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Background “Impulse Control Disorders” are behavioral conditions (e.g., gambling, hypersexuality), which are increasingly reported as reactions to dopamine agonists in Parkinson's disease. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease focuses only on 6 behaviors. Nonetheless, impulsivity could affect the entire range of human practices. Because of their heterogeneity and undefined boundaries, it is not clear what conditions should be considered as Impulse Control Disorders. This results in poorly standardized scientific literature and underdiagnosis. Objective We aimed to create a comprehensive list of possible manifestations of drug-induced Impulse Control Disorders in Parkinson's disease and test it on pharmacosurveillance data. Methods PubMed was used to identify reviews in English about Impulse Control Disorders in Parkinson's disease. Mentioned conditions were charted and translated to the lexicon of MedDRA, ICD-11, and DSM-5. The relevant MedDRA terms were used to test potential association with dopamine agonists on the FDA Adverse Event Reporting System. Results 50 reviews published between 2001 and 2020 were identified. 66 conditions were collected as possible Impulse Control Disorders. Pathological gambling, shopping, eating and sexuality, dopamine dysregulation syndrome, hobbyism and punding were the most frequently mentioned, together with leisure activities, body-focused compulsivity, disruptive, impulse control and conduct disorders, and substance abuse. All these conditions were disproportionately reported with dopamine agonists, except for substance abuse. Conclusions We defined a potential extended list of ICDs, which, along with its conversion to international taxonomies, can support the identification of drug-induced conditions in pharmacovigilance archives, as well as monitoring processes in clinical practice.

Nicolina Conti,1 Milo Gatti,2,3 Emanuel Raschi,2 Igor Diemberger,1,4 Luciano Potena4 1Cardiology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum - University of Bologna, Bologna, Italy; 2Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy; 3SSD Clinical Pharmacology, IRCSS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy; 4Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyCorrespondence: Emanuel RaschiPharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, via Irnerio 48, Bologna, 40126, ItalyTel +39-051-2091802Email emanuel.raschi@unibo.itAbstract: Levosimendan is a distinctive inodilator combing calcium sensitization, phosphodiesterase inhibition and vasodilating properties through the opening of adenosine triphosphate-dependent potassium channels. It was first approved in Sweden in 2000 for the short-term treatment of acutely decompensated severe chronic heart failure when conventional therapy is not sufficient, and in cases where inotropic support is considered appropriate. After more than 20 years, clinical applications have considerably expanded across critical care and emergency medicine, and levosimendan is now under investigation in different cardiac settings (eg, septic shock, pulmonary hypertension) and for non-cardiac applications (eg, amyotrophic lateral sclerosis). This narrative review outlines key milestones in levosimendan history, by addressing regulatory issues, pharmacological peculiarities and clinical aspects (efficacy and safety) of a drug that did not receive great attention in the heart failure guidelines. A brief outlook to the ongoing clinical trials is also offered.Keywords: levosimendan, heart failure, cardiogenic shock, cardiac surgery, amyotrophic lateral sclerosis

utosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder (estimated prevalence of 1 per 1000–1 per 2500 live births)1 characterized by the development and growth of multiple bilateral cysts eventually leading to end-stage renal disease and renal replacement therapy.1 Tolvaptan, a selective vasopressin V2 receptor antagonist, is currently the only pharmacologic agent approved for ADPKD capable of slowing the kidney cyst growth and the progression of kidney disease.2 The resulting aquaretic adverse events (AEs) (polyuria, pollakiuria, and nocturia) may cause dehydration and did not seem to diminish over time,2 thus supporting the need to inform patients for adequate liquid intake and maintaining long-term vigilance. Data on the risk/benefit profile of tolvaptan in ADPKD come mainly from randomized controlled trials and small real-world studies.3 The latest prospective, multinational, open-label safety study enrolling subjects who completed previous trials (median exposure 651 days) confirmed the occurrence of treatmentemergent aquaretic AEs and the importance of tight hepatic monitoring as effective risk minimization strategy.4 Therefore, postmarketing studies are needed to evaluate rare and unexpected AEs, which are not fully appreciated in randomized controlled trials.5 We herein describe the occurrence of acute pulmonary thromboembolism in a patient with risk factors exposed to tolvaptan. To evaluate the possible association between tolvaptan and thromboembolism, we also analyzed the Food and Drug Administration Adverse Event Reporting System

Introduction Short bowel syndrome (SBS) is a rare, highly disabling, life-threatening condition due to extensive intestinal resections, characterized by diarrhea, malabsorption, and malnutrition. SBS is the main cause of intestinal failure (SBS-IF). The primary therapy for SBS-IF is intravenous supplementation (IVS) of nutrients. The pharmacological therapy aims to improve the remnant bowel function, leading to the decrease of IVS requirement. Areas covered This review provides a safety perspective and discusses unmet clinical needs on pharmacotherapy for SBS, ranging from symptomatic agents traditionally used off-label to manage hypersecretion and diarrhea, to curative drugs with selective intestinotrophic properties. Real-world evidence on symptomatic drugs is lacking. Data on teduglutide - the first-in-class glucagon-like peptide-2 (GLP-2) receptor agonist approved in SBS - are mainly derived from clinical trials, with several unsettled safety issues, including the risk of malignancies. Expert opinion Defining the long-term safety of drugs used for SBS is a priority; a unified list of commonly used drugs with consolidated proof of effectiveness is needed to harmonize the symptomatic pharmacological approach to SBS. GLP-2 receptor agonists are a promising curative pharmaco-therapeutic approach, although long-term safety and effectiveness deserve further real-world assessment. Pharmacovigilance and global data sharing are crucial to support safe prescribing in SBS.

Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.

Aims The aim of this study was to characterise clinical priority of adverse events with sacubitril/valsartan for targeting preventive measures. Methods We used the US Food and Drug Administration adverse event reporting system (worldwide pharmacovigilance database) to compare adverse events recording sacubitril/valsartan as suspect with other cardiovascular drugs. Disproportionality analyses were performed by calculating the reporting odds ratios, deemed significant when the lower limit of the 95% confidence interval was greater than 1. Clinical priority was assigned to adverse events with significant disproportionality by scoring (range 0–10 points) five features (number of events, magnitude of the lower limit of the 95% confidence interval, mortality frequency, important/designated medical event, biological plausibility). Results Sacubitril/valsartan was recorded in 20,021 reports, with 178 adverse events associated with significant disproportionality: 71.9%, 25.9% and 2.2% were classified as weak, moderate and strong clinical priorities, respectively. Increased reporting emerged for several cardiovascular adverse events, including ‘renal failure’ (N = 388; lower limit of the 95% confidence interval 2.26), ‘hyperkalaemia’ (314; 2.42) and ‘angioedema’ (309; 1.56). Sudden cardiac death (priority score 9 points) was the only designated medical event with strong clinical priority. Notably, sudden cardiac death occurred early after sacubitril/valsartan administration (average onset 124 days), with concomitant drugs known for pro-arrhythmic potential (e.g. amiodarone, escitalopram, mirtazapine, loop diuretics) in 26.2% of records. Conclusion The increased cardiovascular reporting of sacubitril/valsartan in the real world was largely predictable from pre-approval evidence, underlying disease and likely patients’ comorbidities. The unexpected reporting of sudden cardiac death occurred well before the complete development of positive electrical remodelling induced by sacubitril/valsartan, and calls for stringent clinical monitoring (to reduce the pro-arrhythmic burden related to co-medications), and further investigation on appropriate combination with other preventive measures.

