Showing papers in "Drug Safety in 2018"
TL;DR: Clinicians should be warned that chlorquine- or hydroxychloroquine-related cardiac manifestations, even conduction disorders without repercussion, may be initial manifestations of toxicity, and are potentially irreversible.
Abstract: Chloroquine and hydroxychloroquine are widely used in the long-term treatment of connective tissue disease and usually considered safe. However, chloroquine- or hydroxychloroquine-related cardiac disorder is a rare but severe adverse event, which can lead to death. This systematic review investigates cardiac complications attributed to chloroquine and hydroxychloroquine. PubMED, EMBASE, and Cochrane database searches were conducted using keywords derived from MeSH terms. Reports published prior to 31 July, 2017 were eligible for inclusion, without restriction to study design. Searches were also conducted on reference lists of included studies. Eighty-six articles were identified, reporting individual cases or short series, providing information on 127 patients (65.4% female). A majority of patients were treated with chloroquine (58.3%), with the remaining treated with hydroxychloroquine (39.4%), or both in succession. Most patients had been treated for a long time (median 7 years, minimum 3 days; maximum 35 years) and with a high cumulative dose (median 1235 g for hydroxychloroquine and 803 g for chloroquine). Conduction disorders were the main side effect reported, affecting 85% of patients. Other non-specific adverse cardiac events included ventricular hypertrophy (22%), hypokinesia (9.4%), heart failure (26.8%), pulmonary arterial hypertension (3.9%), and valvular dysfunction (7.1%). For 78 patients reported to have been withdrawn from treatment, some recovered normal heart function (44.9%), while for others progression was unfavorable, resulting in irreversible damage (12.9%) or death (30.8%). The risk of cardiac complications attributed to chloroquine/hydroxychloroquine was not quantified because of the lack of randomized controlled trials and observational studies investigating the association. Clinicians should be warned that chloroquine- or hydroxychloroquine-related cardiac manifestations, even conduction disorders without repercussion, may be initial manifestations of toxicity, and are potentially irreversible. Therefore, treatment withdrawal is required when cardiac manifestations are present.
286 citations
TL;DR: Thromboembolic risks of JAK inhibitors in active rheumatoid arthritis are estimated to be approximately five events per 1000 patient years with 4 mg baricitinib daily, using all publically available data.
Abstract: Two different Janus kinase (JAK) inhibitors—baricitinib and tofacitinib—are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.
117 citations
TL;DR: The safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically, but the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitor.
Abstract: The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA’s Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks. Adverse event (AE) data for tofacitinib, tofacitinib extended-release (XR), and ruxolitinib were obtained from the FAERS. Reporting odds ratios (RORs) and the R package ‘PhViD’ to estimate the empirical Bayesian geometric mean (EBGM) were used to detect AEs with higher-than-expected reporting rates within the FAERS. We did not find evidence in the FAERS for elevated reporting rates for DVT and PE across the three JAK inhibitors we analyzed. However, multiple drug–AE combinations relating to thromboembolic events had both RORs and EBGM values above 1, indicating a trend toward higher-than-expected reporting rates. For pulmonary thrombosis, the ROR values for ruxolitinib, tofacitinib, and tofacitinib XR were 1.46 (95% confidence interval [CI] 0.76–2.80), 2.46 (1.55–3.91), and 2.48 (0.80–7.71), respectively, while the EBGM values were 1.25 (0.70), 2.46 (1.64), and 1.56 (0.57), respectively. Ruxolitinib had ROR values of 4.08 (2.25–7.38) and 1.22 (0.97–1.53) for portal vein thrombosis and thrombosis, respectively. The EBGM values for the same drug–AE combinations were 3.04 (1.79) and 1.16 (0.96). Our safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib. While these FAERS data add to a growing body of evidence that JAK inhibitors may be contraindicated in patients at risk of thromboembolic events, the data need to be confirmed by future AE reporting trends, analysis of electronic health records, and/or future clinical trials.
105 citations
TL;DR: It is suggested that DAA use is associated with an increased risk in the occurrence of an ICD, under the combined influence of various factors.
Abstract: Impulse control disorders (ICDs) are a well-known adverse effect of dopamine agonists (DAAs). This critical review aims to summarize data on the prevalence and factors associated with the development of an ICD simultaneous to DAA use. A search of two electronic databases was completed from inception to July 2017. The search terms were medical subject headings (MeSH) terms including "dopamine agonists" AND "disruptive disorders", "impulse control disorders", or "conduct disorders". Articles had to fulfill the following criteria to be included: (i) the target problem was an ICD; (ii) the medication was a dopaminergic drug; and (iii) the article was an original article. Of the potential 584 articles, 90 met the criteria for inclusion. DAAs were used in Parkinson's disease (PD), restless legs syndrome (RLS) or prolactinoma. The prevalence of ICDs ranged from 2.6 to 34.8% in PD patients, reaching higher rates in specific PD populations; a lower prevalence was found in RLS patients. We found only two studies about prolactinoma. The most robust findings relative to the factors associated with the development of an ICD included the type of DAA, the dosage, male gender, a younger age, a history of psychiatric symptoms, an earlier onset of disease, a longer disease duration, and motor complications in PD. This review suggests that DAA use is associated with an increased risk in the occurrence of an ICD, under the combined influence of various factors. Guidelines to help prevent and to treat ICDs when required do exist, although further studies are required to better identify patients with a predisposition.
