Descriptive analysis of 179 German reports of melanoma reported to an adverse drug reaction database as a drug-related adverse effect, and comparison with melanoma cases contained in German cancer registries

Background: Malignant melanoma (MM) is one of the most aggressive forms of skin cancer. The occurrence of MM associated with drug therapy has been described in the literature. However, there is no analysis of a substantial number of validated reports of drug-associated MM. Aim: To analyse a substantial number of validated spontaneous reports of drug-associated MM with regard to the suspected drug and the reported characteristics, and to compare these analyses with those of MM cases occurring in the general population in Germany. Methods: Spontaneous reports of MM associated with drug therapy in Germany were identified in a large adverse drug reaction database (EudraVigilance). These results were then compared with analyses of MMs in the pooled data from a population-based German cancer registry. Results: The 10 most frequently suspected drugs in the MM reports all target the immune system, with 7 of these being immunosuppressants. The median time to onset to MM diagnosis was 2.0 years. Patients with drug-associated MM were 11 years (median) younger than patients with MM in the cancer registry, and this age difference was greater for female than for male patients. Conclusions: Our results emphasize the importance of regular dermatological examinations of patients being treated with immunosuppressants. Physicians should be aware that in these patients, MM might be detected at younger ages and even within 2 years after initiating therapy.Peer Reviewe

Descriptive analysis of adverse drug reaction reports for hypersensitivity reactions stratified in relation to different beta-lactam antibiotics

β-lactam antibiotics (BLA) are commonly reported to induce hypersensitivity reactions. However, β-lactam antibiotic-stratified analyses are rare. In the presented study, β-lactam antibiotic associated hypersensitivity reactions were analyzed in the European adverse drug reaction (ADR) database. 923, 38, 222, and 99 hypersensitivity reports for penicillins and first-, second- and third-generation cephalosporins were reported. Differences with regard to demographical parameters, seriousness and types of hypersensitivity reactions, as well as in the number of hypersensitivity reports per outpatient prescriptions were observed between the different β-lactam antibiotics. The number of ADR reports classified as serious was higher for all generations of cephalosporins compared to penicillins. Additionally, anaphylactic reactions were more often reported for first- and second-generation cephalosporins compared to third-generation cephalosporins and penicillins, while bullous reactions were more often reported for first- and third-generation cephalo­sporins as opposed to second-generation cephalosporins and penicillins. The observed differences may be caused by differences between β-lactam antibiotics and their routes of administration (oral, intravenous), the patient populations, or the reporting of ADRs. Due to the methodological limitations of ADR database analysis, no conclusions can be drawn whether and to what extent the aforementioned factors influenced our results

Angioedemas associated with renin-angiotensin system blocking drugs: Comparative analysis of spontaneous adverse drug reaction reports

INTRODUCTION: Angioedema is a subcutaneous swelling typically affecting the face, larynx or pharynx. It is a known adverse drug reaction (ADR) of ACE inhibitors (ACEi), angiotensin-II-receptor blockers (ARBs) and aliskiren (renin inhibitor). Several studies have reported pathophysiological mechanisms and risk factors of ACEi-associated angioedemas, whereas little is known for ARBs and aliskiren. The aim of the study was to analyze comparatively ACEi versus ARBs and aliskiren angioedema reports contained in the European ADR database EudraVigilance with regard to reported risk factors and clinical phenotypes. METHODS: All spontaneous angioedema reports received between 01/2010-06/2017 reporting either an ACEi, ARB, or aliskiren as "suspected/interacting" drug were identified using the Standardized MedDRA Query "angioedema (narrow)". In order to perform a comparative analysis, odds ratios (ORs) were calculated for angioedema reports of ACEi (n = 3.194) versus ARBs (n = 687) and aliskiren (n = 162). RESULTS: More patients with a history of allergy were included in angioedema reports of ARBs (6.8%) and aliskiren (13.6%) versus ACEi (4.3%). "Urticaria" as an ADR was reported more frequently in angioedema reports of ARBs (18.5%) and aliskiren (9.0%) versus ACEi (5.0%). ACEi-associated angioedemas were more often designated as "life-threatening" compared to ARBs (OR 2.2 [1.6–2.9]) and aliskiren-associated angioedemas (OR 14.2 (3.5–57.4). Concomitant therapy with mTOR inhibitors (OR 4.3 [1.0–17.9]) and fibrinolytics (OR 7.8 [1.1–57.2]) was reported more often in ACEi versus ARBs angioedema reports. CONCLUSION: The reported clinical phenotypes differed between ACEi versus ARBs and aliskiren angioedema reports. Differences between the patient populations as observed in our study or differences with regard to underlying pathomechanisms could account for this finding. Due to the methodological limitations of spontaneous reporting systems, we cannot draw a firm conclusion in this regard. Hence, further research is necessary to confirm our observation and elucidate the underyling causes

Lymphocyte transformation test for drug allergy detection: When does it work?

BACKGROUND: The lymphocyte transformation test (LTT) is an in vitro test system for the detection of a sensitization in the context of allergies to drugs. Its reported sensitivity varies largely and seems to be affected by different parameters. In review articles, the average LTT performance was often calculated by combining overall mean sensitivities of various published studies, but without considering different patient characteristics or varying patient numbers per publication. OBJECTIVE: To investigate the impact of different patient-specific and methodological parameters on the sensitivity of the LTT based on data on the level of the individual patient extracted from single studies. METHODS: We performed an advanced literature search in PubMed and screened the identified publications according to previously defined inclusion criteria. In total, individual patient data from 721 patients were extracted from 30 studies. Random-effects meta-regression analyses were performed. RESULTS: The analysis indicate that the enzyme-linked immunosorbent assay–based read-out is more sensitive compared with the classical radioactivity method (enzyme-linked immunosorbent assay: 80% vs radioactivity: 66%; P = .08). Interestingly, drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome is associated with a higher probability of a positive LTT test result compared with other investigated clinical phenotypes (“drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome” vs “bullous reaction”; odds ratio, 2.52; P value = .003). Our analysis also revealed an impact of the time to testing period after the occurrence of the allergic event (“< 2 weeks” vs “2 weeks-2 months”; odds ratio, 2.12; P value = .03). CONCLUSION: The read-out method and relevant clinical parameters affect the sensitivity of the LTT. These findings are based on a meta-analysis providing a higher level of evidence than a single study or previous reviews not considering individual patient data

Adverse drug reactions in older adults: a retrospective comparative analysis of spontaneous reports to the German Federal Institute for Drugs and Medical Devices

BACKGROUND: Older adults are more prone to develop adverse drug reactions (ADRs) since they exhibit numerous risk factors. The first aim was to analyse the number of spontaneous ADR reports regarding older adults (> 65) in the ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM) and to set them in relation to i) the number of ADR reports concerning younger adults (19–65), and ii) the number of inhabitants and assumed drug-exposed inhabitants. The second aim was to analyse, if reported characteristics occurred more often in older vs. younger adults. METHODS: All spontaneous ADR reports involving older or younger adults within the period 01/01/2000–10/31/2017 were identified in the ADR database. Ratios concerning the number of ADR reports/number of inhabitants and ADR reports/drug-exposed inhabitants were calculated. The reports for older (n = 69,914) and younger adults (n = 111,463) were compared using descriptive and inferential statistics. RESULTS: The absolute number of ADR reports involving older adults increased from 1615 (2000) up to 5367 ADR reports (2016). The age groups 76–84 and 70–79 had the highest number of ADR reports with 25 ADR reports per 100,000 inhabitants and 27 ADR reports per 100,000 assumed drug-exposed inhabitants. For both ratios, the number of reports was higher for males (26 and 28 ADR reports) than for females (24 and 26 ADR reports). Fatal outcome was reported almost three times more often in older vs. younger adults. Six out of ten drug substances most frequently suspected were antithrombotics (vs. 1/10 in younger adults). For some drug substances (e.g. rivaroxaban) the ADRs reported most frequently differed between older (epistaxis) and younger adults (menorrhagia). CONCLUSIONS: There is a need to further investigate ADRs in older adults since they occurred more frequently in older vs. younger adults and will likely increase in future. Physicians should be aware of different ADRs being attributed to the same drug substances which may be more prominent in older adults. Regular monitoring of older adults taking antithrombotics is recommended

Analyses of Basal and Squamous Cell Carcinoma Reported as an Adverse Drug Reaction and Comparison with Cases from the Cancer Registry from Germany

INTRODUCTION: In Germany, incidence rates of basal cell (BCC) and squamous cell carcinoma (SCC) rose significantly from 1998 to 2010. Ultraviolet (UV) light exposure, immunosuppressants and drugs with photosensitising potential are known to increase the risk to develop BCC and SCC. The aim of our study was to analyse the adverse drug reaction (ADR) reports from Germany referring to BCC and SCC and to compare them to BCC and SCC occurring in the general population. METHODS: We analysed all validated spontaneous ADR reports referring to BCC (n = 191) and SCC (n = 75) from Germany contained in the European ADR database EudraVigilance prior to 6 March 2019. These reports were compared to 1,267,210 BCC and 476,903 SCC cases from the German Centre for Cancer Registry Data recorded from 2006 to 2018. RESULTS: The number of BCC and SCC reports as well as the BCC and SCC incidences in the registry increased in the analysed time period. Patients with drug-associated BCC (60 years) and SCC (64 years) were younger than patients with BCC (72 years) and SCC (76 years) in the registry. In 57.1 and 60.0% of BCC and SCC reports immunosuppressants were reported as suspected. The reported suspected drug was assumed to possess a photosensitising potential in 41.9 and 44.0% of BCC and SCC reports. CONCLUSIONS: In Germany, drug-associated BCC and SCC occurred at a younger age than in the general population. The results underline the necessity for skin cancer screening of patients treated with immunosuppressants or with drugs with photosensitising potential

Descriptive analysis of adverse drug reaction reports in children and adolescents from Germany: frequently reported reactions and suspected drugs

BACKGROUND: Adverse drug reactions (ADRs) in the pediatric population may differ in types and frequencies compared to other populations. Respective studies analyzing ADR reports referring to children have already been performed for certain countries. However, differences in drug prescriptions, among others, complicate the transferability of the results from other countries to Germany or were rarely considered. Hence, the first aim of our study was to analyze the drugs and ADRs reported most frequently in ADR reports from Germany referring to children contained in the European ADR database (EudraVigilance). The second aim was to set the number of ADR reports in relation to the number of drug prescriptions. These were provided by the Research Institute for Ambulatory Health Care in Germany. METHODS: For patients aged 0–17 years 20,854 spontaneous ADR reports were received between 01/01/2000–28/2/2019. The drugs and ADRs reported most frequently were identified. Stratified analyses with regard to age, sex and drugs used “off-label” were performed. Reporting rates (number of ADR reports/number of drug prescriptions) were calculated. RESULTS: Methylphenidate (5.5%), ibuprofen (2.3%), and palivizumab (2.0%) were most frequently reported as suspected. If related to the number of drug prescriptions, the ranking changed (palivizumab, methylphenidate, ibuprofen). Irrespective of the applied drugs, vomiting (5.4%), urticaria (4.6%) and dyspnea (4.2%) were the ADRs reported most frequently. For children aged 0–1 year, drugs for the treatment of nervous system disorders and foetal exposure during pregnancy were most commonly reported. In contrast, methylphenidate ranked first in children older than 6 years and referred 3.5 times more often to males compared to females. If age- and sex-specific exposure was considered, more ADR reports for methylphenidate referred to children 4–6 years and females 13–17 years. Drugs for the treatment of nervous system disorders ranked first among “off-label” ADR reports. CONCLUSIONS: Our analysis underlines the importance of putting the number of ADR reports of a drug in context with its prescriptions. Additionally, differences in age- and sex-stratified analysis were observed which may be associated with age- and sex-specific diseases and, thus, drug exposure. The drugs most frequently included in “off-label” ADR reports differed from those most often used according to literature

Analysis of the reporting of adverse drug reactions in children and adolescents in Germany in the time period from 2000 to 2019.

The objective of this study was to analyse reports on adverse drug reactions (ADRs) from Germany in the particularly vulnerable patient group of children and adolescents. Reporting characteristics, demographic parameters and off-label use were examined among others. The ratio of ADR reports per number of German inhabitants and the ratio of ADR reports per number of German inhabitants exposed to drugs were calculated and compared. These parameters were examined to derive trends in reporting of ADRs. 20,854 spontaneous ADR reports for the age group 0-17 years were identified in the European ADR database EudraVigilance for the time period 01.01.2000-28.02.2019 and analysed with regard to the aforementioned criteria. 86.5% (18,036/20,854) of the ADR reports originated from Healthcare Professionals and 12.2% (2,546/20,854) from non-Healthcare Professionals. 74.4% (15,522/20,854) of the ADR reports were classified as serious. The proportion of ADR reports per age group was 11.8% (0-1 month), 11.0% (2 months-1 year), 7.4% (2-3 years), 9.3% (4-6 years), 25.8% (7-12 years), and 34.8% (13-17 years) years, respectively. Male sex slightly dominated (51.2% vs. 44.8% females). Only 3.5% of the ADR reports reported off-label use. The annual number of ADR reports increased since 2000, even if set in context with the number of inhabitants and assumed drug-exposed inhabitants. The pediatric population declined in the study period which argues against its prominent role for the increase in the total number of ADR reports. Instead, among others, changes in reporting obligations may apply. The high proportion of serious ADR reports underlines the importance of pediatric drug safety