To date, four vaccines have been authorised for emergency use and under conditional approval by the European Medicines Agency to prevent COVID-19: Comirnaty, COVID-19 Vaccine Janssen, Spikevax (previously COVID-19 Vaccine Moderna) and Vaxzevria (previously COVID-19 Vaccine AstraZeneca). Although the benefit–risk profile of these vaccines was proven to be largely favourable in the general population, evidence in special cohorts initially excluded from the pivotal trials, such as pregnant and breastfeeding women, children/adolescents, immunocompromised people and persons with a history of allergy or previous SARS-CoV-2 infection, is still limited. In this narrative review, we critically overview pre- and post-marketing evidence on the potential benefits and risks of marketed COVID-19 vaccines in the above-mentioned special cohorts. In addition, we summarise the recommendations of the scientific societies and regulatory agencies about COVID-19 primary prevention in the same vaccinee categories. Supplementary Information The online version contains supplementary material available at 10.1007/s40264-021-01131-6.

Background: Cyclin-dependent kinase (CDK)-4/6 inhibitors have been associated with dermatologic reactions, especially alopecia, in pivotal trials. Objective: We aimed to comprehensively describe skin toxicities with CDK4/6 inhibitors reported in the real world through the US FDA Adverse Event Reporting System (FAERS). Methods: Cutaneous adverse events (AEs) were characterized in terms of spectrum and clinical features, including seriousness (with fatality proportion), latency, and discontinuation. Disproportionality analyses were performed through the reporting odds ratio (ROR) and 95% confidence interval (CI) by comparing CDK4/6 inhibitors with other anticancer drugs used in breast cancer. Results: As of December 2020, a total of 7986 cutaneous events were reported with CDK4/6 inhibitors (15% of total AEs with CDK4/6 inhibitors), mainly by consumers (39.6%), with 43.5% classified as serious and 25% requiring discontinuation. In 49% of the cases, five or more noncutaneous events were co-reported. The most frequently reported cutaneous events were alopecia (N = 3528), rash (N = 1493), and pruritus (N = 1211): rashes were recorded in the first month (median onset 28 days), whereas alopecia and nail alterations were recorded after a median of 67 and 112 days, respectively. Several cutaneous AEs were associated with increased reporting, including vitiligo (N = 6; ROR 8.88; 95% CI 2.95–22.46) and bullous dermatitis with ribociclib (N = 7; ROR 2.90; 95% CI 1.13–6.27); erythema multiforme with abemaciclib (N = 9; ROR 5.80; 95% CI 2.57–11.48); onychoclasis (N = 142, ROR 2.27; 95% CI 1.83–2.79) and trichorrhexis (N = 22; ROR 3.27; 95% CI 1.78–5.93) with palbociclib. Conclusions: Although causality cannot be demonstrated, a diverse reporting pattern of cutaneous AEs emerged from FAERS, including dermal/epidermal conditions, hair/nail disorders, and serious bullous conditions, with variable onsets and a remarkable proportion ofdiscontinuations. The potential differential reporting among CDK4/6 inhibitors deserves further investigation.

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs). Research design and methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1. Results: After a customized data-mining process, 3,226 reports of MS were retrieved. ‘Antineoplastic and immunomodulating drugs’ (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24–2.74), adalimumab (329; 2.05; 1.83–2.30), and infliximab (119; 2.25; 1.87–2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system. Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.

We analyzed thromboembolic events, recognized (AESIs), with cyclin-dependent kinase (CDK)4/6 inhibitors, using the Food and Drug Administration adverse event reporting system. Methods: Thromboembolic events were characterized in terms of spectrum [venous and arterial thromboembolism (VTE, ATE)] and clinical features by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Results: A total of 1722 thromboembolic events were retained. Increased VTE reporting emerged for CDK4/6 inhibitors in the exploratory analyses (n = 659, ROR = 1.51, 95% CI = 1.39–1.63), with consistent disproportionality in the consolidated analyses (e.g., deep vein thrombosis with abemaciclib: 17, 1.98, 1.22–3.19). Higher-than-expected ATE reporting was found for ribociclib, including myocardial infarction (41, 1.82, 1.33–2.48), with rapid onset (median latency 1 vs. 6 months for other CDK4/6 inhibitors). Causality was highly probable or probable in 83.2% of cases, with a negligible proportion of pre-existing drug- and patient-related risk factors except for cardiovascular comorbidities (26%). Conclusions: Although causal association cannot be firmly inferred, oncologists should proactively monitor the occurrence of VTE with CDK4/6 inhibitors. The unexpected distinctive increased ATE reporting with ribociclib deserves urgent clarification though large comparative population-based studies. We support pharmacovigilance for the post-marketing characterization of AESIs, thus promoting real-time safe prescribing in oncology.

Although immune checkpoint inhibitors (ICIs) are associated with different immune‐related adverse events (irAEs), the potential effect on the skeleton is poorly defined albeit biologically plausible and assessable through pharmacovigilance. We described a case series of patients experiencing skeletal fractures while on ICIs at the National Cancer Institute of Milan. To better characterize the clinical features of skeletal irAEs reported with ICIs, we queried the FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis by means of reporting odds ratios (RORs), deemed significant by a lower limit of the 95% confidence interval (LL95% CI) > 1. Bone AEs emerging as significant were scrutinized in terms of demographic and clinical data, including concomitant irAEs or drugs affecting bone resorption or causing bone damage. Four patients with skeletal events while on ICIs were included in our case series, of which three exhibited vertebral fractures. In FAERS, 650 patients with bone and joint injuries and treated with ICIs were retrieved, accounting for 822 drug‐event pairs. Statistically significant ROR was found for eight, two and one bone AEs respectively with PD‐1, PD‐L1 and CTLA‐4 inhibitors, being pathological fracture (N = 46; ROR = 3.17; LL95%CI = 2.37), spinal compression fracture (42; 2.51; 1.91), and femoral neck fracture (26; 2.38; 1.62) the most common. Concomitant irAEs or drugs affecting bone metabolism were poorly reported. The increased reporting of serious vertebral fractures in patients without concomitant irAEs and no apparent preexisting risk factors could suggest a possible cause‐effect relationship and calls for close clinical monitoring and implementation of dedicated guidelines., What's new? Immune checkpoint inhibitors (ICIs), while potentially improving cancer patient survival, are associated with sometimes severe immune‐related adverse events. While these events affect all host tissues, little is known about their impact on bone in particular. Here, the authors investigated accounts of bone and joint injuries among patients taking ICIs, using clinical data and reports submitted to a pharmacovigilance database. Analyses show that ICIs may precipitate adverse skeletal events and reveal an increased reporting of serious vertebral fractures in patients lacking pre‐existing risk factors. The findings suggest that risk stratification and monitoring for skeletal lesions in patients taking ICIs is warranted.

