The potential of training specialist oncology nurses in real-life reporting of adverse drug reactions.

Specialist oncology nurses (SONs) have the potential to play a major role in monitoring and reporting adverse drug reactions (ADRs); and reduce the level of underreporting by current healthcare professionals. The aim of this study was to investigate the long term clinical and educational effects of real-life pharmacovigilance education intervention for SONs on ADR reporting. This prospective cohort study, with a 2-year follow-up, was carried out in the three postgraduate schools in the Netherlands. In one of the schools, the prescribing qualification course was expanded to include a lecture on pharmacovigilance, an ADR reporting assignment, and group discussion of self-reported ADRs (intervention). The clinical value of the intervention was assessed by analyzing the quantity and quality of ADR-reports sent to the Netherlands Pharmacovigilance Center Lareb, up to 2 years after the course and by evaluating the competences regarding pharmacovigilance of SONs annually. Eighty-eight SONs (78% of all SONs with a prescribing qualification in the Netherlands) were included. During the study, 82 ADRs were reported by the intervention group and 0 by the control group. This made the intervention group 105 times more likely to report an ADR after the course than an average nurse in the Netherlands. This is the first study to show a significant and relevant increase in the number of well-documented ADR reports after a single educational intervention. The real-life pharmacovigilance educational intervention also resulted in a long-term increase in pharmacovigilance competence. We recommend implementing real-life, context- and problem-based pharmacovigilance learning assignments in all healthcare curricula.

The pre- and post-authorisation data published by the European medicines agency on the use of biologics during pregnancy and lactation.

AIMS: The effects of biologics on reproduction/lactation are mostly unknown although many patients that receive biologics are women of reproductive age. The first objective of this study was to investigate the publicly available data on pregnancy/lactation before and after marketing authorization in Europe of biologics for the indications of rheumatologic inflammatory autoimmune diseases and inflammatory bowel disease. Secondary objectives included the assessment of the clinical relevance of the provided data and comparison of initial and post-authorization data. METHODS: Initial and post-authorization data were extracted from the European Public Assessment Reports and the latest versions of Summary of Product Characteristics using publicly available documents on the European Medicines Agency's website. Four sections were categorized regarding pregnancy outcomes: pre-clinical/animal studies, human female fertility, pregnancy-related outcomes and congenital malformations in the human fetus. Three sections were categorized regarding lactation outcomes: pre-clinical/animal studies, excretion in human breast milk and absorption in children through breastfeeding. The clinical applicability of each category was scored by specified criteria, based on scientific literature, and further as defined by the authors. RESULTS: For the 16 included biologics, post-authorization data were delivered only for adalimumab, certolizumab pegol, etanercept and infliximab. For the 12 remaining biologics limited data on pregnancy and lactation during the post-marketing period of 2-21 years were available. CONCLUSIONS: In this article several suggestions are provided for improving a multidisciplinary approach to these issues. The initiation of suitable registries by marketing authorization holders and data transparency for clinicians and academics are highly endorsed.

[Does sexual dysfunction persist upon discontinuation of selective serotonin reuptake inhibitors?]. / Blijvende seksuele functiestoornissen na staken van een SSRI?

BACKGROUND: Cases reported in the literature suggest that in some individuals sexual dysfunction associated with selective serotonin reuptake inhibitors (SSRIS) may persist following the discontinuation of ssris. AIM: To find out how many reports of persistent sexual dysfunction associated with the use of ssris were received by the Netherlands Pharmacovigilance Centre, Lareb. METHOD: The database of the Netherlands Pharmacovigilance Centre Lareb was searched for reports of sexual dysfunction in patients who had been using SSRIS and whose sexual functioning had not returned to normal at the time of notification. RESULTS: The database of the Netherlands Pharmacovigilance Centre Lareb contained 19 reports of persistent sexual dysfunction in patients who had stopped using ssris for two months up to three years and who had not regained normal sexual functioning. The sexual disorders that were reported most frequently were reduced libido, erectile dysfunction and delayed orgasm. It seems likely that these disorders were caused not only by pharmacological effects of ssris but also by psychological factors. CONCLUSION: Although it has previously been assumed that patients always regain normal sexual functioning shortly after discontinuation of ssris, emerging evidence suggests that this may not be the case.

GP consultations for menstrual disorders after COVID-19 vaccination - A self-controlled cohort study based on routine healthcare data from the Netherlands.

