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Journal Cover Drug Safety
  [SJR: 1.359]   [H-I: 103]   [131 followers]  Follow
   Full-text available via subscription Subscription journal
   ISSN (Print) 0114-5916 - ISSN (Online) 1179-1942
   Published by Adis Homepage  [20 journals]
  • EudraVigilance Medicines Safety Database: Publicly Accessible Data for
           Research and Public Health Protection
    • 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.
      PubDate: 2018-03-09
  • Drug-Induced Liver Injury: Why is the Roussel Uclaf Causality Assessment
           Method (RUCAM) Still Used 25 Years After Its Launch'
    • 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.
      PubDate: 2018-03-03
  • Interest in a Mobile App for Two-Way Risk Communication: A Survey Study
           Among European Healthcare Professionals and Patients
    • Abstract: Introduction Previously, an app has been developed for healthcare professionals (HCPs) and patients to report adverse drug reactions (ADRs) to national medicines agencies and to receive drug safety information. Objective This study aimed to assess (1) European HCPs’ and patients’ interest in an app for this two-way risk communication; (2) their preferences and perceptions towards specific app characteristics; and (3) which HCPs and patients are particularly interested in the app. In addition, these aspects were studied specifically for the countries where such an app was already available, i.e. Croatia, The Netherlands, and The UK. Methods European HCPs and patients were asked to complete a web-based survey developed in the context of the Web-Recognizing Adverse Drug Reactions (Web-RADR) project. Data on app interest and preferences and perceptions towards app characteristics were analysed descriptively. Logistic regression analyses were conducted to assess the association of HCP characteristics and patient characteristics on the level of interest in the app (i.e. very interested vs. not/somewhat interested). Results In total, 399 HCPs and 656 patients completed the survey. About half of the patients (48%; ranging from 38% from The Netherlands to 54% from The UK), and 61% of the HCPs (ranging from 42% from The Netherlands to 54% from The UK) were very interested in the app. A faster means of reporting ADRs and easier access to the reporting form were the main perceived benefits. HCPs and patients who already use a health app were particularly interested in the app (HCPs: odds ratio [OR] 3.52; 95% confidence interval [CI] 1.96–6.30, patients: OR 1.64; 95% CI 1.19–2.27). Conclusions An app is positively perceived by HCPs and patients for reporting ADRs quickly and for receiving drug safety information from national medicines agencies. In particular, HCPs and patients who already use other health apps were interested in the app.
      PubDate: 2018-03-02
  • Safety Communication Tools and Healthcare Professionals’ Awareness of
           Specific Drug Safety Issues in Europe: A Survey Study
    • Abstract: Introduction National competent authorities (NCAs) use Direct Healthcare Professional Communications (DHPCs) to communicate new drug safety issues to healthcare professionals (HCPs). More knowledge is needed about the effectiveness of DHPCs and the extent to which they raise awareness of new safety issues among HCPs. Objective The objective was to assess and compare general practitioners’ (GPs’), cardiologists’, and pharmacists’ familiarity with DHPCs as communication tools, their awareness of specific drug safety issues, and the sources through which they had become aware of the specific issues. Methods GPs, cardiologists, and pharmacists from nine European countries (Croatia, Denmark, Ireland, Italy, the Netherlands, Norway, Spain, Sweden, and the UK) completed a web-based survey. The survey was conducted in the context of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) Joint Action. Respondents were asked about their familiarity with DHPCs in general and their awareness of safety issues that had recently been communicated and involved the following drugs: combined hormonal contraceptives, diclofenac, valproate, and ivabradine. Those HCPs who were aware of the specific safety issues were subsequently asked to indicate the source through which they had become aware of them. Differences between professions in familiarity with DHPCs and awareness were tested using a Pearson χ2 test per country and post hoc Pearson χ2 tests in the case of statistically significant differences. Results Of the 3288 included respondents, 54% were GPs, 40% were pharmacists, and 7% were cardiologists. The number of respondents ranged from 67 in Denmark to 916 in Spain. Most respondents (92%) were familiar with DHPCs, with one significant difference between the professions: pharmacists were more familiar than GPs in Italy (99 vs 90%, P = 0.004). GPs’ awareness ranged from 96% for the diclofenac issue to 70% for the ivabradine issue. A similar pattern was shown for pharmacists (91% aware of the diclofenac issue to 66% of the