Background Sodium glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of heart failure and new data show they can prevent atrial fibrillation (AF). We examined the association between SGLT2i and AF in the Food and Drug Administration adverse event reporting system (FAERS). Methods We mined the FAERS from 2014q1 to 2019q4 to compare AF reporting for SGLT-2 i versus reports for other glucose lowering medications (ATC10 class). Several exclusions were sequentially applied for: concomitant medications; diabetes, cardiovascular or renal disease indication; reports for competing adverse events (genitourinary tract infections, ketoacidosis, Fournier’s gangrene, amputation). We provide descriptive statistics and calculated proportional reporting ratios (PRR). Results There were 62,098 adverse event reports for SGLT2i and 642,031 reports for other ATC10 drugs. The reporting of AF was significantly lower with SGLT2i than with other ATC10 drugs (4.8 versus 8.7/1000; p Conclusions In a large pharmacovigilance database, AF was robustly and consistently reported more frequently for diabetes medications other than SGLT2i. This finding complements available evidence from trials supporting a protective role of SGLT2i against the occurrence of AF.

IntroductionEpilepsy is a chronic condition requiring consistent follow-up aimed at seizure control, and monitoring of anti-seizure medication (ASM) levels and side effects. Telemedicine (TM) offers invaluable support to patient follow-up, guaranteeing the prompt availability of a team of experts for persons with epilepsy (PWE) widely distributed across the country. Although many health institutions have endorsed the use of TM, robust data on effectiveness, safety and costs of TM applied to epilepsy are lacking. TELEmedicine for EPIlepsy Care (TELE-EPIC) will evaluate the effectiveness of video consultation (VC) via TM compared with usual care (UC) for the monitoring of PWE (TELE-EPIC_RCT). Moreover, TELE-EPIC will apply an innovative Volumetric Absorptive Microsampling (VAMS) device for quantitation of ASM through finger prick blood sampling as an alternative to venipuncture sampling (TELE-EPIC_VAMS).Methods and analysisTELE-EPIC_RCT is a multicentre, open, pragmatic two-arm randomised controlled trial prospectively including adult and paediatric outpatients with established diagnosis of epilepsy consecutively attending the Epilepsy Centres of Bologna and Rome, respectively. The primary outcome is the non-inferiority of VC on seizure control compared with UC after an 18-month follow-up. Secondary outcomes are adherence to treatment, ASM-related adverse events, quality of life, mood disorders, patient and caregiver satisfaction, safety and costs. TELE-EPIC_VAMS is a cross-validation study for blood ASM quantitation through a novel, VAMS-based device, comparing (1) VAMS versus plasma samples (reference standard method); and (2) nurse-collected versus self-collected blood by VAMS device.Ethics and disseminationThe study has been approved by the local ethics committee (349-2019-SPER-AUSLBO). Complete information about the state of project, relevant events and results will be regularly updated on the project’s webpage on ClinicalTrials.gov. The project’s results and data on the potential impact of TM in epilepsy will be disseminated on social media. A closeout meeting will be convened for the communication and dissemination of the project, highlighting its main achievements and impacts.Trial registration numberNCT04496310

Background: Evidence on whether the influenza vaccine could exacerbate immune-related adverse events, including myopericarditis (MP), in patients treated with immune checkpoint inhibitors (ICIs), is still conflicting. We explored this issue through a global real-world approach. Methods: We queried the Vaccine Adverse Event Reporting System (VAERS) and VigiBase to retrieve cases of MP in which the influenza vaccine and ICIs were recorded as suspect and were concomitantly reported. For the included cases, causality assessment and Drug Interaction Probability Scale (DIPS) algorithms were applied. Results: There were 191 and 399 reports of MP with the influenza vaccine that were retrieved (VAERS and VigiBase, respectively). No case of MP reporting the concomitant use of ICIs and the influenza vaccine was found in VAERS, while three cases of myocarditis were retrieved in VigiBase. All of the cases were unclassifiable for a causality assessment because of the lack of data concerning latency. According to the DIPS, one report was categorized as possible and two as doubtful. Conclusion: The paucity of cases coupled with the doubtful causality assessment make the potential interaction between influenza vaccines and ICIs in cancer patients negligible from clinical and epidemiological standpoints. These findings support the cardiovascular safety of the influenza vaccination, which remains strongly recommended in cancer patients, especially in the current COVID-19 era.

The purpose of this study is to characterize adverse events (AEs) of clinical interest reported with ceftolozane-tazobactam and ceftazidime-avibactam, as an aid in monitoring patients affected by severe multidrug-resistant Gram-negative infections. We queried the worldwide FDA Adverse Event Reporting System (FAERS) and performed disproportionality analysis, selecting only designated medical events (DMEs) where ceftolozane-tazobactam and ceftazidime-avibactam were reported as suspect. Serious neurological AEs were further investigated. The reporting odds ratios were calculated, deemed significant by the lower limit of the 95% confidence interval (LL95% CI) > 1. All other drugs/events recorded in FAERS and cephalosporins showing clinical evidence of neurological AEs were respectively selected as comparator for analysis of DMEs and neurotoxicity. Qualitative analysis including case-by-case assessment and deduplication was also performed. Overall, 654 and 506 reports mentioning respectively ceftolozane-tazobactam and ceftazidime-avibactam were found, with DMEs accounting respectively for 13.1% and 10.9% of cases. Agranulocytosis (N = 12; LL95% CI = 12.40) and pancytopenia (14; 6.18) emerged as unexpected AEs with ceftolozane-tazobactam, while acute pancreatitis (7; 8.63) was an over-reported unexpected DME with ceftazidime-avibactam. After deduplication, four unequivocally different cases of agranulocytosis with ceftolozane-tazobactam were retained, occurring on average after 8.8 days. Causality was probable and possible respectively in three and one case. Among neurological AEs exhibiting significant disproportionality, encephalopathy with both antibiotics and mental status changes with ceftazidime-avibactam were retained in at least three cases after deduplication. Although rare, clinicians should monitor high-risk patients (i.e. individuals affected by haematological malignances, HIV infection, or treated with concomitant myelotoxic agents) for early unexpected occurrence of agranulocytosis with ceftolozane-tazobactam.