INTRODUCTION: Several studies described that COVID-19 vaccinations can cause menstrual disorders. Our study aimed to describe whether this also resulted in more general practitioner (GP) consultations for menstrual disorders after COVID-19 vaccination, based on a large cohort study. METHODS: A retrospective self-controlled cohort study was performed including vaccinated women in 2021 aged 12-49 years from two large, representative GP databases in the Netherlands. Incidence rates and incidence rate ratio's (IRR) were calculated using Poisson regression, adjusting for SARS-CoV-2 infection as time-varying confounder. The exposed period was set at maximum six months after each COVID-19 vaccination and the non-exposed period was defined as all-time outside the exposed period. RESULTS: The cohort included 631,802 women, of which 18,986 (3 %) consulted the GP for a menstrual disorder during 2021. Increased GP consultations were observed among 12-14 year olds for amenorrhea/hypomenorrhea/oligomenorrhea (IRR: 1.85, 95 % CI: 1.30-2.65) and irregular/frequent menstruation (IRR: 1.33, 95 % CI: 1.06-1.69) after COVID-19 vaccination in general, and after Pfizer/BioNTech vaccination (IRR: 1.87, 95 % CI: 1.31-2.67 for amenorrhea/hypomenorrhea/oligomenorrhea and IRR: 1.35, 95 % CI: 1.06-1.70 for irregular/frequent menstruation). Persons from this age group were in general also vaccinated with Pfizer/BioNTech. No increase in the frequency of GP consultations were observed for older age groups, other vaccine brands, and potential risk groups. CONCLUSION: For the majority of women, no increased GP consultations for menstrual disorders was found. Solely for the youngest age group (12-14 year olds) increased GP consultations for specific types of menstrual disorders was found after Pfizer/BioNTech vaccination.

Causality methods in cosmetovigilance: comparison of Colipa and PLM versus global introspection.

The European Cosmetics Regulation requires a post-marketing system for detection of undesirable effects on human health of cosmetic products. Colipa, the European Cosmetic, toiletry and perfumery association, provided guidelines for causality assessment of these effects. In addition another causality method originally designed for causality rating in Post Launch Monitoring (PLM) of novel foods has been employed to assess causality of cosmetic products. In this study these two causality schemes for consumer cosmetic products were validated against clinical assessment, using the method of global introspection (GI) in 100 reported cases. Causality assessments were performed by three experienced assessors in pharmacovigilance. In the event of discordance between the assessors, an adapted Delphi method was used. The overall Spearman correlation coefficient was 0.74 for comparison of Colipa versus GI, whereas this was 0.50 for PLM versus GI. According to current guidelines, the sensitivity was 0.95 for both the Colipa and PLM method, specificity was 0.84 for Colipa and 0.40 for PLM. From these results it can be concluded the performance of the Colipa causality method yielded better correlation to GI than PLM causality method. The factor identified from comparison of these two schemes as having greatest impact was the course of the reaction.

In utero antidepressant exposure not associated with ADHD in the offspring: A case control sibling design.

Recent studies have reported an association between antidepressant (AD) use during pregnancy and the risk to develop attention-deficit/hyperactivity disorder (ADHD) in the offspring. However, the association might be confounded by risk factors in the pregnant parent. To control for unmeasured factors between pregnancies carried by the same parent, we set up a case-control sibling study using the University of Groningen prescription database IADB.nl. Children receiving medication for ADHD (cases) before the age of 16 years were matched to siblings not receiving such medication (controls). Exposure was defined as at least two prescriptions for any AD during pregnancy, i.e., the period of 39 weeks before the birth date of the offspring. Secondary analyses were performed to assess the effects of the degree of exposure (the amount of Defined Daily Doses) and the type of AD exposed to. Univariate and multivariate logistic regression was used to estimate odds ratios (ORs) with corresponding 95% confidence intervals (CI). In total, 2,833 children (1,304 cases and 1,529 controls) were included in the analysis. Exposure rate to ADs among cases and controls was 2.2% and 2.4%, respectively. After adjusting for the birth date of the child (as a proxy for the date of pregnancy), age of the pregnant parent at birth, use of psychostimulants, opioids, and antiepileptic drugs by the pregnant parent in the 15 months before birth of the child, an adjusted OR of 1.11 (95% CI 0.67-1.83) was found for the risk of ADHD in the offspring when exposed in utero to ADs. This indicates no increased risk of ADHD in offspring following in utero exposure to ADs. The secondary analyses revealed no statistically significant associations either. The present study provides further evidence that an association between in utero AD exposure and ADHD in offspring might not exist. This perceived association may be caused (at least partially) by confounding by indication. The extent to which depression in the pregnant parent could cause mental disorders such as ADHD in offspring, and the mechanisms involved, should be investigated in further studies.