90 citations
TL;DR: The aim of this updated narrative review was to examine the evidence on HPV vaccine safety, focusing on the 9vHPV vaccine, special populations and adverse events of special interest (AESI), and identified 109 studies, including 15 population-based studies in over 2.5 million vaccinated individuals across six countries.
Abstract: Human papillomavirus (HPV) vaccines are now included in immunisation programmes in 71 countries. Unfortunately, uptake has been impacted in some countries by reduced confidence in the safety of the HPV vaccine. In 2013, we published an extensive review demonstrating a reassuring safety profile for bivalent (2vHPV) and quadrivalent (4vHPV) vaccines. A nonavalent (9vHPV) vaccine is now available and HPV immunisation programmes have been extended to males in 11 countries. The aim of this updated narrative review was to examine the evidence on HPV vaccine safety, focusing on the 9vHPV vaccine, special populations and adverse events of special interest (AESI). The previous searches were replicated to identify studies to August 2016, including additional search terms for AESI. We identified 109 studies, including 15 population-based studies in over 2.5 million vaccinated individuals across six countries. All vaccines demonstrated an acceptable safety profile; injection-site reactions were slightly more common for 9vHPV vaccine than for 4vHPV vaccine. There was no consistent evidence of an increased risk of any AESI, including demyelinating syndromes or neurological conditions such as complex regional pain or postural orthostatic tachycardia syndromes. The risk–benefit profile for HPV vaccines remains highly favourable.
82 citations
TL;DR: SGLT2i may lead to AKI by effective volume depletion, due to excessive diuresis, particularly in hemodynamically unstable and volume-depleted patients, and induction of renal medullary hypoxic injury, related to enhanced distal tubular transport.
Abstract: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide outstanding long-term cardiovascular and renal protection in high-risk patients with type 2 diabetes mellitus. Yet, despite encouraging renal safety outcomes reported in the EMPA-REG study, scattered reports suggest that there might be a risk for acute kidney injury (AKI), which may occasionally be fatal or might require renal replacement therapy. Reduced trans-glomerular pressure with a modest decline in kidney function, an inherent characteristic of SGLT2i therapy, conceivably forms the basis for the long-term renal protection, resembling agents that block the renin-angiotensin-aldosterone (RAAS) axis. Yet, a major decline in kidney function occasionally occurs, often associated with an acute illness or with specific co-administered medications. SGLT2i may lead to AKI by (a) effective volume depletion, due to excessive diuresis, particularly in hemodynamically unstable and volume-depleted patients; (b) excessive decline in trans-glomerular pressure, specifically in patients on RAAS blockade; and (c) induction of renal medullary hypoxic injury, related to enhanced distal tubular transport, especially with concomitant use of agents impairing medullary oxygenation, such as non-steroidal anti-inflammatory drugs and radiocontrast agents. The risk of developing renal impairment with SGLT2i and the role of these suggested mechanisms are yet to be defined, as there are conflicting data and inconsistent reporting with the various agents currently in use.
67 citations
TL;DR: The Roussel Uclaf Causality Assessment Method (RUCAM) as discussed by the authors is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced Liver injury (HILI).
Abstract: Launched in 1993 and partially based on the results of an international consensus meeting organized under the auspices of the Council of International Organizations of Medical Sciences (CIOMS), the Roussel Uclaf Causality Assessment Method (RUCAM) is the most used causality assessment tool worldwide for the diagnosis of drug-induced liver injury (DILI) and herb-induced liver injury (HILI) in a large number of epidemiological studies, case reports, and case series. The 25-year experience of RUCAM use confirmed that the success was due to its objective, standardized, and liver-injury-specific approach structured with defined key elements derived from a series of DILI cases with positive rechallenge. Using this series, the validation procedure avoided arbitrary definitions and confirmed scores to key items. The algorithm provides a quantitative causality grading of highly probable, probable, possible, unlikely, or excluded relationship between the liver injury and the suspected product(s). Despite challenges, prospective use of RUCAM fosters case data completeness and transparent causality adjudication in real time, as opposed to subjective opinion resulting from several rounds by experts lacking defined key elements and scores. In 2016, RUCAM was updated with specification of alcohol use and Hepatitis E Virus (HEV) biomarkers and simplified item handling to further reduce inter-observer variability. RUCAM-based probable and highly probable DILI and HILI cases are essential for the detection of new hepatotoxins, confirmation of new biomarkers, description of clinical features and risk factors, and determination of incidence in pharmacoepidemiological studies. This article is intended to encourage systematic use of sophisticated causality assessment methods such as RUCAM to improve DILI and HILI case evaluation and to increase confidence in published cases.
65 citations
TL;DR: The main objective of this article is to describe the new access to the database together with the opportunities that this new access can bring for research, intended to promote an appropriate use of the data to support the safe and effective use of medicines.