Background: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug–drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. Methods: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. Results: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration–time curve (AUC) by 138%, 103%, and 161%, respectively. Conclusions: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.

Purpose We assessed pulmonary toxicity of cyclin-dependent kinase (CDK)4/6 inhibitors by analyzing the publicly available FDA Adverse Event Reporting System (FAERS). Methods Reports of interstitial lung disease (ILD) were characterized in terms of demographic information, including daily dose, latency, concomitant drugs known to be associated with ILD, and causality assessment (adapted WHO system). Disproportionality analyses were carried out by calculating reporting odds ratios (RORs) with 95% confidence interval (CI), accounting for major confounders, including notoriety and competition biases. Results ILD reports (N = 161) represented 2.1% and 0.3% of all reports for abemaciclib and palbocilcib/ribociclib, respectively, with negligible proportion of concomitant pneumotoxic drugs. Increased reporting was found for CDK4/6 inhibitors when compared to other drugs (ROR = 1.50; 95%CI = 1.28–1.74), and abemaciclib vs other anticancer agents (4.70; 3.62–5.98). Sensitivity analyses confirmed a strong and consistent disproportionality for abemaciclib. Higher-than-expected reporting emerged for palbociclib (1.38; 1.07–1.77) and ribociclib (2.39; 1.34–3.92) only when removing Japan reports. ILD occurred at recommended daily doses, with median latency ranging from 50 (abemaciclib) to 253 (ribociclib) days. Causality was highly probable in 55% of abemaciclib cases, probable in 68% of palbociclib cases. Conclusions Increased reporting of ILD with CDK4/6 inhibitors calls for further comparative population-based studies to characterize and quantify the actual risk, taking into account drug- and patient-related risk factors. These findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals through FAERS and other real-world data, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of CDK4/6 inhibitors when diagnosing a lung injury.

Background: Drug-induced liver injury (DILI) has been observed in patients with multiple sclerosis (MS), raising concerns on the liver safety of MS drugs. Objective: To describe DILI events with MS drugs by analyzing the FDA Adverse Event Reporting System. Methods: DILI reports were extracted and classified in overall liver injury (OLI), including asymptomatic elevation of liver enzymes, and severe liver injury (SLI). We performed disproportionality analysis by calculating adjusted reporting odds ratios (RORs) with 95% confidence interval (CI) and case-by-case evaluation for concomitant drugs with hepatotoxic potential. Results: Fampridine showed statistically significant ROR for both OLI and SLI, whereas teriflunomide and fingolimod generated solid disproportionality (ROR > 2) only for OLI (ROR, 2.31; 95% CI, 2.12–2.52; and 2.53; 2.40–2.66, respectively). Among monoclonal antibodies, only alemtuzumab generated higher-than-expected ROR for OLI (1.34; 1.09–1.65). We also detected the expected hepatotoxic potential of beta interferon and mitoxantrone. Concomitant reporting of hepatotoxic drugs ranged from 26% (dimethyl fumarate) to 90% (mitoxantrone). Conclusion: These real-world pharmacovigilance findings suggest that DILI might be a common feature of MS drugs and call for (1) formal population-based study to verify the risk of fampridine and (2) awareness by clinicians, who should assess the possible responsibility of MS drugs when they diagnose DILI.

Purpose of Review Cardiotoxicity by anticancer agents has emerged as a multifaceted issue and is expected to affect both mortality and morbidity. This review summarizes clinical challenges in the management of oncological patients requiring anticoagulants for atrial fibrillation (AF) also considering the current outbreak of the COVID-19 (coronavirus disease 2019) pandemic, since this infection can add challenges to the management of both conditions. Specifically, the aims are manyfold: (1) describe the evolving use of direct oral anticoagulants (DOACs) in AF patients with cancer; (2) critically appraise the risk of clinically important drug-drug interactions (DDIs) between DOACs and oral targeted anticancer agents; (3) address expected DDIs between DOACs and candidate anti-COVID drugs, with implications on management of the underlying thrombotic risk; and (4) characterize the proarrhythmic liability in cardio-oncology in the setting of COVID-19, focusing on QT prolongation. Recent Findings AF in cardio-oncology poses diagnostic and management challenges, also due to the number of anticancer drugs recently associated with AF onset/worsening. Oral targeted drugs can potentially interact with DOACs, with increased bleeding risk mainly due to pharmacokinetic DDIs. Moreover, the vast majority of oral anticancer agents cause QT prolongation with direct and indirect mechanisms, potentially resulting in the occurrence of torsade de pointes, especially in susceptible patients with COVID-19 receiving additional drugs with QT liability. Summary Oncologists and cardiologists must be aware of the increased bleeding risk and arrhythmic susceptibility of patients with AF and cancer due to DDIs. High-risk individuals with COVID-19 should be prioritized to target preventive strategies, including optimal antithrombotic management, medication review, and stringent monitoring.

Introduction: After a safety warning was issued for a risk of muscular injury associated with dipeptidyl peptidase-4 (DPP-4) inhibitor use, especially when co-prescribed with statins, spontaneous reporting analyses provided conflicting results. Objective: The aim of this study was to investigate the association between DPP-4 inhibitor use and the risk of muscular injury in individuals with type 2 diabetes mellitus using statins or fibrates. Methods: We conducted a nested case-control study amongst a cohort of individuals with type 2 diabetes using statins or fibrates, identified from a nationwide French health insurance database (2009–2014). Cases of serious muscular injury were defined as subjects hospitalized for rhabdomyolysis or myopathy, or for whom testing for myoglobin or creatine phosphokinase followed by a change in statin or fibrate prescription (dose decrease, treatment switch, or stop) was identified. Up to ten controls were matched to each case according to sex, age, and type of lipid-lowering agent. Associations between DPP-4 inhibitor use and serious muscular injury were estimated using a multivariate conditional logistic regression model, providing odds ratios (ORs) adjusted for alcoholism, chronic renal failure, hypothyroidism, and number of concomitant drugs. Results: Within the 35,117 individuals with type 2 diabetes mellitus constituting the source cohort, 437 statin-user cases were identified who were matched to 4358 statin-user controls. Similarly, 54 fibrate-user cases were identified who were matched to 540 fibrate-user controls. The adjusted OR for DPP-4 inhibitor use and serious muscular injury was estimated at 1.0 (95% confidence interval [CI] 0.7–1.2) in statin users and 0.8 (95% CI 0.4–1.9) in fibrate users. Conclusion: In this study, DPP-4 inhibitor use was not associated with an increased risk of serious muscular injury among patients with type 2 diabetes mellitus using statins or fibrates.