ivabradine issue). Cardiologists’ awareness ranged from 91% for the ivabradine issue to 34% for the valproate issue. Overall, DHPCs were a common source through which GPs (range: 45% of those aware of the contraceptives issue to 60% of those aware of the valproate issue), cardiologists (range: 33% for the contraceptives issue to 61% for the valproate issue), and pharmacists (range: 41% for the contraceptives issue to 51% for the ivabradine issue) had become aware of the specific safety issues, followed by information on websites or in newsletters. Conclusions GPs, cardiologists, and pharmacists were to a similar extent (highly) familiar with DHPCs, but they differed in awareness levels of specific safety issues. Cardiologists were less aware of safety issues associated with non-cardiology drugs even if these had cardiovascular safety concerns. This implies that additional strategies may be needed to reach specialists when communicating safety issues regarding drugs outside their therapeutic area but with risks related to their field of specialisation. DHPCs were an important source for the different professions to become aware of specific safety issues, but other sources were also often used. NCAs should consider the use of a range of sources when communicating important safety issues to HCPs.
      PubDate: 2018-03-02
  • Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid
           Arthritis: How Real is the Risk'
    • 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.
      PubDate: 2018-03-02
  • Utilisation and Safety of Deferasirox: Results from an Observational
           Cohort Study in England
    • Abstract: Introduction Deferasirox (EXJADE®, Novartis, UK) is an oral iron-chelating agent primarily used to reduce chronic iron overload in patients receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. Objective The aim of this study was to examine the utilisation and safety of deferasirox used in general practice in England. Method A single exposure observational cohort study design was used. Patients were identified from dispensed prescriptions for deferasirox between September 2006 and September 2014. Outcome data were collected via postal questionnaires sent to prescribers ≥ 6 months after first dispensed prescription for an individual patient. Summary descriptive statistics were calculated. Results The evaluable cohort consisted of 122 patients, of which 41.8% were aged 2–17 years. Frequent reasons for prescribing were sickle cell anaemia (27/103 where specified, 26.2%) and beta thalassaemia (26, 25.2%). The majority of patients (43/51, 84.3%) were prescribed the licensed doses of 10 or 20 mg/kg/day at start. Prior measurements of serum creatinine were only reported for a small proportion this study (18/122, 14.8%). In total, 91 incident events were reported, including two of raised serum creatinine. Conclusion These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile.
      PubDate: 2018-03-01
  • Authors’ Reply to Mona Kargar and Colleagues’ Comment on “Adverse
           Drug Reaction-Related Hospitalizations in Elderly Australians: A
           Prospective Cross-Sectional Study in Two Tasmanian Hospitals”
    • PubDate: 2018-03-01
  • Reported Adverse Events with Painkillers: Data Mining of the US Food and
           Drug Administration Adverse Events Reporting System
    • Abstract: Introduction One-third of adults in the USA experience chronic pain and use a variety of painkillers, such as nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. However, some serious adverse events (AEs), such as cardiovascular incidents, overdose, and death, have been found to be related to painkillers. Methods We used 2015 and 2016 AE reports from the US FDA’s Adverse Events Reporting System (FAERS) to conduct exploratory analysis on the demographics of those who reported painkiller-related AEs, examine the AEs most commonly associated with different types of painkillers, and identify potential safety signals. Summary descriptive statistics and proportional reporting ratios (PRRs) were performed. Results Out of over 2 million reports submitted to FAERS in 2015 and 2016, a total of 64,354 AE reports were associated with painkillers. Reports of opioid-associated AEs were more likely to be from males or younger patients (mean age 47.6 years). The highest numbers of AEs were reported for NSAID and opioid use, and the most commonly found AEs were related to drug ineffectiveness, administration issues, abuse, and overdose. Death was reported in 20.0% of the reports, and serious adverse reactions, including death, were reported in 67.0%; both adverse outcomes were highest among patients using opioids or combinations of painkillers and were associated with PRRs of 2.12 and 1.87, respectively. Conclusions This study examined the AEs most commonly associated with varying classes of painkillers by mining the FAERS database. Our results and methods are relevant for future secondary analyses of big data and for understanding adverse outcomes related to painkillers.