Abstract: The analysis of safety data from spontaneous reporting systems has a proven value for the detection and analysis of the risks of medicines following their placement on the market and use in medical practice. EudraVigilance is the pharmacovigilance database to manage the collection and analysis of suspected adverse reactions to medicines authorised in the European Economic Area. EudraVigilance first operated in December 2001, with access to the database being governed by the EudraVigilance access policy. We performed a literature search including data up to December 2016 to demonstrate how the data from EudraVigilance has been used in scientific publications. We describe the results, including by type of publication, research topics and drugs involved. In 50% of the publications, the data are used to describe safety issues, in 44% to analyse methodologies used in pharmacovigilance activities and in 6% to support clinical perspectives. We also outline a description of the use of the database by the European Union regulatory network. Driven by the full implementation of the 2010 pharmacovigilance legislation, EudraVigilance has undergone further enhancements together with a major revision of its access policy, taking into account the use of the new individual case safety report standard developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and the International Organization for Standardization. The aim of the broadened access is to facilitate more effective safety monitoring of authorised medicines, to make more data available for research and to provide better access to information on suspected adverse reactions for healthcare professionals and patients. In November 2017, the new full functionalities of EudraVigilance were launched, including the extensive web access to data on suspected adverse drug reactions and the possibilities for academic research institutions to request a more extensive dataset for the purposes of health research. The main objective of this article is to describe the new access to the database together with the opportunities that this new access can bring for research. It is intended to promote an appropriate use of the data to support the safe and effective use of medicines.
62 citations
TL;DR: All-cause and drug-related IPH/ED utilization increased monotonically with degree of overuse, particularly of more than one medication, supporting calls to make gabapentin a controlled substance in the USA.
Abstract: Overuse of gabapentin and/or opioids occurs in a small percentage of patients at > 3-fold labeled dosages. Gabapentin may potentiate opioid effects. The aim was to assess patient harm, defined as use of inpatient hospital (IPH) or emergency department (ED) services, associated with overuse of gabapentin with or without concomitant overuse of opioids. Data were sourced from the Truven Health MarketScan® Commercial Claims and Encounters database, for the years 2013–2015. The eligibility criteria were two or more claims (billed encounters) and ≥120 days of treatment with gabapentin and/or opioids. Cohort identification was based on daily-dosage thresholds of 50 morphine-milligram equivalents and 3600 mg of gabapentin in a 12-month follow-up: (1) no overuse; (2) mild overuse (two or more claims or two or fewer calendar quarters over threshold); and (3) sustained overuse (three or more over-threshold calendar quarters). IPH and ED use were measured for 6 months after the first overuse date (cohorts 2 and 3) or a randomly assigned date (cohort 1). Logistic regression analyses controlled for pre-treatment IPH/ED utilization, indication, addiction diagnosis, concomitant sedative/hypnotic use, and demographics. All-cause and drug-related IPH/ED utilization increased monotonically with degree of overuse, particularly of more than one medication. Sustained overuse of gabapentin multiplied odds of all-cause IPH by 1.366 [95% confidence interval (CI) 1.055–1.769], drug-related IPH by 1.440 (95% CI 1.010–2.053), and IPH/ED for altered mental status (e.g., euphoria, anxiety) by 1.864 (95% CI 1.324–2.624). Sustained overuse of both medications quadrupled odds of all-cause IPH, drug-related IPH, and IPH/ED for altered mental status or respiratory depression. Despite modest effects of gabapentin overuse alone, overuse of gabapentin with opioids may increase risk of harm and health-service utilization, supporting calls to make gabapentin a controlled substance in the USA.
60 citations
TL;DR: The uses of big data for drug safety post-marketing assessment, including signal detection, substantiation and validation of drug or vaccine safety signals, and increasingly new sources of information such as social media are also being considered.
Abstract: In the last decade ‘big data’ has become a buzzword used in several industrial sectors, including but not limited to telephony, finance and healthcare. Despite its popularity, it is not always clear what big data refers to exactly. Big data has become a very popular topic in healthcare, where the term primarily refers to the vast and growing volumes of computerized medical information available in the form of electronic health records, administrative or health claims data, disease and drug monitoring registries and so on. This kind of data is generally collected routinely during administrative processes and clinical practice by different healthcare professionals: from doctors recording their patients’ medical history, drug prescriptions or medical claims to pharmacists registering dispensed prescriptions. For a long time, this data accumulated without its value being fully recognized and leveraged. Today big data has an important place in healthcare, including in pharmacovigilance. The expanding role of big data in pharmacovigilance includes signal detection, substantiation and validation of drug or vaccine safety signals, and increasingly new sources of information such as social media are also being considered. The aim of the present paper is to discuss the uses of big data for drug safety post-marketing assessment.
57 citations
University Medical Center Groningen1, University of Groningen2, University Hospital of Lausanne3, University of Zagreb4, University of Bergen5, Norwegian Institute of Public Health6, French Institute of Health and Medical Research7, Health Service Executive8, Basque Government9, University of Ferrara10, Otto-von-Guericke University Magdeburg11, University of Mainz12, Ulster University13
TL;DR: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found.
Abstract: Introduction
The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy.
TL;DR: The addition of bevacizumab to erlotinib prolonged progression-free survival in EGFR mutation-positive NSCLC and appeared to be manageable, and treatment was well tolerated.