Not available

Introduction The European Medicines Agency has suspended the use of ulipristal acetate (UPA) in the treatment of uterine fibroids and is reassessing its association with a risk of liver injury. Objectives Our objectives were to characterize the post-marketing reporting of drug-induced liver injury (DILI) with UPA and investigate the underlying pharmacological basis. Methods We queried the worldwide FDA Adverse Event Reporting System and performed a disproportionality analysis, selecting only hepatic designated medical events (DMEs) where UPA was reported as suspect. The reporting odds ratios (RORs) were calculated, and we considered a lower limit of the 95% confidence interval (LL95% CI) > 1 as significant. Physiochemical/pharmacokinetic features were extracted to assess the risk of hepatotoxicity by applying predictive DILI risk models. Mifepristone and leuprolide were selected as comparators. Results A significantly higher proportion of liver disorders was reported for UPA than for mifepristone (2.9 vs. 0.8%; p

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of β2glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the in vivo pro-coagulant effect of two groups of 5 sera IgG each reacting selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy, and vascular deposition of β2glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-β2glycoproteinI antibodies served as controls. All the anti-domain 1-positive IgG exhibited potent pro-coagulant activity while the anti-domain 5-positive and the negative control IgG failed to promote blood clot and vessel occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound β2glycoproteinI while being able to interact with fluid-phase β2glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit a thrombogenic effect in vivo, and the interaction of these antibodies with circulating β2glycoproteinI suggests their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining “really at risk” patients for more appropriate treatments to avoid recurrences and disability.

Background This case report describes a patient with pericarditis likely attributed to influenza vaccination (positive rechallenge), with a literature review. Case presentation A 87-year old patient developed pericarditis after influenza vaccination, with acute chest pain, without ECG abnormalities or increased cardiac enzyme levels. Echocardiogram showed moderate pericardial effusion. Recovery was obtained through steroids One year later, few days after re-immunization, the patient experienced the same symptoms and was admitted to hospital with diagnosis of recurrence of pericarditis with severe pericardial effusion, again treated with steroids. Other possible causes were ruled out and the cardiologist recommended against influenza vaccinations in the future; the patient did not experience recurrence of pericarditis in the following 6 years. Cases of pericarditis following influenza immunization in the literature were also reviewed. Conclusions Pericarditis following immunization for influenza is very rarely reported in the literature. In a few cases, influenza vaccination seems likely responsible. We suggest considering recent immunization in patient’s history as part of the differential diagnosis in elderly with chest pain.

The recent position paper of the European Society of Cardiology (ESC) on cardiovascular toxicity of cancer treatments has attracted considerable interest by healthcare professionals, since it is the first concrete help in the difficult task of monitoring and approaching cardiovascular side effects of anticancer treatments. The ESC expert opinion was not intended as a clinical practice guideline; however, it reports major cardiovascular complications grouped into nine categories, addressing current clinical strategies for prevention and mitigation. In this point of view, we discuss key challenges emerging from critical appraisal of the ESC position paper: (1) the wide spectrum of cardiovascular toxicities associated with oncological drugs, focusing on targeted agents, (2) managing strategies in patients with cardiac implantable devices, (3) the underappreciated (but emerging) immune-related cardiovascular toxicities of checkpoint inhibitors, which may also result in severe heart failure and fulminant myocarditis, (4) the evolving role of anticoagulation in oncology, and the evidence supporting (or not) the use of direct-acting oral anticoagulants in cancer-associated thrombosis.

BACKGROUND: Approved in 2006, human papillomavirus (HPV) vaccines were initially targeted for girls aged 9-14 years. Although the safety of these vaccines has been monitored through post-licensure surveillance programmes, cases of neurological events have been reported worldwide. PURPOSE: The present study aimed to assess the risk of developing demyelination after HPV immunization by meta-analysing risk estimates from pharmacoepidemiologic studies. DATA SOURCES: A systematic review was conducted in Medline, Embase, ISI Web of Science and the Cochrane Library from inception to 10 May 2017, without language restriction. STUDY SELECTION: Only observational studies including a control group were retained. Study selection was performed by two independent reviewers with disagreements solved through discussion. DATA EXTRACTION: This meta-analysis was performed using a generic inverse variance random-effect model. Outcomes of interest included a broad category of central demyelination, multiple sclerosis (MS), optic neuritis (ON), and Guillain-Barre syndrome (GBS), each being considered independently. Heterogeneity was investigated; sensitivity and subgroup analyses were performed when necessary. In parallel, post-licensure safety studies were considered for a qualitative review. This study followed the PRISMA statement and the MOOSE reporting guideline. DATA SYNTHESIS: Of the 2863 references identified, 11 articles were selected for meta-analysis. No significant association emerged between HPV vaccination and central demyelination, the pooled odds ratio being 0.96 [95%CI 0.77-1.20], with a moderate but non-significant heterogeneity (I(2)=29%). Similar results were found for MS and ON. Sensitivity analyses did not alter our conclusions. Findings from qualitative review of 14 safety studies concluded in an absence of a relevant signal. LIMITATIONS: Owing to limited data on GBS, no meta-analysis was performed for this outcome. CONCLUSION: This study strongly supports the absence of association between HPV vaccines and central demyelination.

Introduction: Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs. Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs). Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations.

ObjectiveSodium glucose cotransporter-2 inhibitors (SGLT2i) exert cardiorenal protection in people with diabetes. By inducing glycosuria, SGLT2i predispose to genital infections. In addition, rare occurrence of Fournier’s gangrene (FG) has been reported. We aimed to investigate such association through the U.S. Food and Drug Administration (FDA) adverse event (AE) reporting system (FAERS).Research design and methodsWe mined the FAERS up to 2018q3 (before FDA warning about SGLT2i-associated FG) to retrieve reports including FG as an AE and SGLT2i as suspect or concomitant drugs, and calculated proportional reporting ratios (PRR).ResultsWe retrieved 47 cases of FG and 17 cases of other severe AEs of the genital area associated with SGLT2i. Patients with FG were ~10 years older than those with other severe genital AEs. Overall, 77% occurred in men. Three patients were concomitantly treated with systemic immunosuppressive drugs. Increased reporting frequency emerged for SGLT2i compared with other drugs, with a PRR ranging from 5 to 10. The disproportional reporting of FG with SGLT2i remained robust and consistently significant when restricting to the period when SGLT2i were available, to reports filed for glucose-lowering medications or for drugs with the diabetes indication, and after refining the definition of FG. FG was disproportionally associated with psoriasis and with the combination of immunosuppressants and SGLT2i.ConclusionsAlthough causality cannot be demonstrated, SGLT2i may predispose to FG and other severe genital AEs. Since the use of SGLT2i is expected to increase significantly, clinicians should be aware of these severe, although rare, AEs and their predisposing factors.