[COVID-19 during pregnancy and lactation: what do we already know?] / COVID-19 tijdens zwangerschap en borstvoeding.

SARS-CoV-2 has rapidly spread worldwide since December 2019. Obviously, pregnant and lactating women will also be infected with SARS-CoV-2. Pregnant women, however, are a risk population for developing severe respiratory infections. Currently, the knowledge on potential risks and consequences of COVID-19 during pregnancy and lactation is limited. Available data show that pregnant women suffer from similar symptoms compared to non-pregnant patients. There is no evidence as yet that COVID-19 has a more serious course during pregnancy. Although pregnant women might suffer from a wide variety of symptoms, most of them are asymptomatic. Maternal SARS-CoV-2 infection might lead to adverse neonatal outcomes, such as prematurity or respiratory symptoms. There is currently no conclusive evidence of absence of intrauterine transmission of the virus; the virus has not been detected in breastmilk in most studies, although passage into breastmilk cannot be completely excluded.

[Which side effects should I inform patients about?] / Over welke bijwerkingen informeer ik de patiënt?

The law requires that healthcare professionals adequately inform patients about possible side effects when they prescribe new pharmacological treatments. There are several reasons (lack of time, fear of nocebo effect, patient and prescriber preferences) why informing patients in detail could be undesirable or even harmful. Prescribers should focus on two types of side effects: (a) common side effects with significant impact on the quality of life and (b) side effects that should be recognised in time to prevent further harm. During treatment, patients should be monitored regularly for efficacy and side effects in order to weigh benefits and risks and to stop or switch therapy when necessary.

Intrauterine Exposure to Biologics in Inflammatory Autoimmune Diseases: A Systematic Review.

BACKGROUND: Inflammatory autoimmune diseases are chronic diseases that often affect women of childbearing age. Therefore, detailed knowledge of the safety profile of medications used for management of inflammatory autoimmune diseases during pregnancy is important. However, in many cases the potential harmful effects of medications (especially biologics) during pregnancy (and lactation) on mother and child have not been fully identified. OBJECTIVE: Our aim was to update the data on the occurrence of miscarriages and (major) congenital malformations when using biologics during pregnancy based on newly published articles. Additionally, we selected several different secondary outcomes that may be of interest for clinicians, especially information on adverse events in the use of a specific biologic during pregnancy. MATERIAL AND METHODS: A search was conducted from 1 January 2015 until 4 July 2019 in Embase.com, Medline Ovid, Web of Science, Cochrane CENTRAL, and Google Scholar with specific search terms for each database. Selection of publications was based on title/abstract and followed by full text (double blinded, two researchers). An overview was made based on outcomes of interest. References of the included publications were reviewed to include and minimize the missing publications. RESULTS: A total of 143 publications were included. The total number of cases ranged from nine for canakinumab to 4276 for infliximab. The rates of miscarriages and major congenital malformations did not show relevant differences from those rates in the general population. CONCLUSION: Despite limitations to our study, no major safety issues were reported and no trend could be identified in the reported malformations.

HMG-CoA-reductase inhibitors and neuropathy: reports to the Netherlands Pharmacovigilance Centre.

The number of patients taking HMG-CoA-reductase inhibitors for hypercholesterolaemia is growing rapidly. Treatment with HMG-CoA-reductase inhibitors significantly reduces the risk of cardiovascular morbidity and mortality, but may rarely cause serious adverse drug reactions (ADRs). The most serious ADRs of HMG-CoA-reductase inhibitors are musculoskeletal symptoms including myopathy and myositis, (life-threatening) rhabdomyolysis and liver failure. Furthermore, peripheral neuropathy might also occur, especially after long-term use of HMG-CoA-reductase inhibitors. Because of the severity and the relative rarity of HMG-CoA-reductase-induced neuropathy, the Netherlands Pharmacovigilance Centre Lareb has analysed its database of reported ADRs for reports concerning neuropathy associated with the use of HMG-CoA-reductase inhibitors. Until June 2005, Lareb received 17 reports of neuropathy, peripheral neuropathy and polyneuropathy and in addition two reports of aggravation of existing polyneuropathy associated with the use of HMG-CoA-reductase inhibitors. The associations neuropathy, peripheral neuropathy and polyneuropathy and the use of hMg-CoA-reductase inhibitors are statistically significantly more often reported to Lareb. The average time to onset supports conclusions of previous studies and case reports that especially long-term exposure increases the risk for peripheral neuropathy. Considering the increasing number of patients taking HMG-CoA-reductase inhibitors, health care professionals should be aware of the possible role of these drugs in neuropathy.