Abstract: The phase II JO25567 study compared the efficacy and safety of erlotinib plus bevacizumab vs. erlotinib alone as first-line therapy for advanced epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Our objective is to provide updated analyses of safety and the assessment of manageability of specific adverse events. Patients with stage IIIB/IV or recurrent, non-squamous, EGFR mutation-positive NSCLC were randomized to receive erlotinib plus bevacizumab or erlotinib. The primary endpoint was progression-free survival. Adverse event frequency rates, predictability and manageability, reasons for discontinuation, time to onset, and outcomes of specific adverse events were analyzed. The safety analysis population comprised 152 randomized patients (75 erlotinib plus bevacizumab; 77 erlotinib) who received at least one dose of study drug between February 2011 and March 2012. There was no difference in overall incidence of serious adverse events between arms, but more grade 3 or higher adverse events were reported with erlotinib plus bevacizumab (90.7%) than with erlotinib (53.2%), primarily due to grade 3 hypertension. Hypertension was controllable with antihypertensive medications in most cases. Proteinuria and bleeding were also more frequently reported with erlotinib plus bevacizumab than with erlotinib but were manageable and did not lead to early discontinuations. The addition of bevacizumab to erlotinib prolonged progression-free survival in EGFR mutation-positive NSCLC. Follow-up safety data were consistent with the known safety profiles of both erlotinib and bevacizumab in NSCLC; this combination appeared to be manageable, and treatment was well tolerated. JapicCTI-111390.
TL;DR: The basis of and outline for the WHO PV core curriculum for university teaching are addressed and it is expected that PV competencies for students are vital for their contribution to safe use of medicines in the future.
Abstract: Adverse drug reactions (ADRs) can cause serious health problems, as shown in studies about drug-related hospitalizations. To build knowledge of and raise awareness about ADRs among healthcare professionals, more education in the field of ADRs and pharmacovigilance (PV) is needed. No standard exists for teaching PV at universities for medical, pharmacy, dentistry and nursing students, so a core curriculum needs to be developed to teach important aspects of PV to students. In September 2016, a stakeholders’ meeting was initiated on behalf of the World Health Organization (WHO) and organized by the Netherlands Pharmacovigilance Centre Lareb. This meeting addressed and agreed on the PV competencies students need to develop and what key aspects of the subject should be taught. Five key aspects were identified: understanding the importance of PV in the context of pharmacotherapy, and preventing, recognizing, managing and reporting ADRs. Since time and resources for PV education are limited, elements of the WHO PV core curriculum for university teaching were designed to be integrated into existing courses but can be used as a stand-alone programme. The basis of and outline for the WHO PV core curriculum for university teaching are addressed in this paper. It is expected that PV competencies for students are vital for their contribution to safe use of medicines in the future. In addition, this article aims to stimulate discussion on this subject and promote collaboration between universities, national PV centres and other stakeholders to integrate key aspects of PV in their educational programmes.
TL;DR: Potency of a prescription opioid analgesic demonstrates a significant, highly positive linear relationship with exposures resulting in SAEs per 100 kg drug dispensed reported to poison centers, and should be carefully considered from both individual provider and public health perspectives.
Abstract: The epidemic of prescription opioid overdose and mortality parallels the dispensing rates of prescription opioids, and the availability of increasingly potent opioid analgesics. The common assumption that more potent opioid analgesics are associated with higher rates of adverse outcomes has not been adequately substantiated. We compared the rate of serious adverse events among commonly prescribed opioid analgesics of varying potency. Serious adverse events (SAEs; defined as death, major medical effect, or hospitalization) resulting from exposure to tablets containing seven opioid analgesics (oxycodone, hydrocodone, morphine, hydromorphone, oxymorphone, tapentadol, and tramadol) captured by the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program were evaluated from 2010 through 2016. Rates of SAEs were adjusted for availability through outpatient dispensing data and regressed on morphine milligram equivalents (MME). There were 19,480 cases of SAE during the 7-year study period. Hydrocodone and oxycodone contributed to 77% of SAE cases. Comparing rates of outcome by relative potency, a hierarchy was observed with hydromorphone (8.02 SAEs/100 kg) and tapentadol (0.27 SAE/100 kg) as the highest and lowest rates, reflecting a 30-fold difference among individual opioid products. SAE rate and potency were related linearly—SAEs increased 2.04 per 100 kg drug dispensed for each 1-unit rise in MME (p = 0.004). Linear regression of SAE/100 kg drug dispensed and drug potency identified that MME comprised 96% of the variation observed. In contrast, potency did not explain variation seen using other study denominators (prescriptions dispensed, dosage units dispensed, and the number of individuals filling a prescription). Potency of a prescription opioid analgesic demonstrates a significant, highly positive linear relationship with exposures resulting in SAEs per 100 kg drug dispensed reported to poison centers. Potency should be carefully considered from both individual provider and public health perspectives.
TL;DR: The characteristics of some of the most most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials are addressed.
Abstract: Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials.
TL;DR: Although the findings are reassuring, long-term safety assessments of biologics that target the interleukin-13/interleuk in-4 pathways currently in clinical development are needed.