BACKGROUND: An increasing number of reports indicates that vaccines against influenza may interact with specific drugs via drug metabolism. To date, actual impact of vaccine-drug interactions observed in the real world clinical practice has not been investigated. METHODS: From VAERS and VigiBase, we collected Adverse Event Following Immunization (AEFI) reports for individuals receiving vaccines against influenza recorded as suspect and selected cases where predictable toxicity was recorded with oral anticoagulants, antiepileptics and statins (i.e. hemorrhages, overdosage and rhabdomyolysis, respectively). We applied AEFI and Drug Interaction Probability Scale (DIPS) Algorithms to assess causality of drug-vaccine interactions. RESULTS: 116 AEFI reports submitted to VAERS and 83 from Vigibase were included in our analysis; antiepileptics and statins were related to the highest number of indeterminate/consistent (93.7%; 65.3%) and possible/probable (50%; 57.7%) cases according to the AEFI and DIPS, respectively. The majority of cases occurred within the first week after vaccine administration (5-7 days). CONCLUSION: The relative paucity of detected interactions does not impact on the benefit of the vaccination against influenza, which remains strongly recommended; this does not exclude that closer monitoring for selected patients exposed to concomitant chronic pharmacological therapies and affected by predisposing factors may be useful.

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. Areas covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. Expert opinion: The new 5-HT3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.

Introduction Pharmacotherapy used to treat type 2 diabetes mellitus (T2DM) is facing a paradigm shift in clinical practice with recent cardiovascular (CV) outcome trials having a substantial impact on drug prescription with treatment having a more tailored approach. In patients with T2DM, the issue of chronic liver disease is multifaceted. However, a clinical evidence is emerging on the beneficial effect of antidiabetic medications on nonalcoholic fatty liver disease (NAFLD). Areas covered The authors provide a synopsis on the current and upcoming pharmacotherapy for NAFLD, including the challenges with their development, focusing on drugs for T2DM. Clinical data on the potential benefits and safety issues are assessed with the aim of proposing an individualized algorithm for patient management. Both MEDLINE and ClinicalTrials.Gov are used to derive the relevant information. Expert opinion Considering the pivotal role of insulin resistance in NAFLD, insulin sensitizers should be the treatment of choice. Accordingly, pioglitazone is the only drug with a significant effect on liver fibrosis, the driver of disease progression and long-term outcome. Among new glucose-lowering drugs, glucagon-like-peptide 1 receptor agonists or sodium-glucose cotransporter type 2 inhibitors have shown positive effects in phase II studies and are qualifying as potential candidates for NAFLD treatment in diabetes.

Background In systemic sclerosis (SSc), autoantibodies provide the most reliable tool to predict disease subset and the pattern of organ involvement. Objectives Consistently with the diagnostic and prognostic role of these autoantibodies, our group has previously demonstrated that immune complexes (ICs) containing scleroderma specific autoantibodies elicit a pro-inflammatory and pro-fibrotic signalling cascade in healthy skin fibroblasts, thus contributing to SSc aetiopathogenesis. In addition, we showed that SSc-ICs upregulate Toll-like Receptors (TLRs) and that pre-treatment with DNase and RNase prevent SSc-IC-mediated effects in fibroblasts, thus suggesting that SSc-ICs might engage TLRs via their nucleic acid components. The objective of the present study is to investigate the pathogenicity of SSc-ICs in endothelial cells (ECs). Methods Human umbilical vein ECs (HUVECs) have been isolated from umbilical vein and cultured in adequate conditions. ICs have been purified from sera of SSc patients bearing different autoantibody specificities (antibodies against centromeric proteins, DNA topoisomerase I, RNA polymerase and Th/To), patients with systemic lupus erythematosus (SLE), primary anti-phospholipid syndrome (PAPS) or healthy controls using polyethylen glycol precipitation. Cell cultures have been incubated with pathologic and control ICs and TLR3 [Poly(I:C)] and TLR4 (LPS) agonists. Several parameters have been assessed: mRNA levels of endothelin-1 (ET-1) and type I interferons (IFN-α and IFN-β) have been investigated by real-Time PCR; ICAM-1 expression has been evaluated by cell-ELISA and the secretion of IL-6, IL-8, tumour growth factor (TGF)-β1 and Pro-CollagenIα1 in culture supernatants has been measured by commercial ELISA kits. The involvement of intracellular signalling pathways culminating with the activation of p38MAPK has been assessed. Furthermore, skin fibroblasts from healthy controls were stimulated with supernatants from HUVEC incubated with scleroderma and control ICs. The mRNA levels of collagen (col)Iα1 and matrix metalloproteinases (MMP)-1 and the secretion of TGF-β1 were evaluated in fibroblasts. Statistical analysis was performed comparing ICs from SSc and disease controls to NHS-ICs. Results Stimulation of HUVEC with scleroderma and control ICs resulted in the modulation of study mediators, as detailed in Table 1. When skin fibroblasts from healthy controls were stimulated with supernatants from HUVEC incubated with scleroderma and control ICs, we observed a significant modulation of mediators (Table 2). Conclusion These data provide the first demonstration of the pathogenicity of ICs isolated from scleroderma patients with different autoantibody specificities in ECs. According to our preliminary data, the activation of ECs induced by SSc-ICs might ultimately lead to a pro-fibrotic phenotype in healthy skin fibroblasts. SSc-ICs might thus be at the crossroad of scleroderma pathogenesis, contributing to the recruitment of the many cells involved in disease onset. Reference [1] Raschi E, Chighizola CB, Cesana L, et al. Arthritis Res Ther2018;20:187 Disclosure of Interests Cecilia Chighizola Speakers bureau: Inova Diagnostics, Daniela Privitera: None declared, Maria Orietta Borghi: None declared, Pier Luigi Meroni Consultant for: Inova, Thermofisher, Teofarma, Elena raschi: None declared

To estimate the risk of sudden cardiac death (SCD) or sudden unexpected death (SUD) related to individual antipsychotics, a meta-analysis of observational studies was performed. Adjusted odds ratio (OR) of SCD/SUD with 95% confidence intervals (CI) were extracted and pooled; heterogeneity was studied using Q statistic and I(2) index, and its potential causes (e.g., hERG blockade potency) explored using meta-regression. Two cohort (740,306 person-years) and four case-control (2,557 cases; 17,670 controls) studies, investigating nine antipsychotics, were included. Compared with nonusers, the risk was increased for quetiapine (OR = 1.72, 95% CI: 1.33-2.23), olanzapine (OR = 2.04, 1.52-2.74), risperidone (OR = 3.04, 2.39-3.86), haloperidol (OR = 2.97, 1.59-5.54), clozapine (OR = 3.67, 1.94-6.94), and thioridazine (OR = 4.58, 2.09-10.05). Heterogeneity was found (Q = 20.0, P = 0.01; I(2) = 60.0%), and the increasing mean hERG blockade potency (P = 0.01) accounted for 43% of this. The SCD/SUD risk differed between individual antipsychotics, and mean hERG blockade potency could be an explanatory factor. This should be considered when initiating antipsychotic treatment.