Isotretinoin-induced inflammatory bowel disease.

Three case reports on inflammatory bowel disease associated with use of isotretinoin are described. All three patients were male adolescents, in good health when starting isotretinoin (for acne treatment for about six months). Several weeks after discontinuation of isotretinoin the patients developed severe symptoms requiring hospitalisation. The diagnosis of ulcerative colitis was made in two of these patients, while in the third patient Crohn's disease was diagnosed. Although inflammatory bowel disease is described as an adverse drug reaction in the product information of isotretinoin, few cases have been described so far. The link with prior isotretinoin use may not be recognised by the patient or the physician, since the diagnosis of inflammatory bowel disease is often preceded by several years of vague symptoms. On the other hand, spontaneous onset of inflammatory bowel disease (not related to isotretinoin) cannot be excluded. We appeal to the readers for a reaction to this, to shed more light on the likeliness of this alleged association.

[Side effects of tramadol: 12 years of experience in the Netherlands]. / Bijwerkingen van tramadol: 12 jaar ervaring in Nederland.

Tramadol is a synthetic opioid that has been available in the Netherlands since 1992 and is usually used as a centrally-acting analgesic when paracetamol or an NSAID provides insufficient relief. In the period 1 January 1992--30 November 2003, the Netherlands Pharmacovigilance Centre Lareb received 299 reports concerning 522 adverse drug reactions associated with the use of tramadol. Some of the frequently reported side effects with a high reporting odds ratio were nausea, constipation and withdrawal symptoms. These side effects are very similar to those of the other opioids due to the affinity of tramadol for the micro-opioid receptor. Because tramadol is often not recognised as an opioid, it is important that such opiate effects be recognised as an adverse drug reaction on time.

[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.

Pergolide-induced pleuropulmonary fibrosis.

Pleuropulmonary fibrosis is a rare, but well-recognized adverse effect of ergot alkaloids. We report on four patients who developed pleural and/or pulmonary fibrosis during treatment with pergolide and give characteristics of 87 cases with one or more symptoms of serosal fibrosis. Retroperitoneal and pleuropulmonary fibrosis are serious conditions, which are often irreversible after drug withdrawal. Increased awareness may help to diagnose these complications at an earlier stage and to minimize any permanent damage to the patient.

Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case-control study using spontaneous reports.

The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985-99 (n = 24,263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95% confidence interval 1.2-3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7-68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.

[Pill cycle disturbance in simultaneous use of itraconazole and oral contraceptives]. / Verstoring van de pilcyclus tijdens het gelijktijdig gebruik van itraconazol en orale anticonceptiva.

Since the introduction of itraconazole in the Netherlands, the Netherlands Pharmacovigilance Foundation LAREB and the Inspectorate for Health Care received 15 reports of pill cycle disturbances and one of pregnancy occurring during simultaneous use of itraconazole and oral contraceptives. Twelve women used oral contraceptives containing ethinylestradiol and desogestrel. In these women, the withdrawal bleeding was either delayed or did not occur at all; one of these women reported a transiently positive pregnancy test after previous breakthrough bleedings. Three women who used a contraceptive containing ethinylestradiol and levonorgestrel had a breakthrough bleeding. One woman who used an oral contraceptive containing ethinylestradiol and cyproterone acetate became pregnant during the concomitant use of itraconazole. The possible mechanism involved remains to be explained. Although an influence of itraconazole on the reliability of oral contraceptives is uncertain, additional contraceptive measurements might be considered.

[Acute delirium, probably precipitated by clarithromycin]. / Acuut delier, waarschijnlijk uitgelokt door claritromycine.

Clarithromycin is a relatively new antibiotic with many applications. Its frequent use explains why side-effects previously reported seldom now become clear. Two patients, a man aged 74 and a woman aged 56 years, developed delirium after treatment with clarithromycin as part of eradication treatment of Helicobacter pylori, presumably as a result of an ideosyncratic reaction to the clarithromycin. Preclinical and clinical investigations did not reveal side effects on the central nervous system. By now the appearance of a delirium presumably related to the use of clarithromycin has been described in several patients. Furthermore some patients had a positive rechallenge. Finally, 17 reports on psychiatric side effects, of which 7 were delirium, after the use of clarithromycin reached the Netherlands Pharmacovigilance Foundation (Lareb). This combination of facts makes a causal relationship probable.

[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.