Abstract: Interleukin-13 and interleukin-4 are type-II cytokines signalling through the shared type II interleukin-4 receptor. As a result of their structural similarity, interleukin-13 and interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of interleukin-13 alone or interleukin-13 and interleukin-4 in combination. We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of interleukin-13/interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the interleukin-13/interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. Aside from expected evidence that inhibition of interleukin-13 and interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the interleukin-13 pathway alone or the combined interleukin-13/interleukin-4 pathways. Although our findings are reassuring, long-term safety assessments of biologics that target the interleukin-13/interleukin-4 pathways currently in clinical development are needed.
TL;DR: The results clearly suggest that broad-ranging statistical signal detection in Twitter and Facebook, using currently available methods for adverse event recognition, performs poorly and cannot be recommended at the expense of other pharmacovigilance activities.
Abstract: Social media has been proposed as a possibly useful data source for pharmacovigilance signal detection. This study primarily aimed to evaluate the performance of established statistical signal detection algorithms in Twitter/Facebook for a broad range of drugs and adverse events. Performance was assessed using a reference set by Harpaz et al., consisting of 62 US Food and Drug Administration labelling changes, and an internal WEB-RADR reference set consisting of 200 validated safety signals. In total, 75 drugs were studied. Twitter/Facebook posts were retrieved for the period March 2012 to March 2015, and drugs/events were extracted from the posts. We retrieved 4.3 million and 2.0 million posts for the WEB-RADR and Harpaz drugs, respectively. Individual case reports were extracted from VigiBase for the same period. Disproportionality algorithms based on the Information Component or the Proportional Reporting Ratio and crude post/report counting were applied in Twitter/Facebook and VigiBase. Receiver operating characteristic curves were generated, and the relative timing of alerting was analysed. Across all algorithms, the area under the receiver operating characteristic curve for Twitter/Facebook varied between 0.47 and 0.53 for the WEB-RADR reference set and between 0.48 and 0.53 for the Harpaz reference set. For VigiBase, the ranges were 0.64–0.69 and 0.55–0.67, respectively. In Twitter/Facebook, at best, 31 (16%) and four (6%) positive controls were detected prior to their index dates in the WEB-RADR and Harpaz references, respectively. In VigiBase, the corresponding numbers were 66 (33%) and 17 (27%). Our results clearly suggest that broad-ranging statistical signal detection in Twitter and Facebook, using currently available methods for adverse event recognition, performs poorly and cannot be recommended at the expense of other pharmacovigilance activities.
TL;DR: Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women, and optimised dosing schedules and/or new drugs are urgently needed.
Abstract: Benznidazole is the preferred drug for treatment of Chagas disease. However, it is toxic and of limited value in chronic infection. We aimed to estimate the rates of and factors related to adverse reactions (ARs) to benznidazole and treatment discontinuations (TDs). A meta-analysis was performed using an electronic search of the published literature with no language restrictions until June 2017. Prospective studies were included of chronically infected patients in which at least one treatment arm included benznidazole. Data were added from a prospective cohort of patients with Chagas disease at our centre (January 2007–June 2017). Weighted rates of ARs and TDs were estimated, and potentially related factors were analysed. Some 413 studies were found, from which we chose 42 (nine clinical trials and 33 observational studies, including ours), comprising data for 7822 patients. The weighted rate of ARs to benznidazole was 44.1% (95% confidence interval [CI] 37.2–51.2). ARs were more frequent in adults than in children (51.6 vs. 24.5%), with the most common being skin reactions (34%), gastrointestinal complaints (12.6%) and neurological symptoms (11.5%). Grade 4 ARs were recorded in 3% of cases. The weighted rate of TDs was 11.4% (95% CI 8.5–14.5); TDs were more frequent in adults than in children (14.2 vs. 3.8%). In our cohort, only female sex was related to an increased rate of ARs but not to TDs. Benznidazole had a poor tolerability profile, with a high incidence of TDs, especially in adult patients and women. Optimised dosing schedules and/or new drugs are urgently needed.
TL;DR: This study shows that a mobile app is an additional tool used in pharmacovigilance, as types of reporters and adverse drug reactions in VigiBIP were different to those seen in classical methods of reporting.
Abstract: The use of mobile apps is increasing in medicine. In pharmacovigilance, mobile apps may help to increase adverse drug reaction reporting and improve the communication of safety issues. The Toulouse University Pharmacovigilance Center has developed VigiBIP®, a free smartphone app available on Android and Apple stores, for reporting adverse drug reactions and requesting drug safety information. The present study was performed to compare the main characteristics of spontaneous adverse drug reaction reports received through VigiBIP® with classical methods of reporting (phone, e-mail, fax, letter, website) during 25 months (2015–17). Using the Chi squared test, we compared the type of reporter, adverse drug reaction seriousness, drugs involved and reported ADRs using VigiBIP® and classical methods of reporting A total of 4102 reports were received by the Toulouse University Pharmacovigilance Center, including 4.7% through VigiBip®. Patients’ reports were significantly more frequent with VigiBip® (6.7%) than with classical methods (3.4%) [p = 0.01]. Reported adverse drug reactions and involved drugs differed according to the method of reporting used. Our study shows that a mobile app is an additional tool used in pharmacovigilance. Types of reporters and adverse drug reactions in VigiBIP were different to those seen in classical methods of reporting.