Only a small fraction of drugs widely used in neonatal intensive care units (NICU) are specifically authorized for this population. Even if unlicensed or off-label use is necessary, it is associated with increased adverse drug reactions, which must be carefully weighed against expected benefits. In particular, renal damage is frequent among preterm babies, and is considered a predisposing factor for the development of chronic kidney disease in adulthood. Apart from specific conditions affecting premature neonates (e.g. respiratory distress syndrome, perinatal asphyxia), drugs play an important role in impairing renal function because of well-known nephrotoxicity and/or interaction with renal developmental factors. From a review of the available studies on drug use in NICU patients, we identified and described the most commonly administered drugs that are correlated to renal damage. Early detection of kidney injury is becoming an essential aspects for clinicians because of the limited number of biomarkers applicable in the neonatal population. Postnatal changes of biochemical processes that influence pharmacokinetic and pharmacodynamic aspects need to be further investigated in order to better understand the mechanisms of drug toxicity in this population. The most promising strategies for dose adjustment and therapeutic schemes are discussed. The purpose of this review was to describe current knowledge on drug use among premature babies and their implication in kidney injury development, as well as to highlight available strategies for early detection of renal damage. ispartof: Drug Safety vol:38 issue:6 pages:535-551 ispartof: location:New Zealand status: published

Aim: To characterize cases of myocarditis (MC) and pericarditis (PC) recorded in the Vaccine Adverse Event Reporting System (VAERS). Methods: Cases were extracted from VAERS (2011–2015) and assessed for causality using standardized WHO algorithm. Disproportionality analysis was performed through reporting odds ratio (ROR) with 95%CI. MEDLINE was also searched. Results: In VAERS, 199 cases of MC or PC were collected, among which 149 reported smallpox vaccine. The remaining were: 15 cases in ‘YOUNGER GROUP’ (YG; 18 years old). Main reported vaccines were against Human Papilloma Virus (n = 6) in YG and influenza (n = 16) in OG. Causality always resulted “undeterminate” for YG, whereas either “undetermined” (30 cases) and “correlated” (3 cases) for OG. Statistically significant ROR was found in YG for meningococcal vaccine (ROR = 3.55; 95%CI = 1.23–10.24) and in OG for thyphoid vaccine (11.13; 7.73–16.03), Japanese encephalitis vaccine (8.54; 2.7–27.01), anthrax (25.5; 18.8–34.5), and, as expected, smallpox (71.88; 49.25–104.89). In MEDLINE, 91 articles were found: positive/possible causality was frequently reported. Conclusions: MC and PC after immunization appear extremely rare; only in very few cases can a role of vaccine be actually identified. Signals for vaccines against typhus, Japanese encephalitis, anthrax and meningococcus warrant monitoring.

Direct-acting oral anticoagulants (DOACs), by virtue of pharmacological properties perceived as innovative, are changing the therapeutic scenario of patients requiring short- and long-term anticoagulation. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirms that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy, effectiveness and unequivocally documents a clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (AF) and venous thromboembolism. The following issues are attracting considerable clinical interest: (a) identifying specific subpopulations of patients with AF most likely to benefit from one of these agents (the so-called tailored therapy), and (b) expanding therapeutic indications in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk–benefit profile of DOACs, as compared to VKAs or heparins, is still incompletely characterized. In cardiology, the challenging task of selecting a suitable or even the most appropriate DOAC for patients with AF and a particular phenotype prompted experts to provide suggestions based on careful review of subgroups of patients from pivotal RCTs. However, in the past few months, variegated multicenter trials have been published (RE-CIRCUIT, PIONEER-AF-PCI, GEMINI-ACS-1), with potential influence on clinical practice. Therefore, this review aims to update the latest evidence on the evolving therapeutic uses of DOACs in the cardiovascular area, addressing potential impact for clinicians.

Aims Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). Methods Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried. Results From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. Conclusions The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.

Direct-acting oral anticoagulants (DOACs) were claimed to cause a potential paradigm shift in the therapeutic scenario of patients requiring short- and long-term anticoagulation, by virtue of their pharmacological properties, perceived as innovative. The evidence gathered so far (from pre-approval pivotal trials to real-world post-marketing observational data) consistently confirmed that DOACs are overall comparable to vitamin-K antagonists (VKAs) in terms of safety, efficacy and effectiveness and unequivocally documented a consistent and clinically relevant reduced risk of intracranial bleeding in the settings of non-valvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). Interestingly, two parallel paths can be identified in the current research scenario: A) in the aforementioned consolidated therapeutic indications, an innovative approach is directed towards tailored treatment strategies, to identify patients most likely to benefit from one of the different anticoagulant drugs, in particular subpopulations at increased risk of adverse events (e.g., bleeding); B) in unconventional settings, DOACs are gaining interest for potential use in emerging diseases characterized by arterial and venous thromboembolic risk. In these scenarios, the risk-benefit profile of DOACs, as compared to VKAs or heparins, is less defined. The aim of this review is to critically assess the body of evidence underlying emerging therapeutic uses of DOACs (e.g., heparin-induced thrombocytopenia, anti-phospholipid antibody syndrome), including evolving issues in special populations (e.g., patients with VTE and cancer or cirrhosis). This will be achieved by analyzing the strength (i.e., systematic reviews, randomized clinical trials, observational studies, case report/series) and consistency (i.e., concordance) of both published and unpublished evidence registered in major public repositories.

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Acute kidney injury (AKI) is frequently diagnosed in the neonatal population, especially in those admitted to intensive care units, and poses several challenges for clinicians mainly because of difficulties in timely identification of renal impairment and the need to administer drugs with potential nephrotoxicity. In this context, research on biomarkers is growing for their implication in the early detection of renal damage and their higher sensitivity in monitoring renal activity, but also as an important tool for drug development. Areas covered: We described the tools currently used to detect renal damage in neonatal settings, their limits and applicability, as well as the role of drugs on renal toxicity occurrence. Subsequently, we discuss current knowledge on new biomarkers for the detection of kidney injury and drug-induced kidney injury in neonates, and the qualification programs developed by regulatory agencies for biomarkers intended as tools in drug development. Expert opinion: Some molecules are emerging as potential biomarkers for early detection of AKI: promising data has demonstrated higher sensitivity and accuracy compared with tools currently used in the clinical setting. In addition, novel techniques (e.g. high power magnetic resonance imaging) to assess long-term consequences of AKI in neonates are in early steps of development.