      PubDate: 2018-03-01
  • Comment on: “Adverse Drug Reaction-Related Hospitalizations in Elderly
           Australians: A Prospective Cross-Sectional Study in Two Tasmanian
    • PubDate: 2018-03-01
  • Severe Physical Complications among Survivors of Stevens–Johnson
           Syndrome and Toxic Epidermal Necrolysis
    • Abstract: Introduction Few studies have reported the physical complications among Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) survivors. Objective 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. Methods 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. Results 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. Conclusion 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.
      PubDate: 2018-03-01
  • Evaluation of ‘Definite’ Anaphylaxis Drug Allergy Alert Overrides in
           Inpatient and Outpatient Settings
    • Abstract: Introduction Drug–allergy interaction (DAI) alerts are generated when a known adverse sensitivity-inducing substance is prescribed. A recent study at our institution showed that providers overrode most DAI alerts, including those that warned against potentially life-threatening ‘anaphylaxis’. Objective The aim of this study was to determine the rate of anaphylaxis overrides, the reasons for these overrides, whether the overrides were appropriate, and if harm occurred from overrides. Methods All DAI alerts, with a reaction of ‘anaphylaxis’, were analysed for inpatients and outpatients within our health system between January 2009 and December 2011. Only alerts that were triggered by ‘definite’ alerts (i.e. same ordered medication as documented allergen) were included. Patient charts were reviewed to assess the appropriateness of overrides and potential harm, according to a predetermined set of criteria. Results A total of 202 inpatient and 16 outpatient alerts met the inclusion criteria. The rate of overrides for ‘definite’ anaphylaxis DAI alerts was high (inpatient: n = 93, 46.0%; outpatient: n = 11, 68.8%) but appropriate for most overrides in the inpatient (n = 78, 83.9%) and outpatient settings (n = 11, 100%). The most common override reasons in the inpatient and outpatient settings were ‘administer per desensitization protocol’ (n = 64, 31.7%) and ‘patient does not have this allergy’ (n = 7, 63.6%), respectively. No harm was associated with overrides in either setting, particularly because many medications were not administered. Conclusions Overrides of ‘definite’ anaphylaxis DAI alerts were common and often appropriate. Most overrides were due to desensitizations. Allergy reconciliation for patients could further improve critical decision support.
      PubDate: 2018-03-01
  • Using Human ‘Experiments of Nature’ to Predict Drug Safety Issues: An
           Example with PCSK9 Inhibitors
    • Abstract: Introduction When a new drug enters the market, its full array of side effects remains to be defined. Current surveillance approaches targeting these effects remain largely reactive. There is a need for development of methods to predict specific safety events that should be sought for a given new drug during development and postmarketing activities. Objective We present here a safety signal identification approach applied to a new set of drug entities, inhibitors of the serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9). Methods Using phenome-wide association study (PheWAS) methods, we analyzed available genotype and clinical data from 29,722 patients, leveraging the known effects of changes in PCSK9 to identify novel phenotypes in which this protein and its inhibitors may have impact. Results PheWAS revealed a significantly reduced risk of hypercholesterolemia (odds ratio [OR] 0.68, p = 7.6 × 10−4) in association with a known loss-of-function variant in PCSK9, R46L. Similarly, laboratory data indicated significantly reduced beta mean low-density lipoprotein cholesterol (− 14.47 mg/dL, p = 2.58 × 10−23) in individuals carrying the R46L variant. The R46L variant was also associated with an increased risk of spina bifida (OR 5.90, p = 2.7 × 10−4), suggesting that further investigation of potential connections between inhibition of PCSK9 and neural tube defects may be warranted. Conclusion This novel methodology provides an opportunity to put in place new mechanisms to assess the safety and long-term tolerability of PCSK9 inhibitors specifically, and other new agents in general, as they move into human testing and expanded clinical use.