TL;DR: These EHDs provide potential value to post-marketing drug safety surveillance and pharmacoepidemiology in China and are compared for availability and labeled based on specific standards.
Abstract: Electronic healthcare databases (EHDs) are used increasingly for post-marketing drug safety surveillance and pharmacoepidemiology in Europe and North America. However, few studies have examined the potential of these data sources in China. Three major types of EHDs in China (i.e., a regional community-based database, a national claims database, and an electronic medical records [EMR] database) were selected for evaluation. Forty core variables were derived based on the US Mini-Sentinel (MS) Common Data Model (CDM) as well as the data features in China that would be desirable to support drug safety surveillance. An email survey of these core variables and eight general questions as well as follow-up inquiries on additional variables was conducted. These 40 core variables across the three EHDs and all variables in each EHD along with those in the US MS CDM and Observational Medical Outcomes Partnership (OMOP) CDM were compared for availability and labeled based on specific standards. All of the EHDs’ custodians confirmed their willingness to share their databases with academic institutions after appropriate approval was obtained. The regional community-based database contained 1.19 million people in 2015 with 85% of core variables. Resampled annually nationwide, the national claims database included 5.4 million people in 2014 with 55% of core variables, and the EMR database included 3 million inpatients from 60 hospitals in 2015 with 80% of core variables. Compared with MS CDM or OMOP CDM, the proportion of variables across the three EHDs available or able to be transformed/derived from the original sources are 24–83% or 45–73%, respectively. These EHDs provide potential value to post-marketing drug safety surveillance and pharmacoepidemiology in China. Future research is warranted to assess the quality and completeness of these EHDs or additional data sources in China.
TL;DR: An overview of the characteristics and potential challenges in the safety profile assessment of biologics with a focus on the post-marketing setting is provided.
Abstract: In recent years, marketing of highly innovative and costly biologics improved the management of high-burden diseases such as autoimmune diseases, cancers, and chronic renal failure. Several widely prescribed biologics have recently lost or will shortly lose their patents, thus opening avenues to the marketing of a growing number of biosimilars worldwide, which are products similar in terms of quality, safety, and efficacy to already licensed reference products, thus allowing for potential savings in pharmaceutical expenditure. Numerous debates about the interchangeability between biosimilars and reference products are still ongoing, owing to concerns about potential immunogenicity raised by switching, which may cause a lack of effect and toxicity. Patients successfully treated with biologic therapy may theoretically receive biosimilars to contain costs, if reference product and related biosimilar are judged as interchangeable. However, the positions of regulatory agencies on the interchangeability and automatic substitution of biologics with biosimilars are very different. The benefit-risk profile of biosimilars has been often questioned by clinicians owing to the limited amount of pre-marketing information on clinical efficacy and safety, despite biosimilarity being based on a comparability exercise with the reference product to gain the biosimilar approval. Nevertheless, after more than 10 years of marketing from the first biosimilar approval in Europe, no proof of differences in terms of the safety profile of biosimilars and originators has been reported. In this context, post-marketing evaluation of both biologics and biosimilars safety profiles through analyses from spontaneous reporting databases and claims databases is crucial. An important issue for the pharmacovigilance of biologics concerns the traceability, indicating the brand name and batch number in spontaneous adverse drug reaction reports, but this requirement is not frequently addressed. This review aims to provide an overview of the characteristics and potential challenges in the safety profile assessment of biologics with a focus on the post-marketing setting.
TL;DR: This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature and concludes that high-quality epidemiological studies should be conducted to evaluate the association and quantify the risk.
Abstract: Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature. PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs. Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness. The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association. Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.
TL;DR: Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance and identify safety concerns described in patient reports within the World Health Organization programme for international drug monitoring.
Abstract: Patient reporting in pharmacovigilance is important and contributes to signal detection. However, descriptions of methodologies for using patient reports in signal detection are scarce, and published experiences of how patient reports are used in pharmacovigilance are limited to a few individual countries. Our objective was to explore the contribution of patient reports to global signal detection in VigiBase. Data were retrieved from VigiBase in September 2016. Drug–event-combination series were restricted to those with >50% patient reports, defined as reporter type “Consumer/non-health professional” per E2B reporting standard. vigiRank was applied to patient reports to prioritize combinations for assessment. Product information for healthcare professionals (HCPs) as well as patient information leaflets (PILs) were used as reference for information on adverse drug reactions (ADRs). Staff from the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb categorized the combinations. Potential signals proceeded to a more in-depth clinical review to determine whether the safety concern should be communicated as a “signal.” Of the 212 combinations assessed, 20 (9%) resulted in eight signals communicated within the World Health Organization (WHO) programme for international drug monitoring. Review of PILs revealed insufficient ADR descriptions for patients and examples of poor consistency with product information for HCPs. Patient narratives provided details regarding the experience and impact of ADRs and evidence that patients make causality and personal risk assessments. Safety concerns described in patient reports can be identified in a global database including previously unknown ADRs as well as new aspects of known ADRs. Patient reports provide unique information valuable in signal assessment and should be included in signal detection. Novel approaches to highlighting patient reports in statistical signal detection can further improve the contribution of patient reports to pharmacovigilance.
TL;DR: Survivors of SJS/TEN suffer from severe physical complications impacting their health and lives that are mostly under recognized and not sufficiently treated by medical professionals.
Abstract: Few studies have reported the physical complications among Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) survivors. The aim of this study was to comprehensively characterize the physical complications among SJS/TEN survivors and to learn about patients’ perspectives of surviving SJS/TEN. SJS/TEN survivors older than 18 years of age were assessed by different methods: a medical interview; a questionnaire assessing patients’ perspectives; thorough skin, oral mucous membrane, and ophthalmic examinations; and a retrospective assessment of medical records. Our cohort consisted of 17 patients with a mean time of 51.6 ± 74.7 months (median 9, range 1–228) following SJS/TEN. The most common physical complications identified in the medical examination were post-inflammatory skin changes (77%), cutaneous scars (46%), dry eyes (44%), symblepharon, and chronic ocular surface inflammation (33% each). Novel physical sequelae included chronic fatigue (76%) and pruritus (53%). We also found a novel association between the number of mucous membranes affected in the acute phase of SJS/TEN and hair loss during the 6 months following hospital discharge; hair loss was reported in 88% of the group of patients who had three or more mucous membranes affected versus 29% of patients who had less than three mucous membranes involved (p = 0.0406). Following hospital discharge due to SJS/TEN, 59% of patients were followed by a dermatologist, although 88% had dermatological complications; 6% were followed by an ophthalmologist, even though 67% had ophthalmological complications; and 6% of female survivors were followed by a gynecologist, even though 27% had gynecological complications. Survivors of SJS/TEN suffer from severe physical complications impacting their health and lives that are mostly under recognized and not sufficiently treated by medical professionals.
TL;DR: In this large, case-control analysis, there did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use.
Abstract: Long-term use of proton pump inhibitors (PPIs) has been associated with an increased risk of Alzheimer’s disease (AD) in observational studies The role of exposure duration, and whether this applies to other dementia subtypes, has not been explored in these studies The aim was to study the association between long-term use of PPIs (or of histamine-2 receptor antagonists [H2RAs], as a negative control) and the risk of developing AD or vascular dementia (VaD) We conducted a case–control analysis on the UK-based Clinical Practice Research Datalink (CPRD) We identified 41,029 patients aged ≥ 65 years with newly diagnosed AD or VaD between 1998 and 2015 and matched them 1:1 to dementia-free controls on age, sex, calendar time, general practice, and number of years of recorded history We applied conditional logistic regression analyses to calculate adjusted odds ratios (aORs), with 95% confidence intervals (CIs), of developing AD or VaD in relation to previous use of PPIs or H2RAs, categorized by exposure duration As compared to non-use, long-term PPI use (≥ 100 prescriptions) was not associated with an increased risk of developing AD (aOR 088, 95% CI 080–097) or VaD (aOR 118, 95% CI 104–133) Neither was long-term use of H2RAs (≥ 20 prescriptions) associated with an increased risk of developing AD (aOR 094, 95% CI 087–102) or VaD (aOR 099, 95% CI 089–110) In this large, case-control analysis, we did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use
TL;DR: The results of this study indicate that an effective and scalable solution to the challenge of ICSR detection in SDM includes a workflow using an automated ML classifier to identify likely ICSRs for further human SME review.
Abstract: There is increasing interest in social digital media (SDM) as a data source for pharmacovigilance activities; however, SDM is considered a low information content data source for safety data. Given that pharmacovigilance itself operates in a high-noise, lower-validity environment without objective ‘gold standards’ beyond process definitions, the introduction of large volumes of SDM into the pharmacovigilance workflow has the potential to exacerbate issues with limited manual resources to perform adverse event identification and processing. Recent advances in medical informatics have resulted in methods for developing programs which can assist human experts in the detection of valid individual case safety reports (ICSRs) within SDM. In this study, we developed rule-based and machine learning (ML) models for classifying ICSRs from SDM and compared their performance with that of human pharmacovigilance experts. We used a random sampling from a collection of 311,189 SDM posts that mentioned Roche products and brands in combination with common medical and scientific terms sourced from Twitter, Tumblr, Facebook, and a spectrum of news media blogs to develop and evaluate three iterations of an automated ICSR classifier. The ICSR classifier models consisted of sub-components to annotate the relevant ICSR elements and a component to make the final decision on the validity of the ICSR. Agreement with human pharmacovigilance experts was chosen as the preferred performance metric and was evaluated by calculating the Gwet AC1 statistic (gKappa). The best performing model was tested against the Roche global pharmacovigilance expert using a blind dataset and put through a time test of the full 311,189-post dataset. During this effort, the initial strict rule-based approach to ICSR classification resulted in a model with an accuracy of 65% and a gKappa of 46%. Adding an ML-based adverse event annotator improved the accuracy to 74% and gKappa to 60%. This was further improved by the addition of an additional ML ICSR detector. On a blind test set of 2500 posts, the final model demonstrated a gKappa of 78% and an accuracy of 83%. In the time test, it took the final model 48 h to complete a task that would have taken an estimated 44,000 h for human experts to perform. The results of this study indicate that an effective and scalable solution to the challenge of ICSR detection in SDM includes a workflow using an automated ML classifier to identify likely ICSRs for further human SME review.
TL;DR: Implementing evidence-based recommendations developed for the safe use of drugs in patients with liver cirrhosis into clinical practice can possibly enhance medication safety in this vulnerable patient group.
Abstract: The presence of liver cirrhosis can have a major impact on pharmacodynamics and pharmacokinetics, but guidance for prescribing is lacking. The aim of this study is to provide an overview of evidence-based recommendations developed for the safe use of drugs in liver cirrhosis. Recommendations were based on a systematic literature search combined with expert opinion from a panel of 10 experts. The safety of each drug was classified as safe, no additional risks known, additional risks known, unsafe, unknown or the safety class was dependent on the severity of liver cirrhosis (Child–Pugh classification). If applicable, drug-specific dosing advice was provided. All recommendations were implemented in clinical decision support systems and on a website. We formulated 218 recommendations for a total of 209 drugs. For nine drugs, two recommendations were formulated for different administration routes or indications. Drugs were classified as ‘safe’ in 29 recommendations (13.3%), ‘no additional risks known’ in 60 (27.5%), ‘additional risks known’ in 3 (1.4%), and ‘unsafe’ in 30 (13.8%). In 57 (26.1%) of the recommendations, safety depended on the severity of liver cirrhosis and was ‘unknown’ in 39 (17.9%) recommendations. Large alterations in pharmacodynamics were the main reason for classifying a drug as ‘unsafe’. For 67 drugs (31%), a dose adjustment was needed. Over 200 recommendations were developed for the safe use of drugs in patients with liver cirrhosis. Implementing these recommendations into clinical practice can possibly enhance medication safety in this vulnerable patient group.
TL;DR: Coroners’ reports to prevent future deaths provide some information on medication errors and adverse reactions but rarely identify new hazards, which could mean that wider lessons are lost.
Abstract: Since legislation in 2009, coroners in England and Wales must make reports in cases where they believe it is possible to prevent future deaths. We categorised the reports and examined whether they could reveal preventable medication errors or novel adverse drug reactions. We examined 500 coroners’ reports by pre-defined criteria to identify those in which medicines played a part, and to collect information on coroners’ concerns. We identified 99 reports (100 deaths) in which medicines or a part of the medication process or both were mentioned. Reports mentioned anticoagulants (22 reports), opioids (17), antidepressants (17), drugs of abuse excluding opioids (12 deaths) and other drugs. The most important concerns related to adverse reactions to prescribed medicines (22), omission of necessary treatment (21), failure to monitor treatment (17) and poor systems (17). These were related to defects in education or training, lack of clear guidelines or protocols and failure to implement existing guidelines, among other reasons. Most reports went either to NHS Hospital Trusts or to local trusts. The responses of addressees were rarely published. We identified four safety warnings from the Medicines and Healthcare Products Regulatory Agency that were based on coroners’ warnings. Coroners’ reports to prevent future deaths provide some information on medication errors and adverse reactions. They rarely identify new hazards. At present they are often addressed to local bodies, but this could mean that wider lessons are lost.
TL;DR: It is demonstrated that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders, and a low risk of kidney injury with DOAC therapy can also not be excluded.
Abstract: Postmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases. The aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA). SSA was performed using nationwide data from the French National Healthcare databases (Regime General, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA). This study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3 = 2.71, 95% confidence interval (CI) 1.79–4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3 = 1.31, 95% CI 1.27–1.36; and 1.17, 95% CI 1.12–1.22, respectively); and kidney diseases (aSR3 = 1.33, 95% CI 1.29–1.37). Results of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded.
TL;DR: Causality assessment of the case series of 90 reports to Lareb shows it is plausible for the vitamin B6 supplements to have caused complaints such as neuropathies, especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded.
Abstract: In the literature, vitamin B6 has been linked to the development of polyneuropathy. Most often, these complaints were seen when taking high doses of vitamin B6 for a long time. Evidence as to whether a lower dosage range of vitamin B6 (< 50 mg/day) can also induce neuropathy is scarce. We aim to comprehensively describe the cases of neuropathy associated with vitamin B6 received by the Netherlands Pharmacovigilance Centre Lareb and to assess the case series concerning the use of vitamin B6 and neuropathic complaints. We describe the number and nature of the reported cases, including suspect product, dosage, duration of use, and vitamin B6 serum levels. In addition, we describe the causality for the individual cases (Naranjo Probability Scale) and for the entire case series (Bradford Hill criteria). In total, 90 reports on products containing vitamin B6 included at least one adverse drug reaction in the standardized Medical Dictionary for Regulatory Activities (MedDRA®) query (SMQ; broad) ‘peripheral neuropathy’. The amount of vitamin B6 in the products varied between 1.4 and 100 mg per tablet. The serum vitamin B6 level was known in 36 cases (88–4338 nmol/l), and the mean serum vitamin B6 level was 907 nmol/l. However, no statistical correlation between dosage and vitamin B6 blood levels was found. Causality assessment of the case series of 90 reports to Lareb shows it is plausible for the vitamin B6 supplements to have caused complaints such as neuropathies. This is especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded.