Pharmacovigilance Risk Assessment Committee Research Articles

The “Fluad Case” in Italy: Could it have been dealt differently?

ABSTRACTDuring the influenza vaccination campaign 2014–2015, the reporting of 3 deaths within 48 hours of vaccination with Fluad brought the Italian Medicines Agency (AIFA) to pronounce the withdrawal of 2 batches of vaccine, based on the precautionary principle. Investigations by the Italian National Institute of Health, and by the Pharmacovigilance Risk Assessment Committee (PRAC), the committee at the European Medicines Agency (EMA) responsible for monitoring and assessing the safety profiles of human drugs, concluded that there was a lack of causality between the reported deaths and the vaccines administered. However, the media impact of the decision taken by AIFA, resulted in a lower influenza vaccination coverage compared with the previous years. The aim of our study was to identify possible critical points that may have led to a non-perfect management of the event. A review of the regulatory framework in place was performed, with a particular focus on the Guidelines on Good Pharmacovigilance Practices developed by the EMA to facilitate the signal management process. The management of reports involves the following steps: signal detection, its validation and confirmation, analysis and prioritization, assessment, recommendations for action and the exchange of information. In our opinion, both the signal detection phase and the phase of validation have been critical: the withdrawal of vaccine batches is possible even in case of a single suspected serious adverse reaction. However, aspects such as the biological plausibility, the presence of potential alternative causes and previous awareness should also be considered. Furthermore, the number of reported deaths was consistent with the expected background mortality rate in the vaccinated cohort. The disproportionate media coverage given to the AIFA decision resulted in a reduced vaccine confidence in the general population and in a decreased immunization coverage. Improving the communication on vaccine safety issues is crucial at this stage to restore a climate of trust in this powerful tool for primary prevention.

Real-World Safety Experience for Short-Acting Recombinant Human Granulocyte Colony-Stimulating Factor

Introduction: Marketed therapeutic products are subject to periodic benefit-risk evaluation reports (PBRERs), which provide comprehensive worldwide safety assessments and benefit-risk analyses. The short-acting recombinant human granulocyte colony-stimulating factor (rG-CSF) is known as filgrastim (Tevagrastim®, Ratiograstim®, Biograstim®) in Europe (approved in 2008) and tbo-filgrastim (Granix®) in the United States (approved in 2012). In the United States, Granix is indicated for reducing the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Here, we present the accumulated safety data from the PBRER for the rG-CSFs collected in a 3-year period from the 52 countries in which the product was registered.Methods: Cumulative data were collected since initial approval in 2008. This PBRER period includes data captured from September 16, 2012, to September 15, 2015. Data were collected from spontaneous reports submitted by healthcare professionals and consumers, the scientific literature, competent authorities, and solicited case reports. Adverse reactions were categorized by system organ class (SOC), source, and seriousness. Pharmacovigilance in Europe requires screening of all adverse reaction reports and antibody assessment for cases of suspected immunogenicity. Safety concerns identified by the originator during the use of filgrastim were described in the risk management plan (RMP; version 8; dated 14 May 2012).Results: During this PBRER period, the estimated exposure to the rG-CSFs was ~4,314,994 patient-days. As of September 15, 2015, the estimated cumulative exposure to the rG-CSFs was ~8,741,835 patient-days over 7 years. Estimated cumulative exposure to the rG-CSFs in clinical trials were 190 patient-days in healthy subjects and 22,099 patient-days in patients with cancer. The global safety database processed 561 rG-CSFs case reports from initial product approval through September 15, 2015 (~9 years), including 339 (60%) from this PBRER period (~3 years). Postmarketing data sources cumulatively reported 1133 adverse reactions, 702 (62%) from this PBRER period. The most common adverse events (AEs) reported during this PBRER period per SOC are summarized in the figure. The most frequently reported serious AEs associate with general disorders and administration site conditions during this period were pyrexia (11 reports) and ineffective drug (8). Reports of serious bone pain (3 reports), back pain (2), muscular weakness (2), musculoskeletal pain (2), and myalgia (2) were also received during this period. The most common AEs associated with serious skin conditions were pruritus and urticarial (5 reports each). Two additional safety concerns (capillary leak syndrome [CLS] and cytokine release syndrome [CRS]) were identified by the originator during the use of filgrastim and were subsequently added to the RMP based on recommendations from the Pharmacovigilance Risk Assessment Committee. As of September 15, 2015, one report of CLS and no reports of CRS have been received. Overall, reported cases of immunogenicity showed no impact on efficacy or pharmacokinetics/ pharmacodynamics of the rG-CSFs. Updated data will be presented at the conference as available.Conclusions: No significant changes in the safety or risk-benefit profiles were identified for the rG-CSFs relative to other filgrastim products during this reporting period, and reported cases of immunogenicity showed no clinically relevant impact. [Display omitted] DisclosuresAbboud:Teva: Speakers Bureau; Alexion, Baxalta, Pharmacyclics, Takeda, Cardinal Health: Honoraria; Merck, Teva, Novartis, Pfizer, Seattle Genetics: Research Funding; Gerson and Lehman Group (GLG): Consultancy. Lang:Teva ratiopharm: Employment. Lammerich:Teva ratiopharm/Teva Pharmaceuticals, Inc.: Employment. Buchner:Merckle GmbH member of TEVA Group: Employment; Teva Pharmaceuticals, Inc.: Equity Ownership. Liu:Teva Pharmaceuticals, Inc.: Employment. Mueller:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.

Controversial Effects of Exogenous Testosterone on Cardiovascular Diseases.

The use of testosterone (T) among men aged 40 years or older was increased more than 3 times from 0.81% in 2001 to 2.91% in 2011. Until recently, the majority of the studies did not show any increased cardiovascular (CV) risk by using T in male patients with hypogonadism. What is more, some studies had observed a protective effect of using T against CV diseases. However, in 2010, a randomized clinical trial (RCT) was intended to study the advantage of T gel in older men with limitations in mobility; the study was stopped due to unexpected high prevalence of CV adverse outcome. These findings were confirmed by 2 other studies published in November of 2013 and January of 2014. Consequently, the Food and Drug Administration (FDA) had announced in January 2014 that it will reassess the safety of those treatments. Meanwhile, the agency had not reached to a definitive conclusion that FDA-approved testosterone therapy raises the risk of stroke, heart attack, or death. A report released in the broadcast of the NBC Nightly News in September of this year that the FDA says "there's little evidence that T boosting drugs taken by millions of American men are actually effective." NBC notes that the agency also pointed out that it was not convinced that they carry serious risk either. "The condition has been marketed as low 'T', and the medications are offered to help with low sex drive and fatigue among some men," notes NBC. The European Medicines Agency EMA's Pharmacovigilance Risk Assessment Committee has also responded to the concern of potential CV adverse outcomes associated with the use of T, and they have concluded in their October meeting of this year that the use of T in men who do not produce enough T raises the risk of heart diseases. In our review, we highlighted the association between exogenous T and major adverse CV outcomes. Additionally, we focused on the interplay between exogenous T and some endocrine abnormalities such as diabetes mellitus type 2, metabolic syndrome, dyslipidemia, and obesity.

Geographical variation in reporting Interstitial Lung Disease as an adverse drug reaction: findings from an European Medicines Agency analysis of reports in EudraVigilance.

Clinically, interstitial lung disease (ILD) is a heterogeneous group of over 150 respiratory disorders. In the context of its signal evaluation work, the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has seen geographic clustering of case reports of ILD from Japan. To explore this further, EudraVigilance (EV), the EMA's database of adverse drug reactions (ADRs), was analysed. The results have been used to inform on implications for pharmacovigilance including signal detection and evaluation activities. EV was queried for reports of respiratory ADRs coded using MedDRA for the period 1994-2014 for all medicinal products. Descriptive statistics and non-parametric (chi-square) independence tests were produced to compare reporting of ILD from Japan versus the rest of the world. As of 31 December 2014, there were 26 551 case reports of ILD in EV of which 17 526 (66%) originated in Japan. The reporting rate of ILD for Japan has been consistently higher over the period. The odds that a case report from Japan in EV refers to ILD is OR = 20.7, 95% CI 20.2, 21.3 (p < 0.001), compared to OR = 0.60, 95% CI 0.54, 0.67 (p < 0.001) for pulmonary fibrosis. A geographic imbalance between Japan and the rest of the world in reporting respiratory ADRs as ILD is confirmed. Consequently, the PRAC has developed approaches to address this in relation to signals of ILD it assesses to allow for more targeted risk minimisation including updates to the product information in the EU setting. Copyright © 2016 John Wiley & Sons, Ltd.

Changes to protocol in the regulation of adverse drug reactions – historical and current European view

AbstractAdverse drug reactions (ADRs) are an inevitable part of medication use. During clinical trials, limited information was gained on drug safety. After marketing authorization (MA), more safety data is available as more patients use the drug. Major changes in drug regulation came after drug disasters, like with sulphanilamide elixir or thalidomide use. In recent history, withdrawal of rofecoxib has demonstrated the importance of post-marketing safety monitoring. Subsequently, legislation on drug safety changed both in the United States (US) and in the European Union (EU), becoming simplified and more comprehensive. New EU legislation was implemented in 2012 and has broadened ADR definition to medication errors and overdoses. In the EU, the Pharmacovigilance Risk Assessment Committee (PRAC) has been formed within the European Medicines Agency (EMA), regulating all aspects of drug safety. Referral procedures enable a thorough scientific analysis on all issues of medication safety. In both the US and th...

Pharmacovigilance in Europe: Place of the Pharmacovigilance Risk Assessment Committee (PRAC) in organisation and decisional processes

The new European legislation that came into force in July 2012 reinforced the organisation of pharmacovigilance by setting up a committee in charge of risk assessment for medicines, the Pharmacovigilance Risk Assessment Committee (PRAC). The PRAC has a remit covering the assessment of all aspects of the safety and the risk management of medicinal products for human use in the European Union. It deals with issues regarding pharmacovigilance signals, the periodic evaluation of benefit/risk reports from marketing authorization holders (MAH), risk management plans, post-marketing studies, variations or renewals of marketing authorisations, management of under surveillance drugs lists, inspections for pharmacovigilance reasons and audits of pharmacovigilance systems. The PRAC works with the pharmacovigilance systems of the European Member States, which draw up evaluation reports. These evaluations are circulated and discussed by Member States so as to issue recommendations, which serve as a basis for other European medicines committees, the Committee for Medicinal Products for Human Use (CHMP) or the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) which then give their opinion. The final decision, which applies to all Member States and to the concerned MAH, lies with the European Commission (EC). This decisional procedure thus rests on coordination involving the PRAC, the CHMP, the CMDh, the EC, the Member States and the pharmaceutical companies. In the 3 years from July 2012, the PRAC has processed nearly 4500 procedures and is still facing an increasing workload.

Diacerein: Benefits, Risks and Place in the Management of Osteoarthritis. An Opinion-Based Report from the ESCEO.

Diacerein is a symptomatic slow-acting drug in osteoarthritis (SYSADOA) with anti-inflammatory, anti-catabolic and pro-anabolic properties on cartilage and synovial membrane. It has also recently been shown to have protective effects against subchondral bone remodelling. Following the end of the revision procedure by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) constituted a panel of 11 experts to better define the real place of diacerein in the armamentarium for treating OA. Based on a literature review of clinical trials and meta-analyses, the ESCEO confirms that the efficacy of diacerein is similar to that of non-steroidal anti-inflammatory drugs (NSAIDs) after the first month of treatment, and superior to that of paracetamol. Additionally, diacerein has shown a prolonged effect on symptoms of several months once treatment was stopped. The use of diacerein is associated with common gastrointestinal disorders such as soft stools and diarrhoea, common mild skin reactions, and, uncommonly, hepatobiliary disorders. However, NSAIDs and paracetamol are known to cause potentially severe hepatic, gastrointestinal, renal, cutaneous and cardiovascular reactions. Therefore, the ESCEO concludes that the benefit–risk balance of diacerein remains positive in the symptomatic treatment of hip and knee osteoarthritis. Furthermore, similarly to other SYSADOAs, the ESCEO positions diacerein as a first-line pharmacological background treatment of osteoarthritis, particularly for patients in whom NSAIDs or paracetamol are contraindicated.

PRM229 - Do We Need to Strengthen Study Design in Observational Studies?

Guidance and standards are made available by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) as reference tools for methodology and transparency of post-authorization studies. They are cited by the Guideline on good pharmacovigilance practices (GVP) Module VIII as relevant scientific guidances. Here we report an analysis conducted on Pharmacovigilance Risk Assessment Committee (PRAC) minutes regarding methodological issues. All publicly available minutes of PRAC meetings from July 2012 to March 2015 were considered. The number of submitted post-authorization safety study (PASS) protocols requiring endorsement was recorded (excluding advices), as well as endorsement/ refusal and reason. ENCePP documentation was consulted. From July 2012 to March 2015, 33 PASS protocols submitted to PRAC requiring endorsement were considered, increasing with years: 2 in 2012, 8 (17 considering resubmissions) in 2013, 18 (24 considering resubmissions) in 2014. The total number of evaluations was 54. Thirteen were endorsed at the first step (including endorsement with changes requested), while 20 required at least one amendment reaching approval up to 15 months after submission. The most common reasons for refusal concerned study design (20 cases), mainly reporting designs not allowing to fulfil study objectives (N=14). Furthermore, PRAC review asked for alternatives to reduce bias and confounding (N=2), simplifications aiming at reinforcing the observational nature of the study (N=1), further justification of sample size (N=1) and considerations on feasibility (N=1). From 2013 to 2014 an increasing number of endorsed PASS protocols was observed (7/17 and 12/24 respectively). During the same years ENCePP Checklist for Study Protocols and ENCePP Guide on Methodological Standards in Pharmacoepidemiology were reviewed, and the number of studies included in the ENCePP e-register increased. An increasing use of guidance and standards will allow strengthening robustness of design and results of observational studies.

Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization.

HPV Vaccination and Complex Regional Pain Syndrome: Lack of Evidence

HPV Vaccination and Complex Regional Pain Syndrome: Lack of Evidence

Codeine--Restrictions on use for children and teenagers

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency has issued European-wide restrictions on the use of codeine-containing medicines for cough and cold in children at the age of 0-12 because of the risk of serious side effects, including the risk of breathing problems. The PRAC further recommended that "codeine must not be used in people of any age who are known to convert codeine into morphine at a faster rate than normal ('ultra-rapid metabolisers')". The reasons for this variability in codeine biotransformation lay in a genetic polymorphism in the liver enzyme CYP2D6 leading to 3% of the northern European population being ultrarapid metabolisers due to a gene duplication of the enzyme.This is the first restriction of a common drug in CYP2D6 ultrarapid metabolizers, and more use of pharmacogenetic biomarkers for stratified benefit-risk assessment in drug regulation can be expected and will be a first step to Individualized Medicine Regulation.

Off-label use of nicardipine as tocolytic and acute pulmonary oedema: a post-marketing analysis of adverse drug reaction reports in EudraVigilance.

To evaluate a signal of acute pulmonary oedema (APO) due to nicardipine used off-label as tocolytic in pregnant women. All the suspected cases of APO recorded in EudraVigilance database up to 31/01/2013 and associated with nicardipine containing medicinal products were retrieved. The Proportional Reporting Ratio was considered as measure of disproportionality. Individual cases evaluation was conducted. Thirty-four spontaneous cases regarding pregnancy women who experienced APO following nicardipine treatment as tocolytic were collected. The detected proportional reporting ratio was 50.96 (95% confidence interval lower bound equal to 36.75). The analysis focused on 10 serious cases. Most women, aged between 27 and 39 years, were treated with intravenous nicardipine. The most of the suspected adverse reactions occurred between 24 and 96 hours. A potentially causal association between APO and off-label use of nicardipine as tocolytic has been detected during a periodic signal detection activity. The Pharmacovigilance Risk Assessment Committee confirmed our findings, recommending an update of the summary of the product characteristics for medicines containing nicardipine for both intravenous and oral formulations. Then European Medicines Agency reaffirmed that nicardipine use in other indications is no longer recommended.

Benefit-risk assessment of diacerein in the treatment of osteoarthritis.

Osteoarthritis (OA) is the leading musculoskeletal cause of disability. Despite this, there is no consensus on the precise definition of OA and what is the best treatment to improve symptoms and slow disease progression. Current pharmacological treatments include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) inhibitors. None of those treatments are disease-modifying agents that target the core pathological processes in OA. Diacerein, a semi-synthetic anthraquinone derivative, inhibits the interleukin-1-beta (IL-1β) cytokine which, according to animal studies, plays a key role in the pathogenesis of OA. Diacerein was synthesized in 1980 and licensed in some European Union and Asian countries for up to 20 years. It has shown modest efficacy and acceptable tolerability in a number of trials of low to moderate quality. Early this year, the European Medicines Agency (EMA) conducted a review and restricted the use of diacerein-containing medicines. This was because of major concerns about the frequency and severity of diarrhoea and liver disorders in OA patients. In addition, the EMA's Pharmacovigilance Risk Assessment Committee (PRAC) questioned the limited clinical benefits of diacerein, which, in their view, did not outweigh its risks. The aim of this review is to provide a benefit-risk assessment of diacerein in the treatment of OA, based on asystematic evaluation of the published efficacy and safety data. Overall, there is evidence that diacerein is modestly effective for symptoms and possibly for radiographic changes, but this needs to be balanced against higher rates of gastrointestinal toxicity.

The Pharmaceutical Year That Was, 2014

Last year ended with Europe still wallowing in its Eurocrisis, the promise of a Pharmacovigilance Risk Assessment Committee (PRAC) getting into its stride, and the great ‘EMA will be giving away your data’ controversy [1]. One useful thing that PRAC has started doing is announcing the safety signals that it is interested in. This is particularly valuable because such signals may transcend pharmacological class of drug, and rare hazards may only be identifiable with data drawn from multiple products and manufacturers. At about 17 pages each month, the PRAC agenda is an intimidating document. One wonders whether a more efficient system of sub-committees could be devised. As for the EMA transparency initiative, the publication of data process has come to resemble a Freedom of Information request process. The requester applies to EMA, who then notifies the clinical trial sponsor or Marketing Authorization applicant which documents are involved. The permitted redactions are very narrow: mostly restricted to information that could lead to the identification of a patient, and some junior company employees. However, the names of those who are responsible for each aspect of the study in the sponsor’s organisation cannot be redacted, and neither can the identities of principal and associate clinical investigators. However, the EMA has a selective view of transparency [2]. While happy enough to distribute other peoples’ data, the EMA does not share the identity of the requester with the study or application sponsor. The volume of requests has also not been published (one or two pharmacovigilance specialists in different companies describe receiving requests at up to weekly frequency; personal communication). Since risk management plans are also now required in a template that is publication-ready, it is a reasonable presumption that these are popular publications. The EMA have not made any attempt to assess the impact of publishing all these data; since the destination and quantity of publication is unknown (except to the EMA), there cannot be any independent assessment of whether any harm or benefit, is happening. That’s doubtless the way the EMA wants it. Pfizer’s failed flirt with AstraZeneca must be the large pharma event of the year. Three or four priced offers became public knowledge, although the deal structures (e.g., cash/stock components, etc.) were often unclear. Amusingly, the proffered rationale for the transaction evolved within a period of several weeks. Initially, it was to support the Pfizer drug development pipeline. The R&D going on at AstraZeneca was a great compliment. Then people noticed Pfizer’s large cash stockpile, and an acquisition favoured paying less corporation tax in the USA. It then turned out that cash stockpile was not in the USA at all, but in various low-tax paradise islands. With the newspapers’ opinions declining, Pfizer then stated that post-merger it would move its headquarters to the UK, and become a British company. That remarkable offer was promptly termed a ‘tax inversion’. So, then the politicians got involved. If they had been angling in the back rooms before, the politicians on both sides of the Atlantic now came out against Pfizer in public. On May 14, 2014, the A.W. Fox is the Consulting Editor for Pharmaceutical Medicine.

A description of signals during the first 18 months of the EMA pharmacovigilance risk assessment committee.

New pharmacovigilance legislation in the European Union has underlined the importance of signal management, giving the European Medicines Agency's newly established Pharmacovigilance Risk Assessment Committee (PRAC) the mandate to oversee all aspects of the use of medicinal products including detection, assessment, minimization, and communication relating to the risk of adverse reactions. In this study, we describe the signals as brought to the PRAC during the first 18 months of its operation and the ensuing regulatory actions. Data were collected from publicly available sources, for the period July 2012-December 2013, classified according to predefined rules, and described using the appropriate descriptive statistics. Suspected adverse drug reactions were categorized into the Medical Dictionary for Regulatory Affairs and drug names were mapped to the Anatomical Therapeutic Chemical codes. During the study period, 125 signals concerning 96 medicinal products were discussed by the PRAC. The majority of signals were triggered by spontaneous reports (62%) and the median drug age (since marketing authorization) for drugs that prompted a signal was 12 years, significantly less compared with drugs that had no signal within the same period (20 years). The mean time until a decision was reached by the PRAC was 75 days (median 30 days, range 0-273) with 43% of all decisions taken during the first meeting. The decisions to start a referral and to send a direct healthcare professional communication took the least amount of time [54 days (median 27 days, range 0-186) and 51 days (median 0 days, range 0-153)]. The importance of spontaneous reporting in signal detection and monitoring of safety issues throughout the entire life cycle of a medicinal product is confirmed in this study. The amount of time a drug has been on the market is correlated with the number of signals detected. The PRAC decision-making process seems efficient particularly with respect to serious concerns; its role in improving signal prioritization and real-time signal management will be further clarified in its subsequent years of operation.

Periodic Benefit-Risk Evaluation Report: A European Union Regulatory Perspective

New European Union (EU) pharmacovigilance legislation, effective from July 2012, introduced new concepts and procedures to optimise the way medicines are regulated within the Union and provided new channels for public health interventions. Triggered by the EU legislation, the work done by the International Conference on Harmonisation (ICH) has provided a common standard for periodic benefit-risk evaluation reporting within the ICH regions. The present paper provides a review of the concepts behind the use of periodic benefit-risk evaluation reports (PBRER) in supporting safety evaluation and assessment of benefit-risk balance and covers essential points in the documentation of safety information, risk evaluation and benefit-risk assessment. The review incorporates the experience to-date with the PBRER at EU level led by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency. The scope of the PBRER, the main content topics and the challenges relevant to the different stakeholders are highlighted together with key success factors for the report to deliver its objectives and maximise the use of the regulatory assessment procedure. It is clear that the PBRER extends beyond new ways of data presentation and analysis and reflects a further shift in pharmacovigilance in the EU towards more integrated benefit-risk assessment of marketed medicines.

Clinical use of hydroxyethyl starch and serious adverse effects: Need for awareness amongst the medical fraternity

Clinical use of hydroxyethyl starch and serious adverse effects: Need for awareness amongst the medical fraternity

Diclofenac: increase of myocardial infarctions at low doses?

and makes this article in addition to the manuscript published by Bhala et al. [2] the basis of their recent PRAC (Pharmacovigilance Risk Assessment Committee)recommendations (EMA/353084/2013). Indeed, the study deserves specific attention: It appears especially credible since it has been funded by European governmental organizations and not by drug industry. For the same reason it deserves scrutiny and caution. The statement in the abstract of the publication that ‘for diclofenac... the risk of acute myocardial infarctions, AMI, was increased at low and high doses’ has found worldwide attention. It stigmatizes diclofenac as comparatively dangerous even in low doses with respect to cardiovascular events. Indeed, diclofenac would deserve specific risk precautions if the conclusions of this article would be correct, consistent and plausible.

DI-082 Evolution of tetrazepam prescriptions after safety warnings issued in Spain

BackgroundDuring the year 2013, the Spanish Agency for Medicines and Health Products (AEMPS) issued a series of alerts related to medicines containing tetrazepam: 1- Communication of start of the review...

Diacerein for osteoarthritis

Diacerein for osteoarthritis