      PubDate: 2018-03-01
  • Using the Symmetry Analysis Design to Screen for Adverse Effects of
           Non-vitamin K Antagonist Oral Anticoagulants
    • Abstract: Introduction Knowledge on adverse effects (AEs) related to non-vitamin K antagonist oral anticoagulants (NOACs) in real-world populations is sparse. Objective Our objective was to identify signals of potential AEs in patients with atrial fibrillation (AF) initiating NOAC treatment using a hypothesis-free screening approach. Methods Using the nationwide Danish registries, we identified patients with AF initiating dabigatran, rivaroxaban, or apixaban between 2011 and 2015 (n = 50,627). Applying a symmetry analysis design, we screened for AEs of NOAC, as reflected by new drug treatments, incident diagnoses, or procedures. For signals with the lowest number needed for one additional patient to be harmed (NNTH), we evaluated whether they likely represented genuine AEs or other types of associations. Signals assessed as potential AEs were grouped into five categories for analysis of effect modification according to patient and drug characteristics. Results Of the identified signals, 61 were classified as potential AEs. Most signals could be categorized as the following types of AEs: bleedings, non-bleeding gastrointestinal symptoms, mental disease, urinary tract disorders, and musculoskeletal symptoms. Older age and first-ever use of anticoagulants was associated with strengthening of all “NOAC-adverse effect” associations. Conversely, use of low-dose NOAC and apixaban led to attenuation of most associations. Conclusion Through a symmetry analysis-based hypothesis-free screening of large-scale healthcare databases, we were able to confirm well-established AEs of NOAC therapy in clinical practice as well as potential AEs that deserve further investigation.
      PubDate: 2018-03-01
  • Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A
           Systematic Review
    • Abstract: Introduction 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. Methods 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. Results 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. Limitations The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association. Conclusion 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.
      PubDate: 2018-03-01
  • Risk of Psoriasis Following Terbinafine or Itraconazole Treatment for
           Onychomycosis: A Population-Based Case-Control Comparative Study
    • Abstract: Introduction Several case studies have reported an association between antifungal drug use and psoriasis risk. Objective The objective of this study was to investigate the association between terbinafine/itraconazole exposure and psoriasis incidence. Methods Among patients with onychomycosis in the Taiwan National Health Insurance Research Database, 3831 incident psoriasis cases were identified during 2004–2010 and compared with 3831 age- and sex-matched controls with the same look-back period. Multivariate conditional logistic regression was used for the analysis. Results The psoriasis cases were significantly more likely than matched controls to have used terbinafine or itraconazole (59.85 vs. 42.70%, respectively; p < 0.0001). After adjusting for potential confounders and cumulative duration of antifungal drug prescription, terbinafine/itraconazole use was associated with an increased psoriasis risk (adjusted odds ratio 1.33, 95% confidence interval 1.15–1.54). The association was stronger for more recent drug exposure (adjusted odds ratio 2.96, 95% confidence interval 2.25–3.90 for ≤ 90 days before the sampling date; adjusted odds ratio 1.04, 95% confidence interval 0.89–1.22 for > 360 days). In a comparison of patients receiving terbinafine or itraconazole only, psoriasis risk was higher for itraconazole (adjusted odds ratio 1.21, 95% confidence interval 1.05–1.40). Conclusion This large population-based case-control analysis showed that exposure to terbinafine or itraconazole is associated with an increased risk of incident psoriasis. The finding of an increased psoriasis risk for antifungal drug users, particularly for itraconazole, deserves attention in clinical practice although further prospective studies are necessary to confirm our findings and clarify the biological mechanisms that underlie these associations.
      PubDate: 2018-03-01
  • Can SGLT2 Inhibitors Cause Acute Renal Failure' Plausible Role for
           Altered Glomerular Hemodynamics and Medullary Hypoxia
    • 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.
      PubDate: 2018-03-01
  • Liver Safety of Fasiglifam (TAK-875) in Patients with Type 2 Diabetes:
           Review of the Global Clinical Trial Experience
    • Abstract: Introduction Fasiglifam (TAK-875) is a G protein-coupled receptor 40 agonist that was being investigated for treatment of type 2 diabetes mellitus (T2DM). A development program was terminated late in phase III clinical trials due to liver safety concerns. Methods The liver safety of fasiglifam was assessed from data based on six phase II and nine phase III double-blind studies and two open-label studies with emphasis on pooled data from 15 double-blind studies from both global and Japanese development programs. Taking into consideration different daily doses of fasiglifam administered in clinical studies, the primary comparisons were between all patients exposed to fasiglifam (any dose) versus placebo, and, where applicable, versus the two active comparators, sitagliptin or glimepiride. A Liver Safety Evaluation Committee consisting of hepatologists blinded to treatment assignments evaluated hepatic adverse events (AEs) and serious AEs (SAEs) for causal relationship to study drug. Results The analysis included data from 9139 patients with T2DM in 15 double-blind controlled studies who received either fasiglifam (n = 5359, fasiglifam group), fasiglifam and sitagliptin (n = 123), or a comparator agent (n = 3657, non-exposed group consisting of placebo and other antidiabetic agents). Exposure to treatment for more than 1 year ranged from 249 patients in the placebo arm, to 370 patients in the glimepiride arm and 617 patients in the fasiglifam 50 mg arm. The primary focus of the analysis was on the hepatic safety of fasiglifam. The overall safety profile based on treatment-emergent AEs (TEAEs), SAEs, deaths, and withdrawal due to AEs was similar between fasiglifam and placebo (excluding liver test abnormalities). However, there was an increased incidence rate of serum alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN), 5 × ULN, and 10 × ULN in fasiglifam-treated patients compared with those treated with placebo or active comparators. ALT elevations > 3 × ULN for fasiglifam were 2.7% compared with 0.8 and 0.5% for the active comparators and placebo. There did not appear to be a clear dose response in incidence of ALT elevations between patients receiving 25 or 50 mg daily. The cumulative incidence of elevations in serum ALT > 3 × ULN was higher in the first 6 months of treatment with fasiglifam compared with both placebo and the active comparators, but the rate of new ALT elevations appeared to be similar across all treatment groups thereafter. No demographic or baseline patient characteristics were identified to predict elevations exceeding ALT > 3 × ULN in fasiglifam-treated patients. The pattern of liver injury with fasiglifam was hepatocellular, and there were no reports of liver-related deaths, liver failure or life-threatening liver injury. Most fasiglifam-associated ALT elevations were asymptomatic and resolved promptly upon discontinuing treatment, but in two patients the recovery was prolonged. Importantly, three important serious liver injury cases were identified among fasiglifam-treated patients; one case was adjudicated to be a clear Hy’s Law case and the two remaining cases were considered to closely approximate Hy’s Law cases. Conclusions Although the incidence of overall AEs, SAEs, and deaths was similar between fasiglifam and placebo, a liver signal was identified based primarily on the difference in liver chemistry values in the fasiglifam group compared with the placebo and active comparator groups. Three serious liver injuries were attributed to fasiglifam treatment. Clinical development of fasiglifam was halted due to these liver safety concerns.
      PubDate: 2018-02-28
  • Sex Differences in Reported Adverse Drug Reactions of Selective Serotonin
           Reuptake Inhibitors
    • Abstract: Introduction Several studies have investigated sex as a risk factor for the occurrence of adverse drug reactions (ADRs) and found that women are more likely to experience ADRs than men. Objective The aim of this explorative study was to investigate whether differences exist in reported ADRs of selective serotonin reuptake inhibitors (SSRIs) for men and women in the database of the Netherlands Pharmacovigilance Centre Lareb. Methods A ratio of reports concerning women and men, corrected for the number of users, was calculated for all the ADRs reported on SSRIs. Results We found that 16 ADRs were statistically significantly more reported in women than men, and four ADRS were reported more in men than women. Conclusion ADRs more reported in women than men when using SSRIs were usually dose-related ADRs or commonly occurring ADRs. Differences in the pharmacokinetics of SSRIs between men and women may explain why these reports of dose-related ADRs when using SSRIs concern women more than men.
      PubDate: 2018-02-26
  • The Risk for Lung Cancer Incidence with Calcium Channel Blockers: A
           Systematic Review and Meta-Analysis of Observational Studies
    • Abstract: Introduction There are conflicting findings regarding the association between the use of calcium channel blockers (CCBs) and the risk of lung cancer. Considering the public health importance of lung cancer prevention, and emerging evidence of a significant biologic role of calcium channel regulation in the development of lung cancer, we conducted a meta-analysis to assess the risk of lung cancer in CCB users compared with non-CCB users. Materials and Methods We conducted a comprehensive systematic search of leading medical databases for observational studies published up to December 2017 that examined CCB use and the risk of lung cancer. We used random-effects models to pool results. The impact of duration of CCB use on the estimated effect size was explored using random effects meta-regression. Results Ten studies (six cohort and four case–control studies) that evaluated the overall cancer risk among 38,758 CCB users were included in the analysis. Overall risk ratio (RR) for CCB use and lung cancer was 1.15 (95% confidence interval [CI] 1.01–1.32). Subgroup analysis by duration of CCB use suggested that the observed increase in lung cancer risk was driven by the results of five studies with prolonged (≥ 4 years) exposure (RR 1.18; 95% CI 1.08–1.30). Conclusions Our analysis suggests exposure to CCBs is associated with an increased risk of lung cancer. Considering their widespread use, and the paucity of data on the long-term effects of chronic exposure to CCBs, these results are reason for concern and warrant further investigation. Systematic Review Registration The protocol for this study was registered at the PROSPERO registry of systematic reviews (registry number: CRD42017056362).
      PubDate: 2018-02-26
  • Limited Evidence for Risk Factors for Proarrhythmia and Sudden Cardiac
           Death in Patients Using Antidepressants: Dutch Consensus on ECG Monitoring
    • Abstract: Currently, there is a lack of international and national guidelines or consensus documents with specific recommendations for electrocardiogram (ECG) screening and monitoring during antidepressant treatment. To make a proper estimation of the risk of cardiac arrhythmias and sudden (cardiac) death during antidepressant use, both the drug and patient-specific factors should be taken into account; however, solid evidence on how this should be done in clinical practice is lacking. Available recommendations on the management of QT(c) prolongation (with antidepressant treatment) emphasize that special attention should be given to high-risk patients; however, clinicians are in need of more concrete suggestions about how to select patients for ECG screening and monitoring. Based on a review of the literature, a Dutch multidisciplinary expert panel aimed to formulate specific guidelines to identify patients at risk for cardiac arrhythmias and sudden death by developing a consensus statement regarding ECG screening before, and monitoring during, antidepressant use. We first reviewed the literature to identify the relative risks of various risk factors on cardiac arrhythmia and sudden (cardiac) death during antidepressant use. These relative contributions of risk factors could not be determined since no systematic reviews or meta-analyses quantitatively addressed this topic. Because evidence was insufficient, additional expert opinion was used to formulate recommendations. This resulted in readily applicable recommendations for clinical practice for selection of high-risk patients for ECG screening and monitoring. ECG screening and monitoring is recommended before and following the start of QTc-prolonging antidepressants in the presence of vulnerability to QTc prolongation or two or more risk factors (age > 65 years, female sex, concomitant use of a QTc-prolonging drug or concomitant use of a drug that influences the metabolism of a QTc-prolonging drug, cardiac disease, excessive dosing and specific electrolyte disturbances).
      PubDate: 2018-02-26
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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