatory and a scientific level, are being developed with the aim of strengthening pharmacovigilance. On a regulatory level, these include conditional approval and risk management plans; on a scientific level, transparency and increased patient involvement are two important elements. OBJECTIVE: To review and discuss various aspects of pharmacovigilance, including new methodological developments.

[Bruxism as a side effect of serotonin re-uptake inhibitors]. / Bruxisme als bijwerking van serotonineheropnameremmers.

The Netherlands Pharmacovigilance Centre Lareb received 14 reports on drugs which had teeth grinding as a side effect. The majority of reports (12) concerned selective serotonin re-uptake inhibitors. Several case reports in the literature support the association between using selective serotonin re-uptake inhibitors and bruxism. Bruxism can be explained by the effect of selective serotonin re-uptake inhibitors on the central dopamine pathway. Because bruxism can cause serious dental attrition, it is important to ask in diagnosis about the use of antidepressants and more specifically about serotonin re-uptake inhibitors.

Proton pump inhibitor-induced acute interstitial nephritis.

AIM: To investigate the association between the use of proton pump inhibitors (PPIs) and acute interstitial nephritis (AIN). METHODS: The Netherlands Pharmacovigilance Centre Lareb received seven case reports of AIN induced by various PPIs. In five of the reports it was mentioned that the diagnosis was confirmed by a renal biopsy. RESULTS: The time to onset varied between hours to 4 months. In all cases but one the patient spontaneously recovered after withdrawal of the offending agent. In one case the patient received treatment with prednisolone and recovered. In one patient a rechallenge was done 9 days after the initial event. Within 12 h of re-exposure the patient developed symptoms of AIN. CONCLUSIONS: The mechanism of drug-induced AIN is unknown, but an immunological mechanism is suspected. Our reports show no relation between dosage, latency, time to recovery, age or gender, supporting the hypothesis that the aetiology of AIN is immunological. Lareb has received reports of AIN with the use of omeprazole, pantoprazole and rabeprazole. This shows that AIN is a complication associated with the whole group of PPIs and not only omeprazole. It is important for health professionals to be aware of this adverse drug reaction, because an accurate and timely diagnosis and withdrawal of the offending drug can prevent potentially life-threatening renal failure.

[Drug-induced systemic lupus erythematosus: reports to The Netherlands Pharmacovigilance Centre Lareb]. / Geneesmiddelgeïnduceerde lupus erythematodes disseminatus: meldingen aan Nederlands Bijwerkingen Centrum Lareb.

Drug-induced SLE and idiopathic SLE differ in a number of important aspects, for example the male/female ratio and the age of the patients. There are also differences in incidence in different populations. The mechanism of drug-induced SLE is still largely unknown. It is generally assumed to be an allergic reaction to the drug. The database of the Netherlands Pharmacovigilance Centre Lareb contains 31 reports of SLE in relation to the use of 24 different drugs. In 3 of these cases, there was aggravation of pre-existent SLE. Infliximab and terbinafine are the most frequently reported in association with drug-induced SLE. Furthermore, the database contains a small number of reports of SLE associated with the use of antibiotics. It is difficult to determine whether all of the reported cases involve true drug-induced SLE, but a number of factors suggest that this is often the case, such as the presence or absence of skin involvement and the number of patients that recover after withdrawal of the drug. During the diagnosis of SLE, healthcare professionals should be aware of the use of drugs that might be associated with the induction of SLE.

Post Launch Monitoring of food products: what can be learned from pharmacovigilance.

Post Launch Monitoring (PLM) is one of the new approaches that are used in assessing the safety of novel foods or ingredients. It shares a close resemblance with procedures applied in the field of medicines, where Post Marketing Surveillance (PMS) has been carried out since the beginning of the 1960s. For this reason, Unilever and the Netherlands Pharmacovigilance Centre Lareb, maintaining the national reporting scheme in the Netherlands for adverse drug reactions, have been working together to optimize the Unilever's Post Launch Monitoring service. As a result of this cooperation a practical model for conducting PLM for food products has been developed. This model is also applicable for consumer products in general. The system allows for coding and assessing reports and the early detection of 'signals' of unintended health reactions. The methodological issues surrounding reporting of possible health reactions and practical issues surrounding coding and assessment of the reports that were encountered in the first period of this partnership are discussed. In addition, similarities and differences concerning PMS and PLM are described.

[Adverse events following vaccination reported to the Netherlands Pharmacovigilance Center Lareb in 2004-2006]. / Meldingen van bijwerkingen van vaccins bij het Nederlands Bijwerkingen Centrum Lareb in 2004-2006.

OBJECTIVE: To describe the voluntary reports of adverse events associated with vaccination received by the Netherlands Pharmacovigilance Center Lareb in 2004-2006. DESIGN: Descriptive. METHOD: Case-by-case analysis of adverse events associated with vaccination. RESULTS: In 2004, 2005 and 2006 there were 319, 329 and 266 reports of possible adverse events associated with vaccination, respectively. Health professionals who vaccinated frequently reported adverse events more frequently. This group was comprised of municipal health physicians who administered vaccines to travelers and general practitioners who administered influenza vaccines. Most of the reports on travel vaccinations were related to diphtheria-tetanus-poliomyelitis vaccines and hepatitis vaccines administered to adults. The total number of reports related to influenza vaccines at Lareb was low: 25, 9 and 31, respectively. Like the other group, most of these reports involved adult patients. Prior to 2002, when Lareb and the National Institute for Public Health and Environment (RIVM) began exchanging reports, vaccines accounted for 1.5% of the total number of drug-related adverse events reported; after 2002, this proportion increased to approximately 6%. CONCLUSION: It is difficult to assess the causal relationship between vaccine administration and the reported symptoms. The data on possible adverse events related to vaccines found in the Lareb database provide no cause to question the safety of vaccines.

Uterine perforation in women using a levonorgestrel-releasing intrauterine system.

OBJECTIVE: To determine an estimated incidence of uterine perforations related to the insertion of a levonorgestrel-releasing intrauterine system (LNG IUS) and to identify possible risk factors. DESIGN: Retrospective, case report study. SETTING: Hospitals in Limburg, the Netherlands. METHODS: Gynecologists in hospitals in Limburg were asked about uterine perforations related to the insertion of a LNG IUS between 1999 and 2002. The charts of the reported perforations were studied. Data on the patient, doctor, insertion, diagnosis and removal were collected for every reported uterine perforation. RESULTS: In Limburg, the estimated incidence of uterine perforations related to the insertion of a LNG IUS is 2.6 per 1000 insertions. Insertion in lactating women, even beyond 6 weeks after delivery, was shown to be an important risk factor. CONCLUSIONS: Complete registration of complications provides a greater insight into the actual incidence of LNG IUS-related uterine perforations and their possible consequences. This may eventually lead to a decrease in complications.

[Direct reporting of side effects by the patient: favourable experience in the first year]. / Meldingen van bijwerkingen rechtstreeks door patiënten: gunstige ervaringen van het eerste jaar.

OBJECTIVE: To determine the results of establishing a station at which patients can report the side effects of drugs. DESIGN: Descriptive. METHOD: Since 1 April 2003, patients may submit reports of possible adverse drug reactions directly to the Netherlands Pharmacovigilance Centre Lareb. The reports submitted during the period from 1 April 2003 to 31 March 2004 were analysed and compared with the reports submitted by doctors and pharmacists. RESULTS: In the first year, 276 reports were submitted by patients and 3131 by doctors and pharmacists. The reports from patients usually contained sufficient medical information and more frequently referred to serious adverse reactions than reports by health professionals. The reports from patients relatively often concerned psychotherapeutic agents, notably antidepressants. CONCLUSION: Based on the positive results during the first year, the Netherlands Pharmacovigilance Centre Lareb has decided to continue the reporting station for patients. Reports submitted by patients are currently part of the core responsibility of Lareb: the detection of signals of new adverse drug reactions.

The role of hospital and community pharmacists in pharmacovigilance.

In this paper, we give an overview of the role pharmacists actually have and could have in collecting reports of adverse drug reactions (ADRs) and more widely in pharmacovigilance. In the literature, several ways are mentioned in which the pharmacist, both the community pharmacist and the hospital pharmacist, can contribute to the safe use of drugs. In addition to their responsibilities regarding drug dispensing and compliance, they can have a substantial role in ADR reporting. Especially, hospital pharmacists can play a significant role in ADR reporting because the most serious adverse drug events occur in hospitals, and ADRs account for a substantial proportion of hospital admissions. Community pharmacists, however, can also play an important role in ADR reporting. This is, for example, the case in the Netherlands where community pharmacists contribute substantially, both in numbers and in quality of ADR reports. The contribution of the pharmacist to pharmacovigilance should, however, not be limited to ADR reporting. The various pharmaceutical disciplines could also greatly enhance our understanding of the nature of ADRs. If those involved in pharmaceutical disciplines can rise to this challenge, they will significantly help deepen our insights into ADRs.

[Notifications to the Netherlands Pharmacovigilance Foundation Lareb of the expulsion of a vaginal contraceptive ring (NuvaRing) and of pregnancy during the use of it]. / Meldingen bij het Nederlands Bijwerkingen Centrum Lareb van expulsie van een vaginale-anticonceptie-ring (NuvaRing) en van zwangerschap tijdens het gebruik ervan.

Netherlands Pharmacovigilance Foundation Lareb expulsion of the vaginal contraceptive ring NuvaRing was reported 8 times between February 2003 and April 2004. Moreover, in two of these reports pregnancy was reported. In that same period, Lareb received 10 more reports of pregnancy during the use of the ring, in which expulsion was not mentioned explicitly. Additional information on these cases was collected by questionnaire. Expulsion of the ring is described in the product information. The ring should then be placed back within 3 h. However, the Lareb reports show that expulsion of the ring is not always noticed by the user. In those cases the contraceptive efficacy of this method is questionable. The physician should be alert to pre-existing risk factors that increase the chance of expulsion of the ring, and should provide extra detailed advice about the right way of placing the ring, the risk of expulsion and the importance of replacing it in time.

[Severe adverse reactions after the use of sulphur hexafluoride (SonoVue) as an ultrasonographic contrast agent]. / Ernstige bijwerkingen bij gebruik van zwavelhexafluoride (SonoVue) als echografisch contrastmiddel.

European Medicines Agency (EMEA) recently took precautionary measures to limit the use of the ultrasonographic contrast agent sulphur hexafluoride (SonoVue) in patients with cardiac disease. Throughout Europe a number of serious allergic reactions with probable secondary cardiovascular problems have been reported. In addition to this, there have been 3 reports of a fatal outcome soon after the administration of SonoVue. For all of these patients there was a risk of serious cardiac complications as a consequence of underlying cardiac problems. In The Netherlands 3 anaphylactic reactions have been reported, two in women aged 59 and 70 years respectively, and one in a man aged 80 years.

Intensive monitoring of new drugs based on first prescription signals from pharmacists: a pilot study.

BACKGROUND: Intensive monitoring can be a valuable tool in the early detection of adverse drug reactions, especially of new drugs. Aim of this pilot study was to investigate the practical possibilities of a system of intensive monitoring, using the pharmacy computer system to detect the first dispensing of a new drug. METHOD: Eight pharmacists were asked to monitor, using their computer system, when a general practitioner prescribed the target drug (rofecoxib). The pharmacists were also requested to provide the researchers at Lareb with an overview of the patient's medication history. Subsequently, the pharmacist sent the prescribing physician an envelope containing information about the project and a reporting form (all provided by Lareb), which the GP was requested to return to Lareb after the next visit of the patient. The items on the questionnaire concerned characteristics of the patient (anonymous), indication, dose and information about possible adverse drug reactions. RESULTS: During a 4-week period, the participating pharmacists signalled 44 first prescriptions of rofecoxib. For each of these signals, the pharmacist provided Lareb with the medication history of the patient involved. Of the prescribing GPs who had been sent the report form, 70.5% (n = 31) returned the form. Twenty-one of the 31 forms were returned within 4 weeks. The medication histories showed that in 43 of the 44 cases, the dispensing of the target drug was indeed the first delivery. The participating pharmacists and GPs were also sent an evaluation form. All pharmacists returned their evaluations, indicating an overall motivation to participate in the proposed system. In total, seven GPs returned their evaluation forms, three of whom had not reported adverse drug events to the national spontaneous reporting centre before. CONCLUSION: Although the number of participants in this trial was small, we conclude that pharmacists and prescribing physicians are able and willing to contribute to an intensive monitoring system for new drugs.

[Leopold Meyler (1903-1973): a pioneer in the field of side affects of drugs]. / Leopold Meyler (1903-1973): een pionier op het gebied van bijwerkingen van geneesmiddelen.

In 1951, more than a decade before the first rumblings of the thalidomide catastrophe, a remarkable book appeared in the Netherlands under the authorship of Leopold Meyler. It appeared a year later in an English translation, as Side effects of drugs. This was a remarkable book at a time that medical interest in drugs--and particularly new drugs--was limited almost entirely to their proven or possible therapeutic benefits. Meyler was a specialist in internal medicine in Groningen. He was Jewish and was forced to go into hiding during World War II. He suffered a great deal during this time and after the war he was admitted to a sanatorium where he was treated for tuberculosis. It was here that he was advised to start the systematic collection of adverse-drug reactions reported in literature. Initially there was quite a lot of criticism of his work but it gradually gained recognition and he was appointed the first professor of Clinical Pharmacology at Groningen University in 1968. In his own time his was a lone voice crying in the wilderness. Had his voice been heeded earlier, the extent of the thalidomide disaster might well have been much more limited. His work still continues to contribute to the safe use of drugs.

Labelling and 'Dear Doctor' letters: are they noncommittal?

Over the past few years, a number of drugs have been withdrawn for safety reasons, either by drug approval authorities, or by the manufacturer. A recent example is the withdrawal of cerivastatin in connection with rhabdomyolysis. Several other drugs have also been taken off the market as a security measure, not because the nature of the risk involved was unknown but because the risk had proved apparently uncontainable. It seems that the inclusion of a warning or contraindication in the Summary of Product Characteristics (SPC) or sending a 'Dear Doctor' letter is insufficient to ensure compliant prescription behaviour. There appears to be a discrepancy between the careful use of evidence underpinning the SPC content and formal warnings and changes to the SPC and the effect they have on the prescription and dispensing of the drugs involved. This results in undue loss or damage for both the manufacturer and the patient. There are no easy solutions to tackle this problem; the ineffectiveness of labelling and 'Dear Doctor' letters has ramifications for the whole regulatory/ industrial/educational complex. We discuss briefly four possible strategies for improving the current situation, with the emphasis on the place the prescriber has in this process. The first strategy is education-based. Clinicians need to know about the comparative merits of the effectiveness and risk of drugs, as well as how they work pharmacologically, toxicologically, and what interactions they have with each other. The second strategy involves improving the information available for clinicians. Frequently, physicians do not consult the SPC for verification, leaving aside whether they have taken notice of the contents of the official SPC in the first place. It is recommended that the accessibility of SPCs is enhanced for doctors and pharmacists, drawing attention specifically to any changes. There needs to be a single body of information that covers every drug. The third strategy involves communication. There is much to be done in this area both in terms of follow-up and understanding of health professional's behaviour and how to empower best practise. The final strategy involves professional freedom. It goes without saying that doctors who issue off-label prescriptions may need to justify their actions. Deviating from the SPC should always be a considered decision and health professionals need to be aware of the additional responsibilities associated with such a decision. The dispensing pharmacist can play an important role in the implementation of warnings and contraindications.