Background Apart from the underlying cardiovascular (CV) risk associated with migraine, both triptans and ergotamines can induce vasoconstriction and potentially increase the risk of serious ischemic events. Because of the low frequency of such events in eligible patients, randomized controlled trials are not exhaustive to assess the drug-related CV risk. Observational studies are, therefore, an essential source of information to clarify this matter of concern. Aim The aim of this study was to systematically review the available published observational studies investigating the risk of serious CV events in triptan or ergotamine users, as compared to unexposed migraineur controls. Methods We systematically searched MEDLINE and EMBASE electronic databases for cohort or case-control studies up to December 1, 2013. Studies retrieved from CDSR, DARE and HTA databases of the Cochrane Library were used for snowballing. Studies investigating the risk of any CV outcome in patients with a migraine diagnosis and exposed to triptans or ergotamines were considered for inclusion. Selection of studies, data extraction, and risk of bias assessment were conducted independently by two reviewers. Pooled odds ratios (ORs) with 95% confidence interval (95% CI) were computed using a random-effects model for studies and outcomes judged eligible for quantitative data synthesis. Results From a total of 3370 citations retrieved, after duplicate removal and screening, only four studies met the inclusion criteria (three nested case-control analyses and one retrospective cohort study). These studies investigated the risk of different CV outcomes associated with either the recency or the intensity of exposure to the studied drugs. As for the intensity of use, the pooled OR of serious ischemic events was 2.28 (95% CI 1.18–4.41; I2 = 0%) for ergotamine use (two studies), whereas for triptans (three studies) it was 0.86 (95% CI 0.52–1.43; I2 = 24.5%). Recent use of ergotamines was not significantly associated with any CV outcome (only one available study). Two studies investigated the risk of stroke related to recent triptan use: the first study reported an OR of 0.90 (0.64–1.26), and the second one suggested an increased risk of 2.51 (1.10–5.71). In this case, because of the high degree of heterogeneity, results were not pooled. Conclusions To date, few comparative observational studies have investigated the CV safety of migraine-specific drugs in clinical practice. Evidence gathered here suggests that intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues, although no firm conclusions can be drawn. In particular, evidence on stroke risk is conflicting. However, if an increase of the absolute stroke risk in recently exposed patients does actually exist, it must be small. Overall, residual uncontrolled confounding factors reduce the confidence in the risk estimates collected from the included studies. Further investigations are needed to better define the risk for rare but serious CV events related to triptan and ergotamine use for treatment of migraine.

PURPOSE: Data mining in spontaneous reporting databases generates large numbers of signals of disproportionate reporting (SDRs) that need to be prioritised for assessment. The pharmacological relevance of drug-event associations is not considered in SDR prioritisation algorithms. This aimed to propose and test a pharmacological score for SDR prioritisation. METHODS: The Pharmacological Score for SDRs Prioritisation (PS-SP) was developed using a Delphi approach. An expert group agreed that PS-SP should include general criteria concerning SDRs and criteria concerning pharmacological relevance, and that criteria should be weighted for their risk representation. Once defined, the PS-SP was tested for prioritisation of SDRs for extrapyramidal syndrome in the French Pharmacovigilance database; the SDR classification was compared to that obtained using a traditional disproportionality approach. RESULTS: For a given drug, the general criteria retained were the reporting rate of the adverse drug reaction (ADR) and value of the 95% confidence interval (CI) lower boundary of the Reporting Odds Ratio (ROR). Pharmacological criteria consisted of the ADR reporting rate without concomitant at-risk drugs or those indicated for ADR treatment, and the value of the ROR 95% CI lower boundary as estimated in the subset of reports concerning drugs from the same therapeutic and then pharmacological class. Compared with traditional disproportionality, PS-SP prioritised specific drugs within congeners: metoclopramide, indoramin, and trimetazidine appeared as outliers within their classes; conventional antipsychotics had higher prioritisation than atypical antipsychotics. CONCLUSION: The pilot evaluation of PS-SP performed in extrapyramidal syndrome advocates for the use of pharmacological criteria in SDR prioritisation algorithms.

INTRODUCTION: Lubiprostone acts locally (apical membrane of human intestinal epithelial cells) as a highly selective type-2 chloride channel activator. It was approved in the USA for chronic idiopathic constipation (January 2006) and in women aged ≥ 18 years suffering from irritable bowel syndrome with constipation (IBS-C) (April 2008). So far, the only other pro-secretory medication approved in IBS-C and currently available in USA and Europe (since August and November 2012, respectively) is linaclotide. AREAS COVERED: This review outlines the regulatory history, pharmacokinetic, pharmacodynamic and safety data in the treatment of IBS-C with a European perspective. It is based on publicly available data, namely, published literature, drug labels and the FDA's spontaneous reporting system. EXPERT OPINION: Although interesting pharmacodynamic data suggest that lubiprostone may have additional mechanisms of action, its beneficial effects in IBS-C must be confirmed in the actual clinical scenario taking into account the new version of European Medicines Agency's guideline. This is especially important with regard to duration of studies (recommended to be at least 6 months) to adequately assess long-term sustained efficacy, withdrawal, rebound and safety. Further research is warranted in uncertain areas (i.e., males, pediatric and elderly patients). On the basis of current data, it is still too early to draw definite conclusions on the overall risk-benefit balance for IBS-C.

Background Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82–84.60), cyamemazine (11; 15.48, 6.87–34.91), and olanzapine (189; 7.74, 6.45–9.30). Conclusions This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk. Electronic supplementary material The online version of this article (doi:10.1007/s40264-013-0032-z) contains supplementary material, which is available to authorized users.

Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), have entered the market in 2008 with the expected breakthrough potential of circumventing limitations related to treatment with vitamin K antagonists (eg, warfarin) by virtue of their pharmacological properties. Although data derived from premarketing randomized clinical trials have largely demonstrated the clinical benefit of DOACs, especially in terms of reduced risk of intracranial bleeding, it is important to monitor the safety in the postmarketing phase, which better reflects real-world patients with comorbidities and polypharmacotherapy, in order to assess the actual risk-benefit profile. In this critical review, we aimed to evaluate the evidence on the latest debated safety issues. In the first section, we will discuss: 1) the need for pharmacovigilance (ie, the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems in the real-world setting), and 2) the importance of properly interpreting postmarketing data to avoid unnecessary alarm. In the second section, emerging and debated safety issues potentially associated with the use of DOACs in the postmarketing setting will be assessed: 1) the potential coronary risk (which emerged during the preapproval period); 2) the occurrence of liver injury (a risk undetected in clinical trials and highlighted by case reports or series); and 3) the potential for renal damage (a still unclear safety issue). It is anticipated that hepatic and renal issues still require dedicated postauthorization safety studies to ultimately